ID;post_title;pubmed_sticky_authors;pubmed_sticky_equipes;pubmed_pmid;pubmed_journal;pubmed_authors;pubmed_sticky;pubmed_dept;pubmed_dept_timestamp;ajout_le;post_content 16744;"Asymptomatic Leishmania infantum infection in dogs and dog owners in an endemic area in southeast France.";"C. Pomares, P. Marty, G. MICHEL";"Equipe 06, Team 06";38530209;"Parasite (Paris, France)";"Hide M, Michel G, Legueult K, Pin R, Leonard S, Simon L, Bañuls AL, Delaunay P, Marty P, Pomares C";;"Mar 2024";1711411200;;"The prevalence of asymptomatic leishmaniasis in dogs and their owners in the main endemic areas of France has not been studied to date. The objective of this study was to quantify asymptomatic Leishmania infantum infection in southeast France in healthy people and their dogs using molecular and serological screening techniques. We examined the presence of parasitic DNA using specific PCR targeting kinetoplast DNA (kDNA) and specific antibodies by serology (ELISA for dogs and Western blot for humans) among immunocompetent residents and their dogs in the Alpes-Maritimes. Results from 343 humans and 607 dogs were included. 46.9% (n = 161/343) of humans and 18.3% (n = 111/607) of dogs were PCR positive; 40.2% of humans (n = 138/343) and 9.9% of dogs (n = 60/607) were serology positive. Altogether, 66.2% of humans (n = 227) and 25.7% of dogs (n = 156) had positive serologies and/or positive PCR test results. Short-haired dogs were more frequently infected (71.8%, n = 112) than long-haired dogs (12.2%, n = 19) (p = 0.043). Dogs seemed to be more susceptible to asymptomatic infection according to their breed types (higher infection rates in scenthounds, gun dogs and herding dogs) (p = 0.04). The highest proportion of dogs and human asymptomatic infections was found in the Vence Region, corresponding to 28.2% (n = 20/71) of dogs and 70.5% (n = 31/44) of humans (4.5/100,000 people). In conclusion, the percentage of infections in asymptomatic humans is higher than in asymptomatic dogs in the studied endemic area. It is questionable whether asymptomatic infection in humans constitutes a risk factor for dogs." 16742;"Involvement of mutation in a familial context of unexplained infertility and fertilization failure associated with hearing loss: a case report.";"M. Carles";"Equipe 06, Team 06";38524220;"F&S reports";"Guignard S, Guillaume C, Tornero L, Moreau J, Carles M, Isus F, Huyghe É, Ravel C, Vergnolle N, Deraison C, Bonnart C, Gatimel N";;"Mar 2024";1711324800;;"To explore the functional implications of a homozygous (cation channel for sperm) deletion within the acrosome reaction pathway during fertilization in 2 brothers, who have unexplained infertility and hearing loss." 16736;"[Trained immunity : emerging strategies against antibiotic resistance].";"N. Arrighi";"Equipe 01, Team 01";38520110;"Medecine sciences : M/S";"Badin L, Franc C, Gilbert P, Magdeleine JJ, Martin L, Vernaz R, Arrighi N, Garcia-Sanchez JA";;"Mar 2024";1711152000;; 16734;"[PROTAC technology: a promising approach in oncology].";"N. Arrighi";"Equipe 01, Team 01";38520111;"Medecine sciences : M/S";"Azuaga Moreso M, Bertrand C, Duffrene J, Dumont M, Lecouffe A, Muller C, Arrighi N, Onesto C";;"Mar 2024";1711152000;; 16732;"[When ubiquitination intertwines with cutaneous melanoma: a mechanism to explore].";"N. Arrighi";"Equipe 01, Team 01";38520112;"Medecine sciences : M/S";"Arrighi N, Breda L, Kerdilès T, Meyer C, Prugneau L, Rabatel O, Wagner G, Krossa I, Pisibon C";;"Mar 2024";1711152000;; 16730;"A pledge for a better care and consideration of patients with vitiligo.";"T. Passeron";"Equipe 12, Team 12";38513637;"The British journal of dermatology";"Passeron T";;"Mar 2024";1710979200;; 16728;"Transplantation for myelofibrosis patients in the ruxolitinib era: a registry study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.";"M. Loschi";"Equipe 02, Team 02";38514813;"Bone marrow transplantation";"Villar S, Chevret S, Poire X, Joris M, Chevallier P, Bourhis JH, Forcade E, Chantepie S, Beauvais D, Raus N, Bay JO, Loschi M, Devillier R, Duléry R, Ceballos P, Rubio MT, Servais S, Nguyen S, Robin M";;"Mar 2024";1711065600;;"In this SFGM-TC registry study, we report the results after stem cell transplantation (HSCT) in 305 myelofibrosis patients, in order to determine potential risk factors associated with outcomes, especially regarding previous treatment with ruxolitinib. A total of 102 patients were transplanted from an HLA-matched-sibling donor (MSD), and 143 patients received ruxolitinib. In contrast with previous studies, our results showed significantly worse outcomes for ruxolitinib patients regarding overall survival (OS) and non-relapse mortality (NRM), especially in the context of unrelated donors (URD). When exploring reasons for potential confounders regarding the ruxolitinib effect, an interaction between the type of donor and the use of ATG was found, therefore subsequent analyses were performed separately for each type of donor. Multivariable analyses did not confirm a significant negative impact of ruxolitinib in transplantation outcomes. In the setting of URD, only age and Fludarabine-Melphalan (FM) conditioning were associated with increased NRM. For MSD, only Karnoksfy <70% was associated with reduced OS. However, a propensity score analysis showed that ruxolitinib had a negative impact on OS but only in non-responding patients, consistent with previous data. To conclude, with all the precautions due to confounders and bias, ruxolitinib itself does not appear to increase mortality after HSCT." 16726;"French national protocol for the management of congenital ichthyosis.";"C. Chiaverini";"Equipe 12, Team 12";38513308;"Annales de dermatologie et de venereologie";"Severino-Freire M, Granier Tournier C, Chiaverini C, Audouze A, Morice-Picard F, Texier H, Dreyfus I, Bing-Lecointe AC, Mallet S, Bodemer C, Fischer J, Jonca N, Mazereeuw-Hautier J, ";;"Mar 2024";1710979200;;"Congenital ichthyoses (CI) comprise a heterogeneous group of monogenic genetic skin diseases characterized by diffuse scaling, often associated with skin inflammation. Diagnosis of the individual form of ichthyosis is complex and is guided by clinical expertise. CI usually has a major impact on quality of life (QOL) and thus requires lifelong treatment. To date, there are no curative therapies, although various symptomatic treatment options exist. The present protocol for the management of CI has been drawn up in accordance with the recommendations published in 2012 by the French National Authority for Health, based on a literature review, with the help and validation of members of the French network for rare skin diseases (FIMARAD). It provides a summary of evidence and expert-based recommendations and is intended to help clinicians with the management of these rare and often complex diseases." 16723;"Improving nutritional status after allogeneic stem cell transplantation: results of phase 2 ALLONUT clinical trial.";"A. Jacquel, M. Loschi, G. Robert, T. Cluzeau";"Equipe 02, Team 02";38509196;"Bone marrow transplantation";"Estran S, Loschi M, Benachour S, Soldati A, Chiche E, Sammut R, Robert G, Jacquel A, Chibois J, Schneider S, Cluzeau T";;"Mar 2024";1710979200;;"Malnutrition increases the risk of non-relapse mortality after allogeneic stem cell transplantation (aHSCT). Here are the results of the ALLONUT clinical trial designed to improve the nutritional outcome of patients receiving aHSCT. ALLONUT is a prospective open label phase 2 clinical trial assessing the efficacy of a close tailored nutritional support and management with traditional and original solutions to improve patients nutritional status following aHSCT. Nutritional status evaluation was performed before transplantation, on Day 0, 30, 100 and one year after transplantation. The study involved 70 patients treated by aHSCT. 10% of patients were moderately or severely malnutrition at baseline and 26.9 were severely malnutrition at D30. Patients' nutritional status improved thanks to the cooking classes and the personalized outpatient nutrition program. At D100, 23% were still malnutrition, while only 10.8% were severely malnutrition one year after transplantation. The QLQ-C30 show that quality of life (QoL) decreased until D30, and improve to reach the pre-transplant level on D100 before exceeding it on D360. The study confirmed that a close, personalized nutritional program combining traditional and original measures can improve both nutritional status and QoL for patients suffering from moderate or severe malnutrition after aHCST." 16721;"Comparison of clinical outcomes of several risk stratification tools in newly diagnosed AML patients: A real-world evidence in our current therapeutic era.";"M. Loschi, T. Cluzeau";"Equipe 02, Team 02";38506267;"Cancer medicine";"Iat A, Loschi M, Benachour S, Calleja A, Chiche E, Sudaka I, Aquaronne D, Ferrero C, Fenwarth L, Marceau A, Fournier E, Dadone-Montaudie B, Cluzeau T";;"Mar 2024";1710892800;;"AML classification tools have been developed to stratify the risk at AML diagnosis. There is a need to evaluate these tools in the current therapeutic era." 16719;"Unveiling CXCR2 as a promising therapeutic target in renal cell carcinoma: exploring the immunotherapeutic paradigm shift through its inhibition by RCT001.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";38504270;"Journal of experimental & clinical cancer research : CR";"Montemagno C, Jacquel A, Pandiani C, Rastoin O, Dawaliby R, Schmitt T, Bourgoin M, Palenzuela H, Rossi AL, Ambrosetti D, Durivault J, Luciano F, Borchiellini D, Le Du J, Gonçalves LCP, Auberger P, Benhida R, Kinget L, Beuselinck B, Ronco C, Pagès G, Dufies M";;"Mar 2024";1710892800;;"In clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored the potential of enhancing ccRCC treatment by concurrently using CXCR2 inhibitors alongside immunotherapies." 16705;"Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.";"M. Loschi";"Equipe 02, Team 02";38491198;"Bone marrow transplantation";"Robin M, Iacobelli S, Koster L, Passweg J, Avenoso D, Wilson KMO, Salmenniemi U, Dreger P, von dem Borne P, Snowden JA, Robinson S, Finazzi MC, Schroeder T, Collin M, Eder M, Forcade E, Loschi M, Bramanti S, Pérez-Simón JA, Czerw T, Polverelli N, Drozd-Sokolowska J, Raj K, Hernández-Boluda JC, McLornan DP";;"Mar 2024";1710547200;;"We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings." 16703;"Whole F8 gene sequencing identified pathogenic structural variant in the remaining unsolved patients with severe Haemophilia A.";"PS. ROHRLICH";"Equipe 04, Team 04";38484912;"Journal of thrombosis and haemostasis : JTH";"Jourdy Y, Chatron N, Frétigny M, Zawadzki C, Lienhart A, Stieltjes N, Rohrlich PS, Thauvin-Robinet C, Volot F, Hamida YF, Hariti G, Leuci A, Dargaud Y, Sanlaville D, Vinciguerra C";;"Mar 2024";1710374400;;"No F8 genetic abnormality is detected in about 1-2% of patients with severe haemophilia A using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal." 16701;"Mechanisms of melanoma aggressiveness with age.";"C. Bertolotto";"Equipe 01, Team 01";38472453;"Nature aging";"Bertolotto C";;"Mar 2024";1710288000;; 16699;"Secukinumab in patients with moderate to severe hidradenitis suppurativa based on prior biologic exposure: An efficacy and safety analysis from the SUNSHINE and SUNRISE phase III trials.";"T. Passeron";"Equipe 12, Team 12";38470171;"The British journal of dermatology";"Zouboulis CC, Passeron T, Pariser D, Wozniak MB, Li X, Uhlmann L, Lobach I, Martinez AL, Ravichandran S, Alarcon I, Offidani A, Alam MS, Mendes-Bastos P";;"Mar 2024";1710201600;;"Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease associated with a substantial disease burden. Secukinumab has previously been reported to have sustained efficacy with a favourable safety profile in patients with moderate to severe HS. It is unknown if prior biologic exposure impacts the efficacy and safety of secukinumab." 16695;"Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.";"R. ANTY";"Equipe 08, Team 08";38451069;"Liver international : official journal of the International Association for the Study of the Liver";"Lerosey L, Ksiasek E, Abrahamowicz M, Antoine C, Dharancy S, Dumortier J, Doussot A, Di Martino V, Houssel-Debry P, Conti F, Francoz C, Pageaux GP, Salame E, Faitot F, Coilly A, Hardwigsen J, Decaens T, Chermak F, Muscari F, Anty R, Duvoux C, Abergel A, Minello A, Mouillot T, Binquet C, Latournerie M";;"Mar 2024";1709769600;;"In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality." 16693;"Four clinical and biological phenotypes in antiphospholipid syndrome: a cluster analysis of 174 patients with antinuclear antibody tests.";"N. Martis";"Equipe 10, Team 10";38440737;"Frontiers in immunology";"Ottavi M, Toulon P, Casolla B, Martis N";;"Mar 2024";1709596800;;"Antiphospholipid syndrome (APS) is an autoimmune thrombotic disease with various systemic presentations. This study aimed to identify homogeneous groups of patients based on a non-supervised hierarchical cluster analysis and assess the rate of relapse associated with antinuclear antibodies (ANA)." 16691;"A Bayesian network meta-analysis of 14 molecules inhibiting UV daylight-induced pigmentation.";"T. Passeron";"Equipe 12, Team 12";38433524;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Muller B, Flament F, Jouni H, Sextius P, Tachon R, Wang Y, Wang H, Qiu H, Qiu J, Amar D, Delaunay C, Jablonski NG, Passeron T";;"Mar 2024";1709510400;;"Hyperpigmentation disorders are very frequent, affect the quality of life and may become a psychological burden for afflicted patients. Many anti-pigmenting or depigmenting agents are available with various efficacy and almost no comparative data. 2-mercaptonicotinoyl glycine (2-MNG) was recently proposed as a viable candidate showing safe and effective results on hyperpigmentation control in vitro and in vivo." 16689;"On behalf of the SFGM-TC: Real-life use of third-party virus-specific T-cell transfer in immunocompromised transplanted patients.";"M. Loschi, T. Cluzeau";"Equipe 02, Team 02";38434523;HemaSphere;"Leroyer EH, Petitpain N, Morisset S, Neven B, Castelle M, Winter S, Souchet L, Morel V, Le Cann M, Fahd M, Yacouben K, Mechinaud F, Ouachée-Chardin M, Renard C, Wallet HL, Angoso M, Jubert C, Chevallier P, Léger A, Rialland F, Dhedin N, Robin C, Maury S, Beckerich F, Beauvais D, Cluzeau T, Loschi M, Fernster A, Bittencourt MC, Cravat M, Bilger K, Clément L, Decot V, Gauthier M, Legendre A, Larghero J, Ouedrani A, Martin-Blondel G, Pochon C, Reppel L, Rouard H, Nguyen-Quoc S, Dalle JH, D'Aveni M, Bensoussan D";;"Mar 2024";1709510400;; 16687;"Inclusion-body myositis associated with Sjögren's disease: clinical characteristics and comparison with other Sjögren-associated myositis.";"N. Martis";"Equipe 10, Team 10";38430004;"Rheumatology (Oxford, England)";"Astouati Q, Machet T, Houssais C, Noury JB, Allenbach Y, Gallay L, Quere B, Assan F, Benveniste O, Broner J, Duffau P, Espitia A, Grasland A, Hayem G, Guern VL, Martis N, Mariampillai K, Nocturne G, Mariette X, Meyer A, Mulleman D, Devauchelle-Pensec V, Collet A, Launay D, Hachulla E, Cornec D, Guellec D, Sanges S";;"Mar 2024";1709337600;;"To describe the characteristics of patients with Sjögren's disease (SjD) and inclusion-body myositis (IBM), and how they compare to SjD patients with other inflammatory myopathies (IM)." 16678;"Ceftolozane/Tazobactam for the Treatment of Complicated Infections in Hospital Settings-A French Real-world Study.";"R. Ruimy";"Equipe 06, Team 06";38390458;"Open forum infectious diseases";"Timsit JF, Mootien J, Akrich B, Bourge X, Brassac I, Castan B, Mackosso C, Tavares LM, Ruiz F, Boutoille D, Ruimy R";;"Feb 2024";1708646400;;"This study describes the conditions of use of ceftolozane/tazobactam (C/T) and associated outcomes in French hospital settings." 16676;"Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.";"M. Carles";"Equipe 06, Team 06";38380940;"Critical care explorations";"Vaara ST, Serpa Neto A, Bellomo R, Adhikari NKJ, Dreyfuss D, Gallagher M, Gaudry S, Hoste E, Joannidis M, Pettilä V, Wang AY, Kashani K, Wald R, Bagshaw SM, Ostermann M, Bagshaw SM, Wald R, Adhikari NKJ, Bellomo R, Dreyfuss D, Du B, Gallagher MP, Gaudry S, Hoste EA, Lamontagne F, Joannidis M, Liu KD, McAuley DF, McGuinness SP, Nichol AD, Ostermann M, Palevsky PM, Qiu H, Pettilä V, Schneider AG, Smith OM, Vaara ST, Weir M, Bellomo R, Eastwood GM, Peck L, Young H, Kruger P, Laurie G, Saylor E, Meyer J, Venz E, Wetzig K, French C, McGain F, Mulder J, Fennessy G, Koottayi S, Bates S, Towns M, Morgan R, Tippett A, Udy A, Mason C, Licari E, Gantner D, McClure J, Nichol A, McCracken P, Board J, Martin E, Vallance S, Young M, Vladic C, McGloughlin S, Gattas D, Buhr H, Coles J, Hutch D, Wun J, Cole L, Whitehead C, Lowrey J, Masters K, Gresham R, Campbell V, Gutierrez D, Brailsford J, Forbes L, Murray L, Maguire T, NiChonghaile M, Orford N, Bone A, Elderkin T, Salerno T, Chimunda T, Fletcher J, Broadfield E, Porwal S, Knott C, Boschert C, Smith J, Richardson A, Hill D, Duke G, Oziemski P, Cegarra S, Chan P, Welsh D, Hunter S, Roodenburg O, Dyett J, Kokotsis N, Moser M, Yang Y, Padayachee L, Vetro J, Gangopadhyay H, Kaufman M, Ghosh A, Said S, Patel A, Bihari S, Matheson E, Jin X, Shrestha T, Schwartz K, Gallagher MP, Cross R, Cheung W, Wong H, Kol M, Shah A, Wang AY, Endre Z, Bradford C, Janin P, Finfer S, Diel N, Gatward J, Hammond N, Delaney A, Bass F, Yarad E, Buscher H, Reynolds C, Baker N, Joannidis M, Bellmann R, Peer A, Hasslacher J, Koglberger P, Klein S, Zotter K, Brandtner A, Finkenstedt A, Ditlbacher A, Hartig F, Fries D, Bachler M, Schenk B, Wagner M, Staudinger T, Tiller E, Schellongowski P, Bojic A, Hoste EA, Bracke S, De Crop L, Vermeiren D, Thome F, Chiella B, Fendt L, Antunes V, Maisonneuve-Rosemont , Lafrance JP, Lamontagne F, D'Aragon F, St-Arnaud C, Mayette M, Carbonnaeu É, Marchand J, Masse MH, Ladouceur M, Turgeon AF, Lauzier F, Bellemare D, Langis Francoeur C, LeBlanc G, Guilbault G, Grenier S, Cloutier E, Boivin A, Delisle-Thibault C, Giannakouros P, Costerousse O, Cailhier JF, Carrier FM, Ghamraoui A, Lebrasseur M, Benettaib F, Salamé M, Boumahni D, Tung Sia Y, Naud JF, Roy I, Stelfox HT, Ruddell S, Manns BJ, Duggan S, Carney D, Barchard J, Whitlock RP, Belley-Cote E, Savija N, Sabev A, Campbell T, Creary T, Devereaux K, Brodutch S, Rigatto C, Paunovic B, Mooney O, Glybina A, Harasemiw O, Di Nella M, Harmon J, Mehta N, Lakatos L, Haslam N, Lellouche F, Simon M, Tung Y, Lizotte P, Bourchard PA, Rochwerg B, Karachi T, Millen T, Muscedere J, Maslove D, Gordon Boyd J, Sibley S, Drover J, Hunt M, Georgescu I, Wax R, Lenga I, Sridhar K, Steele A, Fusco K, Ghate T, Tolibas M, Robinson H, Weir MA, Taneja R, Ball IM, Garg A, Campbell E, Ovsenek A, Bagshaw SM, van Diepen S, Baig N, Magder S, Yao H, Alam A, Campisi J, MacIntyre E, Rokosh E, Scherr K, Lapinsky S, Mehta S, Shah S, Niven DJ, Stelfox HT, Ruddell S, Russell M, Jim K, Brown G, Oxtoby K, Hall A, Benoit L, Sokolowski C, Prasad B, Rao J, Giebel S, Kutsogiannis DJ, Thompson P, Thompson T, Cirone R, Kavikondala K, Soth M, Clarke F, Takaoka A, Wald R, Mazer D, Burns K, Friedrich J, Klein D, Sandhu G, Santos M, Khalid I, Hodder J, Dodek P, Ayas N, Alcuaz V, Suen G, Rewa O, Singh G, Norris S, Gibson N, Arias C, Shami A, Pelletier C, Adhikari NKJ, Zahirieh A, Amaral A, Marinoff N, Kaur N, Perez A, Wang J, Haljan G, Condin C, McIntyre L, Gomes B, Porteous R, Watpool I, Hiremath S, Clark E, Herridge MS, Backhouse F, Elizabeth Wilcox M, Walczak K, Ki V, Sharman A, Romano M, Bagshaw SM, Noel Gibney RT, Romanovsky AS, Rewa O, McCoshen L, Baig N, Wood G, Ovakim D, Auld F, Carney G, Duan M, Ji X, Guo D, Qi Z, Lin J, Zhang M, Dong L, Liu J, Liu P, Zhi D, Bai G, Qiu Y, Yang Z, Bai J, Liu Z, Zhuang H, Wang H, Li J, Zhao M, Zhou X, Shi X, Ye B, Liu M, Wu J, Fu Y, Long D, Pan Y, Wang J, Mei H, Zhang S, Wen M, Yang E, Mu S, Li J, Hu T, Qin B, Li M, Wang C, Dong X, Wang K, Wang H, Yang J, Du B, Wang C, Wang D, Li N, Yu Z, Xu S, Yao L, Hou G, Liu Z, Lu L, Lian Y, Wang C, Zhang J, Ding R, Qi G, Wang Q, Wang P, Meng Z, Chen M, Hu X, He X, Zhao S, Hang L, Li R, Qin S, Lu K, Dun S, Liu C, Zhou Q, Chen Z, Mei J, Zhang M, Xu H, Lin J, Shi Q, Fu L, Zeng Q, Ma H, Yan J, Gao L, Liu H, Zhang L, Li H, He X, Fan J, Guo L, Liu Y, Wang X, Sun J, Liu Z, Yang J, Ding L, Sheng L, Liu X, Yan J, Wang Q, Wang Y, Zhao D, Zhao S, Hu C, Li J, Deng F, Qiu H, Yang Y, Mo M, Pan C, Wu C, Huang Y, Huang L, Liu A, Pettilä V, Vaara ST, Korhonen AM, Törnblom S, Sutinen S, Pettilä L, Heinonen J, Lappi E, Suhonen T, Karlsson S, Hoppu S, Jalkanen V, Kuitunen A, Levoranta M, Långsjö J, Ristimäki S, Malila K, Wootten A, Varila S, Järvisalo MJ, Inkinen O, Kentala S, Leivo K, Haltia P, Dreyfuss D, Ricard JD, Messika J, Tiagarajah A, Emery M, Dechanet A, Gernez C, Roux D, Martin-Lefevre L, Fiancette M, Vinatier I, Claude Lacherade J, Colin G, Lebert C, Azais MA, Yehia A, Pouplet C, Henry-Lagarrigue M, Seguin A, Crosby L, Maizel J, Titeca-Beauport D, Combes A, Nieszkowska A, Masi P, Demoule A, Mayaux J, Dres M, Morawiec E, Decalvele M, Demiri S, Faure M, Marios C, Mallet M, Amélie Ordon M, Morizot L, Cantien M, Pousset F, Gaudry S, Poirson F, Cohen Y, Argaud L, Cour M, Bitker L, Simon M, Hernu R, Baudry T, De La Salle S, Robine A, Sedillot N, Tchenio X, Bouisse C, Roux S, Barbar D, Trusson R, Tamion F, Grangé S, Carpentier D, Chevrel G, Ensenyat-Martin L, Marque S, Quenot JP, Andreu P, Dargent A, Large A, Chudeau N, Landais M, Derrien B, Christophe Callahan J, Guitton C, Le Moal C, Robert A, Asehnoune K, Cinotti R, Grillot N, Demeure D, Vinsonneau C, Rahmani I, Marzouk M, Dekeyser T, Sejourne C, Verlay M, Thevenin F, Delecolle L, Didier Thevenin L, Souweine B, Coupez E, Adda M, Eraldi JP, Marchalot A, De Prost N, Mekontso Dessap A, Razazi K, Meziani F, Boisrame-Helms J, Clere-Jehl R, Delabranche X, Kummerlen C, Merdji H, Monnier A, Rabouel Y, Rahmani H, Allam H, Chenaf S, Franja V, Pons B, Carles M, Martino F, Richard R, Zuber B, Lacave G, Lakhal K, Rozec B, Dang Van H, Boulet É, Dubos R, Fadel F, Cleophax C, Dufour N, Grant C, Thuong M, Reignier J, Canet E, Nicolet L, Boulain T, Nay MA, Benzekri D, Barbier F, Bretagnol A, Kamel T, Mathonnet A, Muller G, Skarzynski M, Rossi J, Pradet A, Dos Santos S, Guery A, Muller L, Felix L, Bohé J, Thiéry G, Aissaoui N, Vimpere D, Commeureuc M, Diehl JL, Guerot E, Liangos O, Wittig M, Zarbock A, Küllmar M, van Waegeningh T, Rosenow N, Nichol AD, Brickell K, Doran P, Murray PT, Landoni G, Lembo R, Zangrillo A, Monti G, Tozzi M, Marzaroli M, Lombardi G, Paternoster G, Vitiello M, McGuinness S, Parke R, Butler M, Gilder E, Cowdrey KA, Wallace S, Hallion J, Woolett M, Neal P, Duffy K, Long S, McArthur C, Simmonds C, Chen Y, McConnochie R, Newby L, Knight D, Henderson S, Mehrtens J, Morgan S, Morris A, Vander Hayden K, Burke T, Bailey M, Freebairn R, Chadwick L, Park P, Rolls C, Thomas L, Buehner U, Williams E, Albrett J, Kirkham S, Jackson C, Browne T, Goodson J, Jackson D, Houghton J, Callender O, Higson V, Keet O, Dominy C, Young P, Hunt A, Judd H, Lawrence C, Olatunji S, Robertson Y, Latimer-Bell C, Hendry D, Mckay-Vucago A, Beehre N, Lesona E, Navarra L, Robinson C, Jang R, Junge A, Lambert B, Schneider AG, Thibault M, Eckert P, Kissling S, Polychronopoulos E, Poli E, Altarelli M, Schnorf M, Abed Mallaird S, Heidegger C, Perret A, Montillier P, Sangla F, Neils S, De Watteville A, Phull MK, George A, Hussain N, Pogreban T, Lobaz S, Daniels A, Cunningham M, Kerr D, Nicholson A, Shanmugasundaram P, Abrams J, Manso K, Hambrook G, McKerrow E, Salva J, Foulkes S, Wise M, Morgan M, Brooks J, Cole J, Michelle Davies T, Hill H, Thomas E, Vizcaychipi M, Baharlo B, Carungcong J, Costa P, Martins L, Kapoor R, Hazelton T, Moon A, Musselwhite J, Shelley B, McCall P, Ostermann M, Arbane G, Bociek A, Marotti M, Lim R, Campos S, Grau Novellas N, Cennamo A, Slack A, Wyncoll D, Camporota L, Sparkes S, Tilley R, Rattray A, Moreland G, Duffy J, McGonigal E, Hopkins P, Finney C, Smith J, Noble H, Watson H, Harris CL, Clarey E, Corcoran E, Beck J, Howcroft C, Youngs N, Wilby E, Ogg B, Wolverson A, Lee S, Butler S, Okubanjo M, Hindle J, Welters I, Williams K, Johnson E, Patrick-Heselton J, Shaw D, Waugh V, Stewart R, Mwaura E, Wren L, Mew L, Sutherland SB, Adderley J, Ruddy J, Harkins M, Kaye C, Scott T, Mitchell W, Anderson F, Willox F, Jagannathan V, Clark M, Purv S, Sharman A, Meredith M, Ryan L, Conner L, Peters C, Harvey D, Roshdy A, Collins A, Sim M, Henderson S, Chee N, Pitts S, Bowman K, Dilawershah M, Vamplew L, Howe E, Rogers P, Hernandez C, Prendergast C, Benton J, Rosenberg A, Forni LG, Grant A, Carvelli P, Raithatha A, Bird S, Richardson M, Needham M, Hirst C, Ball J, Leaver S, Howlett L, Castro Delgado C, Farnell-Ward S, Farrah H, Gray G, Joseph G, Robinson F, Tridente A, Harrop C, Shuker K, McLaughlan D, Ramsey J, Meehan S, Oliver Rose B, Reece-Anthony R, Gurung B, Whitehouse T, Snelson C, Veenith T, Johnston A, Cooper L, Carrera R, Ellis K, Fellows E, Harkett S, Bergin C, Spruce E, Despy L, Goundry S, Dooley N, Mason T, Clark A, Dignam G, Ward G, Attwood B, Parsons P, Mason S, Margarson M, Lord J, McGlone P, Hodgson LE, Chadbourn I, Gomez R, Margalef J, Pretorius R, Hamshere A, Carter J, Cahill H, Grainger L, Howard K, Forshaw G, Guy Z, Kashani KB, Albright RC, Amsbaugh A, Stoltenberg A, Niven AS, Lynch M, O'Mara A, Naeem S, Sharif S, McKenney Goulart J, Lynch M, O'Mara A, Naeem S, Sharif S, McKenney Goulart J, Tolwani A, Lyas C, Latta L, Bihorac A, Hashemighouchani H, Efron P, Ruppert M, Cupka J, Kiley S, Carson J, White P, Omalay G, Brown S, Velez L, Marceron A, Neyra JA, Carlos Aycinena J, Elias M, Ortiz-Soriano VM, Hauschild C, Dorfman R";;"Feb 2024";1708473600;;"Among patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant." 16627;"High Prevalence of Non-typeable Haemophilus influenzae and Haemophilus haemolyticus Among Vaccinated Children with Community-Acquired Pneumonia in Vietnam.";"P. Marty";"Equipe 06, Team 06";38372891;"Journal of epidemiology and global health";"Tran XD, Hoang VT, Dao TL, Marty P, Gautret P";;"Feb 2024";1708300800;;"Among 467 children under five hospitalized with community-acquired pneumonia, the prevalence of Haemophilus influenzae or Haemophilus haemolyticus was 60.8%, all cases were non-typable H. influenzae (NTHi) or H. haemolyticus. NTHi/H. haemolyticus PCR detection was associated with about twice the risk for severe disease. The results highlight the need for increased awareness and research efforts to investigate the role of NTHi/H. haemolyticus in severe CAP among children." 16623;"Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): a phase 3, randomized, double-blind, placebo-controlled trial.";"J. Courjon";"Equipe 06, Team 06";38367705;"The Journal of infection";"Hites M, Massonnaud CR, Jamard S, Goehringer F, Danion F, Reignier J, de Castro N, Garot D, Lapique EL, Lacombe K, Tolsma V, Faure E, Malvy D, Staub T, Courjon J, Cazenave-Roblot F, Riise AMD, Leturnier P, Martin-Blondel G, Roger C, Akinosoglou K, Moing VL, Piroth L, Sellier P, Lescure X, Trøseid M, Clevenbergh P, Dalgard O, Gallien S, Gousseff M, Loubet P, Vardon-Bounes F, Visée C, Belkhir L, Botelho-Nevers É, Cabié A, Kotanidou A, Lanternier F, Rouveix-Nordon E, Silva S, Thiery G, Poignard P, Carcelain G, Diallo A, Mercier N, Terzic V, Bouscambert-Duchamp M, Gaymard A, Trabaud MA, Destras G, Josset L, Belhadi D, Billard N, Guedj J, Han TH, Couffin-Cadiergues S, Dechanet A, Delmas C, Esperou H, Fougerou-Leurent C, Mestre SL, Métois A, Noret M, Bally I, Dergan-Dylon S, Tubiana S, Kalif O, Bergaud N, Leveau B, Eustace J, Greil R, Hajdu E, Halanova M, Paiva JA, Piekarska A, Baño JR, Tonby K, Trojánek M, Tsiodras S, Unal S, Burdet C, Costagliola D, Yazdanpanah Y, Peiffer-Smadja N, Mentré F, Ader F, ";;"Feb 2024";1708128000;; 16621;"Protective effect of height on long-term survival of resectable lung cancer: a new feature of the lung cancer paradox.";"A. IANNELLI";"Team 08, Equipe 08";38359923;Thorax;"Daffré E, Porcher R, Iannelli A, Prieto M, Brouchet L, Falcoz PE, Le Pimpec Barthes F, Pages PB, Thomas PA, Dahan M, Alifano M";;"Feb 2024";1707955200;;"Unlike most malignancies, higher body mass index (BMI) is associated with a reduced risk of lung cancer and improved prognosis after surgery. However, it remains controversial whether height, one of determinants of BMI, is associated with survival independently of BMI and other confounders." 16611;"Comparative performance of ISAGA IgM and ELISA assays for the diagnosis of maternal and congenital Toxoplasma infections: which technique could replace ISAGA IgM?";"C. Pomares";"Equipe 06, Team 06";38334687;"Parasite (Paris, France)";"Deleplancque AS, Fricker-Hidalgo H, Pomares C, L'Ollivier C, Lemoine JP, Cimon B, Paris L, Houzé S, Villena I, Pelloux H, Villard O";;"Feb 2024";1707436800;;"The ISAGA immunocapture test for the detection of anti-Toxoplasma immunoglobulin M is a manual technique known for its excellent sensitivity and specificity. The purpose of this retrospective, multicenter study was to compare the performances and agreement between ISAGA and other IgM detection techniques before cessation of ISAGA production. The analytic performance of the different tests was evaluated using 1,341 serum samples from adults with positive IgM and negative IgG to Toxoplasma gondii, and 1,206 sera from neonates born to mothers with seroconversion. The agreement between the tests was evaluated on 13,506 adult and 5,795 child serum samples. The sensitivity of Toxo-ISAGA IgM (adults 98.7%, neonates 63.1%) was similar to that of Platelia Toxo IgM (adults 94.4%, neonates 64.6%), and significantly higher than Liaison Toxo IgM (adults 90.6%), Architect/Alinity Toxo IgM (adults 95.7%, neonates 48.6%), and Vidas Toxo IgM (adults 81.8%, neonates 17.5%). However, the specificities varied between 24.4% (Platelia Toxo IgM) and 95.2% (Liaison Toxo IgM) in adults and were >95% for all tests in neonates. An analysis of the kappa coefficients showed better agreement between ISAGA IgM and the other tests in children (0.75-0.83%) than in adults (0.11-0.53%). We conclude that, in the absence of Toxo-ISAGA IgM, the association of a very sensitive technique (Platelia Toxo IgM or Architect/Alinity Toxo IgM) and a very specific technique (Vidas Toxo IgM or Liaison Toxo IgM) is recommended for IgM detection in adult sera. For neonates, Platelia Toxo IgM appeared to be the best alternative to replace Toxo-ISAGA IgM." 16596;"Allogeneic Hematopoietic Cell Transplantation for VEXAS Syndrome: Results of a Multicenter Study of the EBMT.";"M. Loschi";"Equipe 02, Team 02";38330178;"Blood advances";"Gurnari C, Koster L, Baaij LGA, Heiblig M, Yakoub-Agha I, Collin M, Passweg JR, Bulabois CE, Khan AB, Loschi M, Carnevale-Schianca F, Crisà E, Caravelli D, Kuball J, Saraceni F, Olivieri A, Rambaldi A, Kulasekararaj AG, Hayden P, Badoglio M, Onida F, Scheid C, Franceschini F, Mékinian A, Savic S, Voso MT, Drozd-Sokolowska J, Snowden J, Raj K, Alexander T, Robin M, Greco R, McLornan DP";;"Feb 2024";1707350400;; 16594;"The combination of ipilimumab and nivolumab is still not reimbursed for BRAF-mutated melanoma patients in France: An unacceptable medical situation that raises ethical concerns.";"H. Montaudie";"Equipe 12, Team 12";38325268;"Annales de dermatologie et de venereologie";"Amini-Adle M, Arnault JP, Aubin F, Beneton N, Bens G, Brunet-Possenti F, Célerier P, Charles J, Crumbach L, Dalac S, Darras S, De Quatrebarbes J, Dinulescu M, Dutriaux C, Gaudy C, Gérard E, Giacchero D, Granel-Brocard F, Grange F, Jouary T, Kramkimel N, Lebbé C, Le Corre Y, Legoupil D, Lesage C, Lesimple T, Lorphelin JM, Mansard S, Martin L, Mary-Prey S, Maubec E, Meyer N, Mignard C, Montaudie H, Mortier L, Nardin C, Neidhardt Berard EM, Pagès Laurent C, Peuvrel L, Quereux G, Robert C, Saiag P, Saint-Jean M, Samimi M, Sassolas B, Scalbert C, Skowron F, Steff M, Stoebner PE, Trablesi S, Visseaux L, Zehou O, Boespflug A, ";;"Feb 2024";1707264000;; 16592;"Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment.";"E. Verhoeyen, JE. Ricci";"Equipe 03, Team 03";38321568;"Journal of experimental & clinical cancer research : CR";"Krug A, Tosolini M, Madji Hounoum B, Fournié JJ, Geiger R, Pecoraro M, Emond P, Gaulard P, Lemonnier F, Ricci JE, Verhoeyen E";;"Feb 2024";1707177600;;"Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in urgent need of more specific therapeutic strategies. The drivers of malignancy in this disease are CD4 follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option." 16590;"A strange reaction following a hyaluronic acid injection.";"T. Passeron";"Equipe 12, Team 12";38317300;"Arthritis & rheumatology (Hoboken, N.J.)";"Piroth M, Fanjat Y, Cardot-Leccia N, Passeron T, Roux C";;"Feb 2024";1707177600;; 16583;"Clinical picture, outcomes and predictors of relapse in eosinophilia-associated coronary vasospasm: data from a European multicentric study.";"N. Martis";"Equipe 10, Team 10";38307204;"The journal of allergy and clinical immunology. In practice";"Huang F, Khellaf LR, Lefèvre G, Berti A, d'Humières T, Sionis A, Ariza Solé A, Bello F, Bermeo Garrido JA, Crickx E, Delvino P, Emmi G, Gaillet A, Garcia G, Gavand PE, George JL, Gilles F, Golden C, de Groote P, Guffroy A, Martis N, Monti S, Mourlanette P, Pineton de Chambrun M, Prunier F, Regola F, Seret G, Terrier B, Tréfond L, Souteyrand G, Varenne O, Zilio F, Haziza F, Benamer H, Kahn JE, Vallée A, Groh M, ";;"Feb 2024";1706832000;; 16581;"Roles of innate lymphoid cells in metabolic and alcohol-associated liver diseases.";"P. GUAL, R. ANTY, C. LUCI";"Equipe 08, Team 08";38304237;"JHEP reports : innovation in hepatology";"Bourinet M, Anty R, Gual P, Luci C";;"Feb 2024";1706832000;;"Innate lymphoid cells (ILCs) have been identified as potent regulators of inflammation, cell death and wound healing, which are the main biological processes involved in the progression of chronic liver disease. Obesity and chronic alcohol consumption are the leading contributors to chronic liver diseases in developed countries, due to inappropriate lifestyles. In particular, inflammation is a key factor in these liver abnormalities and promotes the development of more severe lesions such as fibrosis, cirrhosis and hepatocellular carcinoma. Opposite roles of ILC subsets have been described in the development of chronic liver disease, depending on the stage and aetiology of the disease. The heterogeneous family of ILCs encompasses cytotoxic natural killer cells, the cytokine-producing type 1, 2 and 3 ILCs and lymphoid tissue inducer cells. Dysfunction of these immune cells provokes uncontrolled inflammation and tissue damage, which are the basis for tumour development. In this review, we provide an overview of the recent and putative roles of ILC subsets in obesity and alcohol-associated liver diseases, which are currently the major contributors to end-stage liver complications such as fibrosis/cirrhosis and hepatocellular carcinoma." 16548;"Pregnancy outcomes in women with primary Sjögren's syndrome: an analysis of data from the multicentre, prospective, GR2 study.";"N. Martis";"Equipe 10, Team 10";38251600;"The Lancet. Rheumatology";"de Frémont GM, Costedoat-Chalumeau N, Lazaro E, Belkhir R, Guettrot-Imbert G, Morel N, Nocturne G, Molto A, Goulenok T, Diot E, Perard L, Ferreira-Maldent N, Le Besnerais M, Limal N, Martis N, Abisror N, Debouverie O, Richez C, Sobanski V, Maurier F, Sauvetre G, Levesque H, Timsit MA, Tieulié N, Orquevaux P, Bienvenu B, Mahevas M, Papo T, Lartigau-Roussin C, Chauvet E, Berthoux E, Sarrot-Reynauld F, Raffray L, Couderc M, Silva NM, Jourde-Chiche N, Belhomme N, Thomas T, Poindron V, Queyrel-Moranne V, Delforge J, Le Ray C, Pannier E, Mariette X, Le Guern V, Seror R, ";;"Jan 2024";1705881600;;"Adverse pregnancy outcomes in women with primary Sjögren's syndrome have only been evaluated retrospectively using heterogeneous methods and with contradictory results. We aimed to describe adverse pregnancy, delivery, and birth outcome risks in pregnant women with primary Sjögren's syndrome compared with those of a matched general population in France, and to identify factors predictive of disease flares or adverse pregnancy outcomes." 16519;"Efficacy of an antimicrobial stewardship intervention for early adaptation of antibiotic therapy in high-risk neutropenic patients.";"J. Courjon, M. Loschi, M. Carles, T. Cluzeau";"Equipe 06, Team 06, Equipe 02, Team 02";38233960;"Antimicrobial resistance and infection control";"Durand C, Risso K, Loschi M, Retur N, Emery A, Courjon J, Cluzeau T, Carles M";;"Jan 2024";1705449600;;"The 4th European Conference on Infections in Leukemia recommends early adaptation of empirical antibiotic therapy (EAT) for febrile neutropenia in stable patients." 16517;"Deucravacitinib in plaque psoriasis: 2-year safety and efficacy results from the phase 3 poetyk trials.";"T. Passeron";"Equipe 12, Team 12";38226713;"The British journal of dermatology";"Lebwohl M, Warren RB, Sofen H, Imafuku S, Paul C, Szepietowski JC, Spelman L, Passeron T, Vritzali E, Napoli A, Kisa RM, Buck A, Banerjee S, Thaçi D, Blauvelt A";;"Jan 2024";1705363200;;"In the phase 3 POETYK PSO-1 and PSO-2 trials, deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, was well-tolerated and efficacious over 1 year in patients with psoriasis." 16512;"COVID-19 patient experiences in prehospital pathways: a processual approach using life-events calendar method and state sequence analysis shows detrimental delays.";"M. Carles";"Equipe 06, Team 06";38216208;"Family medicine and community health";"Lutaud R, Cortaredona S, Delorme L, Peretti-Watel P, Mirouse J, Borg M, Cattaneo L, Thery D, Gentile G, Pradier C, Irit T, Brouqui P, Tardieu S, Carles M, Gentile S";;"Jan 2024";1705017600;;"To our best knowledge, no study in France has comprehensively investigated the prehospital history of patients admitted for severe cases of COVID-19. 'Patients' voice is an excellent means to capture data on primary care pathways.We aimed to identify clusters of COVID-19 hospitalised patients with similar prehospital symptom sequences, and to test whether these clusters were associated with a higher risk of poor clinical outcomes." 16510;"Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.";"F. BOST, N. Mazure, P. Peraldi";"Equipe 05, Team 05";38214418;"Molecular oncology";"Pujalte-Martin M, Belaïd A, Bost S, Kahi M, Peraldi P, Rouleau M, Mazure NM, Bost F";;"Jan 2024";1705017600;;"Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075." 16490;"Bacterial infections in solid organ transplant recipients.";"J. Courjon";"Equipe 06, Team 06";38205868;"Current opinion in organ transplantation";"Courjon J, Neofytos D, van Delden C";;"Jan 2024";1704931200;;"Bacteria are the leading cause of infections in solid organ transplant (SOT) recipients, significantly impacting patient outcome. Recently detailed and comprehensive epidemiological data have been published." 16488;"Remission of nonalcoholic steatohepatitis after bariatric surgery: a single referral center cohort study.";"A. IANNELLI, R. ANTY";"Team 08, Equipe 08";38195314;"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery";"Drai C, Chierici A, Pavone G, Benamran D, Alromayan M, Alamri A, Anty R, Liddo G, Iannelli A";;"Jan 2024";1704758400;;"Obesity is associated with nonalcoholic steatohepatitis (NASH), which leads to an increased rate of primary liver cancers, cirrhosis, and decreased life expectancy. Metabolic/bariatric surgery (MBS) determines long-term weight loss and the resolution of obesity-related medical problems." 16480;"Bone marrow graft versus peripheral blood graft in haploidentical hematopoietic stem cells transplantation: a retrospective analysis in1344 patients of SFGM-TC registry.";"M. Loschi";"Equipe 02, Team 02";38185663;"Journal of hematology & oncology";"Lacan C, Lambert J, Forcade E, Robin M, Chevallier P, Loron S, Bulabois CÉ, Orvain C, Ceballos P, Daguindau E, Charbonnier A, Chalandon Y, Bernard M, Simand C, Rubio MT, Turlure P, Maertens J, Huynh A, Loschi M, Bay JO, Guillerm G, Alani M, Castilla-Llorente C, Poiré X, Chantepie S, Maillard N, Beguin Y, Marçais A, Cornillon J, Malfuson JV, Maury S, Meuleman N, Villate A, Bekadja MA, Walter-Petrich A, Jacque N, Srour M, Devillier R, Nguyen S";;"Jan 2024";1704585600;;"The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HR = 2.0; range [1.17-3.43], p = 0.012)." 16458;"Implicature priming, salience, and context adaptation.";"P. Marty";"Equipe 06, Team 06";38181565;Cognition;"Marty P, Romoli J, Sudo Y, Breheny R";;"Jan 2024";1704412800;;"Recent experimental research has observed two kinds of priming effects on quantity implicatures. One is the Strong-Weak contrast, where more quantity implicatures are observed after prime trials forcing interpretations with quantity implicatures ('Strong primes') than after prime trials forcing interpretations without quantity implicatures ('Weak primes'). The other effect is the Alternative-Weak contrast, where prime trials mentioning alternative expressions ('Alternative primes') similarly lead to more quantity implicatures. It has been claimed that both of these effects should be understood in terms of increased salience of alternative expressions used to compute quantity implicatures. We present experimental evidence that speaks against this hypothesis. With the help of novel baseline conditions, which were absent in previous studies on implicature priming, we observe that the results in the priming paradigm commonly used in the literature are inverse preference effects in the sense that robust priming effects are observed towards interpretations that are normally unexpected, and depending on the baseline expectation, each of the three prime types mentioned above may have priming effects. We furthermore investigated different types of alternative priming for so-called ad hoc implicatures and found that for these implicatures, presenting an alternative expression in a simple sentence does not have a priming effect on the implicature of a similarly simple sentence, but presenting it in a more complex conjunctive construction does. Our results also show that conjunctions of similar but irrelevant expressions have a similarly robust priming effect and that conjunctive sentences with two conjuncts do not give rise to priming effects on the interpretation of sentences of the same syntactic complexity, but those with three conjuncts do. To make sense of these observations, we propose that what crucially matters for priming implicatures is incremental change in one's probabilistic expectations about the current conversational context brought about by a process we call context adaptation." 16456;"Transfusion needs after CAR T-cell therapy for large B-cell lymphoma: predictive factors and outcome. A DESCAR-T study.";"M. Loschi";"Equipe 02, Team 02";38181767;"Blood advances";"Vic S, Thibert JB, Bachy E, Cartron G, Gastinne T, Morschhauser F, Le Bras F, Bouabdallah K, Despas F, Bay JO, Rubio MT, Mohty M, Casasnovas O, Choquet S, Castilla-Llorente C, Guidez S, Loschi M, Guffroy B, Carras S, Drieu La Rochelle L, Guillet M, Houot R";;"Jan 2024";1704412800;;"Chimeric antigen receptor (CAR) T-cells targeting CD19 have been approved for the treatment of relapse/refractory large B-cell lymphoma. Hematotoxicity is the most frequent CAR T-cell-related adverse event. Transfusion support is a surrogate marker of severe cytopenias. Transfusion impacts patients' quality of life, presents specific toxicities and is known to affect immunity through the so-called transfusion-related immunomodulation, that may impact CAR T-cell efficacy. We analyzed data from 671 patients from the French DESCAR-T registry for whom exhaustive transfusion data were available. Overall, 401 (59.8%) and 378 (56.3%) patients were transfused in the 6-month period before and after CAR T-cell, respectively. The number of transfused patients and the mean number of transfused products increased during the 6-month period before CAR-T, peaked during the first month after infusion (early phase) and decreased over time. Predictive factors for transfusion at the early phase were age > 60 years, ECOG PS ≥2, treatment with axi-cel, pre-CAR T-cell transfusions and CAR-HEMATOTOX score ≥ 2. Predictive factors for late transfusion (between 1 and 6 months after infusion) were pre-CAR T-cell transfusions, CAR-HEMATOTOX score ≥ 2, ICANS ≥ 3 (for red blood cells [RBC] transfusion) and tocilizumab use (for platelets transfusion). Early transfusions and late platelets (but not RBC) transfusions were associated with a shorter progression-free survival and overall survival. Lymphoma-related mortality and non-relapse mortality were both increased in the transfused population. Our data shed light on the mechanisms of early and late cytopenia, and on the potential impact of transfusions on CAR T-cell efficacy and toxicity." 16454;"Viral and bacterial microorganisms in Vietnamese children with severe and non-severe pneumonia.";"P. Marty";"Equipe 06, Team 06";38167637;"Scientific reports";"Tran XD, Hoang VT, Goumballa N, Vu TN, Tran TK, Pham TD, Dao TL, Vu TT, Nguyen DC, Nguyen QT, Marty P, Gautret P";;"Jan 2024";1704240000;;"To investigate potential respiratory pathogens in children with community-acquired pneumonia (CAP) and risk factors for severe disease. This prospective study was conducted among 467 children at the Thai Binh Paediatric Hospital, Vietnam between 1 July 2020 and 30 June 2021. Clinical data and laboratory results were collected. Twenty-four respiratory microorganisms were tested from nasopharyngeal swabs using real-time PCR. Logistical regression was used to estimate a factor's adjusted odd ratios of the severity of disease. Mean age of patients = 15.4 ± 13.3 months, 63.0% were male. Over 97% of patients had a positive PCR result. 87% of patients were positive for multiple (up to eight) microorganisms. Rhinovirus (46%), respiratory syncytial virus (RSV) (24%), enterovirus (17%), and parainfluenza viruses-3 (13%) were the most frequent viruses. H. influenzae (61%), S. pneumoniae (45%) and M. catarrhalis (30%) were the most common bacteria. 128 (27%) cases were classified as severe pneumonia. Presence of smokers at home (aOR 2.11, 95% CI 1.27-3.52, P value = 0.004), CRP level ≥ 50 mg/dL (aOR  6.11, 95% CI  3.86-9.68, P value < 0.0001), RSV (aOR  1.78, 95% CI  1.07-2.96, P value = 0.03) and H. influenzae (aOR  1.66, 95% CI  1.03-2.67, P value = 0.04) PCR detection associated with a higher risk of severe pneumonia; ,. Causative agents of pneumonia in children are complex. Children positive with RSV and H. influenzae need to be closely monitored to prevent severe pneumonia." 16452;"Acute Pyelonephritis with Bacteremia in an 89-Year-Old Woman Caused by Two Slow-Growing Bacteria: and .";"R. Ruimy, R. Lotte";"Equipe 06, Team 06";38138052;Microorganisms;"Lotte L, Durand C, Chevalier A, Gaudart A, Cheddadi Y, Ruimy R, Lotte R";;"Dec 2023";1703289600;;" is an aerobic Gram-positive coccus that grows as tiny alpha-hemolytic colonies. is a slow-growing facultative anaerobic Gram-positive rod. These bacteria are part of the urogenital microbiota of healthy patients, but can also be involved in urinary tract infections (UTIs), particularly in elderly men and young children. Because and are fastidious and are difficult to identify with phenotypic methods, they are underestimated causes of UTIs. Their growth is slow and requires a blood-enriched medium incubated under an anaerobic or 5% CO atmosphere for 48 h and from 24 to 48 h for and , respectively. Furthermore, accurate identification is only possible using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or molecular-based methods. In rare cases, these bacteria can be responsible for invasive infections. We describe, here, an unusual case of bacteremic UTI caused by both and in an 89-year-old woman. She presented with dyspnea, and bacteriuria was noted. This challenging clinical and microbiological diagnosis was made in our laboratory by Gram staining urine with a leucocyte count >50/μL and/or a bacterial count >14/μL urinary culture on a blood agar plate. After 10 days of antimicrobial treatment consisting of 2 g amoxicillin PO t.i.d., the patient was discharged with a complete clinical and biological recovery. and are probably still underestimated causes of UTIs. Microbiologists could consider the presence of these two bacteria using appropriate culture and identification methods in cases where a positive direct examination of urine reveals small Gram-positive rods or cocci, where undocumented UTIs are present in elderly patients, but also where a urinary dipstick is negative for nitrites and is associated with leukocyturia." 16450;"Free-electron Ramsey-type interferometry for enhanced amplitude and phase imaging of nearfields.";"R. Ruimy";"Equipe 06, Team 06";38134276;"Science advances";"Bucher T, Ruimy R, Tsesses S, Dahan R, Bartal G, Vanacore GM, Kaminer I";;"Dec 2023";1703203200;;"The complex range of interactions between electrons and electromagnetic fields gave rise to countless scientific and technological advances. A prime example is photon-induced nearfield electron microscopy (PINEM), enabling the detection of confined electric fields in illuminated nanostructures with unprecedented spatial resolution. However, PINEM is limited by its dependence on strong fields, making it unsuitable for sensitive samples, and its inability to resolve complex phasor information. Here, we leverage the nonlinear, overconstrained nature of PINEM to present an algorithmic microscopy approach, achieving far superior nearfield imaging capabilities. Our algorithm relies on free-electron Ramsey-type interferometry to produce orders-of-magnitude improvement in sensitivity and ambiguity-immune nearfield phase reconstruction, both of which are optimal when the electron exhibits a fully quantum behavior. Our results demonstrate the potential of combining algorithmic approaches with state-of-the-art modalities in electron microscopy and may lead to various applications from imaging sensitive biological samples to performing full-field tomography of confined light." 16448;"Design, Synthesis and Biological Evaluation of Novel Anticancer Amidinourea Analogues via Unexpected 1,3,5-Triazin-2-one Ring Opening.";"N. Tekaya, T. Botton, S. Rocchi";"Team 12, Equipe 12";38126619;ChemMedChem;"Grytsai O, Hamouda-Tekaya N, Botton T, Rocchi S, Benhida R, Ronco C";;"Dec 2023";1703116800;;"Amidinoureas are an understudied class of molecules with unique structural properties and biological activities. A simple methodology has been developed for the synthesis of aliphatic substituted amidinoureas via unexpected cycle opening of benzothiazolo-1,3,5-triazine-2-ones and transamination reaction of N-(N-(benzo[d]thiazol-2-yl)carbamimidoyl)aniline-1-carboxamide in good yields. A novel series of amidinoureas derivatives was designed, synthesized, and evaluated for its antiproliferative activity on an aggressive metastatic melanoma A375 cell line model. This evaluation reveals antiproliferative activities in the low micromolar range and establishes a first structure-activity relationship. In addition, analogues selected for their structural diversity were assayed on a panel of cancer cell lines through the DTP-NCI60, on which they showed effectiveness on various cancer types, with promising activities on melanoma cells for two hit compounds. This work paves the way for further optimization of this family of compounds towards the development of potent antimelanoma agents." 16446;"Yellow fever vaccine-associated neurologic and viscerotropic disease: a 10-year case series of the French National Reference Center for arboviruses with clinical and immunological insights.";"M. Carles";"Equipe 06, Team 06";38123499;"Journal of travel medicine";"Le Hir A, Durand GA, Boucraut J, Garnier A, Mura M, Diamantis S, Carles M, Durand C, Schweitzer C, Audouard C, Decroix V, Boyez R, Van Dendriessche A, Leclancher A, Kaphan E, du Closel LB, Verdon R, du Cheyron D, Vabret A, Vergnon D, Grard G, Charrel R, de Lamballerie X, Eldin C";;"Dec 2023";1703030400;;"Immunization against the Yellow fever virus (YFV) with the 17D live-attenuated vaccine is the most effective way to prevent the disease. However, unexpected severe adverse events can occur. They consist in a neurological disease (YEL-AND), a viscerotropic disease (YEL-AVD), or anaphylaxis. In this article, we describe the epidemiology, clinical and biological features of YEL-AND and YEL-AVD cases reported to the French National Reference Center for Arboviruses (NRCA) in the past 10 years." 16434;"Hepatitis E Virus Infection Epidemiology in Recipients of Allogeneic Hematopoietic Cell Transplant.";"J. Courjon";"Equipe 06, Team 06";38094666;"Open forum infectious diseases";"Courjon J, Portillo V, Yerly S, Vetter P, Schibler M, Mappoura M, Morin S, Giannotti F, Mamez AC, van Delden C, Kaiser L, Chalandon Y, Masouridi-Levrat S, Neofytos D";;"Dec 2023";1702512000;;"Among 292 recipients of allogeneic hematopoietic cell transplant (2018-2022), 64 (21.9%) tested positive for anti-hepatitis E virus (HEV) immunoglobulin G. Among 208 recipients tested by plasma/serum HEV polymerase chain reaction (2012-2022), 3 (1.4%) primary HEV infections were diagnosed; in 1 patient, plasma HEV polymerase chain reaction relapsed positive for 100 days. HEV infection remains rare albeit associated with persistent viral replication." 16387;"Impact of rising seawater temperature on a phagocytic cell population during infection in the sea anemone .";"F. LARBRET";"Equipe 11, Team 11";38077367;"Frontiers in immunology";"Billaud M, Larbret F, Czerucka D";;"Dec 2023";1702252800;;"Climate change is increasing ocean temperatures and consequently impacts marine life (e.g., bacterial communities). In this context, studying host-pathogen interactions in marine organisms is becoming increasingly important, not only for ecological conservation, but also to reduce economic loss due to mass mortalities in cultured species. In this study, we used (), an anemone, as an emerging marine model to better understand the effect of rising temperatures on the infection induced by the pathogenic marine bacterium . The effect of temperature on was examined at 6, 24, or 30 h after bath inoculation with 10 CFU of expressing GFP (Vp-GFP) at 27°C (husbandry temperature) or 31°C (heat stress). Morphological observations of and their Hsps expression demonstrated heat stress induced increasing damage to anemones. The kinetics of the infections revealed that Vp-GFP were localized on the surface of the ectoderm and in the mucus during the first hours of infection and in the mesenterial filaments thereafter. To better identify the cells targeted by Vp-GFP infection, we used spectral flow cytometry. cell types were identified based on their autofluorescent properties. corresponding to different cell types (algae and cnidocytes). We identified an AF10 population whose autofluorescent spectrum was identical to that of human monocytes/macrophage, suggesting that this spectral print could be the hallmark of phagocytic cells called ""amebocytes''. AF10 autofluorescent cells had a high capacity to phagocytize Vp-GFP, suggesting their possible role in fighting infection. This was confirmed by microscopy using sorted AF10 and GFP-positive cells (AF10+/GFP+). The number of AF10+/GFP+ cells were reduced at 31°C, demonstrating that increased temperature not only damages tissue but also affects the immune response of . In conclusion, our study provides a springboard for more comprehensive studies of immune defense in marine organisms and paves the way for future studies of the dynamics, activation patterns, and functional responses of immune cells when encountering pathogens." 16385;"Mycobacterium ulcerans-Bordetella trematum chronic tropical cutaneous ulcer: A four-case series, Côte d'Ivoire.";"R. Ruimy";"Equipe 06, Team 06";38060465;"PLoS neglected tropical diseases";"Tchan BGO, Kakou-Ngazoa S, Dizoe S, Hammoudi N, Grine G, Ruimy R, Drancourt M";;"Dec 2023";1701907200;;"Chronic tropical cutaneous ulcers remain a neglected medical condition in West Africa, particularly Buruli ulcer, which is caused by mycolactone cytotoxin-secreting Mycobacterium ulcerans (M. ulcerans). Medical management of this highly debilitating and necrotising skin infection may be modified by colonisation and co-infection of the ulcer by opportunistic and pathogenic microorganisms, which considerably delays and increases the cost of treatment." 16383;"Time is of the Essence: Achieving Prompt and Effective Antimicrobial therapy of Bloodstream infection With Advanced Hospital Information Systems.";"B. Lamy";"Equipe 06, Team 06";38059510;"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America";"Morquin D, Lejeune J, Agostini C, Godreuil S, Reynes J, Le Moing V, Lamy B";;"Dec 2023";1701907200;;"The early administration of appropriate antibiotic therapy is crucial for the survival of patients with bacteremia. Current research focuses on improving analytical times through technology while there have been very few efforts to improve post-analytical times even though they represent 40% of the time between blood taking and appropriate treatment administration. One of the clues is the efficiency and appropriateness of the result communication system. Here, we review all delays in the whole process with the aim of improving time to appropriate treatment administration. We discuss causes for long times to adjust treatment once microbiological results are released. We argue that that the pervasive health information system in this organization serves as both a bottleneck and a rigid framework to focus on. Finally, we explore how should be conceived the next generation hospital information systems to effectively assist the doctors in treating patients with bacteremia." 16347;"Treatment of Severe Palmoplantar Pustular Psoriasis With Bimekizumab.";"T. Passeron";"Equipe 12, Team 12";38054800;"JAMA dermatology";"Passeron T, Perrot JL, Jullien D, Goujon C, Ruer M, Boyé T, Villani AP, Quiles Tsimaratos N";;"Dec 2023";1701820800;;"Palmoplantar pustulosis (PPP) and palmoplantar plaque psoriasis with pustules remain challenging to treat. Studies suggest that an interleukin 17 or interleukin 36 loop acts synergistically in these diseases to induce palmoplantar pustules." 16345;"Opioid-free versus opioid-sparing anaesthesia in ambulatory total hip arthroplasty: a randomised controlled trial.";"P. Marty";"Equipe 06, Team 06";38044236;"British journal of anaesthesia";"Chassery C, Atthar V, Marty P, Vuillaume C, Casalprim J, Basset B, De Lussy A, Naudin C, Joshi GP, Rontes O";;"Dec 2023";1701561600;;"Enhanced recovery after surgery pathways are essential for ambulatory surgery. They usually recommend lower intraoperative opioid use to avoid opioid-related adverse effects. This has led to opioid-sparing anaesthesia (OSA) techniques, with the extreme approach of opioid-free anaesthesia (OFA) mostly with dexmedetomidine. As evidence is lacking in day-case primary total hip arthroplasty, this study was performed to assess the potential benefits in postoperative analgesia of OFA over OSA." 16342;"Moving Forward: Evaluation of Artificial Intelligence Chatbots in Vascular Diseases.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";38040102;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Poggi E, Raffort J";;"Dec 2023";1701388800;; 16340;"Effects of bariatric surgery on severe suppurative hidradenitis: Results of a nationwide administrative data study in France.";"A. IANNELLI";"Team 08, Equipe 08";38041567;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Chierici A, Bulsei J, De Fatico S, Alromayan M, Alamri A, Pavone G, Liddo G, Fontas E, Iannelli A";;"Dec 2023";1701475200;; 16338;"The mitochondrial NADH shuttle system is a targetable vulnerability for Group 3 medulloblastoma in a hypoxic microenvironment.";"F. BOST, N. Mazure";"Equipe 05, Team 05";38036520;"Cell death & disease";"Contenti J, Guo Y, Mazzu A, Irondelle M, Rouleau M, Lago C, Leva G, Tiberi L, Ben-Sahra I, Bost F, Mazure NM";;"Nov 2023";1701302400;;"Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive." 16336;"Inhibition of T-cell activity in alopecia areata: recent developments and new directions.";"T. Passeron";"Equipe 12, Team 12";38022501;"Frontiers in immunology";"Passeron T, King B, Seneschal J, Steinhoff M, Jabbari A, Ohyama M, Tobin DJ, Randhawa S, Winkler A, Telliez JB, Martin D, Lejeune A";;"Nov 2023";1701216000;;"Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8 T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration-approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell-mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell-signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell-signaling pathways is also provided in this review." 16334;"We need more vascular research.";"N. Sadaghianloo";"Equipe 09, Team 09";38023963;"JVS-vascular science";"Dardik A, Curci JA, Tang GL, Hedin U, Sadaghianloo N, Roy TL, Dalman RL";;"Nov 2023";1701216000;; 16332;"Ethical Concerns Regarding the Use of Large Language Models in Healthcare.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";38025830;"EJVES vascular forum";"Lareyre F, Raffort J";;"Nov 2023";1701216000;; 16330;"An exploratory human study investigating the influence of type 2 diabetes on macrophage phenotype after myocardial infarction.";"G. Chinetti, J. Neels, J. Murdaca, E. Ferrari";"Equipe 09, Team 09";38020056;"International journal of cardiology. Heart & vasculature";"Moratal C, Murdaca J, Cruzel C, Zamiti-Smondel A, Heme N, Asarisi F, Neels JG, Ferrari E, Chinetti G";;"Nov 2023";1701216000;;"Myocardial infarction (MI) is the primary cause of death in subjects with type 2 diabetes (T2D) and their in-hospital mortality after MI is still elevated compared with those without T2D. Therefore, it is of crucial importance to identify possible mechanisms of worse clinical outcomes and mortality in T2D subjects. Monocyte/macrophage-mediated immune response plays an important role in heart remodelling to limit functional deterioration after MI. Indeed, first pro-inflammatory macrophages digest damaged tissue, then anti-inflammatory macrophages become prevalent and promote tissue repair. Here, we hypothesize that the worse clinical outcomes in patients with T2D could be the consequence of a defective or a delayed polarization of macrophages toward an anti-inflammatory phenotype." 16320;"Letter re: Machine Learning to Predict Outcomes Following Endovascular Aortic Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";38009698;"Vascular and endovascular surgery";"Lareyre F, Raffort J";;"Nov 2023";1701043200;; 16311;Pentastomiasis.;"P. Marty";"Equipe 06, Team 06";37983909;"The American journal of tropical medicine and hygiene";"Marty P, L'Ollivier C, Simon L";;"Nov 2023";1700438400;; 16307;"LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition.";"C. Bertolotto, F. BOST, K. Bille, L. Yvan-Charvet, N. Mazure, N. Arrighi, R. Ballotti, Y. Cheli";"Equipe 01, Team 01, Equipe 05, Team 05, Equipe 13, Team 13";37966164;"EMBO molecular medicine";"Proteau S, Krossa I, Husser C, Guéguinou M, Sella F, Bille K, Irondelle M, Dalmasso M, Barouillet T, Cheli Y, Pisibon C, Arrighi N, Nahon-Estève S, Martel A, Gastaud L, Lassalle S, Mignen O, Brest P, Mazure NM, Bost F, Baillif S, Landreville S, Turcotte S, Hasson D, Carcamo S, Vandier C, Bernstein E, Yvan-Charvet L, Levesque MP, Ballotti R, Bertolotto C, Strub T";;"Nov 2023";1700006400;;"Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome-wide CRISPR-Cas9 knockout screen, which revealed the LKB1-SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na /Ca ) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria-targeted antioxidant promotes enhanced cell death efficacy in LKB1- and SIK2-negative uveal melanoma cells compared to control cells. Our study also identified an LKB1-loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma." 16305;"Adipocyte glucocorticoid receptor activation with high glucocorticoid doses impairs healthy adipose tissue expansion by repressing angiogenesis.";"JF. Tanti, J. GILLERON, M. Cormont";"Equipe 07, Team 07";37963392;Diabetes;"Vali A, Dalle H, Loubaresse A, Gilleron J, Havis E, Garcia M, Beaupère C, Denis C, Roblot N, Poussin K, Ledent T, Bouillet B, Cormont M, Tanti JF, Capeau J, Vatier C, Fève B, Grosfeld A, Moldes M";;"Nov 2023";1699920000;;"In Human, glucocorticoids (GC) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GC often lead to adverse side effects including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)-deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion associated with a paradoxical improvement of metabolic health compared to control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of the hypoxiainducible factor HIF-1α and the pro-angiogenic Vascular Endothelial Growth Factor-A expression in GR-deficient adipocytes of AdipoGR-KO mice as compared to control mice, together with an increased adipose vascular network, as assessed by 3D-analysis imaging. GR activation reduced HIF-1α recruitment on Vegfa promoter resulting from Hif-1α downregulation at the transcriptional and post-translational levels. Importantly, in CORT-treated AdipoGR-KO mice, the blockade of VEGFA by a soluble decoy receptor prevented AT expansion and the healthy metabolic phenotype. Finally, in subcutaneous AT from Cushing patients, higher VEGFA expression was associated with a better metabolic profile. Collectively, these results highlight that adipocyte GR negatively controls AT expansion and metabolic health through the down-regulation of the major angiogenic effector VEGFA and inhibiting vascular network development. (LIPOCUSH, NCT01688349)." 16297;"Management and outcomes of hemorrhage after distal pancreatectomy: a multicenter study at high volume centers.";"A. IANNELLI";"Team 08, Equipe 08";37951805;"HPB : the official journal of the International Hepato Pancreato Biliary Association";"Duclos C, Durin T, Marchese U, Sauvanet A, Laurent C, Ayav A, Turrini O, Sulpice L, Addeo P, Souche FR, Perinel J, Birnbaum DJ, Facy O, Gagnière J, Gaujoux S, Schwarz L, Regenet N, Iannelli A, Regimbeau JM, Piessen G, Lenne X, El Amrani M, Heyd B, Doussot A, ";;"Nov 2023";1699660800;;"Data on clinically relevant post-pancreatectomy hemorrhage (CR-PPH) are derived from series mostly focused on pancreatoduodenectomy, and data after distal pancreatectomy (DP) are scarce." 16295;"[Linear dermatosis on the forearms].";"N. Martis";"Equipe 10, Team 10";37949530;"La Revue de medecine interne";"Nerson T, Castela E, Leccia N, Martis N";;"Nov 2023";1699574400;; 16293;"Differential gradients of immunotherapy vs targeted therapy efficacy according to the sun-exposure pattern of the site of occurrence of primary melanoma: a multicenter prospective cohort study (MelBase).";"H. Montaudie";"Equipe 12, Team 12";37936607;"Frontiers in oncology";"Russo D, Dalle S, Dereure O, Mortier L, Dalac-Rat S, Dutriaux C, Leccia MT, Legoupil D, Montaudié H, Maubec E, De Quatrebarbes J, Arnault JP, Brocard FG, Saïag P, Dreno B, Allayous C, Oriano B, Lefevre W, Lebbé C, Boussemart L";;"Nov 2023";1699401600;;"The tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment." 16287;"There are Many Ways to Navigate in a Fog: Management of Acute Limb Threat in France.";"F. Lareyre";"Equipe 09, Team 09";37923188;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Behrendt CA, Lareyre F";;"Nov 2023";1698969600;; 16285;"Super-enhancer-driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability.";"C. Bertolotto";"Equipe 01, Team 01";37924516;"Cell reports";"Berico P, Nogaret M, Cigrang M, Lallement A, Vand-Rajabpour F, Flores-Yanke A, Gambi G, Davidson G, Seno L, Obid J, Vokshi BH, Le Gras S, Mengus G, Ye T, Cordero CF, Dalmasso M, Compe E, Bertolotto C, Hernando E, Davidson I, Coin F";;"Nov 2023";1699056000;;"Super-enhancers (SEs) are stretches of enhancers ensuring a high level of expression of key genes associated with cell function. The identification of cancer-specific SE-driven genes is a powerful means for the development of innovative therapeutic strategies. Here, we identify a MITF/SOX10/TFIIH-dependent SE promoting the expression of BAHCC1 in a broad panel of melanoma cells. BAHCC1 is highly expressed in metastatic melanoma and is required for tumor engraftment, growth, and dissemination. Integrative genomics analyses reveal that BAHCC1 is a transcriptional regulator controlling expression of E2F/KLF-dependent cell-cycle and DNA-repair genes. BAHCC1 associates with BRG1-containing remodeling complexes at the promoters of these genes. BAHCC1 silencing leads to decreased cell proliferation and delayed DNA repair. Consequently, BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. Our study identifies BAHCC1 as an SE-driven gene expressed in melanoma and demonstrates how its inhibition can be exploited as a therapeutic target." 16283;"ROLE OF ANTICOAGULATION IN NONAGENARIAN PATIENTS WITH ACUTE LIMB ISCHEMIA.";"E. Jean-Baptiste, N. Sadaghianloo, R. Hassen-Khodja";"Team 09, Equipe 09";37918663;"Annals of vascular surgery";"Carboni J, Sadaghianloo N, Haudebourg P, Declemy S, Hassen-Khodja R, Jean-Baptiste E";;"Nov 2023";1698883200;;"Preoperative anticoagulant therapy is known to have a positive impact on the prognosis of patients with acute limb ischemia (ALI). However, little is known about its efficacy in elderly patients. We aimed to investigate the potential effect of anticoagulation in nonagenarian patients managed for ALI." 16281;"Thirty years of promoting sun safety in France: The messages are heard but not followed!";"T. Passeron";"Equipe 12, Team 12";37915260;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Lim HW, Goh CL, Kang HY, Ribeyre C, Demessant-Flavigny AL, Le Floc'h C, Kerob D, Krutmann J, Comte C, Dreno B, Leccia MT";;"Nov 2023";1698883200;; 16279;"Cefoxitin versus carbapenems as definitive treatment for extended-spectrum β-lactamase-producing Klebsiella pneumoniae bacteremia in intensive care unit: a propensity-matched retrospective analysis.";"M. Carles";"Equipe 06, Team 06";37915017;"Critical care (London, England)";"Dequidt T, Bastian S, Nacher M, Breurec S, Carles M, Thiery G, Camous L, Tressieres B, Valette M, Pommier JD";;"Nov 2023";1698883200;;"Despite cefoxitin's in vitro resistance to hydrolysis by extended-spectrum beta-lactamases (ESBL), treatment of ESBL-producing Klebsiella pneumoniae (KP) infections with cefoxitin remains controversial. The aim of our study was to compare the clinical efficacy of cefoxitin as definitive antibiotic therapy for patients with ESBL-KP bacteremia in intensive care unit, versus carbapenem therapy." 16277;"Successful Treatment of Eosinophilic Pustular Folliculitis With Dupilumab.";"T. Passeron";"Equipe 12, Team 12";37910114;"JAMA dermatology";"Ottavi M, Velin M, Cardot Leccia N, Passeron T";;"Nov 2023";1698796800;; 16275;"HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.";"F. BOST, N. Mazure";"Equipe 05, Team 05";37905067;"bioRxiv : the preprint server for biology";"Contenti J, Guo Y, Larcher M, Mirabal-Ortega L, Rouleau M, Irondelle M, Tiroille V, Mazzu A, Duranton-Tanneur V, Pedeutour F, Ben-Sahra I, Lago C, Leva G, Tiberi L, Robert G, Pouponnot C, Bost F, Mazure NM";;"Oct 2023";1698710400;;"Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity." 16238;"Vitiligo, it was about time!";"T. Passeron";"Equipe 12, Team 12";37877766;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Oct 2023";1698192000;; 16216;"Artificial intelligence-based predictive models in vascular diseases.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37863618;"Seminars in vascular surgery";"Lareyre F, Chaudhuri A, Behrendt CA, Pouhin A, Teraa M, Boyle JR, Tulamo R, Raffort J";;"Oct 2023";1697760000;;"Cardiovascular disease represents a source of major health problems worldwide, and although medical and technical advances have been achieved, they are still associated with high morbidity and mortality rates. Personalized medicine would benefit from novel tools to better predict individual prognosis and outcomes after intervention. Artificial intelligence (AI) has brought new insights to cardiovascular medicine, especially with the use of machine learning techniques that allow the identification of hidden patterns and complex associations in health data without any a priori assumptions. This review provides an overview on the use of artificial intelligence-based prediction models in vascular diseases, specifically focusing on aortic aneurysm, lower extremity arterial disease, and carotid stenosis. Potential benefits include the development of precision medicine in patients with vascular diseases. In addition, the main challenges that remain to be overcome to integrate artificial intelligence-based predictive models in clinical practice are discussed." 16214;"Artificial intelligence in vascular surgical decision making.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37863619;"Seminars in vascular surgery";"Lareyre F, Yeung KK, Guzzi L, Di Lorenzo G, Chaudhuri A, Behrendt CA, Spanos K, Raffort J";;"Oct 2023";1697760000;;"Despite advances in prevention, detection, and treatment, cardiovascular disease is a leading cause of mortality and represents a major health problem worldwide. Artificial intelligence and machine learning have brought new insights to the management of vascular diseases by allowing analysis of huge and complex datasets and by offering new techniques to develop advanced imaging analysis. Artificial intelligence-based applications have the potential to improve prognostic evaluation and evidence-based decision making and contribute to vascular therapeutic decision making. In this scoping review, we provide an overview on how artificial intelligence could help in vascular surgical clinical decision making, highlighting potential benefits, current limitations, and future challenges." 16212;"[Introduction to spatial omics].";"N. Mazure";"Equipe 05, Team 05";37858425;"Bulletin du cancer";"Mazure NM";;"Oct 2023";1697760000;; 16210;"Recurrent Anastomotic Ulcer After Roux-en-Y Gastric Bypass: a Video Case Report and Review of Treatment Options.";"A. IANNELLI";"Team 08, Equipe 08";37861879;"Obesity surgery";"Alromayan M, Thomas S, Abdelrahmane A, Chierici A, Iannelli A";;"Oct 2023";1697760000;; 16197;"Efficacy and safety of cosibelimab, an anti-PD-L1 antibody, in metastatic cutaneous squamous cell carcinoma.";"H. Montaudie";"Equipe 12, Team 12";37848259;"Journal for immunotherapy of cancer";"Clingan P, Ladwa R, Brungs D, Harris DL, McGrath M, Arnold S, Coward J, Fourie S, Kurochkin A, Malan DR, Mant A, Sharma V, Shue H, Tazbirkova A, Berciano-Guerrero MA, Charoentum C, Dalle S, Dechaphunkul A, Dudnichenko O, Koralewski P, Lugowska I, Montaudié H, Muñoz-Couselo E, Sriuranpong V, Oliviero J, Desai J";;"Oct 2023";1697500800;;"Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab." 16195;"Idiopathic dilatation of the submandibular gland duct.";"P. Marty";"Equipe 06, Team 06";37845088;"International journal of oral and maxillofacial surgery";"Graillon N, Marty P, Foletti JM, Chossegros C, Frandjian H";;"Oct 2023";1697414400;;"Lithiasis and stenosis may cause salivary duct dilatation due to the increased pressure in the duct upstream of the obstruction. Idiopathic dilatations, also called megaducts, with no associated increase in pressure, have only been described in the parotid gland. The aim of this study was to describe the characteristics of submandibular duct dilatation unrelated to lithiasis, stenosis, or an imperforate duct, to report the existence of submandibular megaducts. This retrospective single-centre study included patients treated at La Conception University Hospital, Marseille, France, between 2007 and 2019. Patients with submandibular duct dilatation of ≥4 mm confirmed by magnetic resonance imaging sialography (sialo-MRI), who also underwent sialendoscopy to identify any associated stenosis, were included. Patients with lithiasis, stenosis, an imperforate ostium, or a history of trauma or surgery to the floor of the mouth were excluded. Five patients (three female, two male) aged 30-76 years with idiopathic duct dilatations in nine submandibular glands were included. The most commonly reported symptoms were submandibular swelling, pruritus, and discomfort, mostly outside mealtimes. Recurrence of symptoms after treatment was frequent. This study is novel in describing submandibular megaducts as opposed to dilatation caused by high pressure associated with stenosis, with confirmation by sialo-MRI and sialendoscopy." 16193;"Long-Term Results of Sleeve Gastrectomy and Roux-en-Y Gastric Bypass in Individuals Older Than 60 Years with Morbid Obesity.";"A. IANNELLI";"Team 08, Equipe 08";37840091;"Obesity surgery";"Drai C, Chierici A, Schiavo L, Amor IB, Schneider S, Iannelli A";;"Oct 2023";1697328000;;"An increasing Pnumber of individuals with obesity over the age of 60 years require bariatric surgery to treat obesity and its related medical problems. Sleeve gastrectomy and Roux-en-Y gastric bypass have already proven their efficacy in this population, but literature lacks reports of long-term results. The aim of this study is to compare long-term results of sleeve gastrectomy and Roux-en-Y gastric bypass in individuals older than 60 years old." 16191;"Melanogenesis Is Directly Affected by Metabolites of Melatonin in Human Melanoma Cells.";"M. Tulic";"Equipe 12, Team 12";37834395;"International journal of molecular sciences";"Möller JKS, Linowiecka K, Gagat M, Brożyna AA, Foksiński M, Wolnicka-Glubisz A, Pyza E, Reiter RJ, Tulic MK, Slominski AT, Steinbrink K, Kleszczyński K";;"Oct 2023";1697241600;;"Melatonin (-acetyl-5-methoxytryptamine, MEL), its kynurenic (-acetyl--formyl-5-methoxykynurenine, AFMK) and indolic derivatives (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) are endogenously produced in human epidermis. Melatonin, produced by the pineal gland, brain and peripheral organs, displays a diversity of physiological functions including anti-inflammatory, immunomodulatory, and anti-tumor capacities. Herein, we assessed their regulatory effect on melanogenesis using amelanotic (A375, Sk-Mel-28) and highly pigmented (MNT-1, melanotic) human melanoma cell lines. We discovered that subjected compounds decrease the downstream pathway of melanin synthesis by causing a significant drop of cyclic adenosine monophosphate (cAMP) level, the microphthalmia-associated transcription factor (MITF) and resultant collapse of tyrosinase (TYR) activity, and melanin content comparatively to -phenylthiourea (PTU, a positive control). We observed a reduction in pigment in melanosomes visualized by the transmission electron microscopy. Finally, we assessed the role of G-protein-coupled seven-transmembrane-domain receptors. Obtained results revealed that nonselective MT1 and MT2 receptor antagonist (luzindole) or selective MT2 receptor antagonist (4-P-PDOT) did not affect dysregulation of the melanin pathway indicating a receptor-independent mechanism. Our findings, together with the current state of the art, provide a convenient experimental model to study the complex relationship between metabolites of melatonin and the control of pigmentation serving as a future and rationale strategy for targeted therapies of melanoma-affected patients." 16189;"Molecular Characterization of Primary Mediastinal Large B-Cell Lymphomas.";"C. Mauduit";"Equipe 10, Team 10";37835560;Cancers;"Donzel M, Pesce F, Trecourt A, Groussel R, Bachy E, Ghesquières H, Fontaine J, Benzerdjeb N, Mauduit C, Traverse-Glehen A";;"Oct 2023";1697241600;;"Since the description of primary mediastinal large B-cell lymphoma (PMBL) as a distinct entity from diffuse large B-cell lymphomas (DLBCL), numerous studies have made it possible to improve their definition. Despite this, this differential diagnosis can be challenging in daily practice. However, in some centers, PMBL may be treated according to a particular regimen, distinct from those used in DLBCL, emphasizing the importance of accurate identification at diagnosis. This study aimed to describe the histological and molecular characteristics of PMBL to improve the accuracy of their diagnosis. Forty-nine cases of PMBL were retrospectively retrieved. The mean age at diagnosis was 39 years (21-83), with a sex ratio of 0.88. All cases presented a fibrous background with diffuse growth of intermediate to large cells with an eosinophil (26/49, 53%) or retracted cytoplasm (23/49, 47%). ""Hodgkin-like"" cells were observed in 65% of cases (32/49, 65%). The phenotype was: BCL6+ (47/49, 96%), MUM1+ (40/49, 82%), CD30+ (43/49, 88%), and CD23+ (37/49, 75%). Genomic DNAs were tested by next generation sequencing of 33 cases using a custom design panel. Pathogenic variants were found in all cases. The most frequent mutations were: (30/33, 91%), (18/33, 54.5%), (17/33, 51.5%), (16/33, 48.5%), (12/33, 36.4%), (12/33; 36.4%), (11/33, 33.3%) as well as (10/33, 30.3%), (9/33, 27.3%), (8/33, 24%), and (8/33, 24%). The present study describes a PMBL cohort on morphological, immunohistochemical, and molecular levels to provide pathologists with daily routine tools. These data also reinforce interest in an integrated histomolecular diagnosis to allow a precision diagnosis as early as possible." 16187;"[EMDR («Eye Movement Desensitization and Reprocessing») with children and adolescents].";"V. Grandjean";"Equipe 10, Team 10";37830323;"Revue medicale de Liege";"Schweich M, Vervier JF, Grandjean V";;"Oct 2023";1697155200;;"«Eye Movement Desensitization and Reprocessing» is a method for trauma treatment, initially developed for adults, but raising more and more awareness amongst child professionals. The way this therapy can be applied with children and adolescents varies from adult populations, because a child is constantly developing and in relation with his/her parents. The level of evidence also differs, literature offering less studies in this domain. Nevertheless, existing studies are promising and show, on a small scale mostly, that EMDR is effective for treating trauma in children." 16185;"Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy.";"F. BOST";"Equipe 05, Team 05";37827216;"The American journal of pathology";"Dos Santos L, Carbone F, Pacreau E, Diarra S, Luka M, Pigat N, Baures M, Navarro E, Anract J, Barry Delongchamps N, Cagnard N, Bost F, Nemazanyy I, Petitjean O, Hamaï A, Menager M, Palea S, Guidotti JE, Goffin V";;"Oct 2023";1697068800;;"Benign prostate hyperplasia (BPH) is caused by the non-malignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms (LUTS). While current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. We here show that these alterations parallel urodynamic disturbance reminiscent of LUTS. Single cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibit increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with Anethole Trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSC cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, our results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH." 16183;"Comprehensive Review of Natural Language Processing (NLP) in Vascular Surgery.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37822918;"EJVES vascular forum";"Lareyre F, Nasr B, Chaudhuri A, Di Lorenzo G, Carlier M, Raffort J";;"Oct 2023";1697068800;;"The use of Natural Language Processing (NLP) has attracted increased interest in healthcare with various potential applications including identification and extraction of health information, development of chatbots and virtual assistants. The aim of this comprehensive literature review was to provide an overview of NLP applications in vascular surgery, identify current limitations, and discuss future perspectives in the field." 16181;"Machine Learning and Omics Analysis in Aortic Aneurysm.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37817423;Angiology;"Lareyre F, Chaudhuri A, Nasr B, Raffort J";;"Oct 2023";1696982400;;"Aortic aneurysm is a life-threatening condition and mechanisms underlying its formation and progression are still incompletely understood. Omics approach has brought new insights to identify a broad spectrum of biomarkers and better understand cellular and molecular pathways involved. Omics generate a large amount of data and several studies have highlighted that artificial intelligence (AI) and techniques such as machine learning (ML)/deep learning (DL) can be of use in analyzing such complex datasets. However, only a few studies have so far reported the use of ML/DL for omics analysis in aortic aneurysms. The aim of this study is to summarize recent advances on the use of ML/DL for omics analysis to decipher aortic aneurysm pathophysiology and develop patient-tailored risk prediction models. In the light of current knowledge, we discuss current limits and highlight future directions in the field." 16153;"""Do regrets of parents about sun overexposure impact preventive measures applied on their children?";"T. Passeron";"Equipe 12, Team 12";37803519;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Lim HW, Goh CL, Kang HY, Ly F, Morita A, Ocampo-Candiani J, Puig S, Schalka S, Wei L, Demessant AL, Le Floc'h C, Kerob D, Dreno B, Krutmann J";;"Oct 2023";1696636800;; 16151;"Natural Language Processing for Literature Search in Vascular Surgery: A Pilot Study Testing an Artificial Intelligence Based Application.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37799295;"EJVES vascular forum";"Roumengas R, Di Lorenzo G, Salhi A, de Buyer P, Chaudhuri A, Lareyre F, Raffort J";;"Oct 2023";1696550400;;"The use of natural language processing (NLP) for a literature search has been poorly investigated in vascular surgery so far. The aim of this pilot study was to test the applicability of an artificial intelligence (AI) based mobile application for literature searching in a topic related to vascular surgery." 16149;"Appearance of lentigines in an atopic dermatitis patient treated with dupilumab.";"T. Passeron";"Equipe 12, Team 12";37795663;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Grangeon A, Mallet S, Miquel J, Passeron T, Delaporte E, Bellissen A";;"Oct 2023";1696464000;; 16147;"Planktonic ecological networks support quantification of changes in ecosystem health and functioning.";"M. Loschi";"Equipe 02, Team 02";37794097;"Scientific reports";"Loschi M, D'Alelio D, Camatti E, Bernardi Aubry F, Beran A, Libralato S";;"Oct 2023";1696377600;;"Plankton communities are the foundation of marine food webs and have a large effect on the dynamics of entire ecosystems. Changes in physicochemical factors strongly influence planktonic organisms and their turnover rates, making their communities useful for monitoring ecosystem health. We studied and compared the planktonic food webs of Palude della Rosa (Venice Lagoon, Italy) in 2005 and 2007. The food webs were developed using a novel approach based on the Monte Carlo random sampling of parameters within specific and realistic ranges to derive 1000 food webs for July of each year. The consumption flows involving Strombididae, Evadne spp. and Podon spp. were identified as the most important in splitting food webs of the July of the two years. Although functional nodes (FNs) differed both in presence and abundance in July of the two years, the whole system indicators showed very similar results. Sediment resuspension acted as a source of stress for the Venice Lagoon, being the most used resource by consumers while inhibiting primary producers by increasing water turbidity. Primary production in the water column was mainly generated by benthic FNs. Although the system was near an equilibrium point, it tended to increase its resilience at the expense of efficiency due to stress. This study highlights the role of plankton communities, which can serve to assess ecosystem health." 16135;"Ethics and Legal Framework for Trustworthy Artificial Intelligence in Vascular Surgery.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37790247;"EJVES vascular forum";"Lareyre F, Maresch M, Chaudhuri A, Raffort J";;"Oct 2023";1696377600;; 16124;"Cost-effectiveness of NT-proBNP-supported screening of chronic heart failure in patients with or without type 2 diabetes in Austria and Switzerland.";"P. Marty";"Equipe 06, Team 06";37781889;"Journal of medical economics";"Walter E, Arrigo M, Allerstorfer S, Marty P, Hülsmann M";;"Oct 2023";1696204800;;"Heart failure (HF) is a clinical syndrome with a global burden. Signs and symptoms of HF are non-specific and often shared with other conditions. NT-proBNP serves as a useful biomarker for the diagnosis of HF not only in patients with acute symptoms but also in outpatients with an ambiguous clinical presentation. The aim of the analysis is to evaluate the cost-effectiveness of implementing NT-proBNP in the diagnostic algorithm in patients with/without type-2-diabetes-mellitus (T2DM), compared to a diagnosis based primarily on clinical signs or symptoms from the perspective of the Austrian and Swiss health-care-system." 16122;"Free automatic software for quality assurance of computed tomography calibration, edges and radiomics metrics reproducibility.";"M. Carles";"Equipe 06, Team 06";37778209;"Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB)";"Saborido-Moral JD, Fernández-Patón M, Tejedor-Aguilar N, Cristian-Marín A, Torres-Espallardo I, Campayo-Esteban JM, Pérez-Calatayud J, Baltas D, Martí-Bonmatí L, Carles M";;"Oct 2023";1696118400;;"To develop a QA procedure, easy to use, reproducible and based on open-source code, to automatically evaluate the stability of different metrics extracted from CT images: Hounsfield Unit (HU) calibration, edge characterization metrics (contrast and drop range) and radiomic features." 16120;"Multimodal cartography of human lymphopoiesis reveals B and T/NK/ILC lineages are subjected to differential regulation.";"E. Verhoeyen";"Team 03, Equipe 03";37766969;iScience;"Alhaj Hussen K, Chabaane E, Nelson E, Lekiashvili S, Diop S, Keita S, Evrard B, Lardenois A, Delord M, Verhoeyen E, Cornils K, Kasraian Z, Macintyre EA, Cumano A, Garrick D, Goodhardt M, Andrieu GP, Asnafi V, Chalmel F, Canque B";;"Sep 2023";1695859200;;"The developmental cartography of human lymphopoiesis remains incompletely understood. Here, we establish a multimodal map demonstrating that lymphoid specification follows independent direct or stepwise hierarchic routes converging toward the emergence of newly characterized CD117 multi-lymphoid progenitors (MLPs) that undergo a proliferation arrest before entering the CD127 (NK/ILC/T) or CD127 (B) lymphoid pathways. While the differentiation of CD127 early lymphoid progenitors is mainly driven by Flt3 signaling, emergence of their CD127 counterparts is regulated cell-intrinsically and depends exclusively on the divisional history of their upstream precursors, including hematopoietic stem cells. Further, transcriptional mapping of differentiation trajectories reveals that whereas myeloid granulomonocytic lineages follow continuous differentiation pathways, lymphoid trajectories are intrinsically discontinuous and characterized by sequential waves of cell proliferation allowing pre-commitment amplification of lymphoid progenitor pools. Besides identifying new lymphoid specification pathways and regulatory checkpoints, our results demonstrate that NK/ILC/T and B lineages are under fundamentally distinct modes of regulation. (149 words)." 16116;"Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the International Vitiligo Task Force Part 1: towards a new management algorithm.";"T. Passeron";"Equipe 12, Team 12";37746876;"Journal of the European Academy of Dermatology and Venereology : JEADV";"van Geel N, Speeckaert R, Taïeb A, Ezzedine K, Lim HW, Pandya AG, Passeron T, Wolkerstorfer A, Abdallah M, Alomar A, Bae JM, Bekkenk M, Benzekri L, Böhm M, Eleftheriadou V, Esmat S, Ghia D, Goh BK, Grimes P, Gupta S, Hamzavi IH, Harris JE, Oh SH, Huggins R, Katayama I, Lan E, Lee AY, Leone G, Le Poole C, Lui H, Maquignon N, Meurant JM, Monteiro P, Oiso N, Parsad D, Pliszewski G, Raboobee N, Rodrigues M, Rosmarin D, Suzuki T, Tanemura A, Thng S, Xiang F, Zhou Y, Picardo M, Seneschal J";;"Sep 2023";1695600000;;"The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed." 16114;"Combating Stress by Targeting Innate Immunity to Stop the War against Melanocytes in Vitiligo.";"M. Tulic";"Equipe 12, Team 12";37737806;"The Journal of investigative dermatology";"Tulic MK";;"Sep 2023";1695340800;; 16099;"Contribution of serology in congenital toxoplasmosis diagnosis: results from a 10-year French retrospective study.";"C. Pomares";"Equipe 06, Team 06";37728898;"Journal of clinical microbiology";"Denis J, Lemoine JP, L'ollivier C, Deleplancque AS, Fricker Hidalgo H, Pelloux H, Pomares C, Cimon B, Paris L, Houzé S, Villena I, Villard O";;"Sep 2023";1695168000;;"This study aimed to evaluate different serological strategies for the postnatal diagnosis of congenital toxoplasmosis (CT) and establish a biological algorithm for CT diagnosis. The study analyzed serological data of immunoglobulins M, A, and G (IgM, IgA, IgG) performed by immunoenzymatic and compared immunological profile (CIP) assays in 668 newborns with CT diagnosis across four testing periods: P1 (D0- D10), P2 (D11-D35), P3 (D36-D45), and P4 (>D45). Forty-nine percent of the 668 CT cases were diagnosed during P1 and 34%, 4%, and 12% during P2, P3, and P4, respectively. CIP assays detected neosynthetized IgMs/IgGs in 98% of CT cases diagnosed during P1, while IgMs and IgAs were detected in 90% and 57% of CT cases diagnosed during P2 and in 88% and 67% of diagnoses made during P3, respectively. Detection of neosynthesized IgMs/IgGs, IgMs, and IgAs by immunoassay contributed to CT diagnosis in 81%, 77%, and 60% of cases, respectively. In total, 46% of serum samples were positive for all three parameters, 27% for two, and 27% for one of the three. The study recommends using the CIP assay as standard during P1 for CT diagnosis and IgM and IgA immunoassays after P1. A clinical and biological follow-up in a specialized center with a close collaboration between biologists and clinicians is highly recommended to increase the chances of early diagnosis. Overall, this study provides useful information for the development of a biological algorithm for CT diagnosis, which can aid in early detection and appropriate treatment of this disease." 16094;"Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD.";"A. IANNELLI, C. LUCI, S. PATOURAUX, P. GUAL, R. ANTY, S. BONNAFOUS, D. ROUSSEAU, A. TRAN";"Team 08, Equipe 08";37724058;"Obesity (Silver Spring, Md.)";"Soysouvanh F, Rousseau D, Bonnafous S, Bourinet M, Strazzulla A, Patouraux S, Machowiak J, Farrugia MA, Iannelli A, Tran A, Anty R, Luci C, Gual P";;"Sep 2023";1695081600;;"This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T-cell regulation in initiation of obesity-driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic-associated fatty liver disease (MAFLD) development." 16077;"Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations.";"T. Passeron";"Equipe 12, Team 12";37715487;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Seneschal J, Speeckaert R, Taïeb A, Wolkerstorfer A, Passeron T, Pandya AG, Lim HW, Ezzedine K, Zhou Y, Xiang F, Thng S, Tanemura A, Suzuki T, Rosmarin D, Rodrigues M, Raboobee N, Pliszewski G, Parsad D, Oiso N, Monteiro P, Meurant JM, Maquignon N, Lui H, Le Poole C, Leone G, Lee AY, Lan E, Katayama I, Huggins R, Oh SH, Harris JE, Hamzavi IH, Gupta S, Grimes P, Goh BK, Ghia D, Esmat S, Eleftheriadou V, Böhm M, Benzekri L, Bekkenk M, Bae JM, Alomar A, Abdallah M, Picardo M, van Geel N";;"Sep 2023";1694822400;;"The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking." 16059;"Parsnips and Phytophotodermatosis.";"C. Chiaverini";"Equipe 12, Team 12";37696389;"The Journal of pediatrics";"Chene L, Chiaverini C, Kandemir S, Hubiche T";;"Sep 2023";1694390400;; 16048;"Androgenetic/biparental mosaicism in a diploid mole-like conceptus: report of a case with triple paternal contribution.";"C. Mauduit";"Equipe 10, Team 10";37695410;"Virchows Archiv : an international journal of pathology";"Donzel M, Gaillot-Durand L, Joubert M, Aziza J, Beneteau C, Mauduit C, Ploteau S, Hajri T, Bolze PA, Massardier J, Devouassoux-Shisheboran M, Sunde L, Allias F";;"Sep 2023";1694390400;;"Hydatidiform moles (HMs) are divided into two types: partial hydatidiform mole (PHM) which is most often diandric monogynic triploid and complete hydatidiform mole (CHM) which is most often diploid androgenetic. Morphological features and p57 immunostaining are routinely used to distinguish both entities. Genetic analyses are required in challenging cases to determine the parental origin of the genome and ploidy. Some gestations cannot be accurately classified however. We report a case with atypical pathologic and genetic findings that correspond neither to CHM nor to PHM. Two populations of villi with divergent and discordant p57 expression were observed: morphologically normal p57 + villi and molar-like p57 discordant villi with p57 + stromal cells and p57 - cytotrophoblasts. Genotyping of DNA extracted from microdissected villi demonstrated that the conceptus was an androgenetic/biparental mosaic, originating from a zygote with triple paternal contribution, and that only the p57 - cytotrophoblasts were purely androgenetic, increasing the risk of neoplastic transformation." 16044;"Non-Relapse Mortality after CAR T-Cell therapy for Large B-Cell Lymphoma: A LYSA Study from the DESCAR-T Registry.";"M. Loschi";"Equipe 02, Team 02";37672383;"Blood advances";"Lemoine J, Bachy E, Cartron G, Beauvais D, Gastinne T, Di Blasi R, Rubio MT, Guidez S, Mohty M, Casasnovas O, Joris M, Castilla-Llorente C, Haioun C, Hermine O, Loschi M, Carras S, Bories P, Fradon T, Herbaux C, Sesques P, Le Gouill S, Morschhauser F, Thieblemont C, Houot R";;"Sep 2023";1693958400;;"CD19 chimeric antigen receptor (CAR) T-cells can induce prolonged remissions and potentially cure a significant proportion of patients with relapsed/refractory (r/r) large B-cell lymphomas (LBCL). However, some patients may die of causes unrelated to lymphoma after CAR T-cell therapy. To date, little is known about the non-relapse mortality (NRM) following CAR T-cells. Using the French DESCAR-T registry, we analyzed the incidence and causes of NRM, and identified risk factors of NRM. We report 957 patients who received standard-of-care (SOC) axicabtagene ciloleucel (axi-cel; n=598) or tisagenlecleucel (tisacel; n=359) between July 2018 and April 2022, in 27 French centers. With a median follow-up of 12.4 months, overall NRM occurred in 48 patients (5.0% of all patients): early (<day 28 pos-infusion) in 9 patients (0.9% of all patients and 19% of overall NRM), and late (≥day 28 pos-infusion) in 39 patients (4.1% of all patients and 81% of overall NRM). Causes of overall NRM were distributed as follows: 56% of infections (29% non-COVID infection, 27% COVID infection), 10% of cytokine release syndromes (CRS), 6% of strokes, 6% of cerebral hemorrhages, 6% of second malignancies, 4% of immune effector cell associated neurotoxicities (ICANS), and 10% of deaths from other causes. We report risk factors for early NRM and overall NRM. In multivariate analysis, both diabetes and elevated ferritin at lymphodepletion were associated with an increased risk of overall NRM. Our results may help physicians in patient's selection and management in order to reduce the NRM after CAR T-cell therapy." 16042;"High-density mapping of the average complex interval helps localizing atrial fibrillation drivers and predicts catheter ablation outcomes.";"E. Ferrari";"Equipe 09, Team 09";37663412;"Frontiers in cardiovascular medicine";"Squara F, Scarlatti D, Bun SS, Moceri P, Ferrari E, Meste O, Zarzoso V";;"Sep 2023";1693785600;;"Persistent Atrial Fibrillation (PersAF) electrogram-based ablation is complex, and appropriate identification of atrial substrate is critical. Little is known regarding the value of the Average Complex Interval (ACI) feature for PersAF ablation." 16040;"The impact of Methoxypropylamino Cyclohexenylidene Ethoxyethylcyanoacetate (MCE) UVA1 filter on pigmentary and ageing signs: An outdoors prospective 8-week randomized, intra-individual comparative study in two populations of different genetic background.";"T. Passeron";"Equipe 12, Team 12";37655436;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Flament F, Mercurio DG, Muller B, Li J, Tricaud C, Bernerd F, Roudot A, Candau D, Passeron T";;"Sep 2023";1693526400;;"Of all ultraviolet (UV) radiations reaching the earth, UVA1 rays have a higher potential of penetrating and producing clinically harmful consequences. While UV radiations up to 370 nm are well blocked by current sunscreens, a photoprotection gap remains for the UVA1 wavelengths between 370 and 400 nm." 16038;"Allogeneic hematopoietic stem cell transplantation for adults with therapy-related acute myeloid leukaemia: a retrospective multicentre study on behalf of the SFGM-TC.";"M. Loschi";"Equipe 02, Team 02";37653054;"Bone marrow transplantation";"Rey G, Daguenet E, Bonjean P, Devillier R, Fegueux N, Forcade E, Srour M, Chevallier P, Robin M, Suarez F, Micol JB, Labussière-Wallet H, Bilger K, Daguindau E, Bay JO, Fayard A, Bulabois CE, Nguyen-Quoc S, Genthon A, Orvain C, Turlure P, Loschi M, Poiré X, Guillerm G, Beguin Y, Maillard N, Mear JB, Chalayer E, Cornillon J, Tavernier E";;"Aug 2023";1693440000;;"We report the results from a multicentre retrospective study of 220 adult patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) for therapy-related acute myeloid leukaemia (t-AML). Median age at t-AML diagnosis was 56 years, with a prior history of haematological (45%) or breast (34%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. At transplant, around 20% of patients had measurable residual disease and 3% of patients were not in complete remission. The median follow-up was 21.4 months (Q1-Q3, 5.9-52.8). At 12 months, overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS) were 60.7% (95% CI 54.6-67.5), 52.8% (95% CI 46.5-68.4), and 44.1% (95% CI 37.6-51.8), respectively. At 5 years, OS, EFS, and GRFS were 44.1% (95% CI 37.4-52.1), 40.4% (95% CI 33.9-48.1), and 35.3% (95% CI 28.8-43.3), respectively. At last follow-up, 44% of patients were in complete remission (n = 96) and transplant-related mortality accounted for 21% of all deaths (n = 119). Multivariable analysis revealed that uncontrolled t-AML at transplant was associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041). In conclusion, alloHSCT for t-AML shows encouraging results and offers additional opportunity with the emergence of novel pre-graft therapies." 16036;"Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.";"M. Loschi, T. Cluzeau";"Equipe 02, Team 02";37654670;EClinicalMedicine;"Malard F, Loschi M, Huynh A, Cluzeau T, Guenounou S, Legrand F, Magro L, Orvain C, Charbonnier A, Panz-Klapuch M, Desmier D, Mear JB, Cornillon J, Robin C, Daguindau E, Bilger K, Vehreschild MJGT, Chevallier P, Labussière-Wallet H, Mediavilla C, Couturier MA, Bulabois CE, Camus V, Chantepie S, Ceballos P, Gaugler B, Holler E, Doré J, Prestat E, Gasc C, Plantamura E, Mohty M";;"Sep 2023";1693526400;;"Failure of gastrointestinal acute graft--host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD." 16013;"Mild Behavioral Impairment in Psychogeriatric Patients: Clinical Features and Psychopathology Severity.";"E. Ferrari";"Equipe 09, Team 09";37629464;"Journal of clinical medicine";"Elefante C, Brancati GE, Ismail Z, Ricciardulli S, Beatino MF, Lepri V, Famà A, Ferrari E, Giampietri L, Baldacci F, Ceravolo R, Maremmani I, Lattanzi L, Perugi G";;"Aug 2023";1693008000;;"The Mild Behavioral Impairment (MBI) concept was developed to determine whether late-onset persistent neuropsychiatric symptoms (NPSs) may be early manifestations of cognitive decline. Our study aims to investigate the prevalence and differentiating features of MBI with respect to major neurocognitive disorders (MNDs) and primary psychiatric disorders (PPDs). A total of 144 elderly patients who were referred to our psychogeriatric outpatient service were recruited. The severity of mental illness was evaluated by means of the Clinical Global Impression Severity scale, the severity of psychopathology was evaluated by means of the Brief Psychiatric Rating Scale (BPRS), and overall functioning was evaluated by means of the Global Assessment of Functioning scale. The sample included 73 (50.6%) patients with PPDs, 40 (27.8%) patients with MBI, and 31 (21.5%) patients with MNDs. Patients with MNDs reported the greatest severity of mental illness, the highest BPRS Total, Psychosis, Activation, and Negative Symptom scores, and the lowest functioning. Patients with MBI and PPDs had comparable levels of severity of mental illness and overall functioning, but MBI patients reported higher BPRS Total and Negative Symptom scores than PPD patients. Patients with MBI frequently reported specific clinical features, including a higher severity of apathy and motor retardation. These features merit further investigation since they may help the differential diagnosis between MBI and PPDs." 16011;"Efficacy and safety of a novel triple combination cream compared to Kligman's trio for melasma: a 24-week double-blind prospective randomized controlled trial.";"T. Passeron";"Equipe 12, Team 12";37620285;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Bertold C, Fontas E, Singh T, Gastaut N, Ruitort S, Pugliese SW, Passeron T";;"Aug 2023";1692835200;;"Kligman's trio (KT), combining hydroquinone, retinoic acid and corticosteroid, is considered as the gold standard treatment of melasma. Its efficacy has never been matched before, but it is tempered by frequent adverse effects." 16005;"Reliability and agreement testing of a new automated measurement method to determine extent of facial vitiligo using standardized UV images and a dedicated algorithm.";"T. Passeron";"Equipe 12, Team 12";37615581;"The British journal of dermatology";"Bertoud QMD, Bertold C, Ezzedine K, Pandya AG, Cherel M, Martinez AC, Seguy MA, Abdallah M, Bae JM, Böhm M, Parsad D, Rosmarin D, Wolkerstorfer A, Bahadoran P, Blaise M, Dugourd PM, Philippo V, Delaval JM, Passeron T";;"Aug 2023";1692835200;;"Facial repigmentation is the primary outcome measure for most vitiligo trials. The Facial Vitiligo Area Scoring Index (F-VASI) score is often chosen as the primary outcome measure to assess the efficacy of treatments for facial vitiligo. Although useful, this scoring system remains subjective and has several limitations." 16003;"The Antioxidant TEMPOL Protects Human Hematopoietic Stem Cells From Culture-Mediated Loss of Functions.";"P. Auberger";"Equipe 02, Team 02";37616262;"Stem cells translational medicine";"Henry E, Picou F, Barroca V, Dechamps N, Sobrino S, Six E, Gobeaux C, Auberger P, Hérault O, Pflumio F, Arcangeli ML";;"Aug 2023";1692835200;;"In a steady state, hematopoietic stem cells (HSC) exhibit very low levels of reactive oxygen species (ROS). Upon stress, HSC get activated and enter into proliferation and differentiation process to ensure blood cell regeneration. Once activated, their levels of ROS increase, as messengers to mediate their proliferation and differentiation programs. However, at the end of the stress episode, ROS levels need to return to normal to avoid HSC exhaustion. It was shown that antioxidants can prevent loss of HSC self-renewal potential in several contexts such as aging or after exposure to low doses of irradiation suggesting that antioxidants can be used to maintain HSC functional properties upon culture-induced stress. Indeed, in humans, HSC are increasingly used for cell and gene therapy approaches, requiring them to be cultured for several days. As expected, we show that a short culture period leads to drastic defects in HSC functional properties. Moreover, a switch of HSC transcriptional program from stemness to differentiation was evidenced in cultured HSC. Interestingly, cultured-HSC treated with 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-hydroxy-TEMPO or Tempol) exhibited a higher clonogenic potential in secondary colony forming unit cell (CFU-C) assay and higher reconstitution potential in xenograft model, compared to untreated cultured-HSC. By transcriptomic analyses combined with serial CFU-C assays, we show that Tempol, which mimics superoxide dismutase, protects HSC from culture-induced stress partly through VEGFα signaling. Thus, we demonstrate that adding Tempol leads to the protection of HSC functional properties during ex vivo culture." 16001;"Vitiligo Patient Population and Disease Burden in France: VIOLIN Study Results From the CONSTANCES Cohort.";"T. Passeron";"Equipe 12, Team 12";37605309;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Ezzedine K, Seneschal J, Da Silva A, Préaubert N, Lamblin A, Delattre C, Emery C, Nevoret C, Finzi J, Bouée S, Passeron T";;"Aug 2023";1692662400;;"Vitiligo is a chronic autoimmune disease resulting in skin depigmentation." 15997;"Exploring Adipose Tissue Functions.";"J. GILLERON, J. Jager";"Equipe 07, Team 07";37602890;"Journal of visualized experiments : JoVE";"Jager J, Gilleron J";;"Aug 2023";1692576000;;"Cho, D. S., Doles, J. D. Preparation of adipose progenitor cells from mouse epididymal adipose tissues. Journal of Visualized Experiments. (162), doi: 10.3791/61694 (2020). Peics, J. et al. Isolation of adipogenic and fibro-inflammatory stromal cell subpopulations from murine intra-abdominal adipose depots. Journal of Visualized Experiments. (162), doi: 10.3791/61610 (2020). Estrada-Gutierrez, G. et al. Isolation of viable adipocytes and stromal vascular fraction from human visceral adipose tissue suitable for RNA analysis and macrophage phenotyping. Journal of Visualized Experiments. (164), doi: 10.3791/61884 (2020). Gilleron, J. et al. Exploring adipose tissue structure by methylsalicylate clearing and 3D imaging. Journal of Visualized Experiments. (162), doi: 10.3791/61640 (2020). Czepielewski, R. S. et al. Lymphatic and blood network analysis during obesity. Journal of Visualized Experiments. (165), doi: 10.3791/61814 (2020). Jager, J., Gaudfrin, M., Gilleron, J., Cormont, M., Tanti, J. F. An adipocyte cell culture model to study the impact of protein and micro-RNA modulation on adipocyte function. Journal of Visualized Experiments. (171), doi: 10.3791/61925 (2021). Poret, J. M., Molina, P. E., Simon, L. Isolation, proliferation and differentiation of rhesus macaque adipose-derived stem cells. Journal of Visualized Experiments. (171), doi: 10.3791/61732 (2021). Batista Jr., M. L., Meshulam, T., Desevin, K., Rabhi, N., Farmer, S. R. Three-dimensional adipocyte culture as a model to study cachexia-induced white adipose tissue remodeling. Journal of Visualized Experiments. (167), doi: 10.3791/61853 (2021). Akbar, N., Pinnick, K. E., Paget, D., Choudhury, R. P. Isolation and characterization of human adipocyte-derived extracellular vesicles using filtration and ultracentrifugation. Journal of Visualized Experiments. (170), doi: 10.3791/61979 (2021)." 15993;"Clinical and immune features of human parvovirus B19 infection in allogeneic stem cell transplantation recipients: A retrospective monocentric study.";"M. Loschi";"Equipe 02, Team 02";37594199;"Transplant infectious disease : an official journal of the Transplantation Society";"Sammut R, Feghoul L, Xhaard A, Dhedin N, Robin M, Michonneau D, Loschi M, Legoff J, de Peffault de Latour R, de Sicre de Fontbrune F";;"Aug 2023";1692316800;;"Human parvovirus B19 (B19V) infection is associated with pure red cell aplasia (PRCA) in immunocompromised patients; however, the spectrum of manifestations associated with B19V in allogeneic hematopoietic stem cell transplantation recipients (alloHSCT) has rarely been reported." 15991;"Sun exposure behaviors as a compromise to paradoxical injunctions: Insight from a worldwide survey.";"T. Passeron";"Equipe 12, Team 12";37590528;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Lim HW, Goh CL, Kang HY, Ly F, Morita A, Ocampo-Candiani J, Puig S, Schalka S, Wei L, Demessant-Flavigny AL, Le Floc'h C, Kerob D, Dreno B, Krutmann J";;"Aug 2023";1692230400;; 15989;"Persistent organic pollutants promote aggressiveness in prostate cancer.";"F. BOST";"Equipe 05, Team 05";37587334;Oncogene;"Buñay J, Kossai M, Damon-Soubeyrant C, De Haze A, Saru JP, Trousson A, de Joussineau C, Bouchareb E, Kocer A, Vialat M, Dallel S, Degoul F, Bost F, Clavel S, Penault-Llorca F, Valli MP, Guy L, Matthews J, Renaud Y, Ittmann M, Jones J, Morel L, Lobaccaro JM, Baron S";;"Aug 2023";1692144000;;"Increasing evidence points towards a causal link between exposure to persistent organic pollutants (POPs) with increased incidence and aggressivity of various cancers. Among these POPs, dioxin and PCB-153 are widely found in our environment and represent a significant source of contamination. Dioxin exposure has already been linked to cancer such as non-Hodgkin's lymphoma, but remains to be more extensively investigated in other cancers. Potential implications of dioxin and PCB-153 in prostate cancer progression spurred us to challenge both ex vivo and in vivo models with low doses of these POPs. We found that dioxin or PCB-153 exposure increased hallmarks of growth and metastasis of prostate cancer cells ex vivo and in grafted NOD-SCID mice. Exposure induced histopathological carcinoma-like patterns in the Pten mice. We identified up-regulation of Acetyl-CoA Acetyltransferase-1 (ACAT1) involved in ketone bodies pathway as a potential target. Mechanistically, genetic inhibition confirmed that ACAT1 mediated dioxin effect on cell migration. Using public prostate cancer datasets, we confirmed the deregulation of ACAT1 and associated gene encoded ketone bodies pathway enzymes such as OXCT1, BDH1 and HMGCL in advanced prostate cancer. To further explore this link between dioxin and ACAT1 deregulation, we analyzed a unique prostate-tumour tissue collection from the USA veterans exposed to agent orange, known to be highly contaminated by dioxin because of industrial production. We found that ACAT1 histoscore is significantly increased in exposed patients. Our studies reveal the implication of dioxin and PCB-153 to induce a prometastatic programme in prostate tumours and identify ACAT1 deregulation as a key event in this process." 15987;"SARS-CoV-2 vaccination in 361 non-transplanted patients with aplastic anemia and/or paroxysmal nocturnal hemoglobinuria.";"M. Loschi";"Equipe 02, Team 02";37584297;Haematologica;"Griffin M, Eikema DJ, Verheggen I, Kulagin A, Tjon JM, Fattizzo B, Ingram W, Zaidi U, Desnica L, Giammarco S, Drozd-Sokolowska J, Xicoy B, Patriarca A, Loschi M, Szmigielska-Kaplon A, Beier F, Cignetti A, Drexler B, Gavriilaki E, Lanza F, Orvain C, Risitano AM, De la Camara R, De Latour RP";;"Aug 2023";1692144000;; 15985;"Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma: Real-life Data on Liver Disease, Treatment and Prognosis.";"R. ANTY";"Equipe 08, Team 08";37577232;"Journal of clinical and translational hepatology";"Adhoute X, Pietri O, Pénaranda G, Wolf T, Beaurain P, Monnet O, Laquière A, Bonomini J, Neumann F, Levrel O, Buono JP, Hanna X, Castellani P, Perrier H, Bourliere M, Anty R";;"Aug 2023";1691971200;;"Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses." 15983;"Unresectable hepatocellular carcinoma at dawn of immunotherapy era: real-world data from the French prospective CHIEF cohort.";"R. ANTY";"Equipe 08, Team 08";37577805;"European journal of gastroenterology & hepatology";"Nguyen-Khac E, Nahon P, Ganry O, Ben Khadhra H, Merle P, Amaddeo G, Ganne-Carrie N, Silvain C, Peron JM, Mathurin P, Anty R, Uguen T, Decaens T, Riachi G, Bouattour M, Baron A, Bronowicki JP, Pageaux GP, Rosmorduc O, Ducournau G, Gilberg M, Tanang A, Dupin J, Gilbert-Marceau A, Blanc JF, ";;"Aug 2023";1691971200;;"Hepatocellular carcinoma epidemiological data are limited in France. The Epidemio Liver Immunotherapy Tecentriq outcome research (ELITor) retrospective study, based on real-world data from the Carcinome HépatocellulaIrE en France (CHIEF) French cohort of hepatocellular carcinoma patients, aimed to get insight into the treatment patterns, the sociodemographic, clinical, biological, and etiological characteristics, and the quality of life of patients with unresectable hepatocellular carcinoma." 15979;"Standardized Methodology for Duplex Ultrasound Examination of Arteriovenous Access for Hemodialysis: A Proposal of the French Society of Vascular Medicine and the French-Speaking Society of Vascular Access.";"N. Sadaghianloo";"Equipe 09, Team 09";37544830;"Ultrasound in medicine & biology";"Pichot O, Diard A, Bosc JY, Abbadie F, Franco G, Mahé G, Sadaghianloo N, , ";;"Aug 2023";1691280000;;"Duplex ultrasound (DUS) is an essential tool for characterizing and monitoring arteriovenous (AV) access for hemodialysis. The aim of the work described here, requested by the French Society of Vascular Medicine in collaboration with the French-Speaking Vascular Access Society, is to propose a standardized methodology for performing and documenting DUS, taking into account the variety of AV access techniques and the problems routinely encountered. A steering committee reviewed the literature and selected the relevant references. A draft was prepared, and all items with missing or conflicting data were submitted to a Delphi consensus. The final document was discussed and approved by all participants. The principles of DUS evaluation of AV access consist of examination of the afferent artery, the anastomosis and the entire venous drainage system. DUS uses B-mode ultrasound, color flow, pulsed wave and power Doppler analysis. DUS can be used in a variety of clinical situations, which can directly influence the methodology of the examination and the interpretation of the results. Blood flow should be assessed as it correlates with the risk of thrombosis. The measurement should be adapted to the different anatomical and hemodynamic conditions encountered. Characterization of stenosis should take into account the residual diameter of the drainage vein and its hemodynamic consequences. Other complications can be assessed with a standardized DUS examination. When performed according to a rigorous methodology, DUS of the AV access allows a comprehensive assessment of its functionality and eliminates the need for further invasive diagnostic procedures." 15977;"Effectiveness and safety of dalbavancin in France: a prospective, multicenter cohort study.";"J. Courjon";"Equipe 06, Team 06";37543122;"International journal of antimicrobial agents";"Courjon J, Senneville E, Illes HG, Pavese P, Boutoille D, Daoud FC, Dunkel N, Tattevin P";;"Aug 2023";1691193600;;"Dalbavancin is a lipoglycopeptide antibiotic approved for the treatment of acute bacterial skin and skin structure infections. However, several studies suggested that it is mostly used for off-label indications. This prospective, observational, multicenter study conducted in France from September 2018 to April 2020 aimed to describe the use of dalbavancin in patients who received at least 1 dose of the antibiotic. The primary outcome was the clinical response at 30 days after the last dalbavancin dose. A total of 151 patients in 16 centers were included in this study. The main infection sites were bone and joint infections (55.0%), multisite infections (15.9%), and vascular infections (14.6%), and the primary pathogens were coagulase-negative staphylococci (N=82), Staphylococcus aureus (N=51), and enterococci (N=27). Most patients (71.5%) received 3 previous antibiotic treatments. The number of dalbavancin injections per patient was 1 in 26 patients (17.2%), 2 in 95 patients (62.9%), 3 in 17 patients (11.3%), and more than 3 in 13 patients (8.6%), with a mean cumulative dose of 3,089 ± 1,461 mg per patient. Among the 129 patients with a complete follow-up, clinical success was achieved in 119 patients (92.2%). At least 1 adverse event was reported in 67 patients (44.4%), including 12 (7.9%) patients with dalbavancin-related adverse events. The results of the study showed that dalbavancin is mostly used for off-label indications and in heavily pre-treated patients in France. The clinical response at 30 days after the last dose was favorable in most patients, with a good safety profile. clinicaltrials.gov identifier: NCT03726216." 15975;"Evaluation of adapted dermocosmetic regimens for perimenopausal and menopausal women using an artificial intelligence-based algorithm and quality of life questionnaires: An open observational study.";"T. Passeron";"Equipe 12, Team 12";37522490;"Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)";"Flament F, Jiang R, Delaunay C, Kerob D, Leclerc-Mercier S, Kosmadaki M, Roó E, Haag T, Passeron T, Zouboulis CC";;"Jul 2023";1690761600;;"The decline in estrogen levels from several years before (perimenopause) and during menopause has various negative effects, including skin specific issues, which often receive less attention than other menopausal symptoms despite having a significant negative effect on quality of life (QoL). The objective of this study was to evaluate the effectiveness of anti-aging dermocosmetic products designed for women during the perimenopause and menopause." 15971;"Impact of testicular cancer on sperm small non-coding RNA signature: a pilot study.";"M. Stathopoulou, M. Trabucchi, V. Grandjean";"Equipe 10, Team 10";37515809;Epigenetics;"Dupont C, Stathopoulou MG, Illy PJ, Sermondade N, Levy R, Trabucchi M, Prades M, Haj Hamid R, Berthaut I, Grandjean V";;"Jul 2023";1690588800;;"Testicular germ cell tumours (TGCTs) are the most common tumours in young adults of European ancestry. The high heritability and the constantly increased incidence, which has doubled over the last 20 years, strongly suggest that both genetic and environmental factors are likely to shape the TGCT susceptibility. While genome-wide association studies have identified loci associated with TGCT susceptibility, the role played by environmental molecular vectors in TGCT susceptibility remains unclear. Evidence shows that sperm non-coding RNAs provide a good vision of the environmental stresses experienced by men. Here, to determine whether TGCT impacts the abundance of specific non-coding RNAs in sperm, small RNA deep sequencing analysis of sperm of 25 men aged between 19 and 42 years, diagnosed with ( = 16) or without ( = 9) TGCT was performed. The primary analysis showed no statistical significance in the sncRNA population between the TGCT and non-TGCT groups. However, when sperm physiological parameters were considered to look for differentially expressed sncRNA, we evidenced 11 differentially expressed sncRNA between patients and control which allow a clear discrimination between control and TGCT samples after Hierarchical Clustering analysis. Together, these findings indicate that sperm small non-coding RNAs abundance may have the potential for diagnosing men with TGCT. However, specific care should be taken regarding sperm physiological parameters of the TGCT patients. Hence, larger studies are needed to confirm our findings and to determine whether such a signature associates with the risks to develop TGCT." 15969;"Abdominal manifestations with acute on chronic hepatitis related to SARS-CoV-2 infection.";"R. ANTY";"Equipe 08, Team 08";37493207;"Polish archives of internal medicine";"Razzouk-Cadet M, Grangeon-Chapon C, Ouizeman D, Favre G, Anty R";;"Jul 2023";1690329600;; 15967;"Long Term Outcomes After Invasive Treatment of Carotid Artery Stenosis: a Longitudinal Study of German Health Insurance Claims.";"F. Lareyre";"Equipe 09, Team 09";37490978;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Zimmermann M, Larena-Avellaneda A, Rother U, Lareyre F, Søgaard M, Tulamo R, Venermo M, Behrendt CA";;"Jul 2023";1690243200;;"There is a paucity of observational data including long term outcomes after invasive treatment for carotid artery stenosis." 15965;"Exercise-induced myocardial T1 increase and right ventricular dysfunction in recreational cyclists: a CMR study.";"E. Ferrari";"Equipe 09, Team 09";37480391;"European journal of applied physiology";"Ghekiere O, Herbots L, Peters B, Berg BV, Dresselaers T, Franssen W, Padovani B, Ducreux D, Ferrari E, Nchimi A, Demanez S, De Bosscher R, Willems R, Heidbuchel H, La Gerche A, Claessen G, Bogaert J, Eijnde BO";;"Jul 2023";1689984000;;"Although cardiac troponin I (cTnI) increase following strenuous exercise has been observed, the development of exercise-induced myocardial edema remains unclear. Cardiac magnetic resonance (CMR) native T1/T2 mapping is sensitive to the pathological increase of myocardial water content. Therefore, we evaluated exercise-induced acute myocardial changes in recreational cyclists by incorporating biomarkers, echocardiography and CMR." 15963;"Macrophage death in atherosclerosis: potential role in calcification.";"G. Chinetti, J. Neels";"Equipe 09, Team 09";37469518;"Frontiers in immunology";"Neels JG, Gollentz C, Chinetti G";;"Jul 2023";1689811200;;"Cell death is an important aspect of atherosclerotic plaque development. Insufficient efferocytosis of death cells by phagocytic macrophages leads to the buildup of a necrotic core that impacts stability of the plaque. Furthermore, in the presence of calcium and phosphate, apoptotic bodies resulting from death cells can act as nucleation sites for the formation of calcium phosphate crystals, mostly in the form of hydroxyapatite, which leads to calcification of the atherosclerotic plaque, further impacting plaque stability. Excessive uptake of cholesterol-loaded oxidized LDL particles by macrophages present in atherosclerotic plaques leads to foam cell formation, which not only reduces their efferocytosis capacity, but also can induce apoptosis in these cells. The resulting apoptotic bodies can contribute to calcification of the atherosclerotic plaque. Moreover, other forms of macrophage cell death, such as pyroptosis, necroptosis, parthanatos, and ferroptosis can also contribute by similar mechanisms to plaque calcification. This review focuses on macrophage death in atherosclerosis, and its potential role in calcification. Reducing macrophage cell death and/or increasing their efferocytosis capacity could be a novel therapeutic strategy to reduce the formation of a necrotic core and calcification and thereby improving atherosclerotic plaque stability." 15961;"Artificial Intelligence-Powered Technologies for the Management of Vascular Diseases: Building Guidelines and Moving Forward Evidence Generation.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37464795;"Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists";"Lareyre F, Wanhainen A, Raffort J";;"Jul 2023";1689724800;; 15957;"Ischemic cerebral stroke risk under psoriasis and psoriatic arthritis treatment: A real-world observational study from the French national healthcare system database.";"T. Passeron";"Equipe 12, Team 12";37458687;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Bulsei J, Fontas E, Hubiche T, Passeron T";;"Jul 2023";1689552000;; 15949;"Assessment of Different Circulating Tumor Cell Platforms for Uveal Melanoma: Potential Impact for Future Routine Clinical Practice.";"C. Bertolotto";"Equipe 01, Team 01";37446253;"International journal of molecular sciences";"Martel A, Mograbi B, Romeo B, Gastaud L, Lalvee S, Zahaf K, Fayada J, Nahon-Esteve S, Bonnetaud C, Salah M, Tanga V, Baillif S, Bertolotto C, Lassalle S, Hofman P";;"Jul 2023";1689292800;;"Liquid biopsy and circulating tumor cell (CTC) screening has gained interest over the last two decades for detecting almost all solid malignancies. To date, the major limitation in terms of the applicability of CTC screening in daily clinical practice is the lack of reproducibility due to the high number of platforms available that use various technologies (e.g., label-dependent versus label-free detection). Only a few studies have compared different CTC platforms. The aim of this study was to compare the efficiency of four commercially available CTC platforms (Vortex (VTX-1), ClearCell FX, ISET, and Cellsearch) for the detection and identification of uveal melanoma cells (OMM 2.3 cell line). Tumor cells were seeded in RPMI medium and venous blood from healthy donors, and then processed similarly using these four platforms. Melan-A immunochemistry was performed to identify tumor cells, except when the Cellsearch device was used (automated identification). The mean overall recovery rates (with mean recovered cells) were 39.2% (19.92), 22.2% (11.31), 8.9% (4.85), and 1.1% (0.20) for the ISET, Vortex (VTX-1), ClearCell FX, and CellSearch platforms, respectively. Although paramount, the recovery rate is not sufficient to assess a CTC platform. Other parameters, such as the purpose for using a platform (diagnosis, genetics, drug sensitivity, or patient-derived xenograft models), reproducibility, purity, user-friendliness, cost-effectiveness, and ergonomics, should also be considered before they can be used in daily clinical practice and are discussed in this article." 15945;"Surgical Approaches for Repigmenting Vitiligo 2.0.";"T. Passeron";"Equipe 12, Team 12";37436333;"The Journal of investigative dermatology";"Passeron T";;"Jul 2023";1689120000;; 15943;"Time-to-Detection in Culture of M. tuberculosis: performance for assessing index cases contact-positivity.";"J. Courjon, M. Carles";"Equipe 06, Team 06";37433381;"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases";"Risso K, Michelangeli C, Gaudart A, Buscot M, Chamorey E, Courjon J, Carles M";;"Jul 2023";1689033600;;"Time-to-Detection (TTD) in culture on liquid media is inversely correlated to bacillary load and should be a contributing factor for assessing tuberculosis transmission. We wanted to assess if TTD was a better alternative than smear-status to estimate transmission risk." 15941;"Nanoblades allow high-level genome editing in murine and human organoids.";"E. Verhoeyen, F. BOST, F. LARBRET";"Team 03, Equipe 03, Equipe 05, Team 05, Equipe 11, Team 11";37435135;"Molecular therapy. Nucleic acids";"Tiroille V, Krug A, Bokobza E, Kahi M, Bulcaen M, Ensinck MM, Geurts MH, Hendriks D, Vermeulen F, Larbret F, Gutierrez-Guerrero A, Chen Y, Van Zundert I, Rocha S, Rios AC, Medaer L, Gijsbers R, Mangeot PE, Clevers H, Carlon MS, Bost F, Verhoeyen E";;"Jul 2023";1689120000;;"Genome engineering has become more accessible thanks to the CRISPR-Cas9 gene-editing system. However, using this technology in synthetic organs called ""organoids"" is still very inefficient. This is due to the delivery methods for the CRISPR-Cas9 machinery, which include electroporation of CRISPR-Cas9 DNA, mRNA, or ribonucleoproteins containing the Cas9-gRNA complex. However, these procedures are quite toxic for the organoids. Here, we describe the use of the ""nanoblade (NB)"" technology, which outperformed by far gene-editing levels achieved to date for murine- and human tissue-derived organoids. We reached up to 75% of reporter gene knockout in organoids after treatment with NBs. Indeed, high-level NB-mediated knockout for the androgen receptor encoding gene and the cystic fibrosis transmembrane conductance regulator gene was achieved with single gRNA or dual gRNA containing NBs in murine prostate and colon organoids. Likewise, NBs achieved 20%-50% gene editing in human organoids. Most importantly, in contrast to other gene-editing methods, this was obtained without toxicity for the organoids. Only 4 weeks are required to obtain stable gene knockout in organoids and NBs simplify and allow rapid genome editing in organoids with little to no side effects including unwanted insertion/deletions in off-target sites thanks to transient Cas9/RNP expression." 15931;"Accurate diagnosis of acute hemorrhagic edema of infancy: a French multicenter observational study.";"C. Chiaverini";"Equipe 12, Team 12";37432503;"European journal of pediatrics";"Leducq S, Maruani A, Bodemer C, Biscardi S, Boccara O, Chinazzo MF, Mahé E, Plantin P, Fraitag S, Mazereeuw-Hautier J, Chiaverini C, Lemelle I, Bessis D, Bourrat E, Mallet S, Bonniaud B, Grall-Lerosey M, Martin L, Boralevi F, Piram M";;"Jul 2023";1689033600;;"The purpose of the study is to highlight clinical signs that are either suggestive of or against the diagnosis of AHEI to improve diagnosis and management. The medical records of children under 3 years old diagnosed with AHEI were retrospectively reviewed. Clinical data and photographs were reviewed by three independent experts, and the cases were classified as probable, doubtful, or unclear AHEI. Of the 69 cases of children diagnosed with AHEI included in 22 centers, 40 were classified as probable, 22 as doubtful, and 7 as unclear. The median age of patients with probable AHEI was 11 months [IQR 9-15], and they were in overall good condition (n = 33/40, 82.5%). The morphology of the purpura was targetoid in 75% of cases (n = 30/40) and ecchymotic in 70% of cases (n = 28/40) and affected mostly the legs (n = 39/40, 97%), the arms (n = 34/40, 85%), and the face (n = 33/40, 82.5%). Edema was observed in 95% of cases and affected mostly the hands (n = 36/38, 95%) and feet (n = 28/38, 74%). Pruritus was absent in all patients with probable AHEI and described for 6/21 with doubtful AHEI (29%). AHEI was the original diagnosis in only 24 patients (n = 24/40, 60%). The major differential diagnoses were purpura fulminans and urticaria multiforme.  Conclusion: AHEI, which the diagnosis is made on clinical findings, is often misdiagnosed. Purpuric lesions localized on the face/ears, arms/forearms, and thighs/legs with edema of the hands without pruritus in a young child with a good overall condition are highly suggestive of AHEI. What is Known: •Acute hemorrhagic edema of infancy (AHEI) is a cutaneous leukocytoclastic vasculitis affecting children under 3 years old. •Appropriate diagnosis is important to distinguish this benign disease from more serious diseases to avoid investigations and treatments, iatrogenic harm and unnecessary follow-up. What is New: •AHEI is an uncommon disorder often misdiagnosed by pediatricians and dermatologists. •Purpuric lesions localized on the face/ears, arms/forearms, and thighs/legs with edema of the hands without pruritus in an infant with a good overall condition are highly suggestive of AHEI." 15926;"Cardiac surgery simulation: step-by-step Nicks procedure in a preclinical model.";"E. Ferrari";"Equipe 09, Team 09";37428537;"Multimedia manual of cardiothoracic surgery : MMCTS";"Toto F, Torre T, Pozzoli A, Biroova S, Ferrari E, Demertzis S";;"Jul 2023";1688947200;;"We demonstrate the Nicks operation, one of the posterior aortic root enlargement procedures, on a preclinical model (porcine heart). The goal of this operation is to facilitate the implementation of a suitably sized aortic prosthetic valve. The procedure is performed by making a longitudinal incision through the non-coronary sinus without entering the fibrous body between the aortic valve and the anterior leaflet of the mitral valve and inserting a patch to enlarge the annulus." 15924;"Intramuscular capillary-type hemangioma: Diagnosis, treatment, and outcomes. A French multicentric retrospective study of 66 cases.";"C. Chiaverini";"Equipe 12, Team 12";37423018;"European journal of radiology";"Orly J, Bisdorff A, Fraissenon A, Joly A, Boulouis G, Guibaud L, Tavernier E, Mallet S, Marcelin C, Miquel J, Martin L, Droitcourt C, Gusdorf L, Abasq C, Dadban A, Chiaverini C, Vabres P, Herbreteau D, Boccara O, Wassef M, Maruani A";;"Jul 2023";1688860800;;"Intramuscular capillary-type hemangiomas (ICTHs) are rare entities, belonging to the group of intramuscular ""hemangiomas."" The diagnosis remains challenging. We aimed to assess the diagnostic criteria, treatments and outcomes of ICTHs." 15915;"Pathological complete response to neoadjuvant pembrolizumab in a patient with metastatic cutaneous squamous cell carcinoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";37415448;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Blaise M, Poissonnet G, Cardot-Leccia N, Sudaka A, Velin M, Chassang M, Razzouk-Cadet M, Picard-Gauci A, Passeron T, Montaudié H";;"Jul 2023";1688688000;; 15871;"Prevalence of hypothermia and its associated clinical and biological features (such as thrombocytopenia) in emergency department patients: a case series.";"N. Martis";"Equipe 10, Team 10";37395981;"Internal and emergency medicine";"Kouchit Y, Canac B, Levraut J, Martis N";;"Jul 2023";1688342400;; 15869;"Automatic Detection of Visceral Arterial Aneurysms on Computed Tomography Angiography Using Artificial Intelligence Based Segmentation of the Vascular System.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37396440;"EJVES vascular forum";"Lareyre F, Caradu C, Chaudhuri A, Lê CD, Di Lorenzo G, Adam C, Carrier M, Raffort J, ";;"Jul 2023";1688342400;;"Visceral arterial aneurysms (VAAs) are life threatening. Due to the paucity of symptoms and rarity of the disease, VAAs are underdiagnosed and underestimated. Artificial intelligence (AI) offers new insights into segmentation of the vascular system, and opportunities to better detect VAAs. This pilot study aimed to develop an AI based method to automatically detect VAAs from computed tomography angiography (CTA)." 15867;"Corrigendum to ""Acquisition of multidrug-resistant bacteria and colistin resistance genes in French medical students on internships abroad"" [Travel Med Infect Dis. 39 (2021 Jan-Feb) 101940].";"P. Marty";"Equipe 06, Team 06";37385943;"Travel medicine and infectious disease";"Dao TL, Hoang VT, Magmoun A, Ly TDA, Baron SA, Hadjadj L, Canard N, Drali T, Gouriet F, Raoult D, Parola P, Marty P, Rolain JM, Gautret P";;"Jun 2023";1687996800;; 15863;"Corrigendum to ""Infectious disease symptoms and microbial carriage among French medical students travelling abroad: A prospective study"" [Travel Med Infect Dis 34 (2020 Mar-Apr) 101548].";"J. Courjon";"Equipe 06, Team 06";37385944;"Travel medicine and infectious disease";"Dao TL, Hoang VT, Ly TDA, Magmoun A, Canard N, Drali T, Fenollar F, Ninove L, Raoult D, Parola P, Courjon J, Gautret P";;"Jun 2023";1687996800;; 15859;"Comparative Performance of Four Staging Classifications to Select «High-Risk» Head and Neck Cutaneous Squamous Cell Carcinomas.";"H. Montaudie";"Equipe 12, Team 12";37373623;"Journal of clinical medicine";"Elaldi R, Chamorey E, Schiappa R, Sudaka A, Anjuère F, Villarmé A, Culié D, Bozec A, Montaudié H, Poissonnet G";;"Jun 2023";1687910400;;"Many classifications exist to select patients with ""high-risk"" head and neck cutaneous squamous cell carcinoma (HNCSCC)." 15857;"Corrigendum to ""Risk factors for symptoms of infection and microbial carriage among French medical students abroad"" [International Journal of Infectious Diseases, Vol 100 (2020) Pages 104-111].";"P. Marty";"Equipe 06, Team 06";37364433;"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases";"Dao TL, Canard N, Hoang VT, Ly TDA, Drali T, Ninove L, Fenollar F, Raoult D, Parola P, Marty P, Gautret P";;"Jun 2023";1687737600;; 15855;"RANKL treatment releases the negative regulation of the poly(ADP-ribose) polymerase-1 on Tcirg1 gene expression during osteoclastogenesis.";"G. Beranger";"Equipe 12, Team 12";17002555;"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research";"Beranger GE, Momier D, Rochet N, Quincey D, Guigonis JM, Samson M, Carle GF, Scimeca JC";;"Sep 2006";1159401600;;"The Tcirg1 gene encodes the osteoclast-specific a3 isoform of the V-ATPase a subunit. Using the mouse osteoclastic model RAW264.7 cells, we studied Tcirg1 gene expression, and we identified PARP-1 as a transcriptional repressor negatively regulated by RANKL during osteoclastogenesis." 15853;"Differential binding of poly(ADP-Ribose) polymerase-1 and JunD/Fra2 accounts for RANKL-induced Tcirg1 gene expression during osteoclastogenesis.";"G. Beranger";"Equipe 12, Team 12";17419679;"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research";"Beranger GE, Momier D, Guigonis JM, Samson M, Carle GF, Scimeca JC";;"Apr 2007";1176249600;;"We studied Tcirg1 gene expression on RANKL-induced osteoclastic differentiation of the mouse model RAW264.7 cells. We identified a mechanism involving PARP-1 inhibition release and JunD/Fra-2 binding, which is responsible for Tcirg1 gene upregulation." 15777;"Guselkumab for the Treatment of Patients with Moderate-to-severe Hidradenitis Suppurativa: A Phase 2 Randomized Study.";"T. Passeron";"Equipe 12, Team 12";37317022;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Kimball AB, Podda M, Alavi A, Miller M, Shen YK, Li S, Xu Y, Han C, Fakharzadeh S, Yang YW, DePrimo S, Munoz E, Chen Y, Passeron T, Papp K";;"Jun 2023";1686787200;;"Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that causes substantial physical, emotional, and psychological burden. Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin-23, has demonstrated high levels of efficacy for the treatment of inflammatory diseases, including psoriasis and psoriatic arthritis." 15770;"How and when to measure pH in IVF culture media: validation of a portable blood gas analyzer in two IVF culture dishes for time lapse and conventional incubators.";"M. Carles";"Equipe 06, Team 06";37314570;"Journal of assisted reproduction and genetics";"Chansel-Debordeaux L, Carles M, Moreau J, Depuydt C, Gallo S, Genvrin E, Léandri R, Gatimel N";;"Jun 2023";1686700800;;"Maintaining a stable pH at optimal level in human embryo culture media is crucial for embryo development but poses a challenge for all IVF laboratories. We validate analytically reliable conditions for pH measurement that are as close as possible to the embryo microenvironment during IVF." 15758;"Clinical Outcomes in High-Gradient, Classical Low-Flow, Low-Gradient, and Paradoxical Low-Flow, Low-Gradient Aortic Stenosis After Transcatheter Aortic Valve Implantation: A Report From the SwissTAVI Registry.";"E. Ferrari";"Equipe 09, Team 09";37301760;"Journal of the American Heart Association";"Wagener M, Reuthebuch O, Heg D, Tüller D, Ferrari E, Grünenfelder J, Huber C, Moarof I, Muller O, Nietlispach F, Noble S, Roffi M, Taramasso M, Templin C, Toggweiler S, Wenaweser P, Windecker S, Stortecky S, Jeger R";;"Jun 2023";1686355200;;"Background In view of the rising global burden of severe symptomatic aortic stenosis, its early recognition and treatment is key. Although patients with classical low-flow, low-gradient (C-LFLG) aortic stenosis have higher rates of death after transcatheter aortic valve implantation (TAVI) when compared with patients with high-gradient (HG) aortic stenosis, there is conflicting evidence on the death rate in patients with severe paradoxical low-flow, low-gradient (P-LFLG) aortic stenosis. Therefore, we aimed to compare outcomes in real-world patients with severe HG, C-LFLG, and P-LFLG aortic stenosis undergoing TAVI. Methods and Results Clinical outcomes up to 5 years were addressed in the 3 groups of patients enrolled in the prospective, national, multicenter SwissTAVI registry. A total of 8914 patients undergoing TAVI at 15 heart valve centers in Switzerland were analyzed for the purpose of this study. We observed a significant difference in time to death at 1 year after TAVI, with the lowest observed in HG (8.8%) aortic stenosis, followed by P-LFLG (11.5%; hazard ratio [HR], 1.35 [95% CI, 1.16-1.56]; <0.001) and C-LFLG (19.8%; HR, 1.93 [95% CI, 1.64-2.26]; <0.001) aortic stenosis. Cardiovascular death showed similar differences between the groups. At 5 years, the all-cause death rate was 44.4% in HG, 52.1% in P-LFLG (HR, 1.35 [95% CI, 1.23-1.48]; <0.001), and 62.8% in C-LFLG aortic stenosis (HR, 1.7 [95% CI, 1.54-1.88]; <0.001). Conclusions Up to 5 years after TAVI, patients with P-LFLG have higher death rates than patients with HG aortic stenosis but lower death rates than patients with C-LFLG aortic stenosis." 15756;"Ceramide AD™ Restores Skin Integrity and Function following Exposure to House Dust Mite.";"T. Passeron, M. Tulic, S. Rocchi, H. Bzioueche";"Equipe 12, Team 12";37298186;"International journal of molecular sciences";"Bzioueche H, Tamelghaghet M, Chignon-Sicard B, Bazile N, Hauchecorne P, Barbero Calderón M, Meunier P, Rocchi S, Passeron T, Tulic MK";;"Jun 2023";1686355200;;"Ceramides are epidermal lipids important for normal skin barrier function. Reduced Ceramide content is associated with atopic dermatitis (AD). House dust mite (HDM) has been localized in AD skin where it plays an exacerbator role. We set to examine the impact of HDM on skin integrity and the effect of three separate Ceramides (AD™, DS, Y30) on HDM-induced cutaneous damage. The effect was tested in vitro on primary human keratinocytes and ex vivo on skin explants. HDM (100 μg/mL) decreased the expression of adhesion protein E-cadherin, supra-basal (K1, K10) and basal (K5, K14) keratins and increased matrix metallopeptidase (MMP)-9 activity. The presence of Ceramide AD™ in topical cream inhibited HDM-induced E-cadherin and keratin destruction and dampened MMP-9 activity ex vivo which was not seen for the control cream or cream containing DS or Y30 Ceramides. The efficacy of Ceramide AD™ was tested in a clinical setting on moderate to very dry skin (as surrogate for environment-induced skin damage). When applied topically for 21 days, Ceramide AD™ significantly reduced transepidermal water loss (TEWL) in patients with very dry skin compared to their TEWL baseline data. Our study demonstrates Ceramide AD™ cream to be effective in restoring skin homeostasis and barrier function in damaged skin and warrants testing in larger clinical trials for possible treatment of AD and xerosis." 15752;"Groundbreaking outpatient activity in Medical Entomology in France: an eight-year experience in a French university hospital.";"C. Pomares, P. Marty";"Equipe 06, Team 06";37295744;"Infectious diseases now";"Sevestre J, Marty P, Hubiche T, Pomares C, Delaunay P";;"Jun 2023";1686268800;;"Arthropods are known to impair human health in various manners, acting as infectious disease vectors, or as simple nuisances. Even though considerable research is being produced in medical entomology, no reports on patient management in clinical entomology units are available in the literature." 15750;"The Association between Oxytocin and Lower Limb Osteoarthritis: A Prospective Cohort Study.";"A. IANNELLI, G. Chinetti";"Team 08, Equipe 08, Equipe 09, Team 09";37298701;"International journal of molecular sciences";"Roux CH, Rousseau AS, Iannelli A, Gautier N, Ferrero S, Hinault C, Chinetti G, Ngueyon-Sime W, Guillemin F, Amri EZ";;"Jun 2023";1686355200;;"Oxytocin (OT), a neuropeptide best known for its role in emotional and social behaviors, has been linked to osteoarthritis (OA). This study aimed to investigate the serum OT level in hip and/or knee OA patients and to study its association with disease progression. Patients from the KHOALA cohort with symptomatic hip and/or knee OA (Kellgren and Lawrence (KL) scores of 2 and 3) and follow-up at 5 years were included in this analysis. The primary endpoint was structural radiological progression, which was defined as an increase of at least one KL point at 5 years. Logistic regression models were used to estimate the associations between OT levels and KL progression while controlling for gender, age, BMI, diabetes and leptin levels. Data from 174 hip OA patients and 332 knee OA patients were analyzed independently. No differences in OT levels were found between the 'progressors' and 'non-progressors' groups among the hip OA patients and knee OA patients, respectively. No statistically significant associations were found between the OT levels at baseline and KL progression at 5 years, the KL score at baseline or the clinical outcomes. Higher structural damage at baseline and severe structural progression of hip and knee osteoarthritis did not appear to be associated with a low serum OT level at baseline." 15748;"The Impact and Effectiveness of Weight Loss on Kidney Transplant Outcomes: A Narrative Review.";"A. IANNELLI";"Team 08, Equipe 08";37299471;Nutrients;"Sarno G, Frias-Toral E, Ceriani F, Montalván M, Quintero B, Suárez R, García Velasquèz E, Muscogiuri G, Iannelli A, Pilone V, Schiavo L";;"Jun 2023";1686355200;;"Obesity is a worldwide epidemic that leads to several non-communicable illnesses, including chronic kidney disease (CKD). Diet and lifestyle modifications have shown a limited impact in the treatment of obesity. Because the group of end-stage renal disease (ESRD) patients examined in this study had limited access to kidney transplantation (KT), patients with obesity were thought to be at an increased risk of intraoperative and postoperative KT complications. Although bariatric surgery (BS) is now recognized as the gold standard treatment for morbid obesity, its role in ESRD or kidney transplant patients remains unknown. It is critical to know the correlation between weight loss and complications before and after KT, the impact of the overall graft, and patients' survival. Hence, this narrative review aims to present updated reports addressing when to perform surgery (before or after a KT), which surgical procedure to perform, and again, if strategies to avoid weight regain must be specific for these patients. It also analyzes the metabolic alterations produced by BS and studies its cost-effectiveness pre- and post-transplantation. Due to the better outcomes found in KT recipients, the authors consider it more convenient to perform BS before KT. However, more multicenter trials are required to provide a solid foundation for these recommendations in ERSD patients with obesity." 15742;"Ethanol infusion in left atrial appendage vein for treating refractory left atrial appendage tachycardia.";"E. Ferrari";"Equipe 09, Team 09";37293820;"Journal of cardiovascular electrophysiology";"Squara F, Scarlatti D, Baudouy D, Bun SS, Moceri P, Ferrari E";;"Jun 2023";1686268800;;"We describe an unusual case of atrial tachycardia (AT) emanating from the left atrial appendage body (LAA), successfully treated by chemical ablation." 15740;"Distinct subsets of multi-lymphoid progenitors support ontogeny-related changes in human lymphopoiesis.";"E. Verhoeyen";"Team 03, Equipe 03";37294633;"Cell reports";"Keita S, Diop S, Lekiashvili S, Chabaane E, Nelson E, Strullu M, Arfeuille C, Guimiot F, Domet T, Duchez S, Evrard B, Darde T, Larghero J, Verhoeyen E, Cumano A, Macintyre EA, Kasraian Z, Jouen F, Goodhardt M, Garrick D, Chalmel F, Alhaj Hussen K, Canque B";;"Jun 2023";1686268800;;"Changes in lymphocyte production patterns occurring across human ontogeny remain poorly defined. In this study, we demonstrate that human lymphopoiesis is supported by three waves of embryonic, fetal, and postnatal multi-lymphoid progenitors (MLPs) differing in CD7 and CD10 expression and their output of CD127 early lymphoid progenitors (ELPs). In addition, our results reveal that, like the fetal-to-adult switch in erythropoiesis, transition to postnatal life coincides with a shift from multilineage to B lineage-biased lymphopoiesis and an increase in production of CD127 ELPs, which persists until puberty. A further developmental transition is observed in elderly individuals whereby B cell differentiation bypasses the CD127 compartment and branches directly from CD10 MLPs. Functional analyses indicate that these changes are determined at the level of hematopoietic stem cells. These findings provide insights for understanding identity and function of human MLPs and the establishment and maintenance of adaptative immunity." 15736;"Performance of five serological tests in the diagnosis of visceral and cryptic leishmaniasis: a comparative study.";"C. Pomares, P. Marty, G. MICHEL";"Equipe 06, Team 06";37279431;"Journal of infection in developing countries";"Maritati M, Trentini A, Michel G, Hanau S, Guarino M, De Giorgio R, Pomares C, Marty P, Contini C";;"Jun 2023";1686009600;;"Leishmaniasis is a major health problem and its diagnosis still represents a challenge. Since consistent evidence on the comparison of serological methods is lacking, our work aims to compare five serological tests for the diagnosis of visceral and asymptomatic leishmaniasis in southern France, a region where leishmaniasis is endemic." 15734;"Oxidative phosphorylation fueled by fatty acid oxidation sensitizes leukemic stem cells to cold.";"JF. PEYRON, J. Chiche";"Equipe 04, Team 03, Equipe 03";37272750;"Cancer research";"Griessinger E, Pereira-Martins D, Nebout M, Bosc C, Saland E, Boet E, Sahal A, Chiche J, Debayle D, Fleuriot L, Pruis M, Mansat-De Mas V, Vergez F, Récher C, Huls G, Sarry JE, Schuringa JJ, Peyron JF";;"Jun 2023";1685923200;;"Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSCs) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells (HSCs). Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4°C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyzes showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4°C." 15732;"Cholesterol efflux pathways hinder KRAS-driven lung tumor progenitor cell expansion.";"C. Bertolotto, L. Yvan-Charvet, N. Vaillant, S. Marchetti";"Equipe 01, Team 01, Equipe 13, Team 13, Team 03, Equipe 03";37267915;"Cell stem cell";"Guilbaud E, Barouillet T, Ilie M, Borowczyk C, Ivanov S, Sarrazy V, Vaillant N, Ayrault M, Castiglione A, Rignol G, Brest P, Bazioti V, Zaitsev K, Lebrigand K, Dussaud S, Magnone V, Bertolotto C, Marchetti S, Irondelle M, Goldberg I, Huby T, Westerterp M, Gautier EL, Mari B, Barbry P, Hofman P, Yvan-Charvet L";;"Jun 2023";1685664000;;"Cholesterol efflux pathways could be exploited in tumor biology to unravel cancer vulnerabilities. A mouse model of lung-tumor-bearing KRAS mutation with specific disruption of cholesterol efflux pathways in epithelial progenitor cells promoted tumor growth. Defective cholesterol efflux in epithelial progenitor cells governed their transcriptional landscape to support their expansion and create a pro-tolerogenic tumor microenvironment (TME). Overexpression of the apolipoprotein A-I, to raise HDL levels, protected these mice from tumor development and dire pathologic consequences. Mechanistically, HDL blunted a positive feedback loop between growth factor signaling pathways and cholesterol efflux pathways that cancer cells hijack to expand. Cholesterol removal therapy with cyclodextrin reduced tumor burden in progressing tumor by suppressing the proliferation and expansion of epithelial progenitor cells of tumor origin. Local and systemic perturbations of cholesterol efflux pathways were confirmed in human lung adenocarcinoma (LUAD). Our results position cholesterol removal therapy as a putative metabolic target in lung cancer progenitor cells." 15730;"IgM triplet in neonatal diagnosis by immunoblotting and its potential use as a diagnostic marker for congenital toxoplasmosis.";"C. Pomares";"Equipe 06, Team 06";37265252;"Parasite (Paris, France)";"Peyclit L, Villard O, Paris L, Fricker-Hidalgo H, Houzé S, Cimon B, Deleplancque AS, Tournus C, Pelloux H, Villena I, Pomares C, L'Ollivier C";;"Jun 2023";1685664000;;"Primary infection during pregnancy by the protozoan Toxoplasma gondii can be worrisome because transmission to the fetus may lead to congenital toxoplasmosis (CT). Neonatal diagnosis is usually performed by serological profile comparison of the mother and newborn. As previously reported in 2012 by C. L'Ollivier et al., three IgM bands at 75, 90 and 100 kDa called the ""IgM triplet"" has caught our attention and seems to be pathognomonic of CT. This retrospective multicenter study involved nine reference laboratories included in the French National Reference Center for Toxoplasmosis network and concerned determining the specificity and sensitivity of this IgM triplet. On this basis, we were able to propose a new read of the comparison of IgG and IgM immunoblot profiles of mother and infant to increase the sensitivity of this diagnostic marker. The effect of the trimester of pregnancy at the time of infection, but also of maternal treatment with pyrimethamine/sulfadiazine/folinic acid on the presence of this IgM triplet in the infant, could be studied. The presence of the triplet appears pathognomonic for the diagnosis of CT, and it increased the sensitivity of the immunoblot assay from 55.04% to 72.48%. As a result, it would be wise to enhance conventional immunoblot reading by adding the presence of the three IgM bands in the infant pattern for neonatal diagnosis of CT." 15728;"Aetiology of Acute Undifferentiated Fever Among Children Under the Age of Five in Vietnam: A Prospective Study.";"P. Marty";"Equipe 06, Team 06";37258852;"Journal of epidemiology and global health";"Tran XD, Hoang VT, Dang TTD, Vu TP, To MM, Tran TK, Do MD, Nguyen DC, Nguyen QT, Colson P, Parola P, Marty P, Gautret P";;"May 2023";1685491200;;"To investigate the aetiology of acute undifferentiated fever (AUF) among children under the age of five in Vietnam." 15716;"Impact on facial skin aging signs of a one-year standardized photo-protection over a classical skin care routine in skin phototypes II to VI individuals: A prospective randomized trial.";"T. Passeron";"Equipe 12, Team 12";37247191;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Flament F, Mercurio DG, Catalan E, Bouhadanna E, Delaunay C, Miranda DF, Passeron T";;"May 2023";1685318400;;"Data reflecting the impact of photo-protection on cutaneous aging are scarce and mostly limited to fair skin." 15700;"The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.";"B. Bailly-Maitre";"Equipe 13, Team 13";37205565;"bioRxiv : the preprint server for biology";"Hazari Y, Urra H, Garcia Lopez VA, Diaz J, Tamburini G, Milani M, Pihan P, Durand S, Aprahamia F, Baxter R, Huang M, Dong XC, Vihinen H, Batista-Gonzalez A, Godoy P, Criollo A, Ratziu V, Foufelle F, Hengstler JG, Jokitalo E, Bailly-Maitre B, Maiers JL, Plate L, Kroemer G, Hetz C";;"May 2023";1684454400;;"Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl ) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states." 15684;"Scarring after chemical tattoo removal: a retrospective study.";"T. Passeron";"Equipe 12, Team 12";35653091;"European journal of dermatology : EJD";"Kenani Z, Le Duff F, Hachem JP, Le Pillouer-Prost A, Martin-Chico R, Patarin M, Laubach H, Ducamp I, Cante V, Perillat Y, Toubel G, Passeron T, Bahadoran P";;"Jun 2022";1654128000;; 15682;"Systemic sclerosis associated interstitial lung disease: a survey of current practices in France.";"N. Martis";"Equipe 10, Team 10";37187855;"Therapeutic advances in musculoskeletal disease";"Nicolas A, Leroy S, Mouthon L, Uzunhan Y, Cottin V, Mekinian A, Queyrel V, Hachulla E, Gachet B, Launay D, Martis N, ";;"May 2023";1684108800;;"Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc)." 15680;"Inflamed macrophages sans mitochondrial pyruvate carrier?";"L. Yvan-Charvet";"Equipe 13, Team 13";37188820;"Nature metabolism";"Yvan-Charvet L, Thorp EB";;"May 2023";1684108800;; 15678;"Need for a Dedicated Ophthalmic Malignancy Clinico-Biological Biobank: The Nice Ocular MAlignancy (NOMA) Biobank.";"C. Bertolotto";"Equipe 01, Team 01";37190299;Cancers;"Martel A, Gastaud L, Bonnetaud C, Nahon-Esteve S, Washetine K, Bordone O, Salah M, Tanga V, Fayada J, Lespinet V, Allegra M, Lalvee S, Zahaf K, Baillif S, Bertolotto C, Mograbi B, Lassalle S, Hofman P";;"May 2023";1684195200;;"Ophthalmic malignancies include various rare neoplasms involving the conjunctiva, the uvea, or the periocular area. These tumors are characterized by their scarcity as well as their histological, and sometimes genetic, diversity. Uveal melanoma (UM) is the most common primary intraocular malignancy. UM raises three main challenges highlighting the specificity of ophthalmic malignancies. First, UM is a very rare malignancy with an estimated incidence of 6 cases per million inhabitants. Second, tissue biopsy is not routinely recommended due to the risk of extraocular dissemination. Third, UM is an aggressive cancer because it is estimated that about 50% of patients will experience metastatic spread without any curative treatment available at this stage. These challenges better explain the two main objectives in the creation of a dedicated UM biobank. First, collecting UM samples is essential due to tissue scarcity. Second, large-scale translational research programs based on stored human samples will help to better determine UM pathogenesis with the aim of identifying new biomarkers, allowing for early diagnosis and new targeted treatment modalities. Other periocular malignancies, such as conjunctival melanomas or orbital malignancies, also raise specific concerns. In this context, the number of biobanks worldwide dedicated to ocular malignancies is very limited. The aims of this article were (i) to describe the specific challenges raised by a dedicated ocular malignancy biobank, (ii) to report our experience in setting up such a biobank, and (iii) to discuss future perspectives in this field." 15676;"CAR-T Cells and the Kidney: Insights from the WHO Safety Database.";"M. Loschi, T. Cluzeau";"Equipe 02, Team 02";37166707;"BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy";"Gérard AO, Merino D, Charbinat A, Fournier J, Destere A, Loschi M, Cluzeau T, Sicard A, Drici MD";;"May 2023";1683763200;;"Chimeric antigen receptor T (CAR-T) cells have proven to be a game changer for treating several hematologic malignancies. Randomized controlled trials have highlighted potential life-threatening adverse drug reactions (ADRs), including cytokine release syndrome (CRS). Acute renal failure (ARF) has also been reported in 20% of the patients treated. However, an analysis of renal safety supported by large-scale real-life data seems warranted." 15672;"Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial.";"R. ANTY";"Equipe 08, Team 08";37159035;JAMA;"Louvet A, Labreuche J, Dao T, Thévenot T, Oberti F, Bureau C, Paupard T, Nguyen-Khac E, Minello A, Bernard-Chabert B, Anty R, Wartel F, Carbonell N, Pageaux GP, Hilleret MN, Moirand R, Nahon P, Potey C, Duhamel A, Mathurin P";;"May 2023";1683590400;;"The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear." 15667;"Hidradenitis suppurativa and social disadvantage: a nationwide administrative data study of the French hospitalized population.";"T. Passeron";"Equipe 12, Team 12";37147873;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Bulsei J, Fontas E, Passeron T";;"May 2023";1683331200;;"A lower socioeconomical status (SES) has been reported in patients suffering from hidradenitis suppurative (HS). However, limitations in the available studies prevent drawing definitive conclusions." 15665;"Monoclonal B-cell lymphocytosis with a non-CLL immunophenotype - Review of 34 cases.";"C. Mauduit";"Equipe 10, Team 10";37144789;"Annales de biologie clinique";"Heraud I, Mauduit C, Golfier C, Grange B, Baseggio L";;"May 2023";1683244800;;"The monoclonal B-cell lymphocytosis (MBL) introduced as new entities in the 2008 WHO classification, are defined by circulating B-cell clone < 5.109/L without organomegaly and previous and/or simultaneous lymphoproliferative disorders. The MBL were subclassified in MBL CLL type (the most frequent), MBL atypical CLL type and MBL non-CLL type (rarely reported in literature). Here the clinic, cytologic, immunologic and genetic features of MBL non-CLL type were described from a series of 34 cases. As previously reported, present cases presented immunologic and genetic similarities to MZL and could be associated to the new proposed entity CBL-MZ (clonal B-cell lymphocytosis of marginal zone origin). In addition, few cases presented similarities to splenic diffuse red pulp lymphoma (SDRPL). In conclusion, according to the literature, MBL with non-CLL type (assimilated to CBL-MZ) may be a premalignant state of MZL and/or SDRPL." 15663;"The generation, activation, and polarization of monocyte-derived macrophages in human malignancies.";"A. Jacquel, C. Savy, P. Auberger, G. Robert";"Equipe 02, Team 02";37143666;"Frontiers in immunology";"Chaintreuil P, Kerreneur E, Bourgoin M, Savy C, Favreau C, Robert G, Jacquel A, Auberger P";;"May 2023";1683244800;;"Macrophages are immune cells that originate from embryogenesis or from the differentiation of monocytes. They can adopt numerous phenotypes depending on their origin, tissue distribution and in response to different stimuli and tissue environment. Thus, , macrophages are endowed with a continuum of phenotypes that are rarely strictly pro-inflammatory or anti-inflammatory and exhibit a broad expression profile that sweeps over the whole polarization spectrum. Schematically, three main macrophage subpopulations coexist in human tissues: naïve macrophages also called M0, pro-inflammatory macrophages referred as M1 macrophages, and anti-inflammatory macrophages also known as M2 macrophages. Naïve macrophages display phagocytic functions, recognize pathogenic agents, and rapidly undergo polarization towards pro or anti-inflammatory macrophages to acquire their full panel of functions. Pro-inflammatory macrophages are widely involved in inflammatory response, during which they exert anti-microbial and anti-tumoral functions. By contrast, anti-inflammatory macrophages are implicated in the resolution of inflammation, the phagocytosis of cell debris and tissue reparation following injuries. Macrophages also play important deleterious or beneficial roles in the initiation and progression of different pathophysiological settings including solid and hematopoietic cancers. A better understanding of the molecular mechanisms involved in the generation, activation and polarization of macrophages is a prerequisite for the development of new therapeutic strategies to modulate macrophages functions in pathological situations." 15661;"Impact of House-Dust-Mite in Vitiligo Skin: Environmental Contribution to Increased Cutaneous Immunity and Melanocyte Detachment.";"T. Passeron, M. Tulic, S. Marchetti, S. Rocchi";"Equipe 12, Team 12, Team 03, Equipe 03";37140010;"The British journal of dermatology";"Bzioueche H, Boniface K, Drullion C, Marchetti S, Chignon-Sicard B, Sormani L, Rocchi S, Senechal J, Passeron T, Tulic MK";;"May 2023";1683158400;;"Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea." 15657;"GIPR expression is induced by thiazolidinediones in a PPARγ-independent manner and repressed by obesogenic stimuli.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";37130450;"European journal of cell biology";"Cataldi S, Aprile M, Perfetto C, Angot B, Cormont M, Ciccodicola A, Tanti JF, Costa V";;"May 2023";1682985600;;"Adipose tissue (AT) dysfunctions are associated with the onset of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Targeting glucose-dependent insulinotropic peptide receptor (GIPR) is a valid option to increase the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists in T2DM treatment. Nevertheless, the therapeutic potential of targeting the GIP/GIPR axis and its effect on the AT are controversial. In this work, we explored the expression and regulation of GIPR in precursor cells and mature adipocytes, investigating if and how obesogenic stimuli and thiazolidinediones perturb GIPR expression. Using publicly available gene expression datasets, we assessed that, among white adipose tissue (WAT) cells, adipocytes express lower levels of GIPR compared to cells of mesothelial origin, pericytes, dendritic and NK/T cells. However, we report that GIPR levels markedly increase during the in vitro differentiation of both murine and human adipocytes, from 3T3-L1 and human mesenchymal precursor cells (MSCs), respectively. Notably, we demonstrated that thiazolidinediones - ie. synthetic PPARγ agonists widely used as anti-diabetic drugs and contained in the adipogenic mix - markedly induce GIPR expression. Moreover, using multiple in vitro systems, we assessed that thiazolidinediones induce GIPR in a PPARγ-independent manner. Our results support the hypothesis that PPARγ synthetic agonists may be used to increase GIPR levels in AT, potentially affecting in turn the targeting of GIP system in patients with metabolic dysfunctions. Furthermore, we demonstrate in vitro and in vivo that proinflammatory stimuli, and especially the TNFα, represses GIPR both in human and murine adipocytes, even though discordant results were obtained between human and murine cellular systems for other cytokines. Finally, we demonstrated that GIPR is negatively affected also by the excessive lipid engulfment. Overall, we report that obesogenic stimuli - ie. pro-inflammatory cytokines and the increased lipid accumulation - and PPARγ synthetic ligands oppositely modulate GIPR expression, possibly influencing the effectiveness of GIP agonists." 15637;"Prevalence of small intestinal bacterial overgrowth in irritable bowel syndrome (IBS): Correlating H or CH production with severity of IBS.";"R. ANTY";"Equipe 08, Team 08";37125253;"JGH open : an open access journal of gastroenterology and hepatology";"Onana Ndong P, Boutallaka H, Marine-Barjoan E, Ouizeman D, Mroue R, Anty R, Vanbiervliet G, Piche T";;"May 2023";1682899200;;"The prevalence and the role of small intestinal bacterial overgrowth (SIBO) in irritable bowel syndrome (IBS) remain unclear, as the literature provides heterogeneous information on the subject. The aim of this study was to determine the prevalence of SIBO in IBS and to assess the correlation between methane and hydrogen levels measured during breath tests and the severity of IBS." 15635;"Nationwide Study in France To Predict One-Year Major Bleeding and Validate the OAC3-PAD Score in Patients Undergoing Revascularisation for Lower Extremity Artery Disease.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";37121388;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Behrendt CA, Pradier C, Settembre N, Chaudhuri A, Fabre R, Raffort J, Bailly L";;"Apr 2023";1682812800;;"Antithrombotic strategies are currently recommended for the treatment of lower extremity artery disease (LEAD) but specific scores to assess the risk of bleeding in these patients are scarce. To fill the gap, the OAC3-PAD bleeding score was recently developed and validated in German cohorts. The aim of this study was to determine whether this score performs appropriately in another real world nationwide cohort." 15631;"Early intrahepatic recurrence of HBV infection in liver transplant recipients despite antiviral prophylaxis.";"R. ANTY, A. IANNELLI";"Equipe 08, Team 08";37122357;"JHEP reports : innovation in hepatology";"Villeret F, Lebossé F, Radenne S, Samuel D, Roche B, Mabrut JY, Leroy V, Pageaux GP, Anty R, Thevenon S, Ahmed SS, Hamilton A, Heil M, Scholtès C, Levrero M, Testoni B, Zoulim F, ";;"May 2023";1682899200;;"Prophylaxis with nucleos(t)ide analogues (NUCs) and hepatitis B immunoglobulin (HBIG) has decreased the rate of HBV recurrence after orthotopic liver transplantation (OLT), but the duration of this prophylaxis remains debated. Our aim was to investigate the recurrence of both intrahepatic and serum HBV markers after OLT in patients receiving long-term NUC and HBIG prophylaxis." 15629;"Objective and automatic grading system of facial signs from smartphones' pictures in South African men: Validation versus dermatologists and characterization of changes with age.";"T. Passeron";"Equipe 12, Team 12";37113093;"Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)";"Flament F, Jiang R, Houghton J, Cassier M, Amar D, Delaunay C, Balooch G, Bouhadana E, Aarabi P, Passeron T";;"Apr 2023";1682640000;;"To evaluate the capacity of the automatic detection system to accurately grade, from selfie pictures, the severity of eight facial signs in South African men." 15627;"Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study.";"M. Loschi";"Equipe 02, Team 02";37105210;"Lancet (London, England)";"de Masson A, Beylot-Barry M, Ram-Wolff C, Mear JB, Dalle S, d'Incan M, Ingen-Housz-Oro S, Orvain C, Abraham J, Dereure O, Charbonnier A, Cornillon J, Longvert C, Barete S, Boulinguez S, Wierzbicka-Hainaut E, Aubin F, Rubio MT, Bernard M, Schmidt-Tanguy A, Houot R, Pham-Ledard A, Michonneau D, Brice P, Labussière-Wallet H, Bouaziz JD, Grange F, Moins-Teisserenc H, Jondeau K, Michel L, Mourah S, Battistella M, Daguindau E, Loschi M, Picard A, Franck N, Maillard N, Huynh A, Nguyen S, Marçais A, Chaby G, Ceballos P, Le Corre Y, Maury S, Bay JO, Adamski H, Bachy E, Forcade E, Socié G, Bagot M, Chevret S, Peffault de Latour R, , , ";;"Apr 2023";1682553600;;"Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs." 15625;"Very Low-Calorie Ketogenic Diet (VLCKD) as Pre-Operative First-Line Dietary Therapy in Patients with Obesity Who Are Candidates for Bariatric Surgery.";"A. IANNELLI";"Team 08, Equipe 08";37111126;Nutrients;"Barrea L, Verde L, Schiavo L, Sarno G, Camajani E, Iannelli A, Caprio M, Pilone V, Colao A, Muscogiuri G";;"Apr 2023";1682640000;;"Bariatric surgery is currently the most effective method for achieving long-term weight loss and reducing the risk of comorbidities and mortality in individuals with severe obesity. The pre-operative diet is an important factor in determining patients' suitability for surgery, as well as their post-operative outcomes and success in achieving weight loss. Therefore, the nutritional management of bariatric patients requires specialized expertise. Very low-calorie diets and intragastric balloon placement have already been studied and shown to be effective in promoting pre-operative weight loss. In addition, the very low-calorie ketogenic diet has a well-established role in the treatment of obesity and type 2 diabetes mellitus, but its potential role as a pre-operative dietary treatment prior to bariatric surgery has received less attention. Thus, this article will provide a brief overview of the current evidence on the very low-calorie ketogenic diet as a pre-operative dietary treatment in patients with obesity who are candidates for bariatric surgery." 15604;"Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction.";"P. GUAL, D. ROUSSEAU";"Equipe 08, Team 08";37092554;"JCI insight";"Sawaki D, Zhang Y, Mohamadi A, Pini M, Mezdari Z, Lipskaia L, Naushad S, Lamendour L, Altintas DM, Breau M, Liang H, Halfaoui M, Delmont T, Surenaud M, Rousseau D, Yoshimitsu T, Louache F, Adnot S, Henegar C, Gual P, Czibik G, Derumeaux G";;"04 2023";1680307200;;"Adipose tissue macrophages (ATMs) play an important role in obesity and inflammation, and they accumulate in adipose tissue (AT) with aging. Furthermore, increased ATM senescence has been shown in obesity-related AT remodeling and dysfunction. However, ATM senescence and its role are unclear in age-related AT dysfunction. Here, we show that ATMs (a) acquire a senescence-like phenotype during chronological aging; (b) display a global decline of basic macrophage functions such as efferocytosis, an essential process to preserve AT homeostasis by clearing dysfunctional or apoptotic cells; and (c) promote AT remodeling and dysfunction. Importantly, we uncover a major role for the age-associated accumulation of osteopontin (OPN) in these processes in visceral AT. Consistently, loss or pharmacologic inhibition of OPN and bone marrow transplantation of OPN-/- mice attenuate the ATM senescence-like phenotype, preserve efferocytosis, and finally restore healthy AT homeostasis in the context of aging. Collectively, our findings implicate pharmacologic OPN inhibition as a viable treatment modality to counter ATM senescence-mediated AT remodeling and dysfunction during aging." 15572;"Deciphering the spectrum of cutaneous lymphomas expressing TFH markers.";"C. Mauduit";"Equipe 10, Team 10";37081015;"Scientific reports";"Donzel M, Trecourt A, Balme B, Harou O, Mauduit C, Bachy E, Guesquières H, Fontaine J, Ortonne N, Perier-Muzet M, Dalle S, Traverse-Glehen A";;"04 2023";1680307200;;"T-follicular helper (TFH) markers are expressed in the microenvironnement of marginal zone B-cell lymphoma (MZL), and in lymphomas arising from TFH-cells, sometimes making the differential diagnosis difficult. In the skin, the ""TFH-spectrum"" is poorly defined, going from primary cutaneous lymphoproliferative disorder with small/medium CD4+ T-cells (SMLPD) to cutaneous localizations of systemic angioimmunoblastic T-cell lymphoma (cAITL), and may pass through intermediate forms (primary cutaneous T-follicular helper derived lymphoma, not otherwise specified (PCTFHL,NOS)). We retrospectively analyzed 20 MZL, 13 SMLPD, 5 PCTFHL, and 11 cAITL clinically, histologically, and molecularly, to define tools to differentiate them. Characteristics that might favor the diagnosis of MZL over SMLPD are: multiple skin nodules (p < 0.001), nodular architecture (p < 0.01), residual germinal centers with follicular dendritic cell network (p < 0.001), monotypic plasma cells (p < 0.001), and few staining with PD1 (p = 0.016) or CXCL13 (p = 0.03). PCTFHL and cAITL presented as multiple (p < 0.01) lesions, in older patients (p < 0.01), with systemic symptoms and/or biological alterations (p < 0.01). Immunophenotypic loss of T-cell markers (p < 0.001), BCL6 (p = 0.023) and/or CD10 staining (p = 0.08), and a higher proliferative index (≥ 30%, p = 0.039) favoured these diagnoses over SMLPD. Pathogenic variants were observed by genomic sequencing in 47% of MZL (TNFAIP3 (32%), EP300 (21%), NOTCH2 (16%), KMT2D (16%), CARD11 (10.5%)), 8% of SMLPD (TET2), 40% of PCTFHL (SOCS1 (20%), ARID1A (20%)) and 64% of cAITL (TET2 (63.6%), RHOA (36.4%), NOTCH1 (9%)). This study characterizes the various clinical and histological features between cutaneous lymphomas expressing TFH markers and highlights the value of the interest of screening for genomic mutations in difficult cases." 15568;"Breakthrough infections due to SARS-CoV-2 Delta variant: relation to humoral and cellular vaccine responses.";"J. Courjon, M. Carles, L. Boyer";"Equipe 06, Team 06";37063916;"Frontiers in immunology";"Buscot M, Cremoni M, Graça D, Brglez V, Courjon J, Allouche J, Teisseyre M, Boyer L, Barrière J, Chamorey E, Carles M, Seitz-Polski B";;"Apr 2023";1681689600;;"COVID-19 vaccines are expected to provide effective protection. However, emerging strains can cause breakthrough infection in vaccinated individuals. The immune response of vaccinated individuals who have experienced breakthrough infection is still poorly understood." 15566;"Diagnostic significance of antineutrophil cytoplasmic antibody (ANCA) titres: a retrospective case-control study.";"N. Martis";"Equipe 10, Team 10";37055171;"RMD open";"Merindol J, Levraut M, Seitz-Polski B, Morand L, Martis N";;"Apr 2023";1681344000;;"To investigate the reliability of elevated titres of antineutrophil cytoplasmic antibody (ANCA) and to identify a cut-off titre in discriminating between ANCA-associated vasculitides (AAV) and its mimickers." 15562;"Radiomics, a Promising New Discipline: Example of Hepatocellular Carcinoma.";"P. GUAL, R. ANTY";"Equipe 08, Team 08";37046521;"Diagnostics (Basel, Switzerland)";"Lévi-Strauss T, Tortorici B, Lopez O, Viau P, Ouizeman DJ, Schall B, Adhoute X, Humbert O, Chevallier P, Gual P, Fillatre L, Anty R";;"Apr 2023";1681344000;;"Radiomics is a discipline that involves studying medical images through their digital data. Using ""artificial intelligence"" algorithms, radiomics utilizes quantitative and high-throughput analysis of an image's textural richness to obtain relevant information for clinicians, from diagnosis assistance to therapeutic guidance. Exploitation of these data could allow for a more detailed characterization of each phenotype, for each patient, making radiomics a new biomarker of interest, highly promising in the era of precision medicine. Moreover, radiomics is non-invasive, cost-effective, and easily reproducible in time. In the field of oncology, it performs an analysis of the entire tumor, which is impossible with a single biopsy but is essential for understanding the tumor's heterogeneity and is known to be closely related to prognosis. However, current results are sometimes less accurate than expected and often require the addition of non-radiomics data to create a performing model. To highlight the strengths and weaknesses of this new technology, we take the example of hepatocellular carcinoma and show how radiomics could facilitate its diagnosis in difficult cases, predict certain histological features, and estimate treatment response, whether medical or surgical." 15558;"Lesson from the COVID-19 pandemic lockdown: A major change of hospital-diagnosed bacteremia epidemiology.";"B. Lamy, J. Courjon, M. Carles, R. Ruimy, R. Lotte, L. Boyer";"Equipe 06, Team 06";37044247;"Infectious diseases now";"Cauhapé V, Lamy B, Lotte R, Touitou I, Boyer L, Contenti J, Parisot F, Ruimy R, Carles M, Courjon J";;"Apr 2023";1681257600;;"When the COVID-19 pandemic reached France early in 2020, the enforced nationwide lockdown deeply altered lifestyle as well as hospital processes and modalities of care. The aim of the study was to evaluate the impact during the lockdown of the first epidemic wave on the epidemiology of bacteremia in one French University Hospital." 15553;"A fixed-duration, immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial.";"M. Ticchioni";;37026799;"Blood advances";"Michallet AS, Letestu R, Le Garff-Tavernier M, Campos L, Ticchioni M, Dilhuydy MS, Morisset S, Rouille V, Mahe B, Laribi K, Villemagne B, Ferrant EF, Tournilhac O, Delmer AJ, Molina L, Leblond V, Tomowiak C, De Guibert S, Orsini Piocelle F, Banos A, Carassou P, Cartron G, Fornecker LM, Ysebaert L, Dartigeas C, Truchan-Graczyk M, Vilque JP, Aurran Schleinitz T, Cymbalista F, Leprêtre S, Lévy V, Nguyen-Khac F, Feugier P";;"Apr 2023";1680825600;;"In previously untreated, medically fit patients with chronic lymphocytic leukemia, research is focused on developing fixed-duration strategies to improve long-term outcomes whilst sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach where, following obinutuzumab-ibrutinib induction for 9 months, patients (n=10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n=115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 62.2% (84/135) of all patients enrolled achieved CR with BM MRD <0.01%. Here we report follow-up at median 63 months. PB MRD was assessed 6 monthly beyond end of treatment using a highly-sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in PB MRD status were apparent according to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898." 15545;"The 10th Santorini conference: Systems medicine, personalised health and therapy. ""The odyssey from hope to practice: Patient first. "", Santorini, Greece, 23-26 May 2022.";"M. Stathopoulou";"Equipe 10, Team 10";37021002;"Frontiers in genetics";"Visvikis-Siest S, Stathopoulou MG, Sunder-Plassmann R, Alizadeh BZ, Barouki R, Chatzaki E, Dagher G, Dedoussis G, Deloukas P, Haliassos A, Hiegel BB, Manolopoulos V, Masson C, Paré G, Paulmichl M, Petrelis AM, Sipeky C, Süsleyici B, Weryha G, Chenchik A, Diehl P, Everts RE, Haushofer A, Lamont J, Mercado R, Meyer H, Munoz-Galeano H, Murray H, Nhat F, Nofziger C, Schnitzel W, Kanoni S";;"Apr 2023";1680739200;; 15528;"Efficacy and safety of 0.05% ingenol mebutate in the treatment of basal cell carcinoma: A prospective study.";"T. Passeron";"Equipe 12, Team 12";37013127;"Skin health and disease";"Velin M, Cardot-Leccia N, Cathelineau AC, Duteil L, Queille-Roussel C, Passeron T, Bahadoran P";;"Apr 2023";1680566400;; 15525;"Bilateral pedicled scrotal flaps as an alternative to skin graft in penile shaft defects repair.";;;37004847;Urology;"Mendel L, Neuville P, Allepot K, Hadjali L, Boucher F, Paparel P, Ruffion A, Tannour-Louet M, Mbeutcha A, Morel-Journel N";;"Apr 2023";1680393600;;"To analyze surgical and functional outcomes of bilateral pedicled scrotal flaps for penile shaft reconstruction." 15521;"Atrial fibrillation ablation in a single atrium with inferior vena cava interruption.";"E. Ferrari";"Equipe 09, Team 09";37002650;"Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc";"Bun SS, Squara F, Scarlatti D, Moceri P, Ferrari E";;"Apr 2023";1680307200;;"Common atrium (CA), also called three-chambered heart, is one of the rare congenital anomalies, defined by a complete absence of the atrial septum, eventually associated with malformation of the atrioventricular (AV) valves. We report the case of a 57-year-old woman with CA complicated with Eisenmenger syndrome and inferior vena cava interruption, who suffered from symptomatic persistent atrial fibrillation (AF). She underwent an initial successful pulmonary vein isolation procedure. A repeat procedure for perivalvular atrial flutter was complicated with inadvertent complete AV block, due to unusual AV node location in this challenging anatomy." 15519;"[Vitiligo, no longer a fatality in 2023].";"T. Passeron";"Equipe 12, Team 12";36988172;"Revue medicale suisse";"Alvarez Martinez D, Bertold C, Passeron T, Cortes B";;"Mar 2023";1680048000;;"Vitiligo is an acquired auto-inflammatory disorder characterized by a depigmentation. It is a polygenic disease developed in a context of allelic variations. Its pathophysiology is complex, associating intrinsic skin defects, exposome triggering factors and innate then adaptive auto-immune activation leading to the loss of melanocytes. The diagnosis is clinical. Nevertheless, Wood's lamp is mandatory to assess the lesions and their activity, especially in fair-skinned patients. The management of vitiligo is long and aims to halt the depigmentation process and to repigment the affected areas. This requires a combination of immunosuppressive topical or systemic treatment with ultraviolet rays from phototherapy or sun exposure." 15517;"Atherosclerosis Calcification: Focus on Lipoproteins.";"G. Chinetti, J. Neels";"Equipe 09, Team 09";36984897;Metabolites;"Neels JG, Leftheriotis G, Chinetti G";;"Mar 2023";1680048000;;"Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and VC. Both low- and very low-density lipoproteins (LDL and VLDL) and lipoprotein (a) (Lp(a)) stimulate, while high-density lipoproteins (HDL) reduce VC. Apolipoproteins, the protein component of lipoproteins, influence the development of VC in multiple ways. Apolipoprotein AI (apoAI), the main protein component of HDL, has anti-calcific properties, while apoB and apoCIII, the main protein components of LDL and VLDL, respectively, promote VC. The role of lipoproteins in VC is also related to their metabolism and modifications. Oxidized LDL (OxLDL) are more pro-calcific than native LDL. Oxidation also converts HDL from anti- to pro-calcific. Additionally, enzymes such as autotaxin (ATX) and proprotein convertase subtilisin/kexin type 9 (PCSK9), involved in lipoprotein metabolism, have a stimulatory role in VC. In summary, a better understanding of the mechanisms by which lipoproteins and apolipoproteins contribute to VC will be crucial in the development of effective preventive and therapeutic strategies for VC and its associated cardiovascular disease." 15513;"Systemic Infection Model to Study Altered Virulence during Polymicrobial Infection by .";"B. Lamy, R. Ruimy, L. Boyer";"Equipe 06, Team 06";36986327;"Pathogens (Basel, Switzerland)";"Robert A, Talagrand-Reboul E, Figueras MJ, Ruimy R, Boyer L, Lamy B";;"Mar 2023";1680048000;;"Polymicrobial infections are complex infections associated with worse outcomes compared to monomicrobial infections. We need simple, fast, and cost-effective animal models to assess their still poorly known pathogenesis." 15511;"Therapeutic Physical Exercise Programs in the Context of NASH Cirrhosis and Liver Transplantation: A Systematic Review.";"A. IANNELLI, P. GUAL, R. ANTY";"Team 08, Equipe 08";36984770;Metabolites;"Farrugia MA, Le Garf S, Chierici A, Piche T, Gual P, Iannelli A, Anty R";;"Mar 2023";1680048000;;"In recent years, various physical exercise interventions have been developed with a view to reducing comorbidity and morbidity rates among patients with chronic diseases. Regular physical exercise has been shown to reduce hypertension and mortality in patients with type 2 diabetes. Diabetes and obesity are often associated with the development of nonalcoholic fatty liver disease, which can lead to liver fibrosis and then (in some cases) nonalcoholic steatohepatitis cirrhosis. We searched the literature for publications on personalized physical exercise programs in cirrhotic patients before and after liver transplantation. Eleven studies in cirrhotic patients and one study in liver transplant recipients were included in the systematic review, the results of which were reported in compliance with the preferred reporting items for systematic reviews and meta-analyses guidelines. The personalized physical exercise programs lasted for 6 to 16 weeks. Our review evidenced improvements in peak oxygen consumption and six-minute walk test performance and a reduction in the hepatic venous pressure gradient. In cirrhotic patients, personalized physical exercise programs improve quality of life, are not associated with adverse effects, and (for transplant recipients) might reduce the 90-day hospital readmission rate. However, none of the literature data evidenced reductions in the mortality rates before and after transplantation. Further prospective studies are needed to evaluate the benefit of long-term physical exercise programs in cirrhotic patients before and after liver transplantation." 15509;"Mid-Infrared Spectroscopy as a New Tool for Ruling Out Spontaneous Bacterial Peritonitis: A Proof-of-Concept Study.";"P. GUAL, R. ANTY, A. TRAN";"Equipe 08, Team 08";36979817;Biomedicines;"Farrugia MA, Le Corvec M, Renou C, Nousbaum JB, Ouizeman DJ, Sire O, Loréal O, Tariel H, Bernard J, Piche T, Tran A, Ait-Oufella H, Landraud L, Gual P, Anty R, The Cytokine Ascites Group ";;"Mar 2023";1680048000;;"A highly sensitive and specific point-of-care method for diagnosing spontaneous bacterial peritonitis (SBP) is currently lacking. The objective of the present study is to evaluate the diagnostic value of a rapid, easy-to-use, mid-infrared fiber evanescent wave spectroscopy (MIR-FEWS) method for ruling out SBP." 15503;"IL-7 germline variant: setting the stage for immune-related adverse events.";"H. Issaoui, JE. Ricci";"Team 03, Equipe 03";36748568;"Molecular oncology";"Issaoui H, Ricci JE";;"Feb 2023";1675728000;;"Treatment with immune checkpoint inhibitors (ICIs) is frequently associated with immune-related adverse events (irAEs). A new study identified an interleukin 7 (IL-7) allelic variant-rs16906115-as a major risk factor for the development of ICI-associated irAEs. This association is of great significance as it indicates that germline genetic variants influence the occurrence of irAEs, thus opening a new avenue for identifying high-risk patients to enable better management of ICI therapy and associated irAEs." 15501;"New Targeted Therapies and Immunotherapies for Locally Advanced Periocular Malignant Tumours: Towards a New 'Eye-Sparing' Paradigm?";"A. Martel, C. Bertolotto, H. Montaudie, L. Gastaud, S. Nahon-Esteve, S. Baillif";"Equipe 01, Team 01, Equipe 12, Team 12";34198863;Cancers;"Martel A, Lassalle S, Picard-Gauci A, Gastaud L, Montaudie H, Bertolotto C, Nahon-Esteve S, Poissonnet G, Hofman P, Baillif S";;"Jul 2021";1625184000;;"The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly disfiguring and traumatic surgery. The last two decades have been marked by the emergence of a new paradigm shift towards the use of 'eye-sparing' strategies. In the early 2000s, the first step consisted of performing wide conservative eyelid and orbital excisions. Multiple flaps and grafts were needed, as well as adjuvant radiotherapy in selected cases. Although being incredibly attractive, several limitations such as the inability to treat the more posteriorly located orbital lesions, as well as unbearable diplopia, eye pain and even secondary eye loss were identified. Therefore, surgeons should distinguish 'eye-sparing' from 'sight-sparing' strategies. The second step emerged over the last decade and was based on the development of targeted therapies and immunotherapies. Their advantages include their potential ability to treat almost all tumours, regardless of their locations, without performing complex surgeries. However, several limitations have been reported, including their side effects, the appearance of primary or secondary resistances, their price and the lack of consensus on treatment regimen and exact duration. The aim of this article was to review the evolution of the management of locally advanced periocular malignant tumours over the last three decades and highlight the new paradigm shift towards the use of 'eye-sparing' strategies." 15497;"Efficacy of haematopoietic stem cell boost as a rescue for poor graft function after haematopoietic stem cell transplantation: A multicentre retrospective study on behalf of the Francophone Society for Bone Marrow Transplantation and Cell Therapy (SFGM-TC).";"M. Loschi";"Equipe 02, Team 02";36974355;"British journal of haematology";"Gaffet M, Wiedemann A, Dalle JH, Bilger K, Forcade E, Robin M, Cornillon J, Labussière-Wallet H, Ceballos P, Bulabois CE, Loschi M, Orvain C, Rubio MT, Neven B, Pagliuca S, Pochon C";;"Mar 2023";1679961600;;"Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two-year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines." 15495;"Bacillus Calmette-Guerin (BCG)-induced systemic infection and granulomatous lesions of the glans penis following intravesical BCG-therapy.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";36974571;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Sanchez A, Demonchy E, Buscot M, Cardot-Leccia N, Lagha K, Montaudie H, Passeron T";;"Mar 2023";1679961600;; 15493;"Consensus on the safety and risks of laser and intense pulse light (IPL) treatments in vitiligo patients, an e-Delphi study.";"T. Passeron";"Equipe 12, Team 12";36967022;"Journal of the American Academy of Dermatology";"Post NF, Rodrigues MA, Liong-A-Jin C, Lommerts A, Abdallah M, Bae JM, Bekkenk MW, Silva de Castro CC, Eleftheriadou V, Esmat S, Ezzedine K, van Geel N, Hamzavi I, Leone G, Pandya AG, Passeron T, Raboobee N, Seneschal J, Th'ng S, Wolkerstorfer A";;"Mar 2023";1679788800;; 15491;"Can the Middle East-North Africa region mitigate the rise of its food import dependency under climate change?";"P. Marty";"Equipe 06, Team 06";36968261;"Regional environmental change";"Le Mouël C, Forslund A, Marty P, Manceron S, Marajo-Petitzon E, Caillaud MA, Dumas P, Schmitt B";;"Mar 2023";1679875200;;"The dependence on imports of the Middle East and North Africa (MENA) region for its food needs has increased steadily since the early 1960s, from 10% to about 40%. This import dependence could continue to rise in coming decades due to the projected MENA population growth and the expected negative impacts of climate change on the region's natural resources and agricultural performances. To what extent the food import dependency of the MENA region will continue to increase up to 2050 and how the region could mitigate its rising reliance on food imports is both a key question for the region itself and a crucial geopolitical issue for the world as a whole. In this paper, we use a biomass balance model to assess the level of the food import dependency of the MENA region in 2050 resulting from six scenarios. We show that under current trends and severe impacts of climate change the food import dependency of the MENA would continue to rise and reach 50% in 2050. Maghreb would be particularly affected becoming dependent on imports for almost 70% of its food needs. Adopting a Mediterranean diet, reaching faster productivity growth in agriculture or reducing waste and loss along the food chain would contribute to decelerate the rise of the MENA's food import dependency. However, only the combination of these three options could significantly offset the increased import dependency in the most affected sub-regions: Maghreb, the Middle and the Near East. In all scenarios, Turkey strengthens its position as a net exporter of agricultural products." 15489;"cLFM-Qol: a specific quality of life measurement tool for children from 11 to 15 years with low-flow malformations.";"C. Chiaverini";"Equipe 12, Team 12";36972023;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Godeau M, Shourick J, Dreyfus I, Casassa E, Bergeron A, Severino-Freire M, Granier Tournier C, Malloizel-Delaunay J, Boccara O, Aubert H, Maruani A, Chiaverini C, Labrèze C, Mazereeuw-Hautier J";;"Mar 2023";1679875200;;"Low-flow malformations (LFMs) are rare diseases with a significant impact on health-related quality of life (HRQoL), especially in children. No disease-specific questionnaire is available for children with LFMs." 15487;"PK-PD Evaluation of Inhaled Microparticles loaded with Ciprofloxacin-Copper complex in a Rat Model of Chronic Lung Infection.";"B. Lamy";"Equipe 06, Team 06";36970713;"International journal of pharmaceutics: X";"Tewes F, Lamy B, Laroche J, Lamarche I, Marchand S";;"Mar 2023";1679875200;;"The potential gain in efficacy of pulmonary administration over IV administration of some antibiotics such as ciprofloxacin (CIP) may be limited by the short residence time of the drug at the site of infection after nebulization. Complexation of CIP with copper reduced its apparent permeability through a Calu-3 cell monolayer and greatly increased its pulmonary residence time after aerosolisation in healthy rats. Chronic lung infections in cystic fibrosis patients result in airway and alveolar inflammation that may increase the permeability of inhaled antibiotics and alter their fate in the lung after inhalation compared to what was seen in healthy conditions. The objective of this study was to compare the pharmacokinetics and efficacy of CIP-Cu complex-loaded microparticles administered by pulmonary route with a CIP solution administered by IV to model rats with chronic lung infection. After a single pulmonary administration of microparticles loaded with CIP-Cu complex, pulmonary exposure to CIP was increased 2077-fold compared to IV administration of CIP solution. This single lung administration significantly reduced the lung burden of expressed as CFU/lung measured 24 h after administration by 10-fold while IV administration of the same dose of CIP was ineffective compared to the untreated control. This better efficacy of inhaled microparticles loaded with CIP-Cu complex compared with CIP solution can be attributed to the higher pulmonary exposure to CIP obtained with inhaled CIP-Cu complex-loaded microparticles than that obtained with IV solution." 15479;"Expert opinion about laser and intense pulsed light (IPL)-induced leukoderma or vitiligo: a cross-sectional survey study.";"T. Passeron";"Equipe 12, Team 12";36964767;"Archives of dermatological research";"Post NF, Van Broekhoven NX, Lommerts A, Bae JM, Bekkenk MW, de Castro CCS, Eleftheriadou V, Esmat S, Ezzedine K, van Geel N, Hamzavi I, Leone G, Pandya AG, Passeron T, Rodrigues MA, Seneschal J, Th'ng S, Wolkerstorfer A";;"Mar 2023";1679702400;;"Vitiligo patients may desire laser hair removal, skin rejuvenation, vascular treatments, and other laser or intense pulsed light (IPL) assisted treatments. However, there is a risk of inducing new depigmented patches (Koebner phenomenon). In absence of guidelines on the safe use of laser or IPL in vitiligo patients, dermatologists tend to be reluctant to administer these treatments. The aim of this survey study was to provide an estimation of the occurrence and related risk factors of laser/IPL-induced leukoderma or vitiligo. A cross-sectional survey study was performed among 15 vitiligo experts from 11 countries, with 14 questions about affected patients, involved laser/IPL treatments and the physicians' approach. In a total of 11,300 vitiligo patients, laser/IPL-induced leukoderma or vitiligo was reported in 30 patients (0.27%). Of these, 12 (40%) patients had a medical history of vitiligo and seven (58%) of these patients had stable (> 12 months) vitiligo before the treatment. Most frequently reported were hair removal procedures and localization of the face and legs. Side effects like blistering, crusting, and erosions occurred in 56.7% of the cases. These vitiligo experts based their advice on the risk of the laser treatment on stability of the vitiligo (43%) and activity signs (50%), and 50% discuss the risks before starting a laser treatment. Relevant activity signs are the Koebner phenomenon (57.1%), confetti-like lesions (57.1%) and hypochromic borders (50%). Laser-induced leukoderma or vitiligo is an uncommon phenomenon. Remarkably, a minority had a medical history of vitiligo of which 58% were stable. Consequently, most cases could not have been prevented by not treating vitiligo patients. However, a majority had laser/IPL-induced skin damage. Therefore, caution is advised with aggressive settings and test-spots prior to the treatment are recommended. This study showed significant variation in the current recommendations and approach of vitiligo experts regarding laser/IPL-induced leukoderma or vitiligo." 15477;"Immune response to BNT162b2 SARS-CoV-2 vaccine in patients living with HIV: The COVIH-DAPT study.";"M. Ticchioni";;36949938;"Frontiers in immunology";"Manni S, Ruetsch C, Fabre R, Ticchioni M, Graça D, Pradier C, Seitz-Polski B, Lotte L, Brglez V, Vassallo M";;"Mar 2023";1679529600;;"Data on immune response to SARS-CoV-2 vaccine in patients living with HIV (PLWH) over a period longer than 3 months are currently limited. We measured the immune response after BNT162b2 vaccination against SARS-CoV-2 in this population." 15475;"Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia: The ANTICOVID Randomized Clinical Trial.";"N. Martis";"Equipe 10, Team 10";36946232;"JAMA internal medicine";"Labbé V, Contou D, Heming N, Megarbane B, Razazi K, Boissier F, Ait-Oufella H, Turpin M, Carreira S, Robert A, Monchi M, Souweine B, Preau S, Doyen D, Vivier E, Zucman N, Dres M, Fejjal M, Noel-Savina E, Bachir M, Jaffal K, Timsit JF, Picos SA, Mariotte E, Martis N, Juguet W, Melica G, Rondeau P, Audureau E, Mekontso Dessap A, ";;"Mar 2023";1679443200;;"Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative." 15473;"Controlling nutritional status score predicts 2-year outcomes in elderly patients admitted for acute heart failure.";"E. Ferrari";"Equipe 09, Team 09";36941521;"Internal and emergency medicine";"Agnoletti D, Arcaro G, Scaturro G, Turcato E, Grison E, Ferrari E, Bonapace S, Targher G, Valbusa F";;"Mar 2023";1679356800;;"Heart failure (HF) is a major cause of death among the elderly. Its prevalence increases dramatically with age. The prevalence of malnourished subjects is high in hospitalized elderly patients. We aimed to investigate the prognostic role of malnutrition, assessed by controlling nutritional status (CONUT) score, on adverse clinical outcomes in the elderly admitted for acute HF." 15464;"Comment on ""Clinicopathological and molecular analysis of cutaneous leiomyosarcoma: A retrospective multicenter study of 79 cases"".";"H. Montaudie";"Equipe 12, Team 12";36935019;"Journal of the American Academy of Dermatology";"Dadone-Montaudié B, Montaudié H";;"Mar 2023";1679184000;; 15457;"Editorial: Non-genetic adaptive drug resistance in cancer.";"M. Cerezo";"Equipe 12, Team 12";36467421;"Frontiers in cell and developmental biology";"Cerezo M, Sun X, Shen S";;"Dec 2022";1670198400;; 15455;"Spatial patterns of the cap-binding complex eIF4F in human melanoma cells.";"M. Cerezo";"Equipe 12, Team 12";36789267;"Computational and structural biotechnology journal";"Tang X, Pu Y, Peng H, Li K, Faouzi S, Lu T, Pu D, Cerezo M, Xu J, Li L, Robert C, Shen S";;"Feb 2023";1676419200;;"As a central node of protein synthesis, the cap-binding complex, eukaryotic translation initiation factor 4 F (eIF4F), is involved in cell homeostasis, development and tumorigenesis. A large body of literature exists on the regulation and function of eIF4F in cancer cells, however the intracellular localization patterns of this complex are largely unknown. Since different subsets of mRNAs are translated in distinct subcellular compartments, understanding the distribution of translation initiation factors in the cell is of major interest. Here, we developed an detection method for eIF4F at the single cell level. By using an image-based spot feature analysis pipeline as well as supervised machine learning, we identify five distinct spatial patterns of the eIF4F translation initiation complex in human melanoma cells. The quantity of eIF4F complex per cell correlated with the global mRNA translation activity, and its variation is dynamically regulated by cell state or extracellular stimuli. In contrast, the spatial patterns of eIF4F complexes at the single cell level could distinguish melanoma cells harboring different oncogenic driver mutations. This suggests that different tumorigenic contexts differentially regulate the subcellular localization of mRNA translation, with specific localization of eIF4F potentially associated with melanoma cell chemoresistance." 15453;"Novel Therapeutic Targets in Melanoma.";"M. Cerezo, S. Rocchi";"Equipe 12, Team 12";36765705;Cancers;"Cerezo M, Rocchi S";;"Feb 2023";1676073600;;"Melanoma is the most aggressive skin cancer type and ranks amongst the deadliest cancers due to its ability to develop resistance to current therapies [...]." 15450;"Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation.";"P. Dominguez";"Team 14";20193014;"Immunological reviews";"Domínguez PM, Ardavín C";;"Mar 2010";1267574400;;"Although monocytes were originally described as precursors to all the different subpopulations of macrophages found in the steady state and formed under inflammatory and infectious conditions, recent data have demonstrated conclusively that monocytes can also differentiate into dendritic cells (DCs). Monocytes are the precursors to different subsets of DCs, such as Langerhans cells and DCs found in the lamina propria of the gastrointestinal, respiratory, and urogenital tracts. In addition, monocyte-derived DCs (moDCs), newly formed during inflammatory reactions, appear to fulfill an essential role in defense mechanisms against pathogens by participating in the induction of both adaptive and innate immune responses. In this regard, moDCs have the capacity to activate antigen-specific CD4(+) T-cell responses and to cross-prime CD8(+) T cells, during viral, bacterial, and parasitic infections. In addition, monocytes have been recently described as the precursors to a subset of DCs specialized in innate immunity against pathogens, named TipDCs [for TNF-alpha (tumor necrosis factor-alpha)-iNOS (inducible nitric oxide synthase)-producing DCs] that display a remarkable microbicidal activity and also provide iNOS-dependent help for antibody production by B cells. Importantly, in contrast to DCs developing in the steady state, moDCs formed during inflammatory and infectious processes are subjected to diverse soluble mediators that determine the multiple functional specificities displayed by moDCs, as a result of the remarkable developmental plasticity of monocytes. In this review, we discuss recent findings dealing with the differentiation and functional relevance of moDCs that have widened the frontiers of DC immunobiology in relation to innate and adaptive immunity and the etiology of chronic inflammatory diseases." 15448;"Statins inhibit iNOS-mediated microbicidal potential of activated monocyte-derived dendritic cells by an IFN-β-dependent mechanism.";"P. Dominguez";"Team 14";21874649;"European journal of immunology";"Domínguez PM, López-Bravo M, Kalinke U, Ardavín C";;"Aug 2011";1314662400;;"Statins are prescribed to 25 million people worldwide for treating hypercholesterolemia and reducing the risk of cardiovascular diseases. However, the side effects of statins on immunity, and particularly on DC immunobiology, have not been analyzed in-depth. Here, we have investigated the impact of lovastatin treatment during monocyte differentiation into DCs on the responsiveness of the resulting monocyte-derived DCs (moDCs) to TLR-mediated activation. Lovastatin positively regulated TLR4 signaling in LPS-stimulated moDCs, leading to strong activation of p38 MAP-kinase paralleled by increased proinflammatory cytokine and IFN-β production. In contrast, lovastatin promoted negative regulation of IFN-β-mediated autocrine signaling through the IFN-αβ receptor, paralleled by low expression of the transcription factor IRF-1, leading to the inhibition of the enzymes iNOS and HO-1. Defective activation of iNOS/HO-1 resulted in limited cytoprotective capacity against ROS and reduced microbicidal potential. These data were validated using an in vivo model of Listeria monocytogenes infection, which revealed that iNOS activation by splenic inflammatory moDCs, specialized in NO and TNF-α production, was strongly reduced in lovastatin-treated, Listeria-infected mice. Statin treatment could have severe implications in immunity against pathogens due to defective iNOS/HO-1 metabolism activation in inflammatory moDCs that might lead to immune failure." 15446;"IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation.";"P. Dominguez";"Team 14";24139608;"The Journal of allergy and clinical immunology";"López-Bravo M, Minguito de la Escalera M, Domínguez PM, González-Cintado L, del Fresno C, Martín P, Martínez del Hoyo G, Ardavín C";;"Oct 2013";1382400000;;"Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce T(H)1/T(H)17 responses, the functional specialization enabling DCs to polarize T(H)2 responses remains undefined. Because IL-4 is essential during T(H)2 responses not only by acting on CD4(+) T cells through the activation of GATA-3 but also by regulating IgE class-switching, epithelial cell permeability, and muscle contractility, we hypothesized that IL-4 could also have a role in the conditioning of DCs during T(H)2 responses." 15444;"Epigenetic function of activation-induced cytidine deaminase and its link to lymphomagenesis.";"P. Dominguez";"Team 14";25566255;"Frontiers in immunology";"Dominguez PM, Shaknovich R";;"Jan 2015";1420675200;;"Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination of immunoglobulin (Ig) genes during B cell maturation and immune response. Expression of AID is tightly regulated due to its mutagenic and recombinogenic potential, which is known to target not only Ig genes, but also non-Ig genes, contributing to lymphomagenesis. In recent years, a new epigenetic function of AID and its link to DNA demethylation came to light in several developmental systems. In this review, we summarize existing evidence linking deamination of unmodified and modified cytidine by AID to base-excision repair and mismatch repair machinery resulting in passive or active removal of DNA methylation mark, with the focus on B cell biology. We also discuss potential contribution of AID-dependent DNA hypomethylation to lymphomagenesis." 15442;"DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID.";"P. Dominguez";"Team 14";26365193;"Cell reports";"Dominguez PM, Teater M, Chambwe N, Kormaksson M, Redmond D, Ishii J, Vuong B, Chaudhuri J, Melnick A, Vasanthakumar A, Godley LA, Papavasiliou FN, Elemento O, Shaknovich R";;"Sep 2015";1442275200;;"Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient (Aicda(-/-)) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda(-/-) animals. Differentially methylated cytosines (DMCs) between GCBs and naive B cells (NBs) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID, and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells." 15440;"The many layers of epigenetic dysfunction in B-cell lymphomas.";"P. Dominguez";"Team 14";27055146;"Current opinion in hematology";"Jiang Y, Dominguez PM, Melnick AM";;"Apr 2016";1460073600;;"Perturbation of the epigenome is emerging as a central driving force in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma. The purpose of this review is to explain how alteration of different layers of the epigenome contributes to the biology and clinical features of these tumors." 15438;"The new frontier of epigenetic heterogeneity in B-cell neoplasms.";"P. Dominguez";"Team 14";28375986;"Current opinion in hematology";"Dominguez PM, Teater M, Shaknovich R";;"Apr 2017";1491350400;;"There is mounting evidence that heterogeneity of the epigenome is a feature of many cancers, including B-cell lymphomas, and presents important clinical implications. The purpose of this review is to explain the biological and clinical relevance of this epigenetic phenomenon in B-cell neoplasms." 15436;"AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis.";"P. Dominguez";"Team 14";29335468;"Nature communications";"Teater M, Dominguez PM, Redmond D, Chen Z, Ennishi D, Scott DW, Cimmino L, Ghione P, Chaudhuri J, Gascoyne RD, Aifantis I, Inghirami G, Elemento O, Melnick A, Shaknovich R";;"Jan 2018";1516147200;;"Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases." 15434;"Extracellular vesicles in DLBCL provide abundant clues to aberrant transcriptional programming and genomic alterations.";"P. Dominguez";"Team 14";29967128;Blood;"Rutherford SC, Fachel AA, Li S, Sawh S, Muley A, Ishii J, Saxena A, Dominguez PM, Caldas Lopes E, Agirre X, Chambwe N, Correa F, Jiang Y, Richards KL, Betel D, Shaknovich R";;"Jul 2018";1530662400;;"The biological role of extracellular vesicles (EVs) in diffuse large B-cell lymphoma (DLBCL) initiation and progression remains largely unknown. We characterized EVs secreted by 5 DLBCL cell lines, a primary DLBCL tumor, and a normal control B-cell sample, optimized their purification, and analyzed their content. We found that DLBCLs secreted large quantities of CD63, Alix, TSG101, and CD81 EVs, which can be extracted using an ultracentrifugation-based method and traced by their cell of origin surface markers. We also showed that tumor-derived EVs can be exchanged between lymphoma cells, normal tonsillar cells, and HK stromal cells. We then examined the content of EVs, focusing on isolation of high-quality total RNA. We sequenced the total RNA and analyzed the nature of RNA species, including coding and noncoding RNAs. We compared whole-cell and EV-derived RNA composition in benign and malignant B cells and discovered that transcripts from EVs were involved in many critical cellular functions. Finally, we performed mutational analysis and found that mutations detected in EVs exquisitely represented mutations in the cell of origin. These results enhance our understanding and enable future studies of the role that EVs may play in the pathogenesis of DLBCL, particularly with regards to the exchange of genomic information. Current findings open a new strategy for liquid biopsy approaches in disease monitoring." 15432;"TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis.";"P. Dominguez";"Team 14";30274972;"Cancer discovery";"Dominguez PM, Ghamlouch H, Rosikiewicz W, Kumar P, Béguelin W, Fontán L, Rivas MA, Pawlikowska P, Armand M, Mouly E, Torres-Martin M, Doane AS, Calvo Fernandez MT, Durant M, Della-Valle V, Teater M, Cimmino L, Droin N, Tadros S, Motanagh S, Shih AH, Rubin MA, Tam W, Aifantis I, Levine RL, Elemento O, Inghirami G, Green MR, Figueroa ME, Bernard OA, Aoufouchi S, Li S, Shaknovich R, Melnick AM";;"Oct 2018";1538524800;;"somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in -mutant DLBCLs. Accordingly, mutation in patients yields a -mutant gene-expression signature, and mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies somatic mutation. These results advocate for sequencing in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors..." 15430;"TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis.";"P. Dominguez";"Team 14";32596441;"Science advances";"Rosikiewicz W, Chen X, Dominguez PM, Ghamlouch H, Aoufouchi S, Bernard OA, Melnick A, Li S";;"Jun 2020";1593475200;;"The TET2 DNA hydroxymethyltransferase is frequently disrupted by somatic mutations in diffuse large B cell lymphomas (DLBCLs), a tumor that originates from germinal center (GC) B cells. Here, we show that TET2 deficiency leads to DNA hypermethylation of regulatory elements in GC B cells, associated with silencing of the respective genes. This hypermethylation affects the binding of transcription factors including those involved in exit from the GC reaction and involves pathways such as B cell receptor, antigen presentation, CD40, and others. Normal GC B cells manifest a typical hypomethylation signature, which is caused by AID, the enzyme that mediates somatic hypermutation. However, AID-induced demethylation is markedly impaired in TET2-deficient GC B cells, suggesting that AID epigenetic effects are partially dependent on TET2. Last, we find that TET2 mutant DLBCLs also manifest the aberrant TET2-deficient GC DNA methylation signature, suggesting that this epigenetic pattern is maintained during and contributes to lymphomagenesis." 15428;"CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory.";"P. Dominguez";"Team 14";33990344;"Cancer discovery";"Lelliott EJ, Kong IY, Zethoven M, Ramsbottom KM, Martelotto LG, Meyran D, Zhu JJ, Costacurta M, Kirby L, Sandow JJ, Lim L, Dominguez PM, Todorovski I, Haynes NM, Beavis PA, Neeson PJ, Hawkins ED, McArthur GA, Parish IA, Johnstone RW, Oliaro J, Sheppard KE, Kearney CJ, Vervoort SJ";;"May 2021";1621036800;;"Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity. SIGNIFICANCE: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer.." 15426;"Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML.";"P. Dominguez";"Team 14";35311997;"Cancer discovery";"Salmon JM, Todorovski I, Stanley KL, Bruedigam C, Kearney CJ, Martelotto LG, Rossello F, Semple T, Arnau GM, Zethoven M, Bots M, Bjelosevic S, Cluse LA, Fraser PJ, Litalien V, Vidacs E, McArthur K, Matthews AY, Gressier E, de Weerd NA, Lichte J, Kelly MJ, Hogg SJ, Hertzog PJ, Kats LM, Vervoort SJ, De Carvalho DD, Scheu S, Bedoui S, Kile BT, Lane SW, Perkins AC, Wei AH, Dominguez PM, Johnstone RW";;"Mar 2022";1647820800;;"Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies." 15418;"MPox virus: an unusual aetiology of peritonitis.";"J. Courjon, M. Carles";"Equipe 06, Team 06";36928093;"Sexually transmitted infections";"Courdurié A, Buscot M, Gonfrier G, Courjon J, Oncioiu C, Demonchy E, Carles M";;"Mar 2023";1679011200;;"We describe a rare case of severe disseminated monkeypox (MPox) virus infection complicated by peritonitis in a 44-year-old man living with well-controlled HIV. The patient was successfully treated with tecovirimat without requiring surgery. MPox should be considered in the differential diagnosis of non-bacterial peritonitis in patients at risk of infection." 15416;"Reply to ""Paeonol Suppresses Vasculogenesis Through Regulating Vascular Smooth Muscle Phenotypic Switching"".";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36927136;"Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists";"Lareyre F, Clément M, Cong Duy L, Raffort J";;"Mar 2023";1679011200;; 15414;"[Secondary cancers following allogeneic hematopoietic stem cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].";"M. Loschi";"Equipe 02, Team 02";36922321;"Bulletin du cancer";"Loschi M, Alsuliman T, Cabrera Q, Desbrosses Y, Desmier D, Yakoub Agha I, Guillaume T";;"Mar 2023";1678838400;;"The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held the 13th edition of the Clinical Practices Harmonization Workshops. Our workgroup reviewed the current data on the incidence, screening methods and international guidelines for the prevention of secondary solid cancers following allogeneic hematopoietic stem cell transplantation. The purpose of this workshop was to provide recommendations for the screening and prevention of secondary malignancies to Francophone transplantation centers." 15412;"Liver X Receptor Nuclear Receptors Are Transcriptional Regulators of Dendritic Cell Chemotaxis.";"P. Dominguez";"Team 14";29507185;"Molecular and cellular biology";"Beceiro S, Pap A, Czimmerer Z, Sallam T, Guillén JA, Gallardo G, Hong C, A-Gonzalez N, Tabraue C, Diaz M, Lopez F, Matalonga J, Valledor AF, Dominguez P, Ardavin C, Delgado-Martin C, Partida-Sanchez S, Rodriguez-Fernandez JL, Nagy L, Tontonoz P, Castrillo A";;"Mar 2018";1520380800;;"The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DCs), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migration and Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished the LXR-dependent induction of DC chemotaxis. Using the low-density lipoprotein receptor-deficient (LDLR) LDLR mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for the efficient emigration of DCs in response to chemotactic signals during inflammation." 15410;"Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.";"P. Dominguez";"Team 14";35514210;"EMBO molecular medicine";"So J, Lewis AC, Smith LK, Stanley K, Franich R, Yoannidis D, Pijpers L, Dominguez P, Hogg SJ, Vervoort SJ, Brown FC, Johnstone RW, McDonald G, Ulanet DB, Murtie J, Gruber E, Kats LM";;"May 2022";1651795200;;"The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML." 15377;"LONG-TERM OUTCOMES AND RISK FACTORS ANALYSIS FOR PATIENTS UNDERGOING THORACIC ENDOVASCULAR AORTA REPAIR (TEVAR), ACCORDING TO THE AORTIC PATHOLOGIES.";"E. Ferrari";"Equipe 09, Team 09";36907507;"Annals of vascular surgery";"Gallo M, van den Berg JC, Torre T, Riggi M, Demertzis S, Ferrari E";;"Mar 2023";1678579200;;"Thoracic endovascular aortic repair (TEVAR) has become a standard treatment for acute and chronic thoracic aorta diseases. We analysed long-term outcomes and risk factors of TEVAR procedures according to the aortic pathology." 15375;"Clinical outcomes and quality of life after contemporary isolated coronary bypass grafting: a prospective cohort study.";"E. Ferrari";"Equipe 09, Team 09";36912566;"International journal of surgery (London, England)";"Sandner S, Misfeld M, Caliskan E, Böning A, Aramendi J, Salzberg SP, Choi YH, Perrault LP, Tekin I, Cuerpo GP, Lopez-Menendez J, Weltert LP, Böhm J, Krane M, González-Santos JM, Tellez JC, Holubec T, Ferrari E, Doros G, Vitarello CJ, Emmert MY, ";;"Mar 2023";1678665600;;"The objective of the European Multicenter Registry to Assess Outcomes in coronary artery bypass grafting (CABG) patients (DuraGraft Registry) was to determine clinical outcomes and quality of life (QoL) after contemporary CABG that included isolated CABG and combined CABG/valve procedures, using an endothelial damage inhibitor (DuraGraft) intraoperatively for conduit preservation. Here, we report outcomes in the patient cohort undergoing isolated CABG." 15373;"Sexual health of adolescents and place of the dermatologist-venereologist: practice survey of 180 practitioners.";"C. Chiaverini";"Equipe 12, Team 12";36913264;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Sanchez A, Chiaverini C, Reverte M, Hubiche T, ";;"Mar 2023";1678665600;; 15371;"Critical Overview on Endocrine Disruptors in Diabetes Mellitus.";"F. BOST";"Equipe 05, Team 05";36901966;"International journal of molecular sciences";"Hinault C, Caroli-Bosc P, Bost F, Chevalier N";;"Mar 2023";1678492800;;"Diabetes mellitus is a major public health problem in all countries due to its high human and economic burden. Major metabolic alterations are associated with the chronic hyperglycemia that characterizes diabetes and causes devastating complications, including retinopathy, kidney failure, coronary disease and increased cardiovascular mortality. The most common form is type 2 diabetes (T2D) accounting for 90 to 95% of the cases. These chronic metabolic disorders are heterogeneous to which genetic factors contribute, but so do prenatal and postnatal life environmental factors including a sedentary lifestyle, overweight, and obesity. However, these classical risk factors alone cannot explain the rapid evolution of the prevalence of T2D and the high prevalence of type 1 diabetes in particular areas. Among environmental factors, we are in fact exposed to a growing amount of chemical molecules produced by our industries or by our way of life. In this narrative review, we aim to give a critical overview of the role of these pollutants that can interfere with our endocrine system, the so-called endocrine-disrupting chemicals (EDCs), in the pathophysiology of diabetes and metabolic disorders." 15369;"Prolonged response after TPO-RA discontinuation in primary ITP: results of a prospective multicenter study.";"N. Martis";"Equipe 10, Team 10";36893453;Blood;"Guillet S, Crickx E, Azzaoui I, Chappert P, Boutin E, Viallard JF, Riviere E, Gobert D, Galicier L, Malphettes M, Cheze S, Lefrere F, Audia S, Bonnotte B, Lambotte O, Noel N, Fain O, Moulis G, Hamidou M, Gerfaud-Valentin M, Marolleau JP, Terriou L, Martis N, Morin AS, Perlat A, Le Gallou T, Roy-Peaud F, Robbins A, Lega JC, Puyade M, Comont T, Limal N, Languille L, Zarour A, Luka M, Ménager MM, Belmondo T, Hue S, Canoui-Poitrine F, Michel M, Godeau B, Mahevas M";;"Mar 2023";1678320000;;"Sustained response off-treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in ITP. This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response on TPO-RAs. The primary endpoint was the proportion of patients achieving SROT (platelet count > 30x109/L and no bleeding) at W24 with no other ITP-specific medications. Secondary endpoints included the proportion of sustained complete response off-treatment (SCROT, platelet count > 100x109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with median (IQR) age 58.5 years (41-73.5); 30/48 (63%) had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27/48 (56.2%, 95% CI, 41.2-70.5) achieved SROT; 15/48 (31.3%; 95% CI, 18.9-44.5) achieved SCROT at W24, and 25/48 (52.1%; 95% CI, 37.2-66.7) achieved respectively SROT and 14/48 (29.2%; 95% CI, 17.2-42.3) SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients re-challenged with TPO-RA, 11/12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA-seq revealed enrichment of a ""TNFα signaling via NF-κB"" signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based of progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. Clinical trial number: NCT03119974." 15367;"Efficacy and Safety of Risankizumab for the Treatment of Hidradenitis Suppurativa: A Phase 2, Randomized, Placebo-Controlled Trial.";"T. Passeron";"Equipe 12, Team 12";36892753;"Dermatology and therapy";"Kimball AB, Prens EP, Passeron T, Maverakis E, Turchin I, Beeck S, Drogaris L, Geng Z, Zhan T, Messina I, Bechara FG";;"Mar 2023";1678320000;;"Hidradenitis suppurativa (HS) is a chronic, immune-mediated skin condition characterized by inflammatory lesions that can cause pain, impaired physical activity, and reduced quality of life. This study evaluated the efficacy and safety of risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit, for the treatment of HS." 15365;"Versatile modulators for laser-based FEL seeding at SwissFEL.";"E. Ferrari";"Equipe 09, Team 09";36891841;"Journal of synchrotron radiation";"Calvi M, Liang X, Ferrari E, Alarcon A, Prat E, Reiche S, Schmidt T, Voulot D, Zhang K, Ganter R";;"Mar 2023";1678320000;;"The Paul Scherrer Institute is implementing laser-based seeding in the soft X-ray beamline (Athos) of its free-electron laser, SwissFEL, to enhance the temporal and spectral properties of the delivered photon pulses. This technique requires, among other components, two identical modulators for coupling the electron beam with an external laser with a wavelength range between 260 and 1600 nm. The design, magnetic measurements results, alignment, operation and also details of the novel and exotic magnetic configuration of the prototype are described." 15355;"Reduced-toxicity myeloablative conditioning regimen using fludarabine and full doses of intravenous busulfan in pediatric patients not eligible for standard myeloablative conditioning regimens: Results of a multicenter prospective phase 2 trial.";"G. MICHEL, PS. ROHRLICH";"Equipe 06, Team 06, Equipe 04, Team 04";36028757;"Bone marrow transplantation";"Rialland F, Grain A, Labopin M, Michel G, Gandemer V, Paillard C, Pochon C, Clement L, Brissot E, Jubert C, Sirvent A, Rohrlich PS, Plantaz D, Dalle JH, Mohty M";;"Aug 2022";1661472000;;"Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181)." 15353;"Enforced gut homing of murine regulatory T cells reduces early graft-versus-host disease severity.";"M. Loschi";"Equipe 02, Team 02";36878433;"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons";"Larson JH, Jin S, Loschi M, Wagers SB, Thangavelu G, Zaiken MC, McDonald-Hyman C, Saha A, Aguilar EG, Koehn B, Osborn MJ, Panoskaltsis-Mortari A, Macdonald KPA, Hill GR, Murphy WJ, Serody JS, Maillard I, Kean LS, Kim SV, Littman DR, Blazar BR";;"Mar 2023";1678060800;;"Damage to the gastrointestinal tract following allogeneic hematopoietic stem cell transplantation is a significant contributor to the severity and perpetuation of graft-versus-host disease. In preclinical models and clinical trials, we showed that infusing high numbers of regulatory T-cells reduces graft-versus-host disease incidence. Despite no change in in vitro suppressive function, transfer of ex vivo expanded regulatory T-cells transduced to overexpress G-protein coupled receptor 15 or C-C Motif Chemokine Receptor 9, specific homing receptors for colon or small intestine, respectively, lessened graft-versus-host disease severity in mice. Increased regulatory T-cell frequency and retention within the gastrointestinal tissues of mice that received gut homing T-cells correlated with lower inflammation and gut damage early post-transplant, decreased graft-versus-host disease severity and prolonged survival compared to those receiving control transduced regulatory T-cells. These data provide evidence that enforced targeting of ex vivo expanded regulatory T-cells to the gastrointestinal tract diminishes gut injury and is associated with decreased graft-versus-host disease severity." 15351;"Re. 'Artificial Intelligence Outperforms Kaplan-Meier Analyses Estimating Survival After Elective Treatment of Abdominal Aortic Aneurysms'.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36870525;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Raffort J";;"Mar 2023";1677888000;; 15349;"Outdoor clinical testing with reference sunscreens to determine differences in skin response between populations of different ethnicity: a combined data analysis from 128 subjects.";"T. Passeron";"Equipe 12, Team 12";36867064;"Photodermatology, photoimmunology & photomedicine";"Granger C, Passeron T, Trullas C, Hosenally M, Sokeechand BN, Krutmann J, Lim HW";;"Mar 2023";1677801600;;"Two previously published clinical studies by our group assessed erythema and pigmentation responses in outdoor conditions with three reference sunscreens, comparing their effectiveness under the full spectrum of natural sunlight. These studies followed an almost identical protocol but were conducted in two different locations and in two ethnic groups: broadly, Chinese (Singapore) and White European (Mauritius). We analysed the data from these two study populations to compare differences in skin response according to ethnicity." 15345;"Impact of Sex on the Outcomes of Patients Undergoing Repair for Lower Extremity Peripheral Arterial Disease in France.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36858253;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Raffort J, Lareyre F, Pradier C, Fabre R, Behrendt CA, Bailly L";;"Mar 2023";1677628800;; 15336;"Epidemiology and characteristics of acral lentiginous melanoma compared to lentigo melanoma in France: a multicentric retrospective study from the French cohort RIC-Mel database.";"H. Montaudie";"Equipe 12, Team 12";36856380;"European journal of dermatology : EJD";"L'Orphelin JM, Le Naour S, Dalle S, Varey E, Dupuy A, Montaudie H, Lesage C, Mortier L, Leccia MT, Celerier P, Skowron F, Meyer N, Maubec E, Amini-Adle M, Dalac-Rat S, Dutriaux C, Khammari A, Dompmartin A, Dreno B, ";;"Mar 2023";1677628800;;"Skin phototype, latitude and sun exposure are classic risk factors for melanomas but are not relevant to acrolentiginous melanomas (ALM). ALM is not related to chronic sun exposure because the thick stratum corneum acts as a barrier to penetration of UV rays, whereas LMM occurs in skin with high photoaging due to chronic sun exposure." 15331;"Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.";"M. Loschi";"Equipe 02, Team 02";36849078;"Transplantation and cellular therapy";"Kaphan E, Bettega F, Forcade E, Labussière-Wallet H, Fegueux N, Robin M, De Latour RP, Huynh A, Lapierre L, Berceanu A, Marcais A, Debureaux PE, Vanlangendonck N, Bulabois CE, Magro L, Daniel A, Galtier J, Lioure B, Chevallier P, Antier C, Loschi M, Guillerm G, Mear JB, Chantepie S, Cornillon J, Rey G, Poire X, Bazarbachi A, Rubio MT, Contentin N, Orvain C, Dulery R, Bay JO, Croizier C, Beguin Y, Charbonnier A, Skrzypczak C, Desmier D, Villate A, Carré M, Thiebaut-Bertrand A";;"Feb 2023";1677456000;;"Late relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010 and December 31, 2016, considering data from the French national retrospective register ProMISe (SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy)). We included patients presenting LR, defined as a relapse occurring at least two years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, 7,582 AHSCT were performed in 29 centers and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered as LR, representing an incidence of 4.2% from the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia, and 40 (13.8%) with acute lymphoid leukemia. Median delay from AHSCT to LR was 38.2 months (29.2-49.7) and 27.2% of patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (5.6-46.4). The most common salvage therapy was induction regimen (55.5%), with complete remission being obtained for 50.7%. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (7.1-49.1). Non-relapse mortality after second AHSCT was 18.2%. We identified in the Cox model some of the associated factors with delay of LR: the disease status not in first complete remission at first HSCT (odds ratio (OR) 1.31, 1.04-1.64, p=0.02) and the use of post-transplant cyclophosphamide (OR 2.23, 1.21-4.14, p=0.01). Chronic GVHD appeared to be a protective factor (OR 0.64, 0.42-0.96, p=0.04). Prognosis of LR is better than early relapses, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity." 15329;"Convolutional neural network for automatic detection and characterization of abdominal aortic aneurysm.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36852321;"Journal of vascular surgery cases and innovative techniques";"Lareyre F, Adam C, Carrier M, Raffort J";;"Feb 2023";1677542400;; 15327;"Production of CRISPRi-engineered primary human mammary epithelial cells with baboon envelope pseudotyped lentiviral vectors.";"E. Verhoeyen";"Team 03, Equipe 03";36853718;"STAR protocols";"Pastor S, Wicinski J, Charafe-Jauffret E, Verhoeyen E, Guittard G, Ginestier C";;"Feb 2023";1677542400;;"Primary human mammary epithelial cells (pHMECs) are known to be remarkably difficult to engineer genetically. Here, we present a protocol for efficient transduction of pHMECs using a baboon retroviral envelope glycoprotein for pseudotyping of lentiviral vectors (BaEV-LVs). We describe the preparation of the BaEV-LVs, the isolation of pHMECs from breast samples, and the subsequent transduction of pHMECs. We also detail the use of CRISPRi technology to efficiently silence gene expression in pHMECs, which can then be used for functional assays. For complete details on the use and execution of this protocol, please refer to Richart et al. (2022).." 15325;"Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study.";"R. ANTY";"Equipe 08, Team 08";36848175;"Chinese medical journal";"Zhang H, Rios RS, Boursier J, Anty R, Chan WK, George J, Yilmaz Y, Wong VW, Fan J, Dufour JF, Papatheodoridis G, Chen L, Schattenberg JM, Shi JP, Xu L, Wong GL, Lange NF, Papatheodoridi M, Mi Y, Zhou Y, Byrne CD, Targher G, Feng G, Zheng M";;"Feb 2023";1677456000;;"Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH." 15323;"Ultrasound versus fluoroscopy-guided axillary vein access for cardiac device implantation.";"E. Ferrari";"Equipe 09, Team 09";36842633;"Revista espanola de cardiologia (English ed.)";"Bun SS, Taghji P, Squara F, Massoure PL, Deharo JC, Ferrari E";;"Feb 2023";1677369600;; 15321;"Accurate Detection of SARS-CoV-2 by Next-Generation Sequencing in Low Viral Load Specimens.";"J. Courjon, M. Carles";"Equipe 06, Team 06";36834888;"International journal of molecular sciences";"Ilié M, Benzaquen J, Hofman V, Long-Mira E, Lassalle S, Boutros J, Bontoux C, Lespinet-Fabre V, Bordone O, Tanga V, Allegra M, Salah M, Fayada J, Leroy S, Vassallo M, Touitou I, Courjon J, Contenti J, Carles M, Marquette CH, Hofman P";;"Feb 2023";1677283200;;"As new SARS-CoV-2 variants emerge, there is an urgent need to increase the efficiency and availability of viral genome sequencing, notably to detect the lineage in samples with a low viral load. SARS-CoV-2 genome next-generation sequencing (NGS) was performed retrospectively in a single center on 175 positive samples from individuals. An automated workflow used the Ion AmpliSeq SARS-CoV-2 Insight Research Assay on the Genexus Sequencer. All samples were collected in the metropolitan area of the city of Nice (France) over a period of 32 weeks (from 19 July 2021 to 11 February 2022). In total, 76% of cases were identified with a low viral load (Ct ≥ 32, and ≤200 copies/µL). The NGS analysis was successful in 91% of cases, among which 57% of cases harbored the Delta variant, and 34% the Omicron BA.1.1 variant. Only 9% of cases had unreadable sequences. There was no significant difference in the viral load in patients infected with the Omicron variant compared to the Delta variant (Ct values, = 0.0507; copy number, = 0.252). We show that the NGS analysis of the SARS-CoV-2 genome provides reliable detection of the Delta and Omicron SARS-CoV-2 variants in low viral load samples." 15319;"Role of Selective Digestive Decontamination in the Prevention of Ventilator-Associated Pneumonia in COVID-19 Patients: A Pre-Post Observational Study.";"E. Ferrari";"Equipe 09, Team 09";36835966;"Journal of clinical medicine";"Biagioni E, Ferrari E, Gatto I, Serio L, Farinelli C, Coloretti I, Talamonti M, Tosi M, Meschiari M, Tonelli R, Venturelli C, Mussini C, Clini E, Sarti M, Cossarizza A, Busani S, Girardis M, ";;"Feb 2023";1677283200;;"The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator-associated pneumonia (VAP) in COVID-19 patients without changes in the microbiological pattern of antibiotic resistance. This observational pre-post study included adult patients requiring invasive mechanical ventilation (IMV) for severe respiratory failure related to SARS-CoV-2 admitted in three COVID-19 intensive care units (ICUs) in an Italian hospital from 22 February 2020 to 8 March 2022. Selective digestive decontamination (SDD) was introduced from the end of April 2021 in the structured protocol for VAP prevention. The SDD consisted of a tobramycin sulfate, colistin sulfate, and amphotericin B suspension applied in the patient's oropharynx and the stomach via a nasogastric tube. Three-hundred-and-forty-eight patients were included in the study. In the 86 patients (32.9%) who received SDD, the occurrence of VAP decreased by 7.7% ( = 0.192) compared to the patients who did not receive SDD. The onset time of VAP, the occurrence of multidrug-resistant microorganisms AP, the length of invasive mechanical ventilation, and hospital mortality were similar in the patients who received and who did not receive SDD. The multivariate analysis adjusted for confounders showed that the use of SDD reduces the occurrence of VAP (HR 0.536, CI 0.338-0.851; = 0.017). Our pre-post observational study indicates that the use of SDD in a structured protocol for VAP prevention seems to reduce the occurrence of VAP without changes in the incidence of multidrug-resistant bacteria in COVID-19 patients." 15317;"Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";36835566;"International journal of molecular sciences";"Solier S, Mondini M, Meziani L, Jacquel A, Lacout C, Berghe TV, Julé Y, Martinou JC, Pierron G, Rivière J, Deloger M, Dupuy C, Slama-Schwok A, Droin N, Vandenabeele P, Auberger P, Deutsch E, El-Benna J, Dang PM, Solary E";;"Feb 2023";1677283200;;"Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes. Active caspase-7 cleaves p47 at aspartate 34, which promotes the formation of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex NOX2 and the production of cytosolic superoxide anions. Monocyte response to CSF-1 is altered in patients with a chronic granulomatous disease, which are constitutively defective in NOX2. Both caspase-7 down-regulation and radical oxygen species scavenging decrease the migration of CSF-1-induced macrophages. Inhibition or deletion of caspases prevents the development of lung fibrosis in mice exposed to bleomycin. Altogether, a non-conventional pathway that involves caspases and activates NOX2 is involved in CSF1-driven monocyte differentiation and could be therapeutically targeted to modulate macrophage polarization in damaged tissues." 15315;"Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes.";"P. GUAL, A. TRAN";"Equipe 08, Team 08";36830876;Biomedicines;"Cano A, Vazquez-Chantada M, Conde-Vancells J, Gonzalez-Lahera A, Mosen-Ansorena D, Blanco FJ, Clément K, Aron-Wisnewsky J, Tran A, Gual P, García-Monzón C, Caballería J, Castro A, Martínez-Chantar ML, Mato JM, Zhu H, Finnell RH, Aransay AM";;"Feb 2023";1677283200;;"Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene () was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, transcriptomic, and metabolomic techniques. Genotypes of 3 SNPs in a case-control cohort were initially correlated to clinical and serum MAFLD markers. Subsequently, the expression of 84 key genes in response to the loss of was evaluated with the aid of an RT profiler-array. After shRNA-silencing of in THLE2 cells, folate and lipid levels were measured by ELISA and staining techniques, respectively. In addition, up to 482 amino acids and lipid metabolites were semi-quantified in -knockdown (KD) cells through ultra-high-performance liquid chromatography coupled with mass spectrometry. SNPs, rs1051266 and rs3788200, were significantly associated with the development of fatty liver for the single-marker allelic test. The minor alleles of these SNPs were associated with a 0.6/-1.67-fold decreased risk of developing MAFLD. When was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional provoked significant changes in the regulation of genes associated with lipid droplet accumulation within the cell and the onset of NAFLD. Metabolomic analyses showed a highly altered profile, where most of the species that accumulated in -KD-cells belong to the chemical groups of triacylglycerols, diacylglycerols, polyunsaturated fatty acids, and long chain, highly unsaturated cholesterol esters. In conclusion, the lack of gene expression in hepatocytes affects the regulation of key genes for normal liver function, reduces intracellular folate levels, and impairs lipid metabolism, which entails lipid droplet accumulation in hepatocytes." 15313;"[Medulloblastoma: The latest major advances].";"F. BOST, N. Mazure";"Equipe 05, Team 05";36822958;"Bulletin du cancer";"Contenti J, Bost F, Mazure NM";;"Feb 2023";1677110400;;"Medulloblastoma (MB) is a malignant brain tumor that mainly affects children. It is rarely found in adults. Among the four groups of MB defined today according to molecular characteristics, group 3 is the least favorable with an overall survival rate of 50 %. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not sufficiently adapted to the different characteristics of the four MB groups. However, the use of new cellular and animal models has opened new doors to interesting therapeutic avenues. In this review, we detail recent advances in MB research, with a focus on the genes and pathways that drive tumorigenesis, with particular emphasis on the animal models that have been developed to study tumor biology, as well as advances in new targeted therapies." 15311;"A Global Survey of Hypervirulent Aeromonas hydrophila (vAh) Identified vAh Strains in the Lower Mekong River Basin and Diverse Opportunistic Pathogens from Farmed Fish and Other Environmental Sources.";"B. Lamy";"Equipe 06, Team 06";36815836;"Microbiology spectrum";"Xu T, Rasmussen-Ivey CR, Moen FS, Fernández-Bravo A, Lamy B, Beaz-Hidalgo R, Khan CD, Castro Escarpulli G, Yasin ISM, Figueras MJ, Azzam-Sayuti M, Karim MM, Alam KMM, Le TTT, Thao NHP, Addo S, Duodu S, Ali S, Latif T, Mey S, Somony T, Liles MR";;"Feb 2023";1677110400;;"Hypervirulent Aeromonas hydrophila (vAh) has emerged as the etiologic agent of epidemic outbreaks of motile septicemia (MAS) in high-density aquaculture of farmed carp in China and catfish in the United States, which has caused millions of tons of lost fish. We conducted a global survey to better understand the evolution, geographical distribution, and phylogeny of vAh. isolates were isolated from fish that showed clinical symptoms of MAS, and pure cultures were screened for the ability to utilize -inositol as the sole carbon source. A total of 113 inositol-utilizing bacterial strains were included in this study, including additional strains obtained from previously published culture collections. Based on a phylogeny, this collection included 66 A. hydrophila isolates, 48 of which were vAh. This collection also included five new vAh isolates from diseased Pangas catfish (Pangasius pangasius) and striped catfish (Pangasianodon hypophthalmus) obtained in Cambodia and Vietnam, respectively. Genome sequences were generated from representative vAh and non-vAh isolates to evaluate the potential for lateral genetic transfer of the inositol catabolism pathway. Phylogenetic analyses of each of the nine genes required for -inositol utilization revealed the close affiliation of vAh strains regardless of geographic origin and suggested lateral genetic transfer of this catabolic pathway from an Enterobacter species. Prediction of virulence factors was conducted to determine differences between vAh and non-vAh strains in terms of virulence and secretion systems. Core genome phylogenetic analyses on vAh isolates and spp. disease isolates (55 in total) were conducted to evaluate the evolutionary relationships among vAh and other sp. isolates, which supported the clonal nature of vAh isolates. This global survey of vAh brought together scientists that study fish disease to evaluate the evolution, geographical distribution, phylogeny, and hosts of vAh and other sp. isolates. In addition to vAh isolates from China and the United States, four new vAh isolates were isolated from the lower Mekong River basin in Cambodia and Vietnam, indicating the significant threat of vAh to modern aquaculture and the need for improved biosecurity to prevent vAh spread." 15306;"Fungal Integrated Histomolecular Diagnosis Using Targeted Next-Generation Sequencing on Formalin-Fixed Paraffin-Embedded Tissues.";"C. Mauduit";"Equipe 10, Team 10";36809009;"Journal of clinical microbiology";"Trecourt A, Rabodonirina M, Mauduit C, Traverse-Glehen A, Devouassoux-Shisheboran M, Meyronet D, Dijoud F, Ginevra C, Chapey-Picq E, Josse E, Martins-Simoes P, Bentaher A, Dupont D, Miossec C, Persat F, Wallon M, Ferry T, Pham F, Simon B, Menotti J";;"Feb 2023";1677024000;;"Histopathology is the gold standard for fungal infection (FI) diagnosis, but it does not provide a genus and/or species identification. The objective of the present study was to develop targeted next-generation sequencing (NGS) on formalin-fixed tissue samples (FTs) to achieve a fungal integrated histomolecular diagnosis. Nucleic acid extraction was optimized on a first group of 30 FTs with Aspergillus fumigatus or infection by macrodissecting the microscopically identified fungal-rich area and comparing Qiagen and Promega extraction methods through DNA amplification by A. fumigatus and primers. Targeted NGS was developed on a second group of 74 FTs using three primer pairs (ITS-3/ITS-4, MITS-2A/MITS-2B, and 28S-12-F/28S-13-R) and two databases (UNITE and RefSeq). A prior fungal identification of this group was established on fresh tissues. Targeted NGS and Sanger sequencing results on FTs were compared. To be valid, the molecular identifications had to be compatible with the histopathological analysis. In the first group, the Qiagen method yielded a better extraction efficiency than the Promega method (100% and 86.7% of positive PCRs, respectively). In the second group, targeted NGS allowed fungal identification in 82.4% (61/74) of FTs using all primer pairs, in 73% (54/74) using ITS-3/ITS-4, in 68.9% (51/74) using MITS-2A/MITS-2B, and in 23% (17/74) using 28S-12-F/28S-13-R. The sensitivity varied according to the database used (81% [60/74] using UNITE compared to 50% [37/74] using RefSeq [ = 0.000002]). The sensitivity of targeted NGS (82.4%) was higher than that of Sanger sequencing (45.9%; < 0.00001). To conclude, fungal integrated histomolecular diagnosis using targeted NGS is suitable on FTs and improves fungal detection and identification." 15302;"A new reflectance confocal microscopy feature of photoaging: nodular elastosis.";"T. Passeron";"Equipe 12, Team 12";36786047;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Alvarez Martinez D, Long-Mira E, Passeron T, Bahadoran P";;"Feb 2023";1676332800;; 15300;"Cardiac surgery simulation: Step-by-step hemi-Yacoub operation in a preclinical model.";"E. Ferrari";"Equipe 09, Team 09";36786667;"Multimedia manual of cardiothoracic surgery : MMCTS";"Toto F, Torre T, Pozzoli A, Zurfluh C, Ferrari E, Demertzis S";;"Feb 2023";1676332800;;"We demonstrate a hemi-Yacoub operation on a preclinical model (porcine heart). It is an alternative remodelling technique for the management of dilatation of the ascending aorta with the involvement of the aortic root, particularly the noncoronary sinus or in case of an aortic dissection. The goal of this operation is to replace selectively the dilated/dissected portion (noncoronary sinus), thereby avoiding replacement of the entire aortic root." 15298;"From normal hematopoiesis to malignancies: Highlights from the 2021 Meeting of the Club Hematopoiesis and Oncogenesis.";"N. Mazure";"Equipe 05, Team 05";36775700;"Bulletin du cancer";"Troadec MB, Porteu F, Arcangeli ML, Foudi A, Bluteau D, De Sepulveda P, Guillouf C, Mazure NM, Meggetto F, Brunet De La Grange P, Broccardo C";;"Feb 2023";1676160000;;"This article highlights the presentations from the 2021 scientific meeting of the Club Hematopoiesis and Oncogenesis. This annual meeting focuses on hematopoiesis and oncogenic mechanisms. Various topics were presented: expansion of hematopoietic stem cells with in vivo and ex vivo strategies, the role of the hematopoietic stem cell niches in aging and leukemic resistance, the crossroad between hematology and immunology, the importance of the metabolism in normal hematopoiesis and hematopoietic defects, solid tumors and oncogenesis, the noncoding genome, inflammation in monocyte differentiation and leukemia, and importantly, the recent advances in myeloid malignancies, lymphoid leukemia and lymphoma." 15296;"Hemicalcaneal reconstruction with a 3D printed custom-made prosthesis after partial calcanectomy due to a malignant bone tumor.";"E. Ferrari";"Equipe 09, Team 09";36779939;"Acta bio-medica : Atenei Parmensis";"D'Arienzo A, Ipponi E, Ferrari E, Campo FR, Capanna R, Andreani L";;"Feb 2023";1676246400;;"The malignant bone tumors of the calcaneus are extremely uncommon lesions. Surgical approach can consist in either an amputation or in a limb sparing procedure, depending on the width and the location of the neoplasm. Although several reconstructive options have been proposed to fulfill the bone defect in those cases that received a selective resection, to this date a consensus reconstructive approach is far from being established. Among the alternatives described in literature, 3D printed custom-made prostheses represent one of the most intriguing and promising reconstructive options. Herein, we report our experience of a spindle cell bone sarcoma of the calcaneus treated with selective resection of the anterior segment of the calcaneus and further reconstruction with a 3D printed custom-made prosthesis, based on patients' own anatomy. The posterior calcaneus and the insertion of the Achilles tendon were preserved. The resection was performed with wide margins and no major complication occurred through the intra-operative or post-operative intercourse. At her latest follow-up, our patient showed good functional results and was continuously disease free. Our outcomes therefore suggest that a partial prosthetic replacement of the anterior calcaneus with preservation of the Achilles insertion site may represent a safe and effective solution for cases that required the resection of the anterior calcaneus due to a malignant bone tumor." 15294;"Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS.";"M. Loschi";"Equipe 02, Team 02";36774430;"Bone marrow transplantation";"Michel C, Robin M, Morisset S, Blaise D, Maertens J, Chevalier P, Castilla-Llorente C, Forcade E, Ceballos P, Yakoug-Agha I, Poire X, Carre M, Bay JO, Beguin Y, Loschi M, Huynh A, Guillerm G, François S, Mear JB, Duléry R, Suarez F, Bilger K, Cornillon J, Chalandon Y, Maillard N, Labussière-Wallet H, Charbonnier A, Turlure P, Berceanu A, Chantepie S, Maury S, Bazarbachi A, Menard AL, Nguyen-Quoc S, Rubio MT, D'Aveni M";;"Feb 2023";1676073600;;"Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome." 15292;"The mechanical phenotypic plasticity of melanoma cell: an emerging driver of therapy cross-resistance.";"S. Tartare-Deckert, M. Deckert";"Equipe 11, Team 11";36774337;Oncogenesis;"Diazzi S, Tartare-Deckert S, Deckert M";;"Feb 2023";1676073600;;"Advanced cutaneous melanoma is the deadliest form of skin cancer and one of the most aggressive human cancers. Targeted therapies (TT) against BRAF mutated melanoma and immune checkpoints blockade therapies (ICB) have been a breakthrough in the treatment of metastatic melanoma. However, therapy-driven resistance remains a major hurdle in the clinical management of the metastatic disease. Besides shaping the tumor microenvironment, current treatments impact transition states to promote melanoma cell phenotypic plasticity and intratumor heterogeneity, which compromise treatment efficacy and clinical outcomes. In this context, mesenchymal-like dedifferentiated melanoma cells exhibit a remarkable ability to autonomously assemble their own extracellular matrix (ECM) and to biomechanically adapt in response to therapeutic insults, thereby fueling tumor relapse. Here, we review recent studies that highlight mechanical phenotypic plasticity of melanoma cells as a hallmark of adaptive and non-genetic resistance to treatment and emerging driver in cross-resistance to TT and ICB. We also discuss how targeting BRAF-mutant dedifferentiated cells and ECM-based mechanotransduction pathways may overcome melanoma cross-resistance." 15290;"Public Health Residents' Anonymous Survey in Italy (PHRASI): Study Protocol for a Cross-Sectional Study for a Multidimensional Assessment of Mental Health and Its Determinants.";"E. Ferrari";"Equipe 09, Team 09";36767369;"International journal of environmental research and public health";"Catalini A, Mazza C, Cosma C, Minutolo G, De Nicolò V, Gallinoro V, Caminiti M, Ancona A, Stacchini L, Berselli N, Ferrari E, Cedrone F, Gianfredi V, On Behalf Of The Working Group On Public Mental Health Of The Medical Residents' Assembly Of The Italian Society Of Hygiene And Preventive Medicine ";;"Feb 2023";1676073600;;"The COVID-19 pandemic has evolved into a severe psychosocial crisis affecting patients, their relatives, friends, and healthcare professionals. In Italy, public health residents (PHRs) remain essential to the national response to the pandemic. To assess their mental sphere, the ""Public Mental Health"" working group of the medical residents' Assembly of the Italian Society of Hygiene and Preventive Medicine has designed the Public Health Residents' Anonymous Survey in Italy (PHRASI). This is a nation-wide cross-sectional study based on an 88-item self-administered voluntary survey that evaluates how sociodemographic variables are associated with mental issues, including wellness, eating disorders, sleeplessness, alcohol misuse, depression, and anxiety. Data will be gathered by disseminating a Google Forms link across the Assembly network of medical residents. All PHRs enrolled in a four-year program in one of the Italian postgraduate schools of public health will be qualified as participants. PHRASI aims to draw a comprehensive and detailed picture of the mental health state of Italian PHRs. PHRs are a significant group of healthcare professionals that may serve as a future benchmark for developing and enacting regulations intended to support the mental health of healthcare professionals." 15288;"Quality of Life in COVID-Related ARDS Patients One Year after Intensive Care Discharge (Odissea Study): A Multicenter Observational Study.";"E. Ferrari";"Equipe 09, Team 09";36769705;"Journal of clinical medicine";"Deana C, Vetrugno L, Cortegiani A, Mongodi S, Salve G, Mangiagalli M, Boscolo A, Pettenuzzo T, Miori S, Sanna A, Lassola S, Magnoni S, Ferrari E, Biagioni E, Bassi F, Castaldo N, Fantin A, Longhini F, Corradi F, Forfori F, Cammarota G, De Robertis E, Buonsenso D, Spadaro S, Grieco DL, Martino M, Isola M, Mojoli F, Girardis M, Giarratano A, Bignami EG, Navalesi P, Cecconi M, Maggiore SM, On Behalf Of The Italian Odissea Group ";;"Feb 2023";1676073600;;"Investigating the health-related quality of life (HRQoL) after intensive care unit (ICU) discharge is necessary to identify possible modifiable risk factors. The primary aim of this study was to investigate the HRQoL in COVID-19 critically ill patients one year after ICU discharge." 15286;"Prevalence and Clinical Characteristics of Patients with Torsades de Pointes Complicating Acquired Atrioventricular Block.";"E. Ferrari";"Equipe 09, Team 09";36769716;"Journal of clinical medicine";"Bun SS, Heme N, Asarisi F, Squara F, Scarlatti D, Moceri P, Ferrari E";;"Feb 2023";1676073600;;"Female gender, degree of QT prolongation, and genetic susceptibility are known risk factors for developing torsades de pointes (TdP) during high-grade atrioventricular block (HG-AVB). Our objective was to analyze the prevalence and clinical characteristics of patients presenting with TdP and AVB (TdP [+]) in comparison with non-TdP patients with AVB (TdP [-])." 15284;"Repurposing the Bis-Biguanide Alexidine in Combination with Tyrosine Kinase Inhibitors to Eliminate Leukemic Stem/Progenitor Cells in Chronic Myeloid Leukemia.";"D. MARY, E. Verhoeyen, JF. PEYRON";"Equipe 04, Team 04, Team 03, Equipe 03";36765952;Cancers;"Muselli F, Mourgues L, Rochet N, Nebout M, Guerci A, Verhoeyen E, Krug A, Legros L, Peyron JF, Mary D";;"Feb 2023";1676073600;;"In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells self-renewal induced a CCNG2/dependent proliferation arrest leading to elimination of Chronic Myeloid Leukemia (CML) cells. Unfortunately, as of today, pharmacological inhibition of BMI1 has not made its way to the clinic." 15282;"Photoprotection for people with skin of colour: needs and strategies.";"T. Passeron";"Equipe 12, Team 12";36763874;"The British journal of dermatology";"Krutmann J, Piquero-Casals J, Morgado-Carrasco D, Granger C, Trullàs C, Passeron T, Lim HW";;"Feb 2023";1675987200;;"Skin of colour or pigmented skin has unique characteristics: it has a higher eumelanin-to-pheomelanin ratio, more mature melanosomes, an increased amount of melanin distributed in the upper layers of the epidermis, and more efficient DNA repair compared with lighter skin. However, individuals with skin of colour are at a significant risk of skin damage caused by ultraviolet radiation, including the development of photodermatoses and photoageing changes such as uneven skin tone, and are predisposed to pigmentary disorders. In fact, one of the most common conditions leading to dermatology consultations by patients with skin of colour is photoexacerbated pigmentary disorders. Unfortunately, individuals with skin of colour may be less prone to engage in photoprotective measures, including the use of sunscreens. Physicians are also less likely to prescribe sunscreens for them. There is thus a clear need for better education on photodamage and for more efficient and suitable photoprotection in populations with skin of colour. However, this need has thus far only partially been met, and the development of sunscreen products designed to provide optimal photoprotection for people with skin of colour remains a challenge. Targeted sunscreens for individuals with skin of colour require optimal cosmetic appeal (leaving no white residue and not disrupting skin tone). They should include broad-spectrum [ultraviolet (UV)B/UVA] protection with high sun protection factor, as well as protection against long-wave UVA (UVA1) and visible light, as these wavelengths are capable of inducing or augmenting pigmentary disorders. They may also contain depigmenting agents for patients with pigmentary disorders." 15280;"Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.";"T. Passeron";"Equipe 12, Team 12";36763878;"The British journal of dermatology";"King B, Mostaghimi A, Shimomura Y, Zlotogorski A, Choi GS, Blume-Peytavi U, Passeron T, Holzwarth K, Dutronc Y, McCollam J, Yang FE, Stanley S, Wu WS, Sinclair R";;"Feb 2023";1675987200;;"Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan." 15278;"Superficial fungal infections in the south of France - is fusariosis the next emergent onychopathy?";"C. Pomares";"Equipe 06, Team 06";36758968;"Medical mycology";"Landreau A, Simon L, Delaunay P, Pomares C, Hasseine L";;"Feb 2023";1675900800;;"In France, onychomycoses represent about 30% of superficial mycoses seen by the dermatologists. In recent years, it is observed an increased number of mycoses due to non-dermatophytic molds. The purpose of this study was to evaluate the epidemiological profile of identified superficial fungal infections in the Laboratory of Parasitology-Mycology of the University Hospital of Nice over a two-year period. A retrospective study was performed from the nail, skin and scalp samples of patients analyzed from January 2018 to December 2019. In this study, 3074 samples (54.2% nails, 39.7% skin and 6.1% scalp) were analyzed representing 1922 patients. Among them, 809 (42.1%) patients were sampled by dermatologists and 1113 (57.9%) were sampled by our experts in the clinical unit of the University Hospital of Nice. In total, 1159 (37.7%) samples had a positive culture (1195 strains identified) including 712 (59.6%) dermatophytes, 345 (28.9%) yeasts and 138 (11.5%) other filamentous molds. Trichophyton rubrum was the main dermatophyte (563; 47.1%) followed by T. interdigitale (84; 7.0%) and T. soudanense (25; 2.1%). Yeasts were mostly represented by Candida albicans (155; 13.0%). Among the other molds, Fusarium sp. was the most isolated (61; 5.1%). Dermatophytes stay predominant in superficial fungal infections where the anthropophilic species T. rubrum was found in almost half of the positive cultures. Interestingly, molds represented an important part of infections in our population. This study highlights the increasing share of Fusarium sp. superficial fungal infection in our patients' populations, perhaps requiring a major therapeutic adaptation in the years to come." 15276;"BRCA1/2 pathogenic variants are not common in Merkel cell carcinoma: Comprehensive molecular study of 30 cases and meta-analysis of the literature.";"H. Montaudie";"Equipe 12, Team 12";36754117;"The Journal of investigative dermatology";"Gaubert A, Kervarrec T, Montaudié H, Burel-Vandenbos F, Cardot-Leccia N, Di Mauro I, Fabas T, Tallet A, Kubiniek V, Pedeutour F, Dadone-Montaudié B";;"Feb 2023";1675814400;;"Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer. Management of advanced MCC is mainly based on immune-checkpoint inhibitors (ICI). The high failure rate warrants investigation of new therapeutic targets. The recent identification of BRCA1 or BRCA2 (BRCA1/2) mutations in some MCC raises the issue of the use of poly-(ADP-Ribose)-polymerase inhibitors (PARPi) in selected advanced cases. The main objective of our study is to determine the accurate frequency of BRCA1/2 pathogenic variants. We studied a series of 30 MCC and performed a meta-analysis of BRCA1/2 variants of published cases in the literature. In our series, we detected only one BRCA2 pathogenic variant. The low frequencyof BRCA1/2 pathogenic variants in our series of MCC (3%) was confirmed by the meta-analysis of BRCA1/2 variants of the literature. Among the 915 MCC from 13 published series in the literature and studied for molecular alterations of BRCA1/2, only 12 BRCA1/2 pathogenic mutations were identified (1-2% of MCC), while many other BRCA1/2 variants were variants of unknown significance (VUS) or benign. BRCA1/2 pathogenic variants are uncommon in MCC. However, in BRCA-mutated-MCC, PARPi might be a valuable therapeutic option requiring validation by clinical trials." 15274;"Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials.";"T. Passeron";"Equipe 12, Team 12";36746171;"Lancet (London, England)";"Kimball AB, Jemec GBE, Alavi A, Reguiai Z, Gottlieb AB, Bechara FG, Paul C, Giamarellos Bourboulis EJ, Villani AP, Schwinn A, Ruëff F, Pillay Ramaya L, Reich A, Lobo I, Sinclair R, Passeron T, Martorell A, Mendes-Bastos P, Kokolakis G, Becherel PA, Wozniak MB, Martinez AL, Wei X, Uhlmann L, Passera A, Keefe D, Martin R, Field C, Chen L, Vandemeulebroecke M, Ravichandran S, Muscianisi E";;"Feb 2023";1675641600;;"Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials." 15272;"The mechanosensitive TRPV2 calcium channel promotes human melanoma invasiveness and metastatic potential.";"S. Tartare-Deckert";"Equipe 11, Team 11";36744297;"EMBO reports";"Shoji KF, Bayet E, Leverrier-Penna S, Le Devedec D, Mallavialle A, Marionneau-Lambot S, Rambow F, Perret R, Joussaume A, Viel R, Fautrel A, Khammari A, Constantin B, Tartare-Deckert S, Penna A";;"Feb 2023";1675641600;;"Melanoma is a highly aggressive cancer endowed with a unique capacity of rapidly metastasizing, which is fundamentally driven by aberrant cell motility behaviors. Discovering ""migrastatics"" targets, specifically controlling invasion and dissemination of melanoma cells during metastasis, is therefore of primary importance. Here, we uncover the prominent expression of the plasma membrane TRPV2 calcium channel as a distinctive feature of melanoma tumors, directly related to melanoma metastatic dissemination. In vitro as well as in vivo, TRPV2 activity is sufficient to confer both migratory and invasive potentials, while conversely TRPV2 silencing in highly metastatic melanoma cells prevents aggressive behavior. In invasive melanoma cells, TRPV2 channel localizes at the leading edge, in dynamic nascent adhesions, and regulates calcium-mediated activation of calpain and the ensuing cleavage of the adhesive protein talin, along with F-actin organization. In human melanoma tissues, TRPV2 overexpression correlates with advanced malignancy and poor prognosis, evoking a biomarker potential. Hence, by regulating adhesion and motility, the mechanosensitive TRPV2 channel controls melanoma cell invasiveness, highlighting a new therapeutic option for migrastatics in the treatment of metastatic melanoma." 15268;"High risk-myelodysplastic syndrome following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma: A case report and literature review.";"E. Ferrari";"Equipe 09, Team 09";36741006;"Frontiers in oncology";"Accorsi Buttini E, Farina M, Lorenzi L, Polverelli N, Radici V, Morello E, Colnaghi F, Almici C, Ferrari E, Bianchetti A, Leoni A, Re F, Bosio K, Bernardi S, Malagola M, Re A, Russo D";;"Feb 2023";1675641600;;"Chimeric antigen receptor (CAR) T-cell therapy represents the most advanced immunotherapy against relapsed/refractory B cell malignancies. While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are distinctive, known CAR T-cell acute adverse events, hematological toxicity has been increasingly reported. Cytopenia following CAR T-cell treatment is attributed in most cases to lymphodepletion regimens, bridging chemotherapy, or radiotherapy. However, when cytopenia becomes prolonged, the development of myelodysplastic syndrome (MDS) should be considered." 15264;"Development of Low-Resistance Ohmic Contacts with Bilayer NiO/Al-Doped ZnO Thin Films to p-type GaN.";"C. Mauduit";"Equipe 10, Team 10";36732675;"ACS applied materials & interfaces";"Slimani Tlemcani T, Mauduit C, Bah M, Zhang M, Charles M, Gwoziecki R, Yvon A, Alquier D";;"Feb 2023";1675296000;;"The fabrication of low-resistance and thermally stable Ohmic contacts is essential for the realization of reliable GaN power devices. In the particular case of p-type GaN, a thin Ni/Au bilayer is commonly used for Ohmic contacts. However, Au metal contacts are quite expensive, are incompatible with the complementary metal oxide-semiconductor foundries, and also have poor thermal stability. Thus, seeking an alternative that is affordable and thermally stable is crucial. In the present study, we investigate Au-free Ohmic contact formation on p-type GaN using a bilayer Ni/Al-doped ZnO (AZO) thin film. Careful studies were focused on identifying the role of process parameters such as annealing parameters: temperature, time, and atmosphere in order to obtain an excellent Ohmic contact on p-GaN. Our results show that the contact resistance can be significantly reduced using a Ni/AZO bilayer with a suitable rapid thermal process. We demonstrate that the specific contact resistance for Ni/AZO on p-GaN can reach the lowest value of 1.85 × 10 Ω·cm for a sample with a 5 nm Ni layer annealed at 500 °C in air for 5 min. Our work demonstrates that the bilayer Ni/AZO contact could be suitable for efficient GaN power diodes or transistors." 15262;"Dopaminergic connectivity reconfiguration in the dementia with Lewy bodies continuum.";"E. Ferrari";"Equipe 09, Team 09";36724569;"Parkinsonism & related disorders";"Caminiti SP, Pilotto A, Premi E, Galli A, Ferrari E, Gipponi S, Cottini E, Paghera B, Perani D, Padovani A";;"Feb 2023";1675209600;;"The impairment of nigrostriatal dopaminergic network is a core feature of dementia with Lewy bodies (DLB). The involvement and reconfiguration of extranigrostriatal dopaminergic circuitries in the DLB continuum is still theme of debate. We aim to investigate in vivo the dynamic changes of local and long-distance dopaminergic networks across DLB continuum." 15250;"MCB-613 exploits a collateral sensitivity in drug resistant -mutant non-small cell lung cancer through covalent inhibition of KEAP1.";"P. Auberger, G. Robert";"Equipe 02, Team 02";36711936;"bioRxiv : the preprint server for biology";"Bassil CF, Anderson GR, Mayro B, Askin KN, Winter PS, Gruber S, Hall TM, Hoj JP, Cerda-Smith C, Hutchinson HM, Killarney ST, Singleton KR, Qin L, Jubien-Girard K, Favreau C, Martin AR, Robert G, Benhida R, Auberger P, Pendergast AM, Lonard DM, Puissant A, Wood KC";;"Jan 2023";1675036800;;"Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets -mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, -mutant NSCLC cells." 15248;"Planning of graft size and 3D reconstruction using virtual reality technique in aortic valve reimplantation.";"E. Ferrari";"Equipe 09, Team 09";36712278;"Frontiers in cardiovascular medicine";"Reid G, Gehweiler J, Thieringer F, Eckstein F, Ferrari E, Gahl B, Berdajs DA";;"Jan 2023";1675036800;;"To evaluate applicability and feasibility of the virtual imaging technology for diagnosis and planning of the aortic valve sparing procedure." 15199;"Pigmented demodicosis presenting as lentigo maligna diagnosed by reflectance confocal microscopy.";"T. Passeron";"Equipe 12, Team 12";36689529;"The British journal of dermatology";"Bertold C, Martel P, Passeron T, Bahadoran P";;"Jan 2023";1674432000;; 15197;"Superradiant Electron Energy Loss Spectroscopy.";"R. Ruimy";"Equipe 06, Team 06";36689300;"Nano letters";"Ruimy R, Gorlach A, Baranes G, Kaminer I";;"Jan 2023";1674432000;;"We analyze the interaction between a free electron and an ensemble of identical optical emitters. The mutual coherence and correlations between the emitters can enhance the interaction with each electron and become imprinted on its energy spectrum. We present schemes by which such collective interactions can be realized. As a possible application, we investigate free-electron interactions with superradiant systems, showing how electrons can probe the ultrafast population dynamics of superradiance." 15195;"βeta Blocker Interruption after Uncomplicated Myocardial Infarction: Rationale and Design of the randomized ABYSS trial.";"E. Ferrari";"Equipe 09, Team 09";36682596;"American heart journal";"Silvain J, Cayla G, Ferrari E, Range G, Puymirat E, Delarche N, Collet JP, Dumaine R, Slama M, Payot L, Kasty ME, Aacha K, Vicaut E, Montalescot G, ";;"Jan 2023";1674345600;;"The long-term use of β-blocker after myocardial infarction (MI) when global left ventricular ejection fraction (LVEF) is preserved has not been studied in the era of modern myocardial reperfusion and secondary prevention therapies. It is unknown whether β-blockers are useful in stable post-MI patients without reduced LVEF and without heart failure." 15193;"Vascular endothelial growth factor, tissue factor, coagulation and fibrinolysis markers in slow-flow vascular malformations: a prospective study of treatment with sirolimus.";"C. Chiaverini";"Equipe 12, Team 12";36689523;"The British journal of dermatology";"Maruani A, Moineau AG, Boccara O, Mazereeuw-Hautier J, Leducq S, Bessis D, Guibaud L, Vabres P, Mallet S, Barbarot S, Chiaverini C, Droitcourt C, Bursztejn AC, Lengelle C, Woillard JB, Herbreteau D, Le Touze A, Binet A, Morel B, Bourgoin H, Gissot V, Giraudeau B, Gruel Y, Tavernier E, Rollin J";;"Jan 2023";1674432000;; 15191;"Patients Treated for HCV Infection and Listed for Liver Transplantation in a French Multicenter Study: What Happens at Five Years?";"R. ANTY";"Equipe 08, Team 08";36680177;Viruses;"Meunier L, Belkacemi M, Pageaux GP, Radenne S, Vallet-Pichard A, Houssel-Debry P, Duvoux C, Botta-Fridlund D, de Ledinghen V, Conti F, Anty R, Di Martino V, Debette-Gratien M, Leroy V, Gerster T, Lebray P, Alric L, Abergel A, Dumortier J, Besch C, Montialoux H, Samuel D, Duclos-Vallée JC, Coilly A";;"Jan 2023";1674259200;;"Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up." 15189;"Component-Resolved Diagnosis Based on a Recombinant Variant of Mus m 1 Lipocalin Allergen.";"E. Ferrari";"Equipe 09, Team 09";36674705;"International journal of molecular sciences";"Ferrari E, Breda D, Spisni A, Burastero SE";;"Jan 2023";1674259200;;"Exposure to the Mus m 1 aeroallergen is a significant risk factor for laboratory animal allergy. This allergen, primarily expressed in mouse urine where it is characterized by a marked and dynamic polymorphism, is also present in epithelium and dander. Considering the relevance of sequence/structure assessment in protein antigenic reactivity, we compared the sequence of the variant Mus m 1.0102 to other members of the Mus m 1 allergen, and used Discotope 2.0 to predict conformational epitopes based on its 3D-structure. Conventional diagnosis of mouse allergy is based on serum IgE testing, using an epithelial extract as the antigen source. Given the heterogeneous and variable composition of extracts, we developed an indirect ELISA assay based on the recombinant component Mus m 1.0102. The assay performed with adequate precision and reasonable diagnostic accuracy (AUC = 0.87) compared to a routine clinical diagnostic test that exploits the native allergen. Recombinant Mus m 1.0102 turned out to be a valuable tool to study the fine epitope mapping of specific IgE reactivity to the major allergen responsible for mouse allergy. We believe that advancing in its functional characterization will lead to the standardization of murine lipocalins and to the development of allergen-specific immunotherapy." 15187;"Does Bariatric Surgery Reduce the Risk of Colorectal Cancer in Individuals with Morbid Obesity? A Systematic Review and Meta-Analysis.";"A. IANNELLI";"Team 08, Equipe 08";36678338;Nutrients;"Chierici A, Amoretti P, Drai C, De Fatico S, Barriere J, Schiavo L, Iannelli A";;"Jan 2023";1674259200;;"Bariatric surgery has shown to be effective in producing sustained weight loss and the resolution of obesity related medical problems. Recent research focused on the role of obesity and adipose tissue in tumorigenesis, finding a strong crosslink through different mechanisms and highlighting an increase in cancer incidence in individuals with obesity. The aim of this meta-analysis is to find if bariatric surgery reduces the incidence of colorectal cancer in patients with obesity. We performed a meta-analysis including 18 studies (PROSPERO ID: CRD4202235931). Bariatric surgery was found to be significantly protective toward colorectal cancer incidence in individuals with obesity (HR: 0.81, = 0.0142). The protective effect persisted when considering women (RR: 0.54, = 0.0014) and men (RR: 0.74, = 0.2798) separately, although this was not significant for the latter. No difference was found when comparing Roux-en-Y gastric bypass and sleeve gastrectomy. Bariatric surgery reduces the incidence of colorectal cancer in individuals with obesity independently from gender and surgical procedure. Prospective large cohort studies are needed to confirm these findings." 15183;"Burden of cardiovascular disease in a large contemporary cohort of patients with heterozygous familial hypercholesterolemia.";"E. Ferrari";"Equipe 09, Team 09";36643794;"Atherosclerosis plus";"Ferrières J, Farnier M, Bruckert E, Vimont A, Durlach V, Ferrari E, Gallo A, Boccara F, Ferrières D, Béliard S, ";;"Jan 2023";1673827200;;"Heterozygous familial hypercholesterolemia (HeFH) is increasingly better diagnosed and treatments can improve the cardiovascular prognosis. We evaluated the long-term cardiovascular risk of HeFH using the French REgistry of Familial hypERCHOLesterolemia (REFERCHOL)." 15174;"Factors associated with prolonged episodes of mechanical restraint in mental health hospitalization units in Andalusia.";"JA. Garcia-Sanchez";"Equipe 06, Team 06";35088924;"Journal of psychiatric and mental health nursing";"Guzmán-Parra J, Aguilera-Serrano C, Huizing E, Bono Del Trigo A, Villagrán JM, Hurtado Melero V, García-Sanchez JA, Mayoral-Cleries F";;"Jan 2022";1643328000;;"WHAT IS KNOWN ON THE SUBJECT?: Risk factors associated with prolonged episodes of mechanical restraint and other coercive measures are understudied. There have been no studies of this phenomenon in the context of the Andalusian public health system. Knowledge about factors associated with prolonged episodes is essential to increase the understanding of this phenomenon and develop strategies to reduce its occurrence. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: In Andalusia, prolonged restraint is still frequent and varies depending on the unit. It is associated with less time since admission, male gender, diagnosis, reason for restraint and the shift on which it was initiated. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Interventions at the level of the units could be necessary to prevent prolonged episodes of mechanical restraint. The results suggest the need for stricter control during the shifts on which restraint starts, especially in the first days after the patient's admission. Preventive risk assessment considering clinical and sociodemographic risk factors could help to reduce prolonged restraint. ABSTRACT: Introduction Factors associated with prolonged episodes of mechanical restraint and other coercive interventions are not clearly established and have been not studied in Andalusia (Spain). Aim To study factors associated with prolonged episodes of mechanical restraint. Method We analysed retrospectively episodes of mechanical restraint (N = 6267, prolonged episode >9.5 hours) in all public mental health hospitalization units (N = 20, 535 beds) that offer health coverage for the autonomous community of Andalusia. The data came from clinical records. A multivariable mixed logistic regression was used. Results In Andalusia, prolonged restraint is still frequent and varies depending on the unit. It is associated with less time since admission, male gender, diagnosis, reason for restraint and the shift on which it was initiated. Discussion The results provide evidence that prolonged episodes largely depend on the unit where they occur and that stricter control and regulation are necessary to prevent prolonged episodes. Implications for practice Interventions at the level of the unit are necessary. Stricter control in the shifts during which there is more risk of prolonged restraint may be necessary, especially in the first days following admission." 15170;"A Multidisciplinary Approach Establishes a Link between Transglutaminase 2 and the Kv10.1 Voltage-Dependent K Channel in Breast Cancer.";"E. Ferrari";"Equipe 09, Team 09";36612174;Cancers;"Canella R, Brugnoli F, Gallo M, Keillor JW, Terrazzan A, Ferrari E, Grassilli S, Gates EWJ, Volinia S, Bertagnolo V, Bianchi N, Bergamini CM";;"Jan 2023";1673136000;;"Since the multifunctionality of transglutaminase 2 (TG2) includes extra- and intracellular functions, we investigated the effects of intracellular administration of TG2 inhibitors in three breast cancer cell lines, MDA-MB-231, MDA-MB-436 and MDA-MB-468, which are representative of different triple-negative phenotypes, using a patch-clamp technique. The first cell line has a highly voltage-dependent a membrane current, which is low in the second and almost absent in the third one. While applying a voltage protocol to responsive single cells, injection of TG2 inhibitors triggered a significant decrease of the current in MDA-MB-231 that we attributed to voltage-dependent K channels using the specific inhibitors 4-aminopyridine and astemizole. Since the Kv10.1 channel plays a dominant role as a marker of cell migration and survival in breast cancer, we investigated its relationship with TG2 by immunoprecipitation. Our data reveal their physical interaction affects membrane currents in MDA-MB-231 but not in the less sensitive MDA-MB-436 cells. We further correlated the efficacy of TG2 inhibition with metabolic changes in the supernatants of treated cells, resulting in increased concentration of methyl- and dimethylamines, representing possible response markers. In conclusion, our findings highlight the interference of TG2 inhibitors with the Kv10.1 channel as a potential therapeutic tool depending on the specific features of cancer cells." 15168;"Alginate Beads Containing Cerium-Doped Mesoporous Glass and Curcumin: Delivery and Stabilization of Therapeutics.";"E. Ferrari";"Equipe 09, Team 09";36614324;"International journal of molecular sciences";"Carrozza D, Malavasi G, Ferrari E, Menziani MC";;"Jan 2023";1673136000;;"Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile antioxidant, anti-inflammatory, anti-tumor, anti-HIV, and anti-infection properties. Nonetheless, the major problem related to its use is its poor oral bioavailability, which can be overcome by encapsulating it into small particles, such as hydrogel beads containing mesoporous silica. In this work, various systems have been synthesized: starting from mesoporous silica glasses (MGs), cerium-containing MGs have been produced; then, these systems have been loaded with 4 to 6% of curcumin. Finally, various MGs at different compositions have been included in alginate beads. In vitro studies showed that these hybrid materials enable the stabilization and effective delivery of curcumin and that a synergic effect can be achieved if Ce/Ce and curcumin are both part of the beads. From swelling tests, it is possible to confirm a controlled curcumin release compartmentalized into the gastrointestinal tract. For all beads obtained, a curcumin release sufficient to achieve the antioxidant threshold has been reached, and a synergic effect of cerium and curcumin is observed. Moreover, from catalase mimetic activity tests, we confirm the well-known catalytic activity of the couple Ce/Ce. In addition, an extremely good radical scavenging effect of curcumin has been demonstrated. In conclusion, these systems, able to promote an enzymatic-like activity, can be used as drug delivery systems for curcumin-targeted dosing." 15166;"How to deal with right hepatic artery coming from the superior mesenteric artery during minimally invasive pancreaticoduodenectomy: A systematic review.";"A. IANNELLI";"Team 08, Equipe 08";36604294;"Hepatobiliary & pancreatic diseases international : HBPD INT";"Chierici A, Castaldi A, El Zibawi M, Rosso E, Iannelli A";;"Jan 2023";1672876800;;"Anatomical variations in the liver arterial supply are quite common and can affect the surgical strategy when performing a minimally invasive pancreaticoduodenectomy (MIPD). Their presence must be preemptively detected to avoid postoperative liver and biliary complications." 15140;"Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations.";"E. Ferrari";"Equipe 09, Team 09";36591311;"Frontiers in immunology";"Bonetto V, Pasetto L, Lisi I, Carbonara M, Zangari R, Ferrari E, Punzi V, Luotti S, Bottino N, Biagianti B, Moglia C, Fuda G, Gualtierotti R, Blasi F, Canetta C, Montano N, Tettamanti M, Camera G, Grimoldi M, Negro G, Rifino N, Calvo A, Brambilla P, Biroli F, Bandera A, Nobili A, Stocchetti N, Sessa M, Zanier ER";;"Jan 2023";1672617600;;"Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications." 15138;"Is in vitro maturation of oocytes retrieved ex vivo from ovarian tissue an effective fertility preservation technique in the presence of organic ovarian cysts?";"M. Carles";"Equipe 06, Team 06";36586210;"European journal of obstetrics, gynecology, and reproductive biology";"Bourg M, Moreau J, Carles M, Cadoret F, Lesourd F, Tournier A, Léandri RD, Gatimel N";;"Dec 2022";1672444800;;"In vitro maturation (IVM) of oocytes retrieved ex vivo from ovarian tissue (OTO-IVM) could be an additional source of mature oocytes with the potential to optimise medical fertility preservation (FP) after oophorectomy. It is often undertaken at the same time as the ovarian tissue cryopreservation (OTC). In the presence of an organic ovarian cyst, OTO-IVM could prove to be the only technique available to permit FP since ovarian stimulation, transvaginal ovarian needle puncture or future ovarian tissue graft are contraindicated. However, the presence of an organic cyst could alter follicular growth and the number of retrievd oocytes. Our study aims to assess the efficiency of OTO-IVM in such situations." 15136;"High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";36585521;Leukemia;"Aid Z, Robert E, Lopez CK, Bourgoin M, Boudia F, Le Mene M, Riviere J, Baille M, Benbarche S, Renou L, Fagnan A, Thirant C, Federici L, Touchard L, Lecluse Y, Jetten A, Geoerger B, Lapillonne H, Solary E, Gaudry M, Meshinchi S, Pflumio F, Auberger P, Lobry C, Petit A, Jacquel A, Mercher T";;"Dec 2022";1672358400;;"Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death. Patient-derived ETO2::GLIS2 leukemic cells expressed both high CASP3 and high BCL2. While BCL2 inhibition partly inhibited ETO2::GLIS2 leukemic cell proliferation, BH3 profiling revealed that it also sensitized these cells to MCL1 inhibition indicating a functional redundancy between BCL2 and MCL1. We further show that combined inhibition of BCL2 and MCL1 is mandatory to abrogate disease progression using in vivo patient-derived xenograft models. These data reveal that a transcriptional consequence of ETO2::GLIS2 expression includes a positive regulation of the pro-apoptotic CASP3 and associates with a vulnerability to combined targeting of two BCL2 family members providing a novel therapeutic perspective for this aggressive pediatric AML subgroup." 15127;"Proangiogenic actors: From the uterus to peripheral arterial disease?";"N. Sadaghianloo";"Equipe 09, Team 09";36561984;"JVS-vascular science";"Sadaghianloo N";;"Dec 2022";1671753600;; 15125;"Novel pathogenic variants in SLCO2A1 causing autosomal dominant primary hypertrophic osteoarthropathy.";"C. Chiaverini";"Equipe 12, Team 12";36549465;"European journal of medical genetics";"Bloch A, Couture G, Isidor B, Ricquebourg M, Bourrat E, Lipsker D, Taillan B, Combier A, Chiaverini C, Moufle F, Delobel B, Richette P, Collet C";;"Dec 2022";1671667200;;"Primary hypertrophic osteoarthropathy (PHO), or pachydermoperiostosis, is characterized by a clinical association including digital clubbing, periostosis and pachydermia. SLCO2A1 and HPGD genes are both responsible for PHO. The pathology is classically defined as an autosomal recessive disorder with clinical variability ranging from a mild to more severe phenotype. However, the hypothesis for an autosomal dominant form suggested for a long time was only demonstrated for the first time in 2021 for SLCO2A1. We aimed to detect a second pathogenic variant by a deep sequencing of the entire SLCO2A1 and HPGD genes, associated with functional transcription analysis in PHO patients harboring only one heterozygous variant. Among 10 PHO patients, 4 presented a single pathogenic or probably pathogenic novel variant in SLCO2A1 in heterozygous status (NM_005630.3: c.234+1G > A, c.1523_1524delCT, c.1625G > A and c.31delC), and the others carried homozygous pathogenic variants. For heterozygous forms, we found no additional pathogenic variant in HPGD or SLCO2A1. PHO can be a dominant form with age at disease onset later than that for the recessive form. This dominant form is not exceptional in young adults. In conclusion, both modes of inheritance of PHO explain the clinical variability and the difference in age at disease onset. Molecular analysis is especially required in the incomplete form to distinguish it from secondary hypertrophic osteoarthropathy." 15123;"Impact of systemic therapies in metastatic melanoma of unknown primary: A study from MELBASE, a French multicentric prospective cohort.";"H. Montaudie";"Equipe 12, Team 12";36543626;"Journal of the American Academy of Dermatology";"Rousset P, Dalle S, Mortier L, Dereure O, Dalac S, Dutriaux C, Leccia MT, Legoupil D, Brunet-Possenti F, De Quatrebarbes J, Grob JJ, Saiag P, Maubec E, Stoebner PE, Granel-Brocard F, Arnault JP, Allayous C, Oriano B, Lebbe C, Montaudié H";;"Dec 2022";1671580800;;"Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied." 15121;"Cost-Effectiveness Analysis of Sequential Treatment Strategies for Advanced Melanoma in Real Life in France.";"H. Montaudie";"Equipe 12, Team 12";36547139;"Current oncology (Toronto, Ont.)";"Kandel M, Bardet A, Dalle S, Allayous C, Mortier L, Guillot B, Dutriaux C, Leccia MT, Dalac S, Montaudie H, Saiag P, Legoupil D, Brunet-Possenti F, Arnault JP, Quatrebarbes J, Beylot-Barry M, Maubec E, Lesimple T, Aubin F, Grob JJ, Granel-Brocard F, Stoebner PE, Dupuy A, Dreno B, Michiels S, Lebbe C, Borget I";;"Dec 2022";1671667200;;"Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients' characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained." 15119;"Ten-Year Experience with Transapical and Direct Transaortic Transcatheter Aortic Valve Replacement to Address Patients with Aortic Stenosis and Peripheral Vascular Disease.";"E. Ferrari";"Equipe 09, Team 09";36547419;"Journal of cardiovascular development and disease";"Ferrari E, Pozzoli A, Klersy C, Toto F, Torre T, Cassina T, Pedrazzini G, Demertzis S";;"Dec 2022";1671667200;;": Transcatheter aortic valve replacement (TAVR) through alternative access routes is indicated in patients with severe aortic valve stenosis and diseased peripheral arteries. We analysed and compared the outcome of patients undergoing transapical (TA) and direct transaortic (TAO) TAVR procedures. : Preoperative characteristics, procedural details, and thirty-day outcome of patients undergoing transapical (TA-TAVR group) and direct transaortic (TAO-TAVR group) TAVR procedures were prospectively collected and retrospectively analysed. : From March 2012 to March 2022, 81 TA and 82 TAO-TAVR (total: 163 cases) were performed with balloon-expanding ( = 120; 73.6%) and self-expandable ( = 43; 26.4%) valves. The mean age was 79.7 ± 6.2 and 81.9 ± 6.7 years for the TA- and TAO-TAVR groups, respectively ( = 0.032). Females were more represented in the TAO-TAVR group (56% vs. 32%; = 0.003) while TA-TAVR patients showed a higher prevalence of previous vascular surgery (20% vs. 6%; = 0.01), previous cardiac surgery (51% vs. 3.6%; < 0.001), and porcelain aorta (22% vs. 5%; = 0.001). The mean ejection fraction was 49.0 ± 14.6% (TA) and 53.5 ± 12.2% (TAO) ( = 0.035) while mean gradients were 35.6 ± 13.2 mmHg (TA) and 40.4 ± 16.1 mmHg (TAO) ( = 0.045). The median EuroSCORE-II was 5.0% (IQR: 3.0-11.0) and 3.9% (IQR: 2.5-5.4) for the TA- and TAO-TAVR groups, respectively ( = 0.005). The procedural time was shorter for TA procedures (97 min (IQR: 882-118) vs. 102 min (IQR: 88-129); = 0.133). Mortality at day 30 was 6% in both groups ( = 1.000); the permanent pacemaker implantation rate was similar (8.6% vs. 9.7%; = 1.000), and hospital stay was shorter for the TAO group (8 days (IQR: 6-11) vs. 10 days (IQR: 7-13); = 0.025). : Our results show that transapical and direct transaortic TAVR in high-risk patients with diseased peripheral arteries provide satisfactory clinical results with similar thirty-day outcomes." 15117;"Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade.";"C. Bertolotto";"Equipe 01, Team 01";36545256;Oncoimmunology;"Nazerai L, Willis SC, Yankilevich P, Di Leo L, Bosisio FM, Frias A, Bertolotto C, Nersting J, Thastrup M, Buus S, Thomsen AR, Nielsen M, Rohrberg KS, Schmiegelow K, De Zio D";;"Dec 2022";1671667200;;"Immune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thioguanine (6TG) to induce random mutations and thus increase the level of neoepitopes presented by tumor cells. Thiopurines are prodrugs which are converted into thioguanine nucleotides that are incorporated into DNA (DNA-TG), where they can induce mutation through single nucleotide mismatching. In a pre-clinical mouse model of a mutation-low melanoma cell line, we demonstrated that 6TG induced clinical-grade DNA-TG integration resulting in an improved tumor control that was strongly T cell dependent. 6TG exposure increased the tumor mutational burden, without affecting tumor cell proliferation and cell death. Moreover, 6TG treatment re-shaped the tumor microenvironment by increasing T and NK immune cells, making the tumors more responsive to immune-checkpoint blockade. We further validated that 6TG exposure improved tumor control in additional mouse models of melanoma. These findings have paved the way for a phase I/II clinical trial that explores whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy (NCT05276284)." 15115;"Laser-assisted depigmentation for vitiligo universalis: a retrospective monocentric study comparing nano- and pico-second lasers.";"T. Passeron";"Equipe 12, Team 12";36541248;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Alvarez Martinez D, Bertold C, Le Duff F, Bahadoran P, Passeron T";;"Dec 2022";1671580800;; 15113;"Recovery of right ventricular function after intermediate-risk pulmonary embolism: results from the multicentre Pulmonary Embolism International Trial (PEITHO)-2.";"E. Ferrari";"Equipe 09, Team 09";36539534;"Clinical research in cardiology : official journal of the German Cardiac Society";"Mavromanoli AC, Barco S, Ageno W, Bouvaist H, Brodmann M, Cuccia C, Couturaud F, Dellas C, Dimopoulos K, Duerschmied D, Empen K, Faggiano P, Ferrari E, Galiè N, Galvani M, Ghuysen A, Giannakoulas G, Huisman MV, Jiménez D, Kozak M, Lang IM, Meneveau N, Münzel T, Palazzini M, Petris AO, Piovaccari G, Salvi A, Schellong S, Schmidt KH, Verschuren F, Schmidtmann I, Toenges G, Klok FA, Konstantinides SV, ";;"Dec 2022";1671494400;;"Right ventricular (RV) function plays a critical role in the pathophysiology and acute prognosis of pulmonary embolism (PE). We analyzed the temporal changes of RV function in the cohort of a prospective multicentre study investigating if an early switch to oral anticoagulation in patients with intermediate-risk PE is effective and safe." 15109;"Sphingosine-1 Phosphate Receptor Modulators Increase In Vitro Melanoma Cell Line Proliferation at Therapeutic Doses Used in Patients with Multiple Sclerosis.";"S. Tartare-Deckert, M. Deckert";"Equipe 11, Team 11";36534273;"Neurology and therapy";"Ruetsch-Chelli C, Okuda DT, Rocher F, Tartare-Deckert S, Deckert M, Lebrun-Frenay C";;"Dec 2022";1671408000;;"S1P receptor modulators (S1P-RM) are oral disease-modifying therapies (DMTs) for multiple sclerosis (MS). Several authorities have raised doubts that S1P-RM are responsible for an increased risk of melanoma in patients with MS. We studied the in vitro effects of S1P-RM on different melanoma cell lines to compare the effect of available S1P-RM on the proliferation of human melanoma cells." 15107;"Comment on: Dalbavancin in Gram-positive periprosthetic joint infections.";"J. Courjon, M. Carles";"Equipe 06, Team 06";36527681;"The Journal of antimicrobial chemotherapy";"Courjon J, Dinh A, Lemaignen A, Senneville E, Robineau O, Carles M";;"Dec 2022";1671235200;; 15103;"An Interlaboratory Study to Identify Potential Visible Protein-Like Particle Standards.";"E. Ferrari";"Equipe 09, Team 09";36526853;"AAPS PharmSciTech";"Telikepalli SN, Carrier MJ, Ripple DC, Barnett G, Bhirde A, Bolton D, Bou-Assaf GM, Ferrari E, Leigh S, Levitskaya-Seaman S, Menzen T, Nikels F, Riley A, Saggu M, Sahni N, Vernooij E, Wuchner K";;"Dec 2022";1671148800;;"Visible protein-like particle standards may improve visual inspection and/or appearance testing practices used in the biotechnology industry. They may improve assay performance resulting in better alignment and more standardized training among different companies. The National Institute of Standards and Technology (NIST) has conducted an interlaboratory study to test whether the standards under development mimic typical proteinaceous particles found in biotherapeutics and if they can be implemented during the visual inspection process. Fourteen organizations from industry and government have participated. A total of 20 labs from these 14 organizations participated with analysts from 6 formulation, 7 analytical, 4 quality control, and 3 manufacturing labs. The circulated samples consisted of abraded ethylene tetrafluoroethylene (ETFE) particles or photolithographic particles. The results consist of qualitative ratings, which varied substantially among organizations and within labs. Polydisperse ETFE particle suspensions, containing particles enriched in greater than 150 µm in size, were rated more favorably than the photolithographic particles by formulation and analytical scientists. The largest monodisperse photolithographic particles (approximately 300 µm in size) were favored equally compared to ETFE by all scientists. Solution modifications to decrease the settling rate or to alter optical properties of the ETFE solutions yielded lower ratings by the analysts. Both particle types received mixed ratings for their usability and for their application for visual inspection and for training purposes. Industry feedback will assist NIST in developing reference material(s) for visible protein-like particles." 15101;"Taxonomical and functional composition of strawberry microbiome is genotype-dependent.";"E. Ferrari";"Equipe 09, Team 09";36513413;"Journal of advanced research";"Sangiorgio D, Cellini A, Donati I, Ferrari E, Tanunchai B, Fareed Mohamed Wahdan S, Sadubsarn D, Farneti B, Checcucci A, Buscot F, Spinelli F, Purahong W";;"Dec 2022";1670889600;;"Specific microbial communities are associated to host plants, influencing their phenotype and fitness.Despite the rising interest in plant microbiome, the role of microbial communities associated with perennial fruit plants remains overlooked." 15070;"Liver Transplantation Using Allografts With Recent Liver Blunt Trauma: A Nationwide Audit From the French CRISTAL Biomedicine Agency Registry.";"A. IANNELLI";"Team 08, Equipe 08";36477606;Transplantation;"Seckler F, Turco C, Mohkam K, Addeo P, Robin F, Cauchy F, Maulat C, Brustia R, Paquette B, Faitot F, Weil Verhoeven D, Minello A, Lakkis Z, Di Martino V, Latournerie M, Chiche L, El Amrani M, Bucur P, Navarro F, Chopinet S, Chirica M, Gagnière J, Iannelli A, Cheisson G, Chardot C, Sommacale D, Muscari F, Dondero F, Sulpice L, Bachellier P, Scatton O, Mabrut JY, Heyd B, Doussot A";;"Dec 2022";1670457600;;"In the current setting of organ shortage, brain-dead liver donors with recent liver trauma (RLT) represent a potential pool of donors. Yet, data on feasibility and safety of liver transplantation (LT) using grafts with RLT are lacking." 15042;"Tocilizumab for Corticosteroid-Refractory Immune Checkpoint Inhibitor-Induced Generalized Morphea.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";36449277;"JAMA dermatology";"Blaise M, Cardot-Leccia N, Seitz-Polski B, Picard-Gauci A, Bertold C, Passeron T, Montaudié H";;"Nov 2022";1669766400;; 15024;"Targeting Ultrasmall Gold Nanoparticles with cRGD Peptide Increases the Uptake and Efficacy of Cytotoxic Payload.";"E. Ferrari";"Equipe 09, Team 09";36432299;"Nanomaterials (Basel, Switzerland)";"Perrins RD, McCarthy LA, Robinson A, Spry KL, Cognet V, Ferreira A, Porter J, Garcίa CE, Rodriguez MÁ, Lopez D, Perera I, Conlon K, Barrientos A, Coulter T, Pace A, Hale SJM, Ferrari E, Bachrati CZ";;"Nov 2022";1669420800;;"Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVβ3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVβ3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs." 15022;"Plasticity in Classical Hodgkin Composite Lymphomas: A Systematic Review.";"C. Mauduit";"Equipe 10, Team 10";36428786;Cancers;"Trecourt A, Donzel M, Fontaine J, Ghesquières H, Jallade L, Antherieu G, Laurent C, Mauduit C, Traverse-Glehen A";;"Nov 2022";1669420800;;"The co-occurrence of several lymphomas in a patient defines composite/synchronous lymphoma. A common cellular origin has been reported for both contingents of such entities. In the present review, we aimed to gather the available data on composite lymphomas associating a classical Hodgkin lymphoma (cHL) with another lymphoma, to better understand the plasticity of mature B and T-cells. This review highlights that >70% of patients with a composite lymphoma are ≥55 years old, with a male predominance. The most reported associations are cHL with follicular lymphoma or diffuse large B-cell lymphoma, with over 130 cases reported. The cHL contingent is often of mixed cellularity type, with a more frequent focal/weak CD20 expression (30% to 55.6%) compared to de novo cHL, suggesting a particular pathophysiology. Moreover, Hodgkin cells may express specific markers of the associated lymphoma (e.g., BCL2/BCL6 for follicular lymphoma and Cyclin D1 for mantle cell lymphoma), sometimes combined with common or rearrangements, respectively. In addition, both contingents may share similar / rearrangements and identical pathogenic variants, reinforcing the hypothesis of a common clonal origin. Finally, cHL appears to be endowed with a greater plasticity than previously thought, supporting a common clonal origin and a transdifferentiation process during lymphomagenesis of composite lymphomas." 15020;"Gut Microbiota Host-Gene Interaction.";"A. IANNELLI";"Team 08, Equipe 08";36430197;"International journal of molecular sciences";"Cuomo P, Capparelli R, Alifano M, Iannelli A, Iannelli D";;"Nov 2022";1669420800;;"Studies carried out in the last ten years have shown that the metabolites made up from the gut microbiota are essential for multiple functions, such as the correct development of the immune system of newborns, interception of pathogens, and nutritional enrichment of the diet. Therefore, it is not surprising that alteration of the gut microbiota is the starting point of gastrointestinal infection, obesity, type 2 diabetes, inflammatory bowel disease, colorectal cancer, and lung cancer. Diet changes and antibiotics are the major factors damaging the gut microbiota. Early exposure of the newborns to antibiotics may prevent their correct development of the immune system, exposing them to pathogen infections, allergies, and chronic inflammatory diseases. We already know much on how host genes, microbiota, and the environment interact, owing to experiments in several model animals, especially in mice; advances in molecular technology; microbiota transplantation; and comparative metagenomic analysis. However, much more remains to be known. Longitudinal studies on patients undergoing to therapy, along with the identification of bacteria prevalent in responding patients may provide valuable data for improving therapies." 15012;"Commentary: Facial Aesthetic Dermatological Procedures and Photoprotection in Chinese Populations.";"T. Passeron";"Equipe 12, Team 12";36417087;"Dermatology and therapy";"Liu W, Krutmann J, Tian Y, Granger C, Piquero-Casals J, Trullàs C, Passeron T, Lim HW, Lai W";;"Nov 2022";1669161600;;"The medical literature on aesthetic dermatology has primarily focused on a light-skinned patient population, yet patients of darker skin types have different needs and priorities. In Chinese individuals, key concerns include altered pigmentation, which is perceived to age the individual, and also relates to the Chinese cultural standard of beauty of fair skin; many seek aesthetic treatment for this. Non-invasive cosmetic procedures such as lasers and injections are also gaining in popularity in the Chinese market, but this population is prone to hyperpigmentation as an adverse effect of such procedures. Considered and tailored approaches, both to primary concerns of photoaging and the side effects of cosmetic treatments, are warranted." 15010;"Contrast induced nephropathy after elective infrarenal and complex endovascular repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36412463;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Raffort J";;"Nov 2022";1669075200;; 15007;"Comparison of protocols with respiratory-gated (4D) motion compensation in PET/CT: open-source package for quantification of phantom image quality.";"M. Carles";"Equipe 06, Team 06";36394640;"EJNMMI physics";"Martinez-Movilla A, Mix M, Torres-Espallardo I, Teijeiro E, Bello P, Baltas D, Martí-Bonmatí L, Carles M";;"Nov 2022";1668643200;;"Patient's breathing affects the quality of chest images acquired with positron emission tomography/computed tomography (PET/CT) studies. Movement correction is required to optimize PET quantification in clinical settings. We present a reproducible methodology to compare the impact of different movement compensation protocols on PET image quality. Static phantom images were set as reference values, and recovery coefficients (RCs) were calculated from motion compensated images for the phantoms in respiratory movement. Image quality was evaluated in terms of: (1) volume accuracy (VA) with the NEMA phantom; (2) concentration accuracy (CA) by six refillable inserts within the electron density CIRS phantom; and (3) spatial resolution (R) with the Jaszczak phantom. Three different respiratory patterns were applied to the phantoms. We developed an open-source package to automatically analyze VA, CA and R. We compared 10 different movement compensation protocols available in the Philips Gemini TF-64 PET/CT (4-, 6-, 8- and 10-time bins, 20%-, 30%-, 40%-window width in Inhale and Exhale)." 15005;"Real-life challenges using personalized prognostic scoring systems in acute myeloid leukemia.";"M. Loschi, P. Auberger, T. Cluzeau, G. Robert";"Equipe 02, Team 02";36394159;"Cancer medicine";"Calleja A, Loschi M, Bailly L, Morisot A, Marceau A, Mannone L, Robert G, Auberger P, Preudhomme C, Raynaud S, Subtil F, Sujobert P, Cluzeau T";;"Nov 2022";1668643200;;"Personalized medicine is a challenge for patients with acute myeloid leukemia (AML). The identification of several genetic mutations in several AML trials led to the creation of a personalized prognostic scoring algorithm known as the Knowledge Bank (KB). In this study, we assessed the prognostic value of this algorithm on a cohort of 167 real life AML patients. We compared KB predicted outcomes to real-life outcomes. For patients younger than 60-year-old, OS was similar in favorable and intermediate ELN risk category. However, KB algorithm failed to predict OS for younger patients in the adverse ELN risk category and for patients older than 60 years old in the favorable ELN risk category. These discrepancies may be explained by the emergence of several new therapeutic options as well as the improvement of allogeneic stem cell transplantation (aHSCT) outcomes and supportive cares. Personalized medicine is a major challenge and predictions models are powerful tools to predict patient's outcome. However, the addition of new therapeutic options in the field of AML requires a prospective validation of these scoring systems to include recent therapeutic innovations." 15001;"Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy.";"E. Ferrari";"Equipe 09, Team 09";36380143;Leukemia;"Cheung LC, Aya-Bonilla C, Cruickshank MN, Chiu SK, Kuek V, Anderson D, Chua GA, Singh S, Oommen J, Ferrari E, Hughes AM, Ford J, Kunold E, Hesselman MC, Post F, Faulk KE, Breese EH, Guest EM, Brown PA, Loh ML, Lock RB, Kees UR, Jafari R, Malinge S, Kotecha RS";;"Nov 2022";1668470400;;"Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL." 14998;"Twenty-year experience with skeletonized bilateral internal thoracic arteries for surgical myocardial revascularization. A single center experience.";"E. Ferrari";"Equipe 09, Team 09";36378881;"Journal of cardiac surgery";"Torre TM, Toto F, Klersy C, Theologou T, Pozzoli A, Ferrari E, Demertzis S";;"Nov 2022";1668470400;;"The mammary artery shows excellent long-term patency and encourages the use of skeletonized bilateral internal thoracic arteries (BITA) for coronary surgery. We analyzed the long-term outcome of patients operated for myocardial revascularization with BITA in a single center." 14996;"Bariatric surgery reduces the risk of pancreatic cancer in individuals with obesity before the age of 50 years: A nationwide administrative data study in France.";"A. IANNELLI";"Team 08, Equipe 08";36376141;"European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology";"Bulsei J, Chierici A, Alifano M, Castaldi A, Drai C, De Fatico S, Rosso E, Fontas E, Iannelli A";;"Nov 2022";1668384000;;"Obesity is a well-established risk factor for pancreatic cancer. Bariatric surgery has demonstrated superior results in terms of weight loss and obesity-related comorbidities compared to medical and behavioral treatments. The aim of this study is to evaluate the effect of bariatric surgery on pancreatic cancer incidence in individuals with obesity." 14988;"Timely Leukapheresis May Interfere with the ""Fitness"" of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients.";"E. Ferrari";"Equipe 09, Team 09";36358694;Cancers;"Farina M, Chiarini M, Almici C, Accorsi Buttini E, Zuccalà F, Piva S, Volonghi I, Poli L, Bernardi S, Colnaghi F, Re F, Leoni A, Polverelli N, Turra A, Morello E, Galvagni A, Moratto D, Brugnoni D, Cattaneo C, Ferrari E, Bianchetti A, Malagola M, Re A, Russo D";;"Nov 2022";1668124800;;"The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematological diseases. However, approximately 60% of patients relapse after CAR-T cell therapy, and no clear cause for this failure has been identified. The objective of the Bio-CAR-T BS study (ClinicalTrials.gov: NCT05366569) is to improve our understanding of the lymphocyte harvest to maximize the quality of the CAR-T cell product. Of the 14 patients enrolled, 11 were diagnosed with DLBCL, 2 with PMBCL, and 1 with ALL. Five of 11 DLBCL patients met the criteria for ""pre-emptive"" Lymphocytes-apheresis (being at high risk of second relapse), and 6 were included in the standard-of-care Lymphocytes-apheresis group. Previous autologous stem cell transplantation (ASCT) and age were significantly different between the two groups. At the time of Lymphocyte-apheresis, patients in the ""pre-emptive"" group had more ""fit"" lymphocytes (higher CD4+/CD8+ ratio; higher naïve T cells levels) compared with standard group, probably due to the impact of ASCT. At the same time, also being older than 60 years results in a more ""exhausted"" lymphocyte profile. Overall, ""pre-emptive"" Ly-apheresis in DLBCL patients at high risk of relapse appears to be feasible and may allow the timely collection of ""fit"" lymphocytes for CAR-T cell manufacturing." 14986;"Short-Term Exposure to Nanoplastics Does Not Affect Bisphenol A Embryotoxicity to Marine Ascidian .";"E. Ferrari";"Equipe 09, Team 09";36359011;Biomolecules;"Ferrari E, Eliso MC, Bellingeri A, Corsi I, Spagnuolo A";;"Nov 2022";1668124800;;"Plastic pollution is recognized as a global environmental threat and concern is increasing regarding the potential interactions of the smallest fragments, nanoplastics (1 µm), with either physical and chemical entities encountered in the natural environment, including toxic pollutants. The smallest size of nanoplastics (<100nm) rebounds to their safety associated with remarkable biological, chemical and physical reactivity that allow them to interact with cellular machinery by crossing biological barriers and causing damage to living beings. Recent findings on nanoplastic occurrence in marine coastal waters, including the Mediterranean Sea, leave open the question on their ability to act as a vector of other contaminants of emerging concerns (CECs) concomitantly released by wastewater treatment plants and reaching marine coastal waters. Here, we assess for the first time the role of non-functionalized polystyrene nanoparticles (PS NPs, 20 nm) as a proxy for nanoplastics (1 and 10 µg/mL) alone and in combination with bisphenol A (BPA) (4.5 and 10 µM) on embryos (22 h post fertilization, hpf) by looking at embryotoxicity through phenotypic alterations. We confirmed the ability of BPA to impact ascidian embryo development, by affecting sensory organs pigmentation, either alone and in combination with PS NPs. Our findings suggest that no interactions are taking place between PS NPs and BPA in filtered sea water (FSW) probably due to the high ionic strength of seawater able to trigger the sorption surface properties of PS NPs. Further studies are needed to elucidate such peculiarities and define the risk posed by combined exposure to BPA and PS NPs in marine coastal waters." 14984;"AC/DC Thermal Nano-Analyzer Compatible with Bulk Liquid Measurements.";"E. Ferrari";"Equipe 09, Team 09";36364575;"Nanomaterials (Basel, Switzerland)";"Odarchenko Y, Kaźmierczak-Bałata A, Bodzenta J, Ferrari E, Soloviev M";;"Nov 2022";1668124800;;"Nanocalorimetry, or thermal nano-analysis, is a powerful tool for fast thermal processing and thermodynamic analysis of materials at the nanoscale. Despite multiple reports of successful applications in the material sciences to study phase transitions in metals and polymers, thermodynamic analysis of biological systems in their natural microenvironment has not been achieved yet. Simply scaling down traditional calorimetric techniques, although beneficial for material sciences, is not always appropriate for biological objects, which cannot be removed out of their native biological environment or be miniaturized to suit instrument limitations. Thermal analysis at micro- or nano-scale immersed in bulk liquid media has not yet been possible. Here, we report an AC/DC modulated thermal nano-analyzer capable of detecting nanogram quantities of material in bulk liquids. The detection principle used in our custom-build instrument utilizes localized heat waves, which under certain conditions confine the measurement area to the surface layer of the sample in the close vicinity of the sensing element. To illustrate the sensitivity and quantitative capabilities of the instrument we used model materials with detectable phase transitions. Here, we report ca. 10 improvement in the thermal analysis sensitivity over a traditional DSC instrument. Interestingly, fundamental thermal properties of the material can be determined independently from heat flow in DC (direct current) mode, by using the AC (alternating current) component of the modulated heat in AC/DC mode. The thermal high-frequency AC modulation mode might be especially useful for investigating thermal transitions on the surface of material, because of the ability to control the depth of penetration of AC-modulated heat and hence the depth of thermal sensing. The high-frequency AC mode might potentially expand the range of applications to the surface analysis of bulk materials or liquid-solid interfaces." 14982;"Cardiac surgery simulation - part 1: Step-by-step David procedure in a preclinical model.";"E. Ferrari";"Equipe 09, Team 09";36373767;"Multimedia manual of cardiothoracic surgery : MMCTS";"Pozzoli A, Toto F, Torre T, Zurfluh C, Ferrari E, Demertzis S";;"Nov 2022";1668384000;;"We performed this operation on a preclinical model (porcine heart) that has been positioned and fixed inside a plastic mannequin that simulates the human anatomy. This simulation allows surgical operations to be performed at almost the same depth and orientation at which they would be performed on a patient in an operating room. The preclinical model allows the exact simulation of most of the key movements and steps of major coronary and valve surgery. In this case, we show the salient steps of the David I operation." 14980;"BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";36375119;Blood;"Delage L, Lambert M, Bardel E, Kundlacz C, Chartoire D, Conchon A, Peugnet AL, Gorka L, Auberger P, Jacquel A, Soussain C, Destaing O, Delecluse HJ, Delecluse S, Merabet S, Traverse-Glehen A, Salles GA, Bachy E, Billaud M, Ghesquieres H, Genestier L, Rouault JP, Sujobert P";;"Nov 2022";1668384000;;"Understanding the functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B cell lymphoma (DLBCL), which is associated with extranodal dissemination. There, we provide evidence that Btg1 knock-out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. We further show that the scaffolding protein BCAR1 is a BTG1 partner. Furthermore, following BTG1 deletion or expression of BTG1 mutations observed in DLBCL patients, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL." 14978;"Non-V600E/K BRAF Mutations in Metastatic Melanoma: Molecular Description, Frequency, and Effectiveness of Targeted Therapy in a Large National Cohort.";"H. Montaudie";"Equipe 12, Team 12";36356284;"JCO precision oncology";"Girod M, Dalle S, Mortier L, Dalac S, Leccia MT, Dutriaux C, Montaudié H, de Quatrebarbes J, Lesimple T, Brunet-Possenti F, Saiag P, Maubec E, Legoupil D, Stoebner PE, Arnault JP, Lefevre W, Lebbe C, Dereure O";;"Nov 2022";1668038400;;"Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF-mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce." 14962;"Clinical Features, Histological Characteristics, and Disease Outcomes of Mycosis Fungoides in Children and Adolescents: A Nationwide Multicentre Cohort of 46 Patients.";"C. Chiaverini";"Equipe 12, Team 12";36349768;"Dermatology (Basel, Switzerland)";"Welfringer-Morin A, Barroil M, Fraitag S, Szablewski V, Boccara O, Lacour JP, Chiaverini C, Bagot M, Ram-Wolff C, Vignon-Pennamen MD, Dalle S, D'incan M, Amatore F, Beylot-Barry M, Vergier B, Mazereeuw-Hautier J, Tedbirt B, Quereux G, Carpentier O, Skowron F, Bertrand Y, Van Eeckhout P, Dekeuleneer V, Nardin C, Adamski H, Ingen-Housz-Oro S, Dereure O, Bodemer C";;"Nov 2022";1667952000;;"Our objective was to describe the clinical, histological characteristics, and disease outcome of a cohort of mycosis fungoides (MF) diagnosed during childhood including disease status at adulthood." 14960;"An optimized measles virus glycoprotein-pseudotyped lentiviral vector production system to promote efficient transduction of human primary B cells.";"E. Verhoeyen";"Team 03, Equipe 03";35284833;"STAR protocols";"Vamva E, Ozog S, Verhoeyen E, James RG, Rawlings DJ, Torbett BE";;"Mar 2022";1647216000;;"Measles virus envelope pseudotyped LV (MV-LV) can achieve high B cell transduction rates (up to 50%), but suffers from low titers. To overcome current limitations, we developed an optimized MV-LV production protocol that achieved consistent B cell transduction efficiency up to 75%. We detail this protocol along with analytical assays to assess the results of MV-LV mediated B cell transduction, including flow cytometry for B cell phenotypic characterization and measurement of transduction efficiency, and ddPCR for VCN analysis." 14945;"Transcatheter mitral valve replacement in native mitral valve with severe mitral annular calcification: Skirting the Sapien 3 to reduce the risk of paravalvular leaks.";"E. Ferrari";"Equipe 09, Team 09";36337909;"Frontiers in cardiovascular medicine";"Pozzoli A, Torre T, Pedrazzini G, Demertzis S, Ferrari E";;"Nov 2022";1667779200;;"Mitral annular calcification (MAC) may represent a significant challenge for heart surgeons with an extremely high perioperative risk during mitral valve (MV) surgery. The risk is further increased when patients fail to be eligible for any percutaneous treatment, particularly because circumferential calcifications involving the anterior leaflet suggest a critical obstruction of the left ventricular outflow tract (LVOT)." 14943;"[Visual and auditory hallucinations in a 80 year-old man].";"N. Martis";"Equipe 10, Team 10";36335046;"La Revue de medecine interne";"Volle G, Alexandre C, Rotenberg L, Derobertmasure A, Michon A, Flamarion E, Ranque B, Arlet JB, Pouchot J, Martis N";;"Nov 2022";1667606400;; 14941;"24/7 workflow for bloodstream infection diagnostics in microbiology laboratories: the first step to improve clinical management.";"M. Carles, R. Ruimy, R. Lotte";"Equipe 06, Team 06";36326696;"Clinical chemistry and laboratory medicine";"Chirio D, Demonchy E, Le Marechal M, Gaudart A, Lotte R, Carles M, Ruimy R";;"Nov 2022";1667433600;;"We aimed to evaluate the impact of an uninterrupted workflow regarding blood cultures on turnaround time and antibiotic prescription." 14937;"SUN2 regulates mitotic duration in response to extracellular matrix rigidity.";"N. Vaillant";"Equipe 13, Team 13";36322767;"Proceedings of the National Academy of Sciences of the United States of America";"Belaadi N, Pernet L, Aureille J, Chadeuf G, Rio M, Vaillant N, Vitiello E, Lafanechère L, Loirand G, Guilluy C";;"Nov 2022";1667347200;;"How cells adjust their growth to the spatial and mechanical constraints of their surrounding environment is central to many aspects of biology. Here, we examined how extracellular matrix (ECM) rigidity affects cell division. We found that cells divide more rapidly when cultured on rigid substrates. While we observed no effect of ECM rigidity on rounding or postmitotic spreading duration, we found that changes in matrix stiffness impact mitosis progression. We noticed that ECM elasticity up-regulates the expression of the linker of nucleoskeleton and cytoskeleton (LINC) complex component SUN2, which in turn promotes metaphase-to-anaphase transition by acting on mitotic spindle formation, whereas when cells adhere to soft ECM, low levels of SUN2 expression perturb astral microtubule organization and delay the onset of anaphase." 14935;"Risk of subsequent primary oral cancer in a cohort of 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.";"G. MICHEL";"Equipe 06, Team 06";36319851;"British journal of cancer";"Sunguc C, Hawkins MM, Winter DL, Dudley IM, Heymer EJ, Teepen JC, Allodji RS, Belle FN, Bagnasco F, Byrne J, Bárdi E, Ronckers CM, Haddy N, Gudmundsdottir T, Garwicz S, Jankovic M, van der Pal HJH, Mazić MČ, Schindera C, Grabow D, Maule MM, Kaatsch P, Kaiser M, Fresneau B, Michel G, Skinner R, Wiebe T, Sacerdote C, Jakab Z, Gunnes MW, Terenziani M, Winther JF, Lähteenmäki PM, Zaletel LZ, Kuehni CE, Kremer LC, Haupt R, de Vathaire F, Hjorth L, Reulen RC";;"Nov 2022";1667347200;;"Survivors of childhood cancer are at risk of subsequent primary malignant neoplasms (SPNs), but the risk for rarer types of SPNs, such as oral cancer, is uncertain. Previous studies included few oral SPNs, hence large-scale cohorts are required to identify groups at risks." 14933;"Author Correction: Endosomal trafficking in metabolic homeostasis and diseases.";"J. GILLERON";"Equipe 07, Team 07";36316393;"Nature reviews. Endocrinology";"Gilleron J, Zeigerer A";;"Nov 2022";1667260800;; 14929;"LifeSnaps, a 4-month multi-modal dataset capturing unobtrusive snapshots of our lives in the wild.";"E. Ferrari";"Equipe 09, Team 09";36316345;"Scientific data";"Yfantidou S, Karagianni C, Efstathiou S, Vakali A, Palotti J, Giakatos DP, Marchioro T, Kazlouski A, Ferrari E, Girdzijauskas Š";;"Nov 2022";1667260800;;"Ubiquitous self-tracking technologies have penetrated various aspects of our lives, from physical and mental health monitoring to fitness and entertainment. Yet, limited data exist on the association between in the wild large-scale physical activity patterns, sleep, stress, and overall health, and behavioral and psychological patterns due to challenges in collecting and releasing such datasets, including waning user engagement or privacy considerations. In this paper, we present the LifeSnaps dataset, a multi-modal, longitudinal, and geographically-distributed dataset containing a plethora of anthropological data, collected unobtrusively for the total course of more than 4 months by n = 71 participants. LifeSnaps contains more than 35 different data types from second to daily granularity, totaling more than 71 M rows of data. The participants contributed their data through validated surveys, ecological momentary assessments, and a Fitbit Sense smartwatch and consented to make these data available to empower future research. We envision that releasing this large-scale dataset of multi-modal real-world data will open novel research opportunities and potential applications in multiple disciplines." 14927;"RNA-seq analysis of brain aging in wild specimens of short-lived turquoise killifish. Commonalities and differences with aging under laboratory conditions.";"E. Ferrari";"Equipe 09, Team 09";36318827;"Molecular biology and evolution";"Mazzetto M, Caterino C, Groth M, Ferrari E, Reichard M, Baumgart M, Cellerino A";;"Nov 2022";1667260800;;"A vast body of studies is available that describes age-dependent gene expression in relationship to aging in a number of different model species. These data were obtained from animals kept in conditions with reduced environmental challenges, abundant food and deprivation of natural sensory stimulation. Here we compared wild- and captive-aging in the short-lived turquoise killifish (Nothobranchius furzeri). These fish inhabit temporary ponds in the African savannah. When the ponds are flooded, eggs hatch synchronously, enabling a precise timing of their individual and population age. We collected brains of wild fish of different ages and quantified the global age-dependent regulation of transcripts using RNA-seq. A major difference between captive and wild population is that wild population had unlimited access to food, and hence grew to larger sizes and reached asymptotic size more rapidly, enabling the analysis of age-dependent gene expression without the confounding effect of adult brain growth. We found that the majority of differentially-expressed genes show the same direction of regulation in wild and captive population. However, a number of genes were regulated in opposite direction. Genes down-regulated in the wild and up-regulated in captivity were enriched for terms related to neuronal communication. Genes up-regulated in the wild and down-regulated in captive conditions were enriched in terms related to DNA replication. Finally, the rate of age-dependent gene regulation was higher in the wild animals suggesting a phenomenon of accelerated aging." 14925;"Remembering Jean Paul Ortonne.";"T. Passeron";"Equipe 12, Team 12";36306874;"The Journal of investigative dermatology";"Passeron T";;"Oct 2022";1666915200;; 14923;"Editorial: The path towards precision health: Prospects and challenges.";"M. Stathopoulou";"Equipe 10, Team 10";36304186;"Frontiers in medicine";"Ibrahim ME, Hussein A, Stathopoulou MG, Visvikis-Siest S";;"Oct 2022";1666915200;; 14921;"Telemedicine and Digital Health Applications in Vascular Surgery.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36294368;"Journal of clinical medicine";"Lareyre F, Chaptoukaev H, Kiang SC, Chaudhuri A, Behrendt CA, Zuluaga MA, Raffort J";;"Oct 2022";1666828800;;"Telemedicine has the potential to revolutionize healthcare. While the development of digital health technologies for the management of patients with cardiovascular diseases has been increasingly reported, applications in vascular surgery have been far less specifically investigated. The aim of this review is to summarize applications related to telemedicine in vascular surgery, highlighting expected benefits, current limits and future directions." 14916;"MANAGEMENT OF LEFT SUBCLAVIAN ARTERY IN TYPE-B AORTIC DISSECTION TREATED WITH THORACIC ENDOVASCULAR AORTA REPAIR.";"E. Ferrari";"Equipe 09, Team 09";36272506;"Journal of vascular surgery";"Wang C, Pozzoli A, Karl von Segesser L, Berdajs D, Tozzi P, Ferrari E";;"Oct 2022";1666396800;;"Thoracic endovascular aortic repair (TEVAR) is the favoured approach to treat Type-B aortic dissections (TBAD). In order to obtain an adequate proximal landing zone, the coverage of the left subclavian artery (LSA) is often necessary. Possible neurological complications are still under debate. We investigated the management of LSA in TBAD patients undergoing endovascular repair." 14912;"Oral health status in patients with inherited epidermolysis bullosa: a comparative multicenter study.";"C. Chiaverini";"Equipe 12, Team 12";36268944;"Quintessence international (Berlin, Germany : 1985)";"Joseph C, Marty M, Dridi SM, Verhaeghe V, Bailleul-Forestier I, Chiaverini C, Hubiche T, Mazereeuw-Hautier J, Deny O, Declerck D, Kémoun P";;"Oct 2022";1666310400;;"Epidermolysis bullosa (EB) is a rare genetic mucocutaneous disorder characterized by epithelial fragility leading to blister formation on skin and mucous membranes with even minor mechanical trauma. Most EB oral health publications give fragmented information, focusing on only one oral health aspect or one EB type. The aim of this study was to expand the knowledge of the overall oral health status of individuals with dystrophic, junctional, and simplex EB." 14910;"Additional prognostic value of echocardiographic follow-up in pulmonary hypertension-role of 3D right ventricular area strain.";"E. Ferrari";"Equipe 09, Team 09";36265185;"European heart journal. Cardiovascular Imaging";"Moceri P, Duchateau N, Baudouy D, Squara F, Bun SS, Ferrari E, Sermesant M";;"Oct 2022";1666224000;;"Outcomes in pulmonary hypertension (PH) are related to right ventricular (RV) function and remodelling. We hypothesized that changes in RV function and especially area strain (AS) could provide incremental prognostic information compared to the use of baseline data only. We therefore aimed to assess RV function changes between baseline and 6-month follow-up and evaluate their prognostic value for PH patients using 3D echocardiography." 14908;"Textile microfibers in wild Antarctic whelk Neobuccinum eatoni (Smith, 1875) from Terra Nova Bay (Ross Sea, Antarctica).";"E. Ferrari";"Equipe 09, Team 09";36265599;"Environmental research";"Bergami E, Ferrari E, Löder MGJ, Birarda G, Laforsch C, Vaccari L, Corsi I";;"Oct 2022";1666224000;;"Antarctica has been affected directly and indirectly by human pressure for more than two centuries and recently plastic pollution has been recognized as a further potential threat for its unique biodiversity. Global long-range transport as well as local input from anthropogenic activities are potential sources of plastic pollution in both terrestrial and marine Antarctic territories. The present study evaluated the presence of microplastics in specimens of the Antarctic whelk Neobuccinum eatoni, a key species in benthic communities of the Ross Sea, one of the largest marine protected areas worldwide. To this aim, a thermo-oxidative extraction method was applied for microplastic isolation and quantification, and polymer identification was performed by manual μ-FTIR spectroscopy. Textile (semi-)synthetic or composite microfibers (length range: 0.8-5.7 mm) were found in 27.3% of whelk specimens, suggesting a low risk of bioaccumulation along Antarctic benthic food webs in the Ross Sea. Their polymer composition (of polyethylene terephthalate and cellulose-polyamide composites) matched those of outdoor technical clothing in use by the personnel of the Italian ""Mario Zucchelli"" station near Terra Nova Bay in the Ross Sea. Such findings indicate that sewage from base stations may act as potential local sources of textile microplastic fibers in this remote environment. More in-depth monitoring studies aiming at defining the extent of microplastic contamination related to such sources in Antarctica are encouraged." 14906;"The Role of mRNA Translational Control in Tumor Immune Escape and Immunotherapy Resistance.";"M. Cerezo";"Equipe 12, Team 12";34470777;"Cancer research";"Cerezo M, Robert C, Liu L, Shen S";;"Sep 2021";1630540800;;"Tremendous advances have been made in cancer immunotherapy over the last decade. Among the different steps of gene expression, translation of mRNA is emerging as an essential player in both cancer and immunity. Changes in mRNA translation are both rapid and adaptive, and translational reprogramming is known to be necessary for sustaining cancer cell proliferation. However, the role of mRNA translation in shaping an immune microenvironment permissive to tumors has not been extensively studied. Recent studies on immunotherapy approaches have indicated critical roles of mRNA translation in regulating the expression of immune checkpoint proteins, tuning the secretion of inflammation-associated factors, modulating the differentiation of immune cells in the tumor microenvironment, and promoting cancer resistance to immunotherapies. Careful consideration of the role of mRNA translation in the tumor-immune ecosystem could suggest more effective therapeutic strategies and may eventually change the current paradigm of cancer immunotherapy. In this review, we discuss recent advances in understanding the relationship between mRNA translation and tumor-associated immunity, the potential mechanisms of immunotherapy resistance in cancers linked to translational reprogramming, and therapeutic perspectives and potential challenges of modulating translational regulation in cancer immunotherapy." 14904;"Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma.";"M. Cerezo";"Equipe 12, Team 12";30374200;"Nature medicine";"Cerezo M, Guemiri R, Druillennec S, Girault I, Malka-Mahieu H, Shen S, Allard D, Martineau S, Welsch C, Agoussi S, Estrada C, Adam J, Libenciuc C, Routier E, Roy S, Désaubry L, Eggermont AM, Sonenberg N, Scoazec JY, Eychène A, Vagner S, Robert C";;"Oct 2018";1540944000;;"Preventing the immune escape of tumor cells by blocking inhibitory checkpoints, such as the interaction between programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) receptor, is a powerful anticancer approach. However, many patients do not respond to checkpoint blockade. Tumor PD-L1 expression is a potential efficacy biomarker, but the complex mechanisms underlying its regulation are not completely understood. Here, we show that the eukaryotic translation initiation complex, eIF4F, which binds the 5' cap of mRNAs, regulates the surface expression of interferon-γ-induced PD-L1 on cancer cells by regulating translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor. eIF4F complex formation correlates with response to immunotherapy in human melanoma. Pharmacological inhibition of eIF4A, the RNA helicase component of eIF4F, elicits powerful antitumor immune-mediated effects via PD-L1 downregulation. Thus, eIF4A inhibitors, in development as anticancer drugs, may also act as cancer immunotherapies." 14902;"Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo.";"T. Passeron";"Equipe 12, Team 12";36260792;"The New England journal of medicine";"Rosmarin D, Passeron T, Pandya AG, Grimes P, Harris JE, Desai SR, Lebwohl M, Ruer-Mulard M, Seneschal J, Wolkerstorfer A, Kornacki D, Sun K, Butler K, Ezzedine K, ";;"Oct 2022";1666137600;;"Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo." 14881;"Lysine Methyltransferase NSD1 and Cancers: Any Role in Melanoma?";"C. Bertolotto, R. Ballotti";"Equipe 01, Team 01";36230787;Cancers;"Krossa I, Strub T, Aplin AE, Ballotti R, Bertolotto C";;"Oct 2022";1665705600;;"Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers." 14879;"Long-Term Results at 10 Years of Pouch Resizing for Roux-en-Y Gastric Bypass Failure.";"A. IANNELLI";"Team 08, Equipe 08";36235686;Nutrients;"Drai C, Chierici A, Schiavo L, Mazahreh TS, Schneck AS, Iannelli A";;"Oct 2022";1665705600;;"Roux-en-Y gastric bypass (RYGB) is currently one of the most performed bariatric procedures and it is associated with rapid weight loss. However, weight loss failure and weight regain after RYGB occurs in approximately 30% and 3-5% of patients, respectively, and represent a serious issue. RYGB pouch resizing is a surgical option that may be offered to selected patients with RYGB failure. The aim of this study is to assess long-term results of pouch resizing for RYGB failure." 14877;"Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division.";"A. Doye, J. GILLERON";"Equipe 06, Team 06, Equipe 07, Team 07";36229487;"Nature communications";"Petracchini S, Hamaoui D, Doye A, Asnacios A, Fage F, Vitiello E, Balland M, Janel S, Lafont F, Gupta M, Ladoux B, Gilleron J, Maia TM, Impens F, Gagnoux-Palacios L, Daugaard M, Sorensen PH, Lemichez E, Mettouchi A";;"Oct 2022";1665619200;;"Extracellular matrix (ECM) elasticity is perceived by cells via focal adhesion structures, which transduce mechanical cues into chemical signalling to conform cell behavior. Although the contribution of ECM compliance to the control of cell migration or division is extensively studied, little is reported regarding infectious processes. We study this phenomenon with the extraintestinal Escherichia coli pathogen UTI89. We show that UTI89 takes advantage, via its CNF1 toxin, of integrin mechanoactivation to trigger its invasion into cells. We identify the HACE1 E3 ligase-interacting protein Optineurin (OPTN) as a protein regulated by ECM stiffness. Functional analysis establishes a role of OPTN in bacterial invasion and integrin mechanical coupling and for stimulation of HACE1 E3 ligase activity towards the Rac1 GTPase. Consistent with a role of OPTN in cell mechanics, OPTN knockdown cells display defective integrin-mediated traction force buildup, associated with limited cellular invasion by UTI89. Nevertheless, OPTN knockdown cells display strong mechanochemical adhesion signalling, enhanced Rac1 activation and increased cyclin D1 translation, together with enhanced cell proliferation independent of ECM stiffness. Together, our data ascribe a new function to OPTN in mechanobiology." 14875;"Low baseline IFN-γ response could predict hospitalization in COVID-19 patients.";"M. Carles, M. Ticchioni";"Equipe 06, Team 06, Equipe 11, Team 11";36225915;"Frontiers in immunology";"Cremoni M, Allouche J, Graça D, Zorzi K, Fernandez C, Teisseyre M, Benzaken S, Ruetsch-Chelli C, Esnault VLM, Dellamonica J, Carles M, Barrière J, Ticchioni M, Brglez V, Seitz-Polski B";;"Oct 2022";1665619200;;"The SARS-CoV-2 infection has spread rapidly around the world causing millions of deaths. Several treatments can reduce mortality and hospitalization. However, their efficacy depends on the choice of the molecule and the precise timing of its administration to ensure viral clearance and avoid a deleterious inflammatory response. Here, we investigated IFN-γ, assessed by a functional immunoassay, as a predictive biomarker for the risk of hospitalization at an early stage of infection or within one month prior to infection. Individuals with IFN-γ levels below 15 IU/mL were 6.57-times more likely to be hospitalized than those with higher values (p65 years, and no vaccination were independently associated with hospitalization. In addition, we found a significant inverse correlation between low IFN-γ response and high level of IL-6 in plasma (Spearman's rho=-0.38, p=0.003). Early analysis of the IFN-γ response in a contact or recently infected subject with SARS-CoV-2 could predict hospitalization and thus help the clinician to choose the appropriate treatment avoiding severe forms of infection and hospitalization." 14871;"Avdoralimab (Anti-C5aR1 mAb) Versus Placebo in Patients With Severe COVID-19: Results From a Randomized Controlled Trial (FOR COVID Elimination [FORCE]).";"M. Carles, J. Courjon";"Equipe 06, Team 06";36218354;"Critical care medicine";"Carvelli J, Meziani F, Dellamonica J, Cordier PY, Allardet-Servent J, Fraisse M, Velly L, Barbar SD, Lehingue S, Guervilly C, Desgrouas M, Camou F, Piperoglou C, Vely F, Demaria O, Karakunnel J, Fares J, Batista L, Rotolo F, Viotti J, Boyer-Chammard A, Lacombe K, Le Dault E, Carles M, Schleinitz N, Vivier E, ";;"Oct 2022";1665446400;;"Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19." 14869;"Endosomal trafficking in metabolic homeostasis and diseases.";"J. GILLERON";"Equipe 07, Team 07";36216881;"Nature reviews. Endocrinology";"Gilleron J, Zeigerer A";;"Oct 2022";1665360000;;"The global prevalences of obesity and type 2 diabetes mellitus have reached epidemic status, presenting a heavy burden on society. It is therefore essential to find novel mechanisms and targets that could be utilized in potential treatment strategies and, as such, intracellular membrane trafficking has re-emerged as a regulatory tool for controlling metabolic homeostasis. Membrane trafficking is an essential physiological process that is responsible for the sorting and distribution of signalling receptors, membrane transporters and hormones or other ligands between different intracellular compartments and the plasma membrane. Dysregulation of intracellular transport is associated with many human diseases, including cancer, neurodegeneration, immune deficiencies and metabolic diseases, such as type 2 diabetes mellitus and its associated complications. This Review focuses on the latest advances on the role of endosomal membrane trafficking in metabolic physiology and pathology in vivo, highlighting the importance of this research field in targeting metabolic diseases." 14867;"Outcomes after allogeneic hematopoietic stem cell transplantation for adults with primary mediastinal B cell lymphoma: a SFGM-TC and LYSA study.";"M. Loschi";"Equipe 02, Team 02";36214787;"Acta oncologica (Stockholm, Sweden)";"Le Calvez B, Tessoullin B, Renaud L, Botella-Garcia C, Srour M, Le Gouill S, Guillerm G, Gressin R, Nguyen Quoc S, Furst S, Chauchet A, Sibon D, Lewalle P, Poiré X, Maillard N, Villate A, Loschi M, Paillassa J, Beguin Y, Dulery R, Tudesq JJ, Fayard A, Béné MC, Camus V, Chevallier P, Le Bourgeois A";;"Oct 2022";1665360000;;" Despite therapeutic progress, 10 to 30% of adult patients with primary mediastinal B cell lymphoma (PMBCL) are primary refractory or experience early relapse (R/R). Allogeneic stem cell transplantation (allo-HSCT) thus remains a potentially curative option in this setting. In this multicenter retrospective study, the outcomes of 33 French and Belgian adult patients allo-transplanted for R/R PMBCL between January 1999 and December 2018, were examined. At allo-HSCT time, patients had received a median of 3 treatment lines, 50% of them were in complete response, 40% in partial response and 10% had a progressive disease. Forty-two percent of the donors were siblings and 39% matched related. The median follow-up for alive patients was 78 months (3.5-157). Considering the whole cohort, 2-year overall survival (OS), progression free survival (PFS) and graft-versus-host disease-free/relapse-free survival (GRFS) were 48% (95%CI: 33-70), 47% (95%CI: 33-68) and 38.5% (95%CI: 25-60) respectively. Cumulative incidence of relapse and non-relapse mortality rates were respectively 34% (95%CI: 18-50) and 18% (95%CI: 7-34). Disease status at transplant was the only factor predicting survivals, patients with progressive disease showing significant lower 2-year PFS (HR: 6.12, 95%CI: 1.32-28.31,  = 0.02) and OS (HR: 7.04, 95%CI: 1.52-32.75,  = 0.013). A plateau was observed for OS and PFS after 4 years with 10 patients alive after this date, suggesting that almost one third of the patients effectively salvaged and undergoing allo-SCT could be cured. This study indicates that allo-HSCT is a valid therapeutic option for R/R PMBCL, providing durable remissions." 14865;"Leishmaniasis epidemiology in endemic areas of metropolitan France and its overseas territories from 1998 to 2020.";"P. Marty";"Equipe 06, Team 06";36206322;"PLoS neglected tropical diseases";"Pasquier G, Demar M, Lami P, Zribi A, Marty P, Buffet P, Desbois-Nogard N, Gangneux JP, Simon S, Blaizot R, Couppié P, Thiebaut L, Pratlong F, Dedet JP, Bastien P, Sterkers Y, Ravel C, Lachaud L, ";;"Oct 2022";1665100800;;"In France, leishmaniasis is endemic in the Mediterranean region, in French Guiana and to a lesser extent, in the French West Indies. This study wanted to provide an updated picture of leishmaniasis epidemiology in metropolitan France and in its overseas territories." 14850;"Standard Versus Rapid-Deployment Aortic Valve Replacement and Concomitant Myocardial Revascularization: 5-year Bi-Center Clinical Outcomes.";"E. Ferrari";"Equipe 09, Team 09";36190347;"European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery";"Bottio T, Piperata A, Guariento A, Lorenzoni G, Cavicchiolo AG, Gemelli M, Pesce R, Evangelista G, Michelotti S, Gastino E, Gregori D, Ferrari E, Gerosa G";;"Oct 2022";1664755200;;"Clinical outcomes of two generations of pericardial bioprostheses in concomitant aortic valve and coronary artery bypass graft surgery were analyzed." 14846;"Outcomes in the Treatment of Aberrant Subclavian Arteries using Hybrid Approach.";"E. Jean-Baptiste, N. Sadaghianloo, R. Hassen-Khodja";"Team 09, Equipe 09";36179094;"Interactive cardiovascular and thoracic surgery";"Ben Ahmed S, Settembre N, Touma J, Brouat A, Favre JP, Jean Baptiste E, Chaufour X, Rosset E, ";;"Sep 2022";1664496000;;"Aberrant subclavian artery is rare but one of the most frequent anatomical variations of the supra-aortic trunks. No consensus has been established on its best treatment. The aim of this study was to report the outcomes of aberrant subclavian artery treated by hybrid approach." 14844;"Evaluation of a Sunscreen Product Compared with Reference Standards P3, P5 and P8 in Outdoor Conditions: a Randomized, Double-Blinded, Intra-individual Study in Healthy Subjects.";"T. Passeron";"Equipe 12, Team 12";36173595;"Dermatology and therapy";"Granger C, Petkar G, Hosenally M, Bustos J, Trullàs C, Passeron T, Krutmann J";;"Sep 2022";1664409600;;"The shortcomings of standardized sunscreen testing have been discussed in recent years, noting differences between how sunscreens perform in indoor clinical (in vivo) laboratory testing compared with real-life conditions. We previously developed an outdoor clinical method for ranking sunscreens by performance level. We used this method to test the performance of a new broad-spectrum sunscreen against International Organization for Standardization (ISO) reference products P3, P5 and P8." 14834;"Improving plant disease classification by adaptive minimal ensembling.";"E. Ferrari";"Equipe 09, Team 09";36160929;"Frontiers in artificial intelligence";"Bruno A, Moroni D, Dainelli R, Rocchi L, Morelli S, Ferrari E, Toscano P, Martinelli M";;"Sep 2022";1664150400;;"A novel method for improving plant disease classification, a challenging and time-consuming process, is proposed. First, using as baseline EfficientNet, a recent and advanced family of architectures having an excellent accuracy/complexity trade-off, we have introduced, devised, and applied refined techniques based on transfer learning, regularization, stratification, weighted metrics, and advanced optimizers in order to achieve improved performance. Then, we go further by introducing adaptive minimal ensembling, which is a unique input to the knowledge base of the proposed solution. This represents a leap forward since it allows improving the accuracy with limited complexity using only two EfficientNet-b0 weak models, performing ensembling on feature vectors by a trainable layer instead of classic aggregation on outputs. To the best of our knowledge, such an approach to ensembling has never been used before in literature. Our method was tested on PlantVillage, a public reference dataset used for benchmarking models' performances for crop disease diagnostic, considering both its original and augmented versions. We noticeably improved the state of the art by achieving 100% accuracy in both the original and augmented datasets. Results were obtained using PyTorch to train, test, and validate the models; reproducibility is granted by providing exhaustive details, including hyperparameters used in the experimentation. A Web interface is also made publicly available to test the proposed methods." 14832;"Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching.";"R. ANTY, A. TRAN";"Equipe 08, Team 08";36160737;"World journal of gastrointestinal oncology";"Adhoute X, De Matharel M, Mineur L, Pénaranda G, Ouizeman D, Toullec C, Tran A, Castellani P, Rollet A, Oules V, Perrier H, Si Ahmed SN, Bourliere M, Anty R";;"Sep 2022";1664150400;;"Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available." 14820;"Association between metabolic disorders and seminal plasma miRNA levels: a pilot study.";"V. Grandjean";"Equipe 10, Team 10";35668388;"Basic and clinical andrology";"Saget S, Kappeler L, Grandjean V, Leneuve P, Berthaut I, Faure C, Czernichow S, Racine C, Lévy R, Dupont C, ";;"Jun 2022";1654473600;;"Excess weight and metabolic disorders have a negative impact on male reproductive functions. The mechanisms involved are numerous and complex and epigenetic mechanisms may also be involved, notably through the small non-coding RNAs. Among them, microRNAs (miRNAs) are of particular interest. This preliminary study aimed to identify the miRNAs differentially enriched in seminal plasma related to metabolic disorders and if some are also associated with spermatic parameters alterations. One hundred and sixty men between 18 to 45 years, partners of infertile couple, were included in this cohort. The miRNAs associated with metabolism were selected from the literature and assayed by quantitative real-time PCR using TaqMan gene expression assays. A subset of those with an interesting profile in seminal plasma were secondarily tested in blood." 14818;"[HIV budding, a target for innate antiviral response].";"V. Giordanengo";"Equipe 06, Team 06";36131476;"Virologie (Montrouge, France)";"Giordanengo V, Lemichez E";;"Sep 2022";1663804800;;"The curvature of host cell membranes during the budding of HIV viruses occurs by an opposite topology, as compared to endocytosis and phagocytosis phenomena. This topology of vesicle formation is indeed observed during the formation of internal vesicles of late endosomal compartments called multivesicular bodies (MVB). Formation of these vesicles is controlled by ubiquitylation and the recruitment of the endosomal sorting complex required for transport (ESCRT). The sorting of HIV-1 structural protein Pr55gag into the viral bud requires the recruitment of the ESCRT complex, potentiated by Pr55gag ubiquitylation. Interestingly, in response to viral infection, type I interferon triggers the expression of the ubiquitin-like polypeptide ISG15 which then inhibits the recruitment of the ESCRT machinery by inhibiting Pr55gag ubiquitylation." 14816;"Marrow ring sideroblasts are highly predictive for TP53 mutation in MDS with excess blasts.";"T. Cluzeau";"Equipe 02, Team 02";34975158;Leukemia;"Swoboda DM, Kanagal-Shamanna R, Brunner AM, Cluzeau T, Chan O, Al Ali N, Montalban-Bravo G, Gesiotto QJ, Gavralidis A, Hunter AM, Lee JH, Kuykendall AT, Talati C, Sweet KL, Lancet JE, Padron E, Hussaini M, Song J, Garcia-Manero G, Komrokji RS, Sallman DA";;"Jan 2022";1641168000;; 14814;"Author Correction: Genome-wide association study identifies susceptibility loci for acute myeloid leukemia.";"T. Cluzeau";"Equipe 02, Team 02";34983928;"Nature communications";"Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, Allan JM";;"Jan 2022";1641340800;; 14812;"Defibrotide-treated patients with anicteric or icteric veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic cell transplantation: an EBMT study.";"T. Cluzeau";"Equipe 02, Team 02";35115668;"Bone marrow transplantation";"Mohty M, Cluzeau T, Jubert C, Lawson S, Ryan RJ, Hanvesakul R, Perruccio K";;"Feb 2022";1643932800;; 14810;"High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL.";"T. Cluzeau";"Equipe 02, Team 02";35263986;Haematologica;"Cabannes-Hamy A, Brissot E, Leguay T, Huguet F, Chevallier P, Hunault M, Escoffre-Barbe M, Cluzeau T, Balsat M, Nguyen S, Pasquier F, Alexis M, Lheritier V, Pastoret C, Delabesse E, Clappier E, Dombret H, Boissel N";;"Mar 2022";1646870400;;"Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and <0.1% respectively. Among relapsed patients, 23 received blinatumomab with overt relapse and 15 were in complete response (CR) after bridging chemotherapy. At 3 years, overall CR rate was 68% and complete MRD response rate was 84%. Patients who directly received blinatumomab had shorter relapse-free survival (P=0.033) and OS (P=0.003) than patients bridged to blinatumomab. Three-year OS was 66% in the latter group compared to 16% in the former group. Our observations suggest that pre-blinatumomab tumor burden should help to design more tailored strategies including tumor load reduction in relapsed patients." 14808;"Measurable Residual Disease in High-Risk Acute Myeloid Leukemia.";"T. Cluzeau";"Equipe 02, Team 02";35267586;Cancers;"Cluzeau T, Lemoli RM, McCloskey J, Cooper T";;"Mar 2022";1646870400;;"Mounting evidence suggests measurable residual disease (MRD) assessments are prognostic in acute myeloid leukemia (AML). High-risk AML encompasses a subset of AML with poor response to therapy and prognosis, with features such as therapy-related AML, an antecedent hematologic disorder, extramedullary disease (in adults), and selected mutations and cytogenetic abnormalities. Historically, few patients with high-risk AML achieved deep and durable remission with conventional chemotherapy; however, newer agents might be more effective in achieving MRD-negative remission. CPX-351 (dual-drug liposomal encapsulation of daunorubicin/cytarabine at a synergistic ratio) demonstrated MRD-negativity rates of 36-64% across retrospective studies in adults with newly diagnosed high-risk AML and 84% in pediatric patients with first-relapse AML. Venetoclax (BCL2 inhibitor) demonstrated MRD-negativity rates of 33-53% in combination with hypomethylating agents for high-risk subgroups in studies of older adults with newly diagnosed AML who were ineligible for intensive therapy and 65% in combination with chemotherapy in pediatric patients with relapsed/refractory AML. However, there is no consensus on optimal MRD methodology in AML, and the use of different techniques, sample sources, sensitivity thresholds, and the timing of assessments limit comparisons across studies. Robust MRD analyses are needed in future clinical studies, and MRD monitoring should become a routine aspect of AML management." 14806;"A randomised phase II study of azacitidine (AZA) alone or with Lenalidomide (LEN), Valproic acid (VPA) or Idarubicin (IDA) in higher-Risk MDS or low blast AML: GFM's ""pick a winner"" trial, with the impact of somatic mutations.";"T. Cluzeau";"Equipe 02, Team 02";35438802;"British journal of haematology";"Adès L, Duployez N, Guerci-Bresler A, Laribi K, Peterlin P, Vey N, Thepot S, Wickenhauser S, Zerazhi H, Stamatoullas A, Wattel E, Recher C, Toma A, Dimicoli-Salazar S, Braun T, Beyne-Rauzy O, Marolleau JP, Cheze S, Park S, Cluzeau T, Nimubona S, Bordessoule D, Benramdane R, Quesnel B, Amé S, de Botton S, Chermat F, Preudhomme C, Chevret S, Fenaux P";;"Apr 2022";1650326400;;"In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a ""pick a winner"" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our ""pick a winner"" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA." 14804;"Red blood cell transfusion burden in myelodysplastic syndromes (MDS) with ring Sideroblasts (RS): A retrospective multicenter study by the Groupe Francophone des Myélodysplasies (GFM).";"T. Cluzeau";"Equipe 02, Team 02";35452143;Transfusion;"Jouzier C, Cherait A, Cony-Makhoul P, Hamel JF, Veloso M, Thepot S, Cluzeau T, Stamatoullas A, Garnier A, Guerci-Bresler A, Dimicoli-Salazar S, Pica GM, Cheze S, Santana C, Chermat F, Fenaux P, Park S";;"Apr 2022";1650585600;;"MDS-RS patients are characterized by chronic anemia and a low risk of Acute Myeloid Leukemia (AML) progression and they generally become Red Blood Cell (RBC) transfusion dependent (TD)." 14802;"Scarring after chemical tattoo removal: a retrospective study.";"T. Passeron";"Equipe 12, Team 12";35171788;"European journal of dermatology : EJD";"Kenani Z, Le Duff F, Hachem JP, Le Pillouer-Prost A, Martin-Chico R, Patarin M, Laubach H, Ducamp I, Cante V, Perillat Y, Toubel G, Passeron T, Bahadoran P";;"Feb 2022";1644969600;; 14800;"Accuracy and clinical relevance of an automated, algorithm-based analysis of facial signs from selfie images of women in the United States of various ages, ancestries and phototypes: A cross-sectional observational study.";"T. Passeron";"Equipe 12, Team 12";35986708;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Flament F, Jiang R, Houghton J, Zhang Y, Kroely C, Jablonski NG, Jean A, Clarke J, Steeg J, Sehgal C, McParland J, Delaunay C, Passeron T";;"Aug 2022";1660953600;;"Real-life validation is necessary to ensure our artificial intelligence (AI) skin diagnostic tool is inclusive across a diverse and representative US population of various ages, ancestries and skin phototypes." 14772;"Role of extracellular matrix architecture and signaling in melanoma therapeutic resistance.";"S. Tartare-Deckert";"Equipe 11, Team 11";36119516;"Frontiers in oncology";"Popovic A, Tartare-Deckert S";;"Sep 2022";1663545600;;"The extracellular matrix (ECM) is critical for maintaining tissue homeostasis therefore its production, assembly and mechanical stiffness are highly regulated in normal tissues. However, in solid tumors, increased stiffness resulting from abnormal ECM structural changes is associated with disease progression, an increased risk of metastasis and poor survival. As a dynamic and key component of the tumor microenvironment, the ECM is becoming increasingly recognized as an important feature of tumors, as it has been shown to promote several hallmarks of cancer biochemical and biomechanical signaling. In this regard, melanoma cells are highly sensitive to ECM composition, stiffness and fiber alignment because they interact directly with the ECM in the tumor microenvironment cell surface receptors, secreted factors or enzymes. Importantly, seeing as the ECM is predominantly deposited and remodeled by myofibroblastic stromal fibroblasts, it is a key avenue facilitating their paracrine interactions with melanoma cells. This review gives an overview of melanoma and further describes the critical roles that ECM properties such as ECM remodeling, ECM-related proteins and stiffness play in cutaneous melanoma progression, tumor cell plasticity and therapeutic resistance. Finally, given the emerging importance of ECM dynamics in melanoma, future perspectives on therapeutic strategies to normalize the ECM in tumors are discussed." 14746;"Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.";"R. ANTY";"Equipe 08, Team 08";35202597;"The lancet. Gastroenterology & hepatology";"Louvet A, Labreuche J, Moreno C, Vanlemmens C, Moirand R, Féray C, Dumortier J, Pageaux GP, Bureau C, Chermak F, Duvoux C, Thabut D, Leroy V, Carbonell N, Rolland B, Salamé E, Anty R, Gournay J, Delwaide J, Silvain C, Lucidi V, Lassailly G, Dharancy S, Nguyen-Khac E, Samuel D, Duhamel A, Mathurin P, ";;"Feb 2022";1645660800;;"Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence." 14744;"Management of alcohol-related liver disease: the French Association for the Study of the Liver and the French Alcohol Society clinical guidelines.";"R. ANTY";"Equipe 08, Team 08";35488390;"Liver international : official journal of the International Association for the Study of the Liver";"Louvet A, Trabut JB, Moreno C, Moirand R, Aubin HJ, Ntandja Wandji LC, Nourredine M, Ningarhari M, Ganne-Carrié N, Pageaux GP, Bailly F, Boursier J, Daeppen JB, Luquiens A, Nguyen-Khac E, Anty R, Orban T, Donnadieu-Rigole H, Mallat A, Bureau C, Pariente EA, Paupard T, Benyamina A, Perney P, Mathurin P, Rolland B, ";;"Apr 2022";1651276800;;"Excessive alcohol consumption is the leading cause of liver diseases in Western countries, especially in France. Alcohol-related liver disease (ARLD) is an extremely broad context and there remains much to accomplish in terms of identifying patients, improving prognosis and treatment, and standardising practices. The French Association for the Study of the Liver wished to organise guidelines together with the French Alcohol Society in order to summarise the best evidence available about several key clinical points in ARLD. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe how patients with ARLD should be managed nowadays and discuss the main unsettled issues in the field." 14742;"Application and Challenge of 3rd Generation Sequencing for Clinical Bacterial Studies.";"R. Ruimy";"Equipe 06, Team 06";35163319;"International journal of molecular sciences";"Ben Khedher M, Ghedira K, Rolain JM, Ruimy R, Croce O";;"Feb 2022";1644883200;;"Over the past 25 years, the powerful combination of genome sequencing and bioinformatics analysis has played a crucial role in interpreting information encoded in bacterial genomes. High-throughput sequencing technologies have paved the way towards understanding an increasingly wide range of biological questions. This revolution has enabled advances in areas ranging from genome composition to how proteins interact with nucleic acids. This has created unprecedented opportunities through the integration of genomic data into clinics for the diagnosis of genetic traits associated with disease. Since then, these technologies have continued to evolve, and recently, long-read sequencing has overcome previous limitations in terms of accuracy, thus expanding its applications in genomics, transcriptomics and metagenomics. In this review, we describe a brief history of the bacterial genome sequencing revolution and its application in public health and molecular epidemiology. We present a chronology that encompasses the various technological developments: whole-genome shotgun sequencing, high-throughput sequencing, long-read sequencing. We mainly discuss the application of next-generation sequencing to decipher bacterial genomes. Secondly, we highlight how long-read sequencing technologies go beyond the limitations of traditional short-read sequencing. We intend to provide a description of the guiding principles of the 3rd generation sequencing applications and ongoing improvements in the field of microbial medical research." 14740;"Genomic analysis of CTX-M-115 and OXA-23/-72 co-producing Acinetobacter baumannii, and their potential to spread resistance genes by natural transformation.";"R. Ruimy";"Equipe 06, Team 06";35412620;"The Journal of antimicrobial chemotherapy";"Vuillemenot JB, Bour M, Beyrouthy R, Bonnet R, Laaberki MH, Charpentier X, Ruimy R, Plésiat P, Potron A";;"Apr 2022";1649721600;;"To characterize Acinetobacter baumannii strains co-producing the ESBL CTX-M-115 and carbapenem-hydrolysing class D β-lactamases (CHDLs), and to assess the potential diffusion of their resistance genes by horizontal transfer." 14738;"Evaluation of an Antibiotic Susceptibility Testing Method on -Positive Blood Cultures in Less Than 8 h Using the Rapid Mueller-Hinton Diffusion Method in Conjunction with the SIRscan 2000 Automatic Reading Device.";"R. Ruimy, R. Lotte";"Equipe 06, Team 06";35889096;Microorganisms;"Payen M, Gaudart A, Legueult K, Kasprzak J, Emery A, Mutambayi G, Pradier C, Robin F, Lotte R, Ruimy R";;"Jul 2022";1658880000;;" bloodstream infections are life-threatening and require rapid, targeted antibiotherapy based on antibiotic susceptibility testing (AST). A new method using Muller-Hinton Rapid-SIR (MHR-SIR) agar (i2a, Montpellier, France) allows complete direct AST (dAST) to be read from positive blood culture bottles (BCBs) for all species after 6-8 h of incubation. We evaluated (i) the performance of dAST from positive BCBs on MHR-SIR agar using two different inoculum protocols; (ii) the categorical agreement between dAST results obtained with MHR-SIR agar vs. those obtained with Muller-Hinton (MH) agar; and (iii) the ability of the MHR-SIR medium to detect β-lactam resistant Finally, we estimated the saved turnaround time (TAT) with MHR-SIR compared with MH agar in our 24/7 laboratory. Our results showed that the most suitable inoculation protocol for dAST on MHR-SIR agar was 1 drop of BCB/5 mL HO. For monomicrobial BCBs, dAST performed on MHR-SIR medium showed 99.3% categorical agreement with AST on MH agar. Furthermore, MHR-SIR agar allows early detection of β-lactam resistance mechanisms, including AmpC hyperproduction, extended-spectrum β-lactamase, and carbapenemase. Finally, TAT reduction in our 24/7 laboratory was 16 h, enabling a significantly faster provision of antibiotic advice." 14734;"[Tropical diseases and poverty: impact on women's and children's rights - scientific day of the Sfmtsi, 25 may 2022].";"P. Marty";"Equipe 06, Team 06";35919253;"Medecine tropicale et sante internationale";"Jannin J, Chandenier J, Delmont J, Epelboin A, Gay-Andrieu F, Gazin P, Goujon C, Marty P, Tantet C";;"Aug 2022";1659484800;; 14732;"Benchmark problems for transcranial ultrasound simulation: Intercomparison of compressional wave models.";"P. Marty";"Equipe 06, Team 06";36050189;"The Journal of the Acoustical Society of America";"Aubry JF, Bates O, Boehm C, Butts Pauly K, Christensen D, Cueto C, Gélat P, Guasch L, Jaros J, Jing Y, Jones R, Li N, Marty P, Montanaro H, Neufeld E, Pichardo S, Pinton G, Pulkkinen A, Stanziola A, Thielscher A, Treeby B, van 't Wout E";;"Sep 2022";1661990400;;"Computational models of acoustic wave propagation are frequently used in transcranial ultrasound therapy, for example, to calculate the intracranial pressure field or to calculate phase delays to correct for skull distortions. To allow intercomparison between the different modeling tools and techniques used by the community, an international working group was convened to formulate a set of numerical benchmarks. Here, these benchmarks are presented, along with intercomparison results. Nine different benchmarks of increasing geometric complexity are defined. These include a single-layer planar bone immersed in water, a multi-layer bone, and a whole skull. Two transducer configurations are considered (a focused bowl and a plane piston operating at 500 kHz), giving a total of 18 permutations of the benchmarks. Eleven different modeling tools are used to compute the benchmark results. The models span a wide range of numerical techniques, including the finite-difference time-domain method, angular spectrum method, pseudospectral method, boundary-element method, and spectral-element method. Good agreement is found between the models, particularly for the position, size, and magnitude of the acoustic focus within the skull. When comparing results for each model with every other model in a cross-comparison, the median values for each benchmark for the difference in focal pressure and position are less than 10% and 1 mm, respectively. The benchmark definitions, model results, and intercomparison codes are freely available to facilitate further comparisons." 14728;"Clinical phenotype and cytokine profile of adult IgA vasculitis with joint involvement.";"N. Martis";"Equipe 10, Team 10";35041109;"Clinical rheumatology";"Delapierre A, Terrier B, Pillebout E, Baudart P, Jourde-Chiche N, Lioger B, Martis N, Moulis G, Rivière E, Le Gouellec N, Raffray L, Urbanski G, Sanges S, Maurier F, Deroux A, Mekinian A, Monteiro R, Marcelli C, Guillevin L, Maillot F, Lucas B, Aouba A, Audemard-Verger A, ";;"Jan 2022";1642464000;;"Joint involvement can be observed during the course of adult IgA vasculitis (IgAV). However, clinical picture, prognosis, or pathophysiological data associated with this condition have been overlooked. We aimed to describe the clinical characteristics and outcome of IgAV patients with joint involvement and look to a specific cytokine profile." 14726;"Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.";"N. Martis";"Equipe 10, Team 10";35074934;"Journal of the American Society of Nephrology : JASN";"Nezam D, Porcher R, Grolleau F, Morel P, Titeca-Beauport D, Faguer S, Karras A, Solignac J, Jourde-Chiche N, Maurier F, Sakhi H, El Karoui K, Mesbah R, Carron PL, Audard V, Ducloux D, Paule R, Augusto JF, Aniort J, Tiple A, Rafat C, Beaudreuil S, Puéchal X, Gobert P, Massy Z, Hanrotel C, Bally S, Martis N, Durel CA, Desbuissons G, Godmer P, Hummel A, Perrin F, Néel A, De Moreuil C, Goulenok T, Guerrot D, Grange S, Foucher A, Deroux A, Cordonnier C, Guilbeau-Frugier C, Modesto-Segonds A, Nochy D, Daniel L, Moktefi A, Rabant M, Guillevin L, Régent A, Terrier B, ";;"Jan 2022";1643068800;;"Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX." 14724;"Mortality and its risk factors in critically ill patients with connective tissue diseases: A meta-analysis.";"N. Martis";"Equipe 10, Team 10";35151541;"European journal of internal medicine";"Kouchit Y, Morand L, Martis N";;"Feb 2022";1644710400;;"Systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM) and rheumatoid arthritis (RA) are connective tissue diseases (CTD) whose complications can lead to management in the intensive care unit (ICU)." 14722;"Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.";"N. Martis";"Equipe 10, Team 10";35579092;"Clinical and experimental rheumatology";"Péan de Ponfilly-Sotier M, Jachiet V, Benhamou Y, Lahuna C, De Renzis B, Kottler D, Voillat L, Dimicoli-Salazar S, Banos A, Chauveheid MP, Alexandra JF, Grignano E, Liferman F, Laborde M, Broner J, Michel M, Lambotte O, Laribi K, Venon MD, Dussol B, Martis N, Thepot S, Park S, Couret D, Roux-Sauvat M, Terriou L, Hachulla E, Bally C, Galland J, Allain JS, Parcelier A, Peterlin P, Cohen-Bittan J, Regent A, Ackermann F, Le Guen J, Algrin C, Charles P, Daguindau E, Puechal X, Dunogue B, Blanchard-Delaunay C, Beyne-Rauzy O, Grobost V, Schmidt J, Le Gallou T, Dubos-Lascu G, Sonet A, Denis G, Roy-Peaud F, Fenaux P, Adès L, Fain O, Mekinian A, ";;"May 2022";1652745600;;"Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE." 14720;"[Cardiopulmonary exercise testing in the management of systemic sclerosis].";"N. Martis";"Equipe 10, Team 10";35691757;"La Revue de medecine interne";"Martis N, Leroy S";;"Jun 2022";1654992000;;"Cardiopulmonary complications are the leading cause of mortality in patients with systemic sclerosis (SSc) requiring an early identification. A global and comprehensive approach is needed due to the complexity of the overlapping aetiologies of dyspnoea in SSc. Through its integrative approach of ventilatory, metabolic, cardiovascular, skeletal muscular and gas exchange findings, cardiopulmonary exercise testing (CPET) has been known to identify and sort competing mechanisms of exercise limitation in scleroderma patients presenting with dyspnoea. CPET may be used to screen for pulmonary arterial hypertension, suspect interstitial lung disease and guide therapeutic strategies including exercise rehabilitation. This review focuses on the clinical value of CPET in the decision-making processes for a more personalised diagnostic approach to SSc-related complications." 14718;"[Is uveal melanoma similar to cutaneous melanoma?]";"N. Arrighi";"Equipe 01, Team 01";36094246;"Medecine sciences : M/S";"Ch Papasotiriou E, Ben Abdeljelil R, Benhammou I, Bertin L, Chadeuf E, Colve G, Arrighi N";;"Sep 2022";1662940800;; 14716;"[Transcription factor HES6, a key player in uveal melanoma].";"N. Arrighi";"Equipe 01, Team 01";36094249;"Medecine sciences : M/S";"Nucera L, Perrée E, Pujas P, Rouchon C, Wachich M, Selveswaran S, Arrighi N";;"Sep 2022";1662940800;; 14714;"Dual Mechanism of Action of Curcumin in Experimental Models of Multiple Sclerosis.";"M. Benahmed";"Equipe 10, Team 10";35955792;"International journal of molecular sciences";"ELBini-Dhouib I, Manai M, Neili NE, Marzouki S, Sahraoui G, Ben Achour W, Zouaghi S, BenAhmed M, Doghri R, Srairi-Abid N";;"Aug 2022";1660262400;;"Multiple sclerosis (MS) is characterized by a combination of inflammatory and demyelination processes in the spinal cord and brain. Conventional drugs generally target the autoimmune response, without any curative effect. For that reason, there is a great interest in identifying novel agents with anti-inflammatory and myelinating effects, to counter the inflammation and cell death distinctive of the disease." 14704;"Third dose of anti-SARS-CoV-2 vaccine for patients with cancer: Should humoral responses be monitored? A position article.";"M. Carles";"Equipe 06, Team 06";35016032;"European journal of cancer (Oxford, England : 1990)";"Barrière J, Carles M, Audigier-Valette C, Re D, Adjtoutah Z, Seitz-Polski B, Gounant V, Descamps D, Zalcman G";;"Jan 2022";1641859200;;"Taking into account higher risk of severe coronavirus disease 2019 or death among patients with cancer, as well as impaired immunogenicity after anti-SARS-CoV-2 vaccines, in addition to waning immunity, booster dosing appears mandatory in this patient population. This review sought to provide reasonable evidence so as to assist oncologists in their daily practice, helping them decide when an anti-SARS-Cov2 antibody (Ab) dosage should be scheduled after a full two-dose vaccination and, if necessary, propose an early third dose (D3). Such D3 could apply to non-responder patients with anti-Spike (S) Abs titres <40 binding Ab unit (BAU)/mL. For lowresponder patients with anti-S Ab titres between 40 BAU/mL and 100/260 BAU/mL (suggested area of uncertainty), an early D3 may similarly be proposed. Nevertheless, this D3 could be administered in a less urgent manner, taking into account associated comorbidities and regional epidemic incidence rates. This latter strategy may comprise a monthly dosage of anti-S titres so as to better assess the kinetics of waning immunity. For responder patients with anti-S titres above 260 BAU/mL, we suggest to follow the recommendations outlined for the general population. Given this context, patients with anti-S titres above 1000 BAU/mL should be given the possibility to undergo anti-S titre control after three months, designed to assess rapid humoral waning immunity. We strongly recommend that patients with cancer be included into observational serological monitoring studies or clinical trials that are dedicated to severe immunocompromised patients without any humoral seroconversion after D3." 14702;"[Recommendations to protect patients with cancer against the Omicron variant].";"M. Carles";"Equipe 06, Team 06";35031126;"Bulletin du cancer";"Barrière J, Zalcman G, Fignon L, Peiffer-Smadja N, Audigier-Valette C, Carles M";;"Jan 2022";1642204800;; 14700;"Omicron variant: A clear and present danger for patients with cancer.";"M. Carles";"Equipe 06, Team 06";35189538;"European journal of cancer (Oxford, England : 1990)";"Barrière J, Zalcman G, Fignon L, Peiffer-Smadja N, Audigier-Valette C, Carles M";;"Feb 2022";1645401600;; 14698;"A follow-up of pain reported by children undergoing outpatient surgery using a smartphone application: AlgoDARPEF multicenter descriptive prospective study.";"M. Carles";"Equipe 06, Team 06";35239543;Pain;"Walrave Y, Carles M, Evain JN, Ikonomoff T, Marie A, Ludot H, Bourdaud N, Kern D, Lejus-Bourdeau C, Orliaguet G, Rosello O, Ecoffey C, Savoldelli C, Perissier C, Delacquis M, Varé B, Donzeau D, Cousin C, Langlais E, Breaud J, Jonckheer K, Dadure C, De la Brière F, ";;"Mar 2022";1646265600;;"In pediatric patients, pain remains the most common complaint after surgery. This French multicenter epidemiological study (AlgoDARPEF) aimed to evaluate the use of a smartphone application (App) to assess the duration and severity of pain experienced by children undergoing outpatient surgery. Children younger than 18 years scheduled for an elective outpatient procedure in one of the participating centers were eligible. Parents were invited to provide daily information for 10 days regarding their child's pain and comfort through a smartphone App using the Parents' Postoperative Pain Measure-Short-Form (PPPM-SF). Children older than 6 years could also provide self-assessments of pain using a numerical rating scale (NRS)-11. Data regarding pain medication, preoperative anxiety, postoperative nausea and vomiting, and parent satisfaction were also analyzed. Repeated-measures analyses of variances (ANOVAs) were used to compare the self-assessments and hetero-assessments of pain. Eleven centers participated in the study, and 1573 patients were recruited. Forty-nine percentage of parents (n = 772) actually used the App at least once. In all surgeries, the average pain rating on the PPPM-SF scale did not exceed 3/10 throughout the follow-up period, as well as for 4 main surgical specialties. Age, visceral surgery, and preoperative anxiety ≥ 4/10 were identified as independent risk factors for experiencing at least 1 episode of pain ≥4/10 during the first 48 postoperative hours. Although these findings indicated that postoperative pain management seems to be satisfactory in the families who used the App, some improvements in anxiety management are suggested. This study shows that inviting parents to use a smartphone App to assess and report the quality of postoperative management in pediatric patients provides useful information. A continuous report regarding pain and adverse events over a 10-day postoperative period by a self-reporting or parent's contribution is possible. Future studies should investigate the ability of live data collection using an App to ensure fast, efficient interactions between patients and physicians." 14696;"Emergence of Lyme Disease on the French Riviera, a Retrospective Survey.";"M. Carles";"Equipe 06, Team 06";35391881;"Frontiers in medicine";"Sevestre J, Benichou A, Rio V, Delaunay P, Gonfrier G, Martaresche C, Carlo V, Nakam S, Mondain V, Carles M, Jeandel PY, Durant J";;"Apr 2022";1649376000;;"The French Riviera has been declared free of Lyme Borreliosis (LB) for years. Many patients are referred for presumed LB, sometimes with atypical clinical signs and/or doubtful serology, calling the diagnosis into question." 14694;"Who Were Hospitalized Deceased Patients from COVID-19 During the First Year of Pandemic? Retrospective Analysis of 1104 Deceased Patients in South of France.";"M. Carles";"Equipe 06, Team 06";35486358;"Journal of epidemiology and global health";"Arlotto S, Legueult K, Blin A, Cortaredona S, Giraud-Gatineau A, Bailly L, Jimeno MT, Delorme L, Brouqui P, Lagier JC, Million M, Dellamonica J, Colson P, Carles M, Raoult D, Pradier C, Gentile S";;"Apr 2022";1651190400;;"Following the first year of the COVID-19 pandemic, a complete analysis of the characteristics of the deceased hospitalized patients was performed, to identify factors related to premature mortality and to compare patient profiles according to the epidemic periods." 14692;"Nuclear-medicine probes: Where we are and where we are going.";"M. Carles";"Equipe 06, Team 06";35526220;"Medical physics";"Gonzalez-Montoro A, Vera-Donoso CD, Konstantinou G, Sopena P, Martinez M, Ortiz JB, Carles M, Benlloch JM, Gonzalez AJ";;"May 2022";1651968000;;"Nuclear medicine probes turned into the key for the identification and precise location of sentinel lymph nodes and other occult lesions (i.e., tumors) by using the systemic administration of radiotracers. Intraoperative nuclear probes are key in the surgical management of some malignancies as well as in the determination of positive surgical margins, thus reducing the extent and potential surgery morbidity. Depending on their application, nuclear probes are classified into two main categories, namely, counting and imaging. Although counting probes present a simple design, are handheld (to be moved rapidly), and provide only acoustic signals when detecting radiation, imaging probes, also known as cameras, are more hardware-complex and also able to provide images but at the cost of an increased intervention time as displacing the camera has to be done slowly. This review article begins with an introductory section to highlight the relevance of nuclear-based probes and their components as well as the main differences between ionization- (semiconductor) and scintillation-based probes. Then, the most significant performance parameters of the probe are reviewed (i.e., sensitivity, contrast, count rate capabilities, shielding, energy, and spatial resolution), as well as the different types of probes based on the target radiation nature, namely: gamma (γ), beta (β) (positron and electron), and Cherenkov. Various available intraoperative nuclear probes are finally compared in terms of performance to discuss the state-of-the-art of nuclear medicine probes. The manuscript concludes by discussing the ideal probe design and the aspects to be considered when selecting nuclear-medicine probes." 14690;"In vitro maturation of oocytes from stimulated IVF-ICSI cycles using autologous cumulus cell co-culture: A preliminary study.";"M. Carles";"Equipe 06, Team 06";35764505;"Morphologie : bulletin de l'Association des anatomistes";"Carles M, Lefranc E, Bosquet D, Capelle S, Scheffler F, Copin H, Cabry R, Benkhalifa M";;"Jun 2022";1656374400;;"In stimulated IVF-ICSI cycles, follicles at different stages of maturation can be aspirated during oocyte pickup. Nowadays, only mature oocytes (metaphase 2 stage) are used and immature oocytes (germinal vesicle and metaphase 1 stages), which are judged unfit for fertilization, are non-used at day 0. In our IVF center, the rate of immature oocytes recovered is around 25%. A significant number of this precious resource is therefore non-used every day in IVF laboratories. The objective of our study was to evaluate the competence of our in vitro maturation autologous coculture method on the maturation and developmental potential of immature oocytes obtained from stimulated IVF-ICSI cycles, in order to obtain additional embryos for the couple as a rescue system to increase the changes of cumulative pregnancy." 14688;"Second biopsy for embryos with inconclusive results after preimplantation genetic testing: Impact on pregnancy outcomes.";"M. Carles";"Equipe 06, Team 06";35793773;"Journal of gynecology obstetrics and human reproduction";"Carles M, Sonigo C, Binois O, Hesters L, Steffann J, Romana S, Frydman N, Mayeur A";;"Jul 2022";1657065600;;"In this study, we aimed to evaluate the pregnancy outcomes for embryos biopsied twice at cleavage and blastocyst stage for preimplantation genetic testing (PGT). This retrospective monocentric study, conducted between January 2016 and March 2021, described all PGT results on one hand and the PGT results for undiagnosed embryos submitted to a second biopsy on the other hand. Among the 5865 embryos biopsied during the study period, 510 embryos were genetic undiagnosed after the first embryo biopsy at cleavage stage (8.7%). The rate of undiagnosed embryos was significantly higher for PGT for structural rearrangement (PGT-SR) than PGT for monogenic disease (PGT-M) (10.2% vs 7.4% respectively, p < 0.001). Thirty-three embryos were compatible with a second biopsy at blastocyst stage before being directly frozen. Among them 17 were diagnosed as healthy for the researched pathology (51.5%). At the time of our study, 11 of the 17 preserved embryos were thawed and transferred. Embryo survival at thawing was 100% and 5 pregnancies were obtained (clinical pregnancy rate of 45.5% per transfer), including 3 live births. A second biopsy for inconclusive embryos after PGT does not seem to have an impact on thaw survival and implantation rate. For couple, this strategy avoids to discard transferable embryos." 14686;"Retinoic acid signaling acts as a rheostat to balance Treg function.";"M. Loschi";"Equipe 02, Team 02";35581350;"Cellular & molecular immunology";"Thangavelu G, Andrejeva G, Bolivar-Wagers S, Jin S, Zaiken MC, Loschi M, Aguilar EG, Furlan SN, Brown CC, Lee YC, Hyman CM, Feser CJ, Panoskaltsis-Mortari A, Hippen KL, MacDonald KP, Murphy WJ, Maillard I, Hill GR, Munn DH, Zeiser R, Kean LS, Rathmell JC, Chi H, Noelle RJ, Blazar BR";;"May 2022";1652745600;;"Regulatory T cells (Tregs) promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses. Under certain inflammatory conditions, Tregs can lose their lineage stability and function. Previous studies have reported that ex vivo exposure to retinoic acid (RA) enhances Treg function and stability. However, it is unknown how RA receptor signaling in Tregs influences these processes in vivo. Herein, we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor (DN) RARα in all T cells. Despite the fact that DNRARα conventional T cells are hypofunctional, Tregs had increased CD25 expression, STAT5 pathway activation, mTORC1 signaling and supersuppressor function. Furthermore, DNRARα Tregs had increased inhibitory molecule expression, amino acid transporter expression, and metabolic fitness and decreased antiapoptotic proteins. Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist. Unexpectedly, Treg-specific expression of DNRARα resulted in distinct phenotypes, such that a single allele of DNRARα in Tregs heightened their suppressive function, and biallelic expression led to loss of suppression and autoimmunity. The loss of Treg function was not cell intrinsic, as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARα and wild-type bone marrow maintained the enhanced suppressive capacity. Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling. Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner." 14684;"[New drug approval: Lisocabtagene maraleucel for patients with relapsed or refractory diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma or follicular lymphoma grade 3B after two or more lines of systemic treatment].";"M. Loschi";"Equipe 02, Team 02";35717220;"Bulletin du cancer";"Chiche E, Loschi M";;"Jun 2022";1655510400;; 14682;"Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).";"M. Loschi";"Equipe 02, Team 02";35773347;"Bone marrow transplantation";"Nagler A, Labopin M, Cornelissen JJ, Forcade E, Chevallier P, Fegueux N, Sierra J, Desmier D, Labussière-Wallet H, Byrne JL, Loschi M, Blaise D, Baron F, Ruggeri A, Mohty M";;"Jun 2022";1656547200;;"We compared transplantation outcomes of adult patients with AML that underwent cord blood transplantation (CBT) in CR1 following 1 versus 2 induction courses. Study included 325 patients, 243 (75%) with 1 and 82 (25%) with 2 induction courses. Engraftment was lower for patients achieving CR1 after 1 vs. 2 induction courses: 91% vs. 99% (p = 0.02). Incidence of acute GVHD was similar, 38% and 36% (p = 0.81), as was 2-year chronic GVHD at 23.4% and 27.5%, respectively (p = 0.65). Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were not statistically different between patients achieving CR1 with 1 vs. 2 induction courses with 23% vs. 24% (p = 0.87), 25% vs. 30% (p = 0.4), 52% vs. 46% (p = 0.3), 59% vs. 50% (p = 0.2), and 44% vs. 41% (p = 0.66), respectively. Results were confirmed by multivariable analysis, NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p = 0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p = 0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p = 0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p = 0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p = 0.5). Overall, outcomes of AML patients undergoing CBT in CR1 achieved after 1 or 2 induction courses are similar." 14680;"A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma.";"M. Loschi";"Equipe 02, Team 02";36138152;"Nature medicine";"Bachy E, Le Gouill S, Di Blasi R, Sesques P, Manson G, Cartron G, Beauvais D, Roulin L, Gros FX, Rubio MT, Bories P, Bay JO, Llorente CC, Choquet S, Casasnovas RO, Mohty M, Guidez S, Joris M, Loschi M, Carras S, Abraham J, Chauchet A, Drieu La Rochelle L, Deau-Fischer B, Hermine O, Gastinne T, Tudesq JJ, Gat E, Broussais F, Thieblemont C, Houot R, Morschhauser F";;"Sep 2022";1663804800;;"Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P < 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46-0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45-0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1-2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1-2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL." 14678;"How I Treat -Mutated Acute Myeloid Leukemia and Myelodysplastic Syndromes.";"M. Loschi, T. Cluzeau";"Equipe 02, Team 02";36139679;Cancers;"Loschi M, Fenaux P, Cluzeau T";;"Sep 2022";1663891200;;"-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the myeloid malignancies with the poorest prognosis. In this review, we analyze the prognosis of these two diseases, focussing particularly on the extent of the mono or biallelic mutation status of mutation, which is largely correlated with cytogenetic complexity. We discuss the possible/potential improvement in outcome based on recent results obtained with new drugs (especially eprenetapopt and magrolimab). We also focus on the impact of allogeneic hematopoietic stem cell transplantation (aHSCT) including post aHSCT treatment." 14664;"Impact of topical emollient, steroids alone or combined with calcipotriol, on the immune infiltrate and clinical outcome in psoriasis.";"S. Rocchi, T. Passeron, M. Tulic";"Equipe 12, Team 12";36054319;"Experimental dermatology";"Heim M, Irondelle M, Duteil L, Cardot-Leccia N, Rocchi S, Passeron T, Tulic MK";;"Sep 2022";1662076800;;"Psoriasis is a chronic inflammatory disease whereby long-term disease control remains a challenge for the patients. Latest evidence suggests that combined topical treatment with steroids and vitamin D analogue foam (Calcipotriol/Betamethasone) is efficient in long-term management of the disease and reducing the number of relapses. Its effects on cellular inflammation and cytokine production remain to be explored. We set out to examine the effect of topical therapies on cellular infiltrate and cytokine profile in the lesional skin of psoriasis patients. This was a monocentric, double-blind, randomized trial with 30 patients. Patients were treated with the combined Calcipotriol/Betamethasone foam, Betamethasone foam alone, Clobetasol Propionate ointment or placebo. 4 mm skin biopsies from lesional and non-lesional sites were taken before and 4 weeks after treatment. Cellular infiltrate, IFNγ and IL-17 were studied by immunofluorescence. Each patient was their own control. Evolution in skin inflammation was studied in parallel with changes in patient's epidermal thickness and their tPASI clinical score. Lesional skin was characterized by increased epidermal thickness, increased number of IL-17 and IFNγ producing CD8+ T cells, NK cells and neutrophils. All treatment reduced epidermal thickness and improved patients tPASI scores. Only the combined Calcipotriol/Betamethasone foam completely abolished epidermal and dermal influx of CD8+ T cells, reduced number of CD8 + IFNγ+ cells (but not CD8 + IL-17+ cells) and significantly reduced the number of MPO+ neutrophils which were predominantly IL-17+. None of the treatments had effect on NK cells. We have shown the combined topical treatment with Calcipotriol/Betamethasone foam to be effective in reducing cellular influx into lesional skin of psoriasis patients and this effect to be superior to emollient or Betamethasone alone. Its previously described efficacy in the clinic may be attributed to its unique and rapid ability to inhibit both adaptive CD8+ T cell and innate immune neutrophilia influx into the skin, which was not observed for the other treatments." 14662;"Functional Impairment of Endothelial Colony Forming Cells (ECFC) in Patients with Severe Atherosclerotic Cardiovascular Disease (ASCVD).";"M. Stathopoulou";"Equipe 10, Team 10";36012229;"International journal of molecular sciences";"Simoncini S, Toupance S, Labat C, Gautier S, Dumoulin C, Arnaud L, Stathopoulou MG, Visvikis-Siest S, Rossi PM, Benetos A, Dignat-George F, Sabatier F";;"Aug 2022";1661472000;;"Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context." 14658;"T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice.";"L. Yvan-Charvet";"Equipe 13, Team 13";35778407;"Nature communications";"Bazioti V, La Rose AM, Maassen S, Bianchi F, de Boer R, Halmos B, Dabral D, Guilbaud E, Flohr-Svendsen A, Groenen AG, Marmolejo-Garza A, Koster MH, Kloosterhuis NJ, Havinga R, Pranger AT, Langelaar-Makkinje M, de Bruin A, van de Sluis B, Kohan AB, Yvan-Charvet L, van den Bogaart G, Westerterp M";;"Jul 2022";1656633600;;"Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generate mice with T cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr) background. T cell Abca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cell Abca1/Abcg1-deficiency induces a premature T cell aging phenotype in middle-aged (12-13 months) Ldlr mice, reflected by upregulation of senescence markers. Despite T cell senescence and enhanced T cell activation, T cell Abca1/Abcg1-deficiency decreases atherosclerosis and aortic inflammation in middle-aged Ldlr mice, accompanied by decreased T cells in atherosclerotic plaques. We attribute these effects to T cell apoptosis downstream of T cell activation, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-aged Ldlr mice." 14638;"Bacillus cereus Invasive Infections in Preterm Neonates: an Up-to-Date Review of the Literature.";"L. Boyer, R. Ruimy, R. Lotte";"Equipe 06, Team 06";35138121;"Clinical microbiology reviews";"Lotte R, Chevalier A, Boyer L, Ruimy R";;"Feb 2022";1644364800;;"Bacillus cereus group species are widespread, Gram-positive, spore-forming environmental bacteria. B. cereus sensu stricto is one of the major causes of food poisoning worldwide. In high-risk individuals, such as preterm neonates, B. cereus infections can cause fatal infections. It is important to note that the phenotypic identification methods commonly used in clinical microbiology laboratories make no distinction between B. cereus sensu stricto and the other members of the group (Bacillus anthracis excluded). As a result, all the invasive infections attributed to B. cereus are not necessarily due to B. cereus sensu stricto but likely to other closely related species of the B. cereus group. Next-generation sequencing (NGS) should be used to characterize the whole genome of the strains belonging to the B. cereus group. This could confirm whether the strains involved in previously reported B. cereus invasive infections preferentially belong to formerly known or emerging individual species. Moreover, infections related to B. cereus group species have probably been overlooked, since their isolation in human bacteriological samples has for a long time been regarded as an environmental contaminant of the cultures. Recent studies have questioned the emergence or reemergence of B. cereus invasive infections in preterm infants. This review reports our current understanding of B. cereus infections in neonates, including taxonomical updates, microbiological characteristics, bacterial identification, clinical features, host-pathogen interactions, environmental sources of contamination, and antimicrobial resistance." 14600;"[Take-home messages from the COPD 2021 biennial of the French Society of Respiratory Diseases. Understanding to so as to better innovate].";"L. Boyer";"Equipe 06, Team 06";35568574;"Revue des maladies respiratoires";"Ancel J, Guecamburu M, Marques Da Silva V, Schilfarth P, Boyer L, Pilette C, Martin C, Devillier P, Berger P, Zysman M, Le Rouzic O, Gonzalez-Bermejo J, Degano B, Burgel PR, Ahmed E, Roche N, Deslee G";;"May 2022";1652486400;;"The first COPD biennial organized by the French Society of Respiratory Diseases (SPLF) took place on 17 December 2021." 14598;"Long-term exposure to ambient air pollution is associated with an increased incidence and mortality of acute respiratory distress syndrome in a large French region.";"L. Boyer";"Equipe 06, Team 06";35569534;"Environmental research";"Gutman L, Pauly V, Orleans V, Piga D, Channac Y, Armengaud A, Boyer L, Papazian L";;"May 2022";1652572800;;"Air pollution exposure is suspected to alter both the incidence and mortality in acute respiratory distress syndrome (ARDS). The impact of chronic air pollutant exposure on the incidence and mortality of ARDS from various aetiologies in Europe remains unknown. The main objective of this study was to evaluate the incidence of ARDS in a large European region, 90-day mortality being the main secondary outcome." 14596;"Metastatic melanoma treated by immunotherapy: discovering prognostic markers from radiomics analysis of pretreatment CT with feature selection and classification.";"L. Boyer";"Equipe 06, Team 06";35650345;"International journal of computer assisted radiology and surgery";"Ungan G, Lavandier AF, Rouanet J, Hordonneau C, Chauveau B, Pereira B, Boyer L, Garcier JM, Mansard S, Bartoli A, Magnin B";;"Jun 2022";1654041600;;"Immunotherapy has dramatically improved the prognosis of patients with metastatic melanoma (MM). Yet, there is a lack of biomarkers to predict whether a patient will benefit from immunotherapy. Our aim was to create radiomics models on pretreatment computed tomography (CT) to predict overall survival (OS) and treatment response in patients with MM treated with anti-PD-1 immunotherapy." 14594;"Creating a new chapter in the DSM for late-onset depressive disorders.";"L. Boyer";"Equipe 06, Team 06";35667820;L'Encephale;"Gerolymos C, Masson M, Lancon C, Richieri R, Boyer L, Fond G";;"Jun 2022";1654473600;; 14592;"Short-term Outcomes in a Nurse Coordinator-led and Nurse Practitioner-led Sotrovimab Initiative for Solid Organ Transplant Recipients During the Omicron Surge.";"L. Boyer";"Equipe 06, Team 06";35675440;Transplantation;"Cochran W, Langlee J, Barker L, Freed K, Brown A, McDade H, Carter D, Boyer L, Sullivan S, Shagena K, Belden M, Marino R, Adams E, Lee J, McCarthy M, Lee-Young K, Ellis S, Young S, Morrison M, Penny CC, Al Ammary F, Hartman L, Horn J, Miller T, Miller S, Purekal S, Siddiqui Z, Segev DL, Brennan DC, Shah P, Avery RK";;"Jun 2022";1654646400;; 14590;"The Impact of Statewide Limitations of Practice on High School Injury Incidence During the COVID-19 Season: An Ecological Study.";"L. Boyer";"Equipe 06, Team 06";35766456;"Sports health";"Bullock G, Prats-Uribe A, Thigpen CA, Boyer L, Varnado K, Pequette J, Shanley E";;"Jun 2022";1656460800;;"Abrupt training stoppage can increase injury incidence and risk following return to sport. The rate of coronavirus disease 2019 (COVID-19) infections in the general population has resulted in the abrupt stoppage of high school education and sport. The objective of this study was to (1) compare injury incidence proportion (IP) and excess injury in high school athletes before and during the COVID-19 pandemic; and (2) stratify by identified gender." 14588;"[Role of inflammasome NLRP3 in the pathophysiology of viral infections: A focus on SARS-CoV-2 infection].";"L. Boyer";"Equipe 06, Team 06";35766852;"Medecine sciences : M/S";"Chemarin M, Dufies O, Mazet A, Mellan E, Coudereau R, Py BF, Boyer L, Venet F";;"Jun 2022";1656460800;;"NLRP3 is one of the best characterized innate immune cytosolic sensor. As part of the innate immune response, the NLRP3 inflammasome detects a wide range of danger signals such as pathogens, tissue damages, cellular stress. The priming and activation of NLRP3 lead to the formation of an oligomeric intracellular complex and to the recruitment and activation of caspase-1. Once activated, not only this inflammasome complex controls the processing and release of pro-inflammatory factors including IL-1β and IL-18, but also the inflammatory cell death pyroptosis mediated by gasdermin D pores. In this review, we describe the role of the NLRP3 inflammasome activation in viral infections with a particular interest on SARS-CoV-2 infection. In addition, we present therapies evaluated or under evaluation targeting the NLRP3 inflammasome pathway as COVID-19 treatment." 14552;"Clindamycin Efficacy for Shoulder Device-Related Infections.";"J. Courjon, M. Carles, R. Ruimy, R. Lotte";"Equipe 06, Team 06";35625252;"Antibiotics (Basel, Switzerland)";"Courdurié A, Lotte R, Ruimy R, Cauhape V, Carles M, Gauci MO, Boileau P, Courjon J";;"May 2022";1653696000;;"Clindamycin is an antibiotic with high bioavailability and appropriate bone diffusion, often proposed as an alternative in guidelines for prosthetic joint infections. We aimed to evaluate the efficacy of clindamycin in the treatment of shoulder implant joint infections (SIJI)." 14550;"Efficacy and safety of anakinra in adults presenting deteriorating respiratory symptoms from COVID-19: A randomized controlled trial.";"J. Courjon";"Equipe 06, Team 06";35925914;"PloS one";"Audemard-Verger A, Le Gouge A, Pestre V, Courjon J, Langlois V, Vareil MO, Devaux M, Bienvenu B, Leroy V, Goulabchand R, Colombain L, Bigot A, Guimard T, Douadi Y, Urbanski G, Faucher JF, Maulin L, Lioger B, Talarmin JP, Groh M, Emmerich J, Deriaz S, Ferreira-Maldent N, Cook AR, Lengellé C, Bourgoin H, Mekinian A, Aouba A, Maillot F, Caille A";;"Aug 2022";1659571200;;"We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients." 14528;"Identification of a circulating immunological signature predictive of response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.";"J. Neels";"Equipe 09, Team 09";35994416;"Clinical and translational medicine";"Khatir W, Humbert O, Benzaquen J, Bontoux C, Neels J, Berland L, Rivera FAG, Allegra M, Salah M, Tanga V, Bordone O, Fayada J, Lespinet-Fabre V, Bohly D, Long-Mira E, Lassalle S, Vouret V, Brest P, Mograbi B, Maniel C, Otto J, Boutros J, Heeke S, Hofman V, Marquette CH, Hofman P, Ilié M";;"Aug 2022";1661126400;; 14526;"Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case-control study.";"H. Montaudie";"Equipe 12, Team 12";35788496;"Annals of the rheumatic diseases";"Plaçais L, Dalle S, Dereure O, Trabelsi S, Dalac S, Legoupil D, Montaudié H, Arnault JP, De Quatrebarbes J, Saiag P, Brunet-Possenti F, Lesimple T, Maubec E, Aubin F, Granel-Brocard F, Grob JJ, Stoebner PE, Allayous C, Oriano B, Dutriaux C, Mortier L, Lebbe C";;"Jul 2022";1656979200;;"To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma." 14524;"Impact of radiotherapy schedule on survival of patients treated with immune-checkpoint inhibitors for advanced melanoma and non-small cell lung cancer.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";35927166;"Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique";"Sumodhee S, Guo L, Bouhlel L, Picard A, Otto J, Naghavi AO, Richier Q, Lévy A, Bondiau PY, Poudenx M, Passeron T, Lacour JP, Montaudié H, Doyen J";;"Aug 2022";1659571200;;"Preclinical and clinical data suggest a potential benefit in the addition of radiotherapy (RT) to immune-checkpoint inhibitors (ICI) during the treatment of advanced cancers. Nevertheless, the ideal patients for this approach and the optimal RT regimen is still debated." 14470;"Childhood cancer survivorship care during the COVID-19 pandemic: an international report of practice implications and provider concerns.";"G. MICHEL";"Equipe 06, Team 06";35020136;"Journal of cancer survivorship : research and practice";"van den Oever SR, Pluijm SMF, Skinner R, Glaser A, Mulder RL, Armenian S, Bardi E, Berger C, Ehrhardt MJ, Gilleland Marchak J, Haeusler GM, Hartogh JD, Hjorth L, Kepak T, Kriviene I, Langer T, Maeda M, Márquez-Vega C, Michel G, Muraca M, Najib M, Nathan PC, Panasiuk A, Prasad M, Roganovic J, Uyttebroeck A, Winther JF, Zadravec Zaletel L, van Dalen EC, van der Pal HJH, Hudson MM, Kremer LCM, ";;"Jan 2022";1641945600;;"Long-term follow-up (LTFU) care is essential to optimise health outcomes in childhood cancer survivors (CCS). We aimed to assess the impact of the COVID-19 pandemic on LTFU services and providers." 14468;"""Muscle Pics"", a new body-checking behavior in muscle dysmorphia?";"G. MICHEL";"Equipe 06, Team 06";35164942;L'Encephale;"Cuadrado J, Reynaud D, Legigan C, O'Brien K, Michel G";;"Feb 2022";1644883200;;"The internalization of ideal hypermuscular body and pro-muscularity media's influence have shown their importance in muscle dysmorphia development. The aim of the current study is to have a better understanding of links between specific body checking behaviors and muscle dysmorphia in social network context." 14466;"Ripple Collision of Three Epidemics: Vaping, Opioid Use, and COVID-19.";"G. MICHEL";"Equipe 06, Team 06";35178200;"Addiction & health";"Sarfraz Z, Sarfraz A, Sarfraz M, Pandav K, Michel G";;"Feb 2022";1645142400;; 14444;"Association of propofol induction dose and severe pre-incision hypotension among surgical patients over age 65.";"G. MICHEL";"Equipe 06, Team 06";35489305;"Journal of clinical anesthesia";"Schonberger RB, Dai F, Michel G, Vaughn MT, Burg MM, Mathis M, Kheterpal S, Akhtar S, Shah N, Bardia A";;"Apr 2022";1651276800;;"We aimed to study the association between propofol induction dose (mg/kg) and pre-incision severe hypotension (Mean Arterial Pressure (MAP) ≤ 55 mmHg) among patients ≥65 years of age." 14442;"ASB4 modulates central melanocortinergic neurons and calcitonin signaling to control satiety and glucose homeostasis.";"G. MICHEL";"Equipe 06, Team 06";35536884;"Science signaling";"Vagena E, Crneta J, Engström P, He L, Yulyaningsih E, Korpel NL, Cheang RT, Bachor TP, Huang A, Michel G, Attal K, Berrios DI, Valdearcos M, Koliwad SK, Olson DP, Yi CX, Xu AW";;"May 2022";1652140800;;"Variants in the gene encoding ankyrin repeat and SOCS box-containing 4 () are linked to human obesity. Here, we characterized the pathways underlying the metabolic functions of ASB4. Hypothalamic expression was suppressed by fasting in wild-type mice but not in mice deficient in , which encodes Agouti-related protein (AgRP), an appetite-stimulating hormone, suggesting that ASB4 is a negative target of AgRP. Many ASB4 neurons in the brain were adjacent to AgRP terminals, and feeding induced by AgRP neuronal activation was disrupted in -deficient mice. Acute knockdown of in the brain caused marked hyperphagia due to increased meal size, and deficiency led to increased meal size and food intake at the onset of refeeding, when very large meals were consumed. -deficient mice were resistant to the meal-terminating effects of exogenously administered calcitonin and showed decreased neuronal expression of , which encodes the calcitonin receptor. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus in mice are involved in glucose homeostasis, and deficiency specifically in POMC neurons resulted in glucose intolerance that was independent of obesity. Furthermore, individuals with type 2 diabetes showed reduced ASB4 abundance in the infundibular nuclei, the human equivalent of the arcuate nucleus. Together, our results indicate that ASB4 acts in the brain to improve glucose homeostasis and to induce satiety after substantial meals, particularly those after food deprivation." 14440;"Connecting Algal Polysaccharide Degradation to Formaldehyde Detoxification.";"G. MICHEL";"Equipe 06, Team 06";35561127;"Chembiochem : a European journal of chemical biology";"Brott S, Thomas F, Behrens M, Methling K, Bartosik D, Dutschei T, Lalk M, Michel G, Schweder T, Bornscheuer UT";;"May 2022";1652400000;;"Formaldehyde is a toxic metabolite that is formed in large quantities during bacterial utilization of the methoxy sugar 6-O-methyl-d-galactose, an abundant monosaccharide in the red algal polysaccharide porphyran. Marine bacteria capable of metabolizing porphyran must therefore possess suitable detoxification systems for formaldehyde. We demonstrate here that detoxification of formaldehyde in the marine Flavobacterium Zobellia galactanivorans proceeds via the ribulose monophosphate pathway. Simultaneously, we show that the genes encoding the key enzymes of this pathway are important for maintaining high formaldehyde resistance. Additionally, these genes are upregulated in the presence of porphyran, allowing us to connect porphyran degradation to the detoxification of formed formaldehyde." 14438;"MarvelD3 Is Upregulated in Ulcerative Colitis and Has Attenuating Effects during Colitis Indirectly Stabilizing the Intestinal Barrier.";"G. MICHEL";"Equipe 06, Team 06";35563847;Cells;"Weiß F, Czichos C, Knobe L, Voges L, Bojarski C, Michel G, Fromm M, Krug SM";;"May 2022";1652486400;;"In inflammatory bowel disease (IBD), the impaired intestinal barrier is mainly characterized by changes in tight junction protein expression. The functional role of the tight junction-associated MARVEL protein MARVELD3 (MD3) in IBD is yet unknown. (i) In colon biopsies from IBD patients we analyzed MD3 expression and (ii) in human colon HT-29/B6 cells we studied the signaling pathways of different IBD-relevant cytokines. (iii) We generated a mouse model with intestinal overexpression of MD3 and investigated functional effects of MD3 upregulation. Colitis, graded by the disease activity index, was induced by dextran sodium sulfate (DSS) and the intestinal barrier was characterized electrophysiologically. MD3 was upregulated in human ulcerative colitis and MD3 expression could be increased in HT-29/B6 cells by IL-13 via the IL13Rα1/STAT pathway. In mice DSS colitis, MD3 overexpression had an ameliorating, protective effect. It was not based on direct enhancement of paracellular barrier properties, but rather on regulatory mechanisms not solved yet in detail. However, as MD3 is involved in regulatory functions such as proliferation and cell survival, we conclude that the protective effects are hardly targeting the intestinal barrier directly but are based on regulatory processes supporting stabilization of the intestinal barrier." 14436;"Lifetime and Child Sexual Violence, Risk Factors and Mental Health Correlates Among a Nationally Representative Sample of Adolescents and Young Adults in Haiti: A Public Health Emergency.";"G. MICHEL";"Equipe 06, Team 06";35576436;"Journal of interpersonal violence";"Cénat JM, Dalexis RD, Clorméus LA, Lafontaine MF, Guerrier M, Michel G, Hébert M";;"May 2022";1652659200;;"Very little is known in Haiti and the Caribbean regarding child and lifetime sexual victimization. Using a nationally representative sample of adolescents and young adults aged 15-24, this study aimed to document the prevalence, risk factors and mental health correlates of lifetime and child sexual violence in Haiti. A national cross-sectional surrvey was conducted in Haiti, using a multistage sampling frame, stratified by geographical department, urban or rural setting, gender, and age groups (15-19 and 20-24 years). The final sample included 3586 household participants (47.6% female). A weighted sample of 3945 individuals was obtained and used in the following analyses. Overall rate of lifetime and child sexual violence was, respectively, 27.44% (95% CI 25.94-28.94) and 11.27% (95% CI 10.18-12.35). Lifetime sexual violence rate was significantly higher among female participants (29.02%; 95% CI 27.5-30.55) compared to male (25.73%, 95% CI 24.26-27.2), χ = 4.63, < .05, but there was no significant gender difference for child sexual victimization. Experiences of family physical violence, emotional abuse by mother and father, divorce of parents, and other physical violence were strongly associated with higher odds of sexual victimization. Participants who reported having experienced sexual violence are more at risk to meet criteria of PTSD (OR = 1.96, 95% CI 1.66-2.32; < .0001), depression (OR = 1.73, 95% CI 1.47-2.02; < .0001), psychological distress (OR =1.72, 95% CI 1.47-2.02; < .0001), and substance abuse (OR = 1.33, 95% CI 1.13-1.57; < .0001). Findings demonstrate that sexual violence is a public health emergency in Haiti. They provide evidence for the development of prevention and intervention programs." 14398;"Impact of Diabetes on Outcomes of Patients With Lower Extremity Artery Disease.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35138186;Angiology;"Behrendt CA, Lareyre F, Raffort J";;"Feb 2022";1644364800;; 14396;"Incidence of Contrast-Induced Nephropathy and Post-Operative Outcomes in Patients Undergoing Chimney Endovascular Aortic Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35188412;Angiology;"Caradu C, Coatsaliou Q, Colacchio EC, Ducasse E, Lareyre F, Raffort J";;"Feb 2022";1645401600;;"Chimney endovascular aortic aneurysm repair (ch-EVAR) has become a valid alternative to treat complex aneurysms but the occurrence of contrast-induced kidney injury (CI-AKI) is poorly known. This study investigated the incidence and the impact of CI-AKI on post-operative outcomes after ch-EVAR. Consecutive patients who underwent ch-EVAR between July 2010 and 2021 were retrospectively included. CI-AKI was defined based on plasma creatinine levels within 7 days after the intervention according to the ""Kidney Disease Improving Global Outcomes"" (KDIGO) classification. Among 102 patients included, CI-AKI occurred in 14 cases (13.7%). The 30-day post-operative mortality and complications were significantly higher in patients who developed CI-AKI compared with those who did not (50 vs 9.1%, = .001 and 57.1 vs 20.5%, = .007). Over a median follow-up of 24 months (3-39), overall mortality was also significantly higher (78.6 vs 33.0%, = .002). The pre-operative platelet-to-lymphocyte ratio (PLR) was significantly higher in patients who developed CI-AKI (224.5 vs 147.6, = .008). CI-AKI is frequent after ch-EVAR and is associated with worse post-operative outcomes. This should increase awareness of clinicians to optimize preventive and therapeutic strategies." 14394;"Decreased Angiogenesis in Diabetes: New Insights into the Mechanisms Involved in the Negative Association Between Diabetes and Abdominal Aortic Aneurysm.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35283004;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Lê CD, Raffort J";;"Mar 2022";1647216000;; 14392;"Impact of Female Sex on Outcomes of Patients Undergoing Thoracic Endovascular Aortic Aneurysm Repair: A Ten-Year Retrospective Nationwide Study in France.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35456346;"Journal of clinical medicine";"Lareyre F, Raffort J, Behrendt CA, Chaudhuri A, Lê CD, Fabre R, Pradier C, Bailly L";;"Apr 2022";1650672000;;"The impact of sex on the outcomes of patients with cardiovascular disease is still incompletely understood. The aim of this nationwide multicenter observational study was to investigate the impact of sex on post-operative outcomes in patients undergoing thoracic endovascular aortic repair (TEVAR) for intact thoracic aortic aneurysm (iTAA). The French National Health Insurance Information System was searched to identify these patients over a ten-year retrospective period. Post-operative outcomes, 30-day and overall mortality were recorded. Among the 7383 patients included (5521 men and 1862 women), females were significantly older than males (66.8 vs. 64.8 years, < 0.001). They were less frequently diagnosed with cardiovascular comorbidities. Post-operatively, women had less frequently respiratory (10.9 vs. 13.7%, = 0.002) as well as cardiac complications (34.3 vs. 37.3%, = 0.023), but they had more frequently arterial complications (52.8 vs. 49.8%, = 0.024). There was no significant difference on overall mortality for a mean follow-up of 2.2 years (26.9 vs. 27.6%, = 0.58). In the multivariable regression model, female sex was not associated with 30-day or overall mortality. Although women had a favorable comorbidity profile, the short-term and long-term survival was similar. The significantly higher rate of arterial complications suggests that women may be at higher risk of access-vessel-related complications." 14390;"A pilot study investigating the feasibility of using a fully automatic software to assess the RENAL and PADUA score.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35589469;"Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie";"Carlier M, Lareyre F, Lê CD, Adam C, Carrier M, Chikande J, Guidi L, Augène E, Durand M, Raffort J";;"May 2022";1652918400;;"Image-based morphometric scoring systems such as the RENAL and PADUA scores are useful to evaluate the complexity of partial nephrectomy for renal cell carcinoma (RCC). The main aim of this study was to develop a new imaging software to enable an automatic detection and a 3D visualization of RCC from CT angiography (CTA) and to address the feasibility to use it to evaluate the features of the RENAL and the PADUA scores." 14388;"Bibliometric Analysis on Artificial Intelligence and Machine Learning in Vascular Surgery.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35798225;"Annals of vascular surgery";"Lareyre F, Lê CD, Adam C, Carrier M, Raffort J";;"Jul 2022";1657152000;; 14386;"Big Data and Artificial Intelligence in Vascular Surgery: Time for Multidisciplinary Cross-Border Collaboration.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35815537;Angiology;"Lareyre F, Behrendt CA, Chaudhuri A, Ayache N, Delingette H, Raffort J";;"Jul 2022";1657497600;; 14384;"Applications of artificial intelligence for patients with peripheral artery disease.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35921995;"Journal of vascular surgery";"Lareyre F, Behrendt CA, Chaudhuri A, Lee R, Carrier M, Adam C, Lê CD, Raffort J";;"Aug 2022";1659484800;;"Applications of artificial intelligence (AI) have been reported in several cardiovascular diseases but its interest in patients with peripheral artery disease (PAD) has been so far less reported. The aim of this review was to summarize current knowledge on applications of AI in patients with PAD, to discuss current limits, and highlight perspectives in the field." 14382;"e-Health in Vascular Diseases: Integrating Digital Innovation in Everyday Clinical Practice.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36012995;"Journal of clinical medicine";"Lareyre F, Behrendt CA, Raffort J";;"Aug 2022";1661472000;;"Healthcare systems are confronted with major challenges [...]." 14380;"Artificial Intelligence in Vascular Surgical Departments: Slowly But Surely.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";36042693;Angiology;"Lareyre F, Behrendt CA, Chaudhuri A, Raffort J";;"Aug 2022";1661904000;; 14378;"Antithrombotic Treatment Patterns of Patients with Symptomatic Peripheral Arterial Occlusive Disease in Germany: Evidence from Health Insurance Claims Data.";"F. Lareyre";"Equipe 09, Team 09";36143102;"Journal of clinical medicine";"Peters F, Kuchenbecker J, Acar L, Marschall U, L'Hoest H, Lareyre F, Spanos K, Behrendt CA";;"Sep 2022";1663891200;;"Patients with peripheral arterial occlusive disease (PAOD) are at risk of worsening limb symptoms, major adverse cardiovascular events and exhibit an impaired life expectancy. There is a lack of evidence on the extent of pharmacological secondary prevention in PAOD patients. This study assesses treatment patterns of antithrombotic agents in symptomatic PAOD patients." 14376;"In Vitro Evaluation of Curcumin- and Quercetin-Loaded Nanoemulsions for Intranasal Administration: Effect of Surface Charge and Viscosity.";"E. Ferrari";"Equipe 09, Team 09";35057089;Pharmaceutics;"Vaz G, Clementino A, Mitsou E, Ferrari E, Buttini F, Sissa C, Xenakis A, Sonvico F, Dora CL";;"Jan 2022";1642723200;;"The nose-to-brain delivery of neuroprotective natural compounds is an appealing approach for the treatment of neurodegenerative diseases. Nanoemulsions containing curcumin (CUR) and quercetin (QU) were prepared by high-pressure homogenization and characterized physicochemically and structurally. A negative (CQ_NE-), a positive (CQ_NE+), and a gel (CQ_NEgel) formulation were developed. The mean particle size of the CQ_NE- and CQ_NE+ was below 120 nm, while this increased to 240 nm for the CQ_NEgel. The formulations showed high encapsulation efficiency and protected the CUR/QU from biological/chemical degradation. Electron paramagnetic resonance spectroscopy showed that the CUR/QU were located at the interface of the oil phase in the proximity of the surfactant layer. The cytotoxicity studies showed that the formulations containing CUR/QU protected human nasal cells from the toxicity evidenced for blank NEs. No permeation across an in vitro model nasal epithelium was evidenced for CUR/QU, probably due to their poor water-solubility and instability in physiological buffers. However, the nasal cells' drug uptake showed that the total amount of CUR/QU in the cells was related to the NE characteristics (CQ_NE- > CQ_NE+ > CQ_NEgel). The method used allowed the obtainment of nanocarriers of an appropriate size for nasal administration. The treatment of the cells showed the protection of cellular viability, holding promise as an anti-inflammatory treatment able to prevent neurodegenerative diseases." 14374;"Neurophysiological Correlates of Motor and Cognitive Dysfunction in Prodromal and Overt Dementia with Lewy Bodies.";"E. Ferrari";"Equipe 09, Team 09";35094996;"Journal of Alzheimer's disease : JAD";"Benussi A, Pilotto A, Cantoni V, Ferrari E, Borroni B, Padovani A";;"Jan 2022";1643587200;;"The neurophysiological correlates of cognitive and motor symptoms in prodromal and overt dementia with Lewy bodies (DLB) are still to be elucidated." 14372;"One-Year Major Cardiovascular Events After Restrictive Versus Liberal Blood Transfusion Strategy in Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Trial.";"E. Ferrari";"Equipe 09, Team 09";35130052;Circulation;"Gonzalez-Juanatey JR, Lemesle G, Puymirat E, Ducrocq G, Cachanado M, Arnaiz JA, Martínez-Sellés M, Silvain J, Ariza-Solé A, Ferrari E, Calvo G, Danchin N, Avendano-Solá C, Rousseau A, Vicaut E, Gonzalez-Ferrero T, Steg PG, Simon T, ";;"Feb 2022";1644192000;; 14370;"Efficacy of Intraoperative Vein Graft Storage Solutions in Preserving Endothelial Cell Integrity during Coronary Artery Bypass Surgery.";"E. Ferrari";"Equipe 09, Team 09";35207364;"Journal of clinical medicine";"Toto F, Torre T, Turchetto L, Lo Cicero V, Soncin S, Klersy C, Demertzis S, Ferrari E";;"Feb 2022";1645747200;;"(1) Introduction: Intraoperative preservation solutions for saphenous vein grafts may influence the endothelial structure and increase the risk of graft failure after coronary surgery. The aim of the study was to compare the efficacy of three solutions in maintaining the endothelial cell integrity of venous segments. (2) Methods: We tested the efficacy of physiological saline solution (PSS), heparinized autologous blood (HAB) and DuraGraft in preserving the endothelium of vein segments by evaluating the degree of endothelial cell apoptosis. Two incubation times (2 and 4 h from harvesting) were used for each solution. The quantification of apoptotic cells was computed as the intensity nuclei/intensity area ratio. (3) Results: After 2 h of ischemia, the degree of apoptosis decreased progressively across the use of DuraGraft, HAB and PSS ( = 0.004), although only the difference between DuraGraft and PSS yielded a statistical significance ( = 0.002). After 4 h, a similar decrease in apoptosis was shown across the three media; however, statistical significance was not reached. The analysis of the elapsed time (2 or 4 h of incubation) showed that this was a relevant factor in maintaining the endothelial structural integrity independently from the storage solution (test for interaction of media and time = 0.010). (4) Conclusion: Within 2 h of incubation, endothelial structural integrity depended on the incubating medium. DuraGraft better protected the SVG against ischemic-induced apoptosis when compared to saline solution. Prolonged ischemia was associated with extended endothelium damage and none of the studied solutions protected the vein graft." 14368;"Apical closure device for full-percutaneous transapical structural and valve procedures with large-sized introducer sheaths: The final preclinical study.";"E. Ferrari";"Equipe 09, Team 09";35249236;"Journal of cardiac surgery";"Ferrari E, Pozzoli A, Maisano F, von Segesser LK";;"Mar 2022";1646524800;;"Closed-chest transapical valve implantations (aortic, mitral, and tricuspid) and cardiac structural procedures requiring large-sized introducer sheaths cannot be safely performed with the available technology. We tested a self-expanding apical closure device in a closed-chest animal model, using large-sized introducer sheaths and human-sized animals to establish the technique for future tests in humans." 14366;"The use of balloon-expandable Sapien-3 valve in redo aortic valve replacement and the potential risk of left main stem occlusion.";"E. Ferrari";"Equipe 09, Team 09";35362212;"Journal of cardiac surgery";"Theologou T, Clivio S, Younes A, Demertzis S, Ferrari E";;"Apr 2022";1648771200;;"Redo aortic valve surgery for the failure of a previously implanted valve is always challenging. In case of small-sized implanted valves, the use of a balloon-expanding Sapien-3 valve can enhance the final effective orifice area, avoid annulus enlargement complex techniques, and can reduce operative time and morbidities. We describe a case where after explanting a failed 19 mm St. Jude mechanical aortic valve and further deployment of a 23 mm Sapien-3 valve, the left coronary ostia was obstructed by the skirt of the transcatheter prosthesis. After careful removal of a little part of the skirt, we were able to restore the coronary flow and the patient had a favorable outcome." 14364;"Diuretics Versus Volume Expansion in the Initial Management of Acute Intermediate High-Risk Pulmonary Embolism.";"E. Ferrari";"Equipe 09, Team 09";35381867;Lung;"Ferrari E, Sartre B, Labbaoui M, Heme N, Asarisi F, Redjimi N, Fourrier E, Squara F, Bun S, Berkane N, Breittmayer JP, Doyen D, Moceri P";;"Apr 2022";1649203200;;"The very early management of pulmonary embolism (PE), a part from antithrombotic treatment, has been little studied. Our aim was to compare the effects of diuretic therapy (DT) versus volume expansion (VE) in patients hospitalized for PE with RV dysfunction." 14362;"Percutaneous Venous Cannulation for Minimally Invasive Cardiac Surgery: The Safest and Effective Technique Described Step-by-Step.";"E. Ferrari";"Equipe 09, Team 09";35392055;"Frontiers in surgery";"Pozzoli A, Torre T, Toto F, Theologou T, Ferrari E, Demertzis S";;"Apr 2022";1649376000;;"The current cardiac surgical landscape, with the expansion of minimally invasive operations, ECMO, and some interventional therapies, requires a thorough knowledge of peripheral cannulation techniques. In particular, venous cannulation may appear trivial and complication-free, but this does not reflect the reality. A venous cannulation which is not perfectly performed can lead to serious life-threatening complications in several steps. The technique we describe step by step is the current gold standard in terms of safety and efficacy: from the use of ultrasound for ultrasound-guided puncture to safe advancement of super stiff guidewires by means of a sentinel catheter, and concluding with smooth insertion of the venous cannula over the stiff guidewire up to the SVC. Moreover, a list of bailout maneuvers to solve complications is presented along with a report of institutional clinical experience since the adoption of this technique." 14360;"Differences Between Plasma and Cerebrospinal Fluid p-tau181 and p-tau231 in Early Alzheimer's Disease.";"E. Ferrari";"Equipe 09, Team 09";35404280;"Journal of Alzheimer's disease : JAD";"Pilotto A, Parigi M, Bonzi G, Battaglio B, Ferrari E, Mensi L, Benussi A, Caratozzolo S, Cosseddu M, Turrone R, Archetti S, Ashton NJ, Zetterberg H, Giliani S, Padovani A";;"Apr 2022";1649635200;;"Plasma phosphorylated tau species have been recently proposed as peripheral markers of Alzheimer's disease (AD) pathology. In this cross-sectional study including 91 subjects, plasma and cerebrospinal fluid (CSF) p-tau181 and p-tau231 levels were elevated in the early symptomatic stages of AD. Plasma p-tau231 and p-tau181 were strongly related to CSF phosphorylated tau, total tau and amyloid and exhibited a high accuracy-close to CSF p-tau231 and p-tau181-to identify AD already in the early stage of the disease. The findings might support the use as diagnostic and prognostic peripheral AD biomarkers in both research and clinical settings." 14358;"Assessing the Epidemiology of Rotavirus A, B, C and H in Diarrheic Pigs of Different Ages in Northern Italy.";"E. Ferrari";"Equipe 09, Team 09";35456143;"Pathogens (Basel, Switzerland)";"Ferrari E, Salogni C, Martella V, Alborali GL, Scaburri A, Boniotti MB";;"Apr 2022";1650672000;;"Rotaviruses are classified in 10 groups (A to J), where rotavirus A (RVA) is the major cause of diarrhea in humans and animals. With some exceptions, there is scarce information on the epidemiology of non-A rotaviruses in human and animal hosts. Currently, five species (A, B, C, E and H) have been identified in pigs. In the present study we investigated the prevalence of RVA, RVB, RVC and RVH among diarrheic pigs of different ages, in different seasons and in the presence of co-infections. Two molecular assays were developed for the detection of porcine RVA, RVB, RVC and RVH and were used to screen 962 stool specimens from suckling, weaning and fattening pigs with acute enteritis. Overall, rotaviruses were detected in a high percentage of samples (78%), with RVA being predominant (53%), followed by RVC (45%), RVB (43%) and RVH (14%). RVA was more common in the suckling (58%) and weaning cohorts (64%), while RVB, RVC and RVH were also frequently detected in fattening pigs. Only RVA and RVB infections followed a seasonal trend and exhibited age-related differences. Rotavirus infections were frequently present in combination with other pathogens. The present study depicts a portrait of rich rotavirus diversity in porcine herds, identifying seasonal and age-related patterns of circulation of the different rotavirus species in the surveyed areas." 14356;"Effective high-throughput isolation of enriched platelets and circulating pro-angiogenic cells to accelerate skin-wound healing.";"E. Ferrari";"Equipe 09, Team 09";35474498;"Cellular and molecular life sciences : CMLS";"Erratico S, Belicchi M, Meregalli M, Di Silvestre D, Tripodi L, De Palma A, Jones R, Ferrari E, Porretti L, Trombetta E, Merlo GR, Mauri P, Torrente Y";;"Apr 2022";1651017600;;"Delayed wound healing and chronic skin lesions represent a major health problem. Over the past years, growth factors mediated by platelet-rich plasma (PRP) and cell-based therapies were developed as effective and affordable treatment able to improve wound healing capacity. We have advanced existing concepts to develop a highly efficient high-throughput protocol with proven application for the isolation of PRP and pro-angiogenic cells (Angio). This protocol outlines the effectiveness of Angio in promoting the critical healing process including wound closure, re-epithelialization, granulation tissue growth, and blood vessel regeneration. We coupled this effect with normalization of mechanical properties of rescued mouse wounds, which is sustained by a correct arrangement of elastin and collagen fibers. Proteomic analysis of treated wounds demonstrated a fingerprint of Angio based on the up-regulation of detoxification pathway of glutathione metabolism, correlated to a decrease in inflammatory response. Overall, these results have enabled us to provide a framework for how Angio supports wound healing, opening avenues for further clinical advances." 14354;"Management of fever in infants and children in the emergency setting and during home discharge: recommendations from an Italian panel.";"E. Ferrari";"Equipe 09, Team 09";35511631;"Minerva pediatrics";"Silvagni D, Castagno E, Cardinale F, Chiappa S, Chiaretti A, Corsini I, Ferrari E, Masi S, Meli M, Peccarisi LG, Piccotti E, Tipo V, Vitale A, Zampogna S, Zangardi T";;"May 2022";1651708800;;"In infants and children, fever is very common in the emergency setting. The overall aim of the present publication was to overview guidance and provide an algorithm for use in the emergency setting as well as recommendations to inform parents for home care. To obtain consensus, a core steering committee drafted a management algorithm and general consensus was obtained by remote voting among experts. A number of common messages are found in current guidelines: management of fever depends on age, antipyretics are indicated only for discomfort; paracetamol or ibuprofen can be recommended; physical methods for lowering temperature are discouraged. A consensus algorithm is presented in which infants 28 days and <90 days are divided into those ill or well appearing. All infants <28 days with fever ≥37.5 °C should undergo complete work-up for sepsis, strongly considered to receive empirical antibiotics ± acyclovir, and be hospitalized. All infants (between 28 and 90 days) ill appearing should undergo diagnostic work-up for sepsis, receive empirical antibiotics, and be hospitalized. In well appearing infants, diagnostic work-up should be carried out to decide admission to hospital and administration of antibiotics. Specific recommendations are also given for home discharge that can be used to inform parents about the actions to take during home care in the attempt to reinforce existing guidelines. At present, physical examination and laboratory tests, along with best clinical judgement and postdischarge guidance following a defined algorithm, are the foundation of management of febrile children." 14352;"Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.";"E. Ferrari";"Equipe 09, Team 09";35543133;Stroke;"Paciaroni M, Caso V, Agnelli G, Mosconi MG, Giustozzi M, Seiffge DJ, Engelter ST, Lyrer P, Polymeris AA, Kriemler L, Zietz A, Putaala J, Strbian D, Tomppo L, Michel P, Strambo D, Salerno A, Remillard S, Buehrer M, Bavaud O, Vanacker P, Zuurbier S, Yperzeele L, Loos CMJ, Cappellari M, Emiliani A, Zedde M, Abdul-Rahim A, Dawson J, Cronshaw R, Schirinzi E, Del Sette M, Stretz C, Kala N, Reznik M, Schomer A, Grory BM, Jayaraman M, McTaggart R, Yaghi S, Furie KL, Masotti L, Grifoni E, Toni D, Risitano A, Falcou A, Petraglia L, Lotti EM, Padroni M, Pavolucci L, Lochner P, Silvestrelli G, Ciccone A, Alberti A, Venti M, Traballi L, Urbini C, Kargiotis O, Rocco A, Diomedi M, Marcheselli S, Caliandro P, Zauli A, Reale G, Antonenko K, Rota E, Tassinari T, Saia V, Palmerini F, Aridon P, Arnao V, Monaco S, Cottone S, Baldi A, D'Amore C, Ageno W, Pegoraro S, Ntaios G, Sagris D, Giannopoulos S, Kosmidou M, Ntais E, Romoli M, Pantoni L, Rosa S, Bertora P, Chiti A, Canavero I, Saggese CE, Plocco M, Giorli E, Palaiodimou L, Bakola E, Tsivgoulis G, Bandini F, Gasparro A, Terruso V, Mannino M, Pezzini A, Ornello R, Sacco S, Popovic N, Scoditti U, Genovese A, Denti L, Flomin Y, Mancuso M, Ferrari E, Caselli MC, Ulivi L, Giannini N, De Marchis GM";;"May 2022";1652227200;;"In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain." 14350;"Molecular Effects of Biogenic Zinc Nanoparticles on the Growth and Development of L. Revealed by Proteomics and Transcriptomics.";"E. Ferrari";"Equipe 09, Team 09";35548317;"Frontiers in plant science";"Sohail , Sawati L, Ferrari E, Stierhof YD, Kemmerling B, Mashwani ZU";;"May 2022";1652400000;;"Plants are indispensable on earth and their improvement in terms of food security is a need of time. The current study has been designed to investigate how biogenic zinc nanoparticles (Zn NPs) can improve the growth and development of L. In this study, Zn NPs were synthesized utilizing aqueous extracts, and their morphological and optical properties were assessed using UV-Visible spectrophotometry, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). The synthesized Zn NPs were irregular in shape, indicating aggregation in pattern, with an average particle size of 30 nm, while XRD analysis revealed the crystalline structure of nanoparticles. The growth and development of varieties (Faisal canola and Shiralee) were assessed after foliar treatments with different concentrations of biogenic Zn NPs. In varieties, exposure to 15 mg/L Zn NPs dramatically increased chlorophyll, carotenoid content, and biomass accumulation. Similarly, proteomic analyses, on the other hand, revealed that proteins associated with photosynthesis, transport, glycolysis, and stress response in both varieties were substantially altered. Such exposure to Zn NPs, differential expression of genes associated with photosynthesis, ribosome structural constituents, and oxidative stress response were considerably upregulated in var. (Faisal and Shiralee canola). The results of this study revealed that foliar applications of biogenic Zn NPs influence the transcriptome and protein profiling positively, therefore stimulating plant growth and development." 14348;"A causal learning framework for the analysis and interpretation of COVID-19 clinical data.";"E. Ferrari";"Equipe 09, Team 09";35588440;"PloS one";"Ferrari E, Gargani L, Barbieri G, Ghiadoni L, Faita F, Bacciu D";;"May 2022";1652918400;;"We present a workflow for clinical data analysis that relies on Bayesian Structure Learning (BSL), an unsupervised learning approach, robust to noise and biases, that allows to incorporate prior medical knowledge into the learning process and that provides explainable results in the form of a graph showing the causal connections among the analyzed features. The workflow consists in a multi-step approach that goes from identifying the main causes of patient's outcome through BSL, to the realization of a tool suitable for clinical practice, based on a Binary Decision Tree (BDT), to recognize patients at high-risk with information available already at hospital admission time. We evaluate our approach on a feature-rich dataset of Coronavirus disease (COVID-19), showing that the proposed framework provides a schematic overview of the multi-factorial processes that jointly contribute to the outcome. We compare our findings with current literature on COVID-19, showing that this approach allows to re-discover established cause-effect relationships about the disease. Further, our approach yields to a highly interpretable tool correctly predicting the outcome of 85% of subjects based exclusively on 3 features: age, a previous history of chronic obstructive pulmonary disease and the PaO2/FiO2 ratio at the time of arrival to the hospital. The inclusion of additional information from 4 routine blood tests (Creatinine, Glucose, pO2 and Sodium) increases predictive accuracy to 94.5%." 14346;"Risk stratification of patients with SARS-CoV-2 by tissue factor expression in circulating extracellular vesicles.";"E. Ferrari";"Equipe 09, Team 09";35597450;"Vascular pharmacology";"Burrello J, Caporali E, Gauthier LG, Pianezzi E, Balbi C, Rigamonti E, Bolis S, Lazzarini E, Biemmi V, Burrello A, Frigerio R, Martinetti G, Fusi-Schmidhauser T, Vassalli G, Ferrari E, Moccetti T, Gori A, Cretich M, Melli G, Monticone S, Barile L";;"May 2022";1653091200;;"Inflammatory response following SARS-CoV-2 infection results in substantial increase of amounts of intravascular pro-coagulant extracellular vesicles (EVs) expressing tissue factor (CD142) on their surface. CD142-EV turned out to be useful as diagnostic biomarker in COVID-19 patients. Here we aimed at studying the prognostic capacity of CD142-EV in SARS-CoV-2 infection. Expression of CD142-EV was evaluated in 261 subjects admitted to hospital for pneumonia and with a positive molecular test for SARS-CoV-2. The study population consisted of a discovery cohort of selected patients (n = 60) and an independent validation cohort including unselected consecutive enrolled patients (n = 201). CD142-EV levels were correlated with post-hospitalization course of the disease and compared to the clinically available 4C Mortality Score as referral. CD142-EV showed a reliable performance to predict patient prognosis in the discovery cohort (AUC = 0.906) with an accuracy of 81.7%, that was confirmed in the validation cohort (AUC = 0.736). Kaplan-Meier curves highlighted a high discrimination power in unselected subjects with CD142-EV being able to stratify the majority of patients according to their prognosis. We obtained a comparable accuracy, being not inferior in terms of prediction of patients' prognosis and risk of mortality, with 4C Mortality Score. The expression of surface vesicular CD142 and its reliability as prognostic marker was technically validated using different immunocapture strategies and assays. The detection of CD142 on EV surface gains considerable interest as risk stratification tool to support clinical decision making in COVID-19." 14344;"Economic evaluation of Restrictive Vs. Liberal Transfusion Strategy Following Acute Myocardial Infarction (REALITY): trial-based cost effectiveness and cost utility analyses.";"E. Ferrari";"Equipe 09, Team 09";35612990;"European heart journal. Quality of care & clinical outcomes";"Durand-Zaleski I, Ducrocq G, Mimouni M, Frenkiel J, Avendano-Solá C, Gonzalez-Juanatey JR, Ferrari E, Lemesle G, Puymirat E, Berard L, Cachanado M, Arnaiz JA, Martínez-Sellés M, Silvain J, Ariza-Solé A, Calvo G, Danchin N, Paco S, Drouet E, Abergel H, Rousseau A, Simon T, Steg PG, ";;"May 2022";1653436800;;"To estimate the cost effectiveness and cost utility ratios of a restrictive vs liberal transfusion strategy in acute myocardial infarction (AMI) patients with anemia." 14342;"Environmentally Acquired and Their Role in Colonization Resistance.";"E. Ferrari";"Equipe 09, Team 09";35625667;Biomedicines;"Ferreira WT, Hong HA, Adams JRG, Hess M, Kotowicz NK, Tan S, Ferrari E, Brisson A, Zentek J, Soloviev M, Cutting SM";;"May 2022";1653696000;;" is an environmentally acquired, anaerobic, spore-forming bacterium which ordinarily causes disease following antibiotic-mediated dysbiosis of the intestinal microbiota. Although much is understood regarding the life cycle of , the fate of spores upon ingestion remains unclear, and the underlying factors that predispose an individual to colonization and subsequent development of infection (CDI) are not fully understood. Here, we show that , a ubiquitous and environmentally acquired, spore-forming bacterium is associated with colonization resistance to . Using animal models, we first provide evidence that animals housed under conditions that mimic reduced environmental exposure have an increased susceptibility to CDI, correlating with a loss in . Lipopeptide micelles (~10 nm) produced by some isolated from the gastro-intestinal (GI)-tract and shown to have potent inhibitory activity to have recently been reported. We show here that these micelles, that we refer to as heterogenous lipopeptide lytic micelles (HELMs), act synergistically with components present in the small intestine to augment inhibitory activity against . Finally, we show that provision of HELM-producing to microbiota-depleted animals suppresses colonization thereby demonstrating the significant role played by in colonization resistance. In the wider context, our study further demonstrates the importance of environmental microbes on susceptibility to pathogen colonization." 14340;"The Potential of Epigallocatechin Gallate (EGCG) in Targeting Autophagy for Cancer Treatment: A Narrative Review.";"E. Ferrari";"Equipe 09, Team 09";35682754;"International journal of molecular sciences";"Ferrari E, Bettuzzi S, Naponelli V";;"Jun 2022";1654819200;;"Autophagy is an evolutionarily conserved process for the degradation of redundant or damaged cellular material by means of a lysosome-dependent mechanism, contributing to cell homeostasis and survival. Autophagy plays a multifaceted and context-dependent role in cancer initiation, maintenance, and progression; it has a tumor suppressive role in the absence of disease and is upregulated in cancer cells to meet their elevated metabolic demands. Autophagy represents a promising but challenging target in cancer treatment. Green tea is a widely used beverage with healthy effects on several diseases, including cancer. The bioactive compounds of green tea are mainly catechins, and epigallocatechin-gallate (EGCG) is the most abundant and biologically active among them. In this review, evidence of autophagy modulation and anti-cancer effects induced by EGCG treatment in experimental cancer models is presented. Reviewed articles reveal that EGCG promotes cytotoxic autophagy often through the inactivation of PI3K/Akt/mTOR pathway, resulting in apoptosis induction. EGCG pro-oxidant activity has been postulated to be responsible for its anti-cancer effects. In combination therapy with a chemotherapy drug, EGCG inhibits cell growth and the drug-induced pro-survival autophagy. The selected studies rightly claim EGCG as a valuable agent in cancer chemoprevention." 14338;"Cognitive predictors of Social processing in congenital atypical development.";"E. Ferrari";"Equipe 09, Team 09";35729297;"Journal of autism and developmental disorders";"Ferrari E, Butti N, Gagliardi C, Romaniello R, Borgatti R, Urgesi C";;"Jun 2022";1655769600;;"According to current accounts of social cognition, the emergence of verbal and non-verbal components of social perception might rely on the acquisition of different cognitive abilities. These components might be differently sensitive to the pattern of neuropsychological impairments in congenital neurodevelopmental disorders. Here, we explored the association between social and non-social cognitive domains by administering subtests of the NEPSY-II battery to 92 patients with Intellectual and Developmental Disability (IDD). Regardless the level of intellectual functioning and presence of congenital brain malformations, results revealed that visuospatial skills predicted emotion recognition and verbal component of Theory of Mind, whereas imitation predicted the non-verbal one. Future interventions might focus on spatial and sensorimotor abilities to boost the development of social cognition in IDD." 14336;"Transesophageal Echocardiography For The Assessment of Left Atrial Pressure After Trans-Septal Mitral Valve Interventions.";"E. Ferrari";"Equipe 09, Team 09";35738912;"The American journal of cardiology";"Gavazzoni M, Zuber M, Taramasso M, Cascella A, Voci D, Pozzoli A, Ferrari E, Maisano F";;"Jun 2022";1655942400;;"The measure of left atrial pressure (LAP) is an ideal marker for the clinical efficacy of transcatheter mitral valve intervention. Currently, only the invasive measurement of LAP (i-LAP) is available and no echocardiographic methods are reliable in the setting of transcatheter mitral valve intervention. This study sought to validate a new echocardiographic method for the estimation of LAP (e-LAP) by comparing it with i-LAP. During percutaneous edge-to-edge procedure with MitraClip, the i-LAP was routinely monitored. Across the iatrogenic interatrial septum defect, the flow was sampled with continuous-wave Doppler echocardiography for deriving the mean pressure gradient between the left atrium and the right atrium, and the central venous pressure was added to obtain the e-LAP. The correlation between the measures derived from these 2 methods was explored. A total of 34 consecutive patients were included. Intraclass correlation coefficient between e-LAP and i-LAP was high (intraclass correlation coefficient [95% confidence interval] 0.809 [0.625 to 0.902], R Pearson 0.6, p <0.001); a bias of -1.3 mm Hg for e-LAP versus i-LAP was found (p = 0.32). The median follow-up was 108 days (interquartile range 40 to 264). No death occurred and 6 patients were rehospitalized for heart failure. Postimplant e-LAP was correlated with rehospitalization at follow-up (hazard ratio 1.46, 95% confidence interval 1.022 to 2.1, p = 0.038). A cut-off value of 9.5 mm Hg for the e-LAP was identified as predictor of rehospitalization for heart failure. The evaluation of e-LAP has optimal reliability compared with i-LAP; a value more than 9.5 mm Hg was found to be related to higher risk of events at short follow-up." 14334;"Impact of Continuous Flow Left Ventricular Assist Device on Heart Transplant Candidates: A Multi-State Survival Analysis.";"E. Ferrari";"Equipe 09, Team 09";35743495;"Journal of clinical medicine";"Carrozzini M, Bottio T, Caraffa R, Bejko J, Bifulco O, Guariento A, Lombardi CM, Metra M, Azzolina D, Gregori D, Fedrigo M, Castellani C, Tarzia V, Toscano G, Gambino A, Jorgji V, Ferrari E, Angelini A, Gerosa G";;"Jun 2022";1656028800;;"(1) Objectives: The aim of this study was to investigate the impact of the prolonged use of continuous-flow left ventricular assist devices (LVADs) on heart transplant (HTx) candidates. (2) Methods: Between January 2012 and December 2019, we included all consecutive patients diagnosed with end-stage heart failure considered for HTx at our institution, who were also eligible for LVAD therapy as a bridge to transplant (BTT). Patients were divided into two groups: those who received an LVAD as BTT (LVAD group) and those who were listed without durable support (No-LVAD group). (3) Results: A total of 250 patients were analyzed. Of these, 70 patients (28%) were directly implanted with an LVAD as BTT, 11 (4.4%) received delayed LVAD implantation, and 169 (67%) were never assisted with an implantable device. The mean follow-up time was 36 ± 29 months. In the multivariate analysis of survival before HTx, LVAD implantation showed a protective effect: LVAD vs. No-LVAD HR 0.01 ( < 0.01) and LVAD vs. LVAD delayed HR 0.13 ( = 0.02). Mortality and adverse events after HTx were similar between LVAD and No-LVAD ( = 0.65 and = 0.39, respectively). The multi-state survival analysis showed a significantly higher probability of death for No-LVAD vs. LVAD patients with ( = 0.03) or without ( = 0.04) HTx. (4) Conclusions: The use of LVAD as a bridge to transplant was associated with an overall survival benefit, compared to patients listed without LVAD support." 14332;"The role of the agricultural sector in Ghanaian development: a multiregional SAM-based analysis.";"E. Ferrari";"Equipe 09, Team 09";35757163;"Journal of economic structures";"Ferreira V, Almazán-Gómez MÁ, Nechifor V, Ferrari E";;"Jun 2022";1656288000;;"Ghana shows remarkable differences in employment and welfare between the southern and northern regions. The promotion of policy focus on the development of the northern regions requires the elaboration of specific databases describing the regional economies. Hence, this work outlines the construction of a Social Accounting Matrix (SAM) for Ghana for the year 2015 with a high disaggregation of sectors, household income groups and education levels across 10 administrative regions. Linear multisectoral models have been applied to this SAM to estimate socio-economic impacts of potential final demand policies down to a regional level in the Ghanaian economy. Further on, the structural path analysis is used to investigate the role played by different agriculture commodities in transmitting income to different types of households. The results allow for an identification of the most suitable sectors to be promoted due to their ability to generate the highest increases in output, employment and value added in the rest of the economy, as well as those with a significant impact on household income generation. As a result, the primary sector will play a key role in the economic and employment growth of the country. Notably, sorghum and millet, pulses, tobacco, cotton and fibres can be considered favourable crops for development in the Northern region." 14330;"The Kids Are Alright (?). Infants' Development and COVID-19 Pandemic: A Cross-Sectional Study.";"E. Ferrari";"Equipe 09, Team 09";35795098;"International journal of public health";"Ferrari E, Palandri L, Lucaccioni L, Talucci G, Passini E, Trevisani V, Righi E";;"Jul 2022";1657152000;;" The study aimed to assess and compare the global development in six-month-old infants before and during the pandemic restrictive social distancing measures. This cross-sectional nested study involved infants assessed through the Griffiths Scales of Child Development (GSCD) between September 2019 and April 2021. Infants were classified in a pre-COVID or a COVID group, considering the evaluation date and the restrictive measures in place. GSCD subscales and General Development Scores (GDS) were calculated and compared. One hundred and four healthy term-born infants were evaluated. GDS in the COVID group (n:70; median: 94; IQR: 90-100) appeared significantly lower than in the pre-COVID group (n:34; median: 98; IQR: 97-103; < 0.001). Language and personal-social-emotional subareas scores appeared the most affected. A decreasing trend of GDS along with the severity of restriction was observed. A reduction in infant development scores was observed during pandemic social distancing. Further studies are needed to systematize these findings and to address effective public health policies for infants and families during long-term forced isolation periods." 14328;"Efficient ABAC based information sharing within MQTT environments under emergencies.";"E. Ferrari";"Equipe 09, Team 09";35818399;"Computers & security";"Colombo P, Ferrari E, Tümer ED";;"Jul 2022";1657584000;;"Recent emergencies, such as the COVID-19 pandemic have shown how timely information sharing is essential to promptly and effectively react to emergencies. Internet of Things has magnified the possibility of acquiring information from different sensors and using it for emergency management and response. However, it has also amplified the potential of information misuse and unauthorized access to information by untrusted users. Therefore, this paper proposes an access control framework tailored to MQTT-based IoT ecosystems. By leveraging Complex Event Processing, we can enforce controlled and timely data sharing in emergency and ordinary situations. The system has been tested with a case study that targets patient monitoring during the COVID-19 pandemic, showing promising results." 14326;"NMDA and AMPA Receptors at Synapses: Novel Targets for Tau and α-Synuclein Proteinopathies.";"E. Ferrari";"Equipe 09, Team 09";35884851;Biomedicines;"Italia M, Ferrari E, Diluca M, Gardoni F";;"Jul 2022";1658880000;;"A prominent feature of neurodegenerative diseases is synaptic dysfunction and spine loss as early signs of neurodegeneration. In this context, accumulation of misfolded proteins has been identified as one of the most common causes driving synaptic toxicity at excitatory glutamatergic synapses. In particular, a great effort has been placed on dissecting the interplay between the toxic deposition of misfolded proteins and synaptic defects, looking for a possible causal relationship between them. Several studies have demonstrated that misfolded proteins could directly exert negative effects on synaptic compartments, altering either the function or the composition of pre- and post-synaptic receptors. In this review, we focused on the physiopathological role of tau and α-synuclein at the level of postsynaptic glutamate receptors. Tau is a microtubule-associated protein mainly expressed by central nervous system neurons where it exerts several physiological functions. In some cases, it undergoes aberrant post-translational modifications, including hyperphosphorylation, leading to loss of function and toxic aggregate formation. Similarly, aggregated species of the presynaptic protein α-synuclein play a key role in synucleinopathies, a group of neurological conditions that includes Parkinson's disease. Here, we discussed how tau and α-synuclein target the postsynaptic compartment of excitatory synapses and, specifically, AMPA- and NMDA-type glutamate receptors. Notably, recent studies have reported their direct functional interactions with these receptors, which in turn could contribute to the impaired glutamatergic transmission observed in many neurodegenerative diseases." 14324;"Privacy-Preserving Design of Scalar LQG Control.";"E. Ferrari";"Equipe 09, Team 09";35885079;"Entropy (Basel, Switzerland)";"Ferrari E, Tian Y, Sun C, Li Z, Wang C";;"Jul 2022";1658880000;;"This paper studies the agent identity privacy problem in the scalar linear quadratic Gaussian (LQG) control system. The agent identity is a binary hypothesis: Agent A or Agent B. An eavesdropper is assumed to make a hypothesis testing the agent identity based on the intercepted environment state sequence. The privacy risk is measured by the Kullback-Leibler divergence between the probability distributions of state sequences under two hypotheses. By taking into account both the accumulative control reward and privacy risk, an optimization problem of the policy of Agent B is formulated. This paper shows that the optimal deterministic privacy-preserving LQG policy of Agent B is a linear mapping. A sufficient condition is given to guarantee that the optimal deterministic privacy-preserving policy is time-invariant in the asymptotic regime. It is also shown that adding an independent Gaussian random process noise to the linear mapping of the optimal deterministic privacy-preserving policy cannot improve the performance of Agent B. The numerical experiments justify the theoretic results and illustrate the reward-privacy trade-off." 14322;"Metabolic Plasticity of in Response to Different Environmental Conditions.";"E. Ferrari";"Equipe 09, Team 09";35887478;"Journal of fungi (Basel, Switzerland)";"Gallo M, Giovati L, Magliani W, Pertinhez TA, Conti S, Ferrari E, Spisni A, Ciociola T";;"Jul 2022";1658880000;;"The ubiquitous commensal , part of the human microbiota, is an opportunistic pathogen able to cause a wide range of diseases, from cutaneous mycoses to life-threatening infections in immunocompromised patients. adapts to different environments and survives long-time starvation. The ability to switch from yeast to hyphal morphology under specific environmental conditions is associated with its virulence. Using hydrogen nuclear magnetic resonance spectroscopy, we profiled the intracellular and extracellular metabolome of kept in water, yeast extract-peptone-dextrose (YPD), and M199 media, at selected temperatures. Experiments were carried out in hypoxia to mimic a condition present in most colonized niches and fungal infection sites. Comparison of the intracellular metabolites measured in YPD and M199 at 37 °C highlighted differences in specific metabolic pathways: () alanine, aspartate, glutamate metabolism, () arginine and proline metabolism, () glycerolipid metabolism, attributable to the diverse composition of the media. Moreover, we hypothesized that the subtle differences in the M199 metabolome, observed at 30 °C and 37 °C, are suggestive of modifications propaedeutic to a subsequent transition from yeast to hyphal form. The analysis of the metabolites' profiles of allows envisaging a molecular model to better describe its ability to sense and adapt to environmental conditions." 14320;"Curcumin-Based β-Diketo Ligands for Ga: Thermodynamic Investigation of Potential Metal-Based Drugs.";"E. Ferrari";"Equipe 09, Team 09";35890151;"Pharmaceuticals (Basel, Switzerland)";"Mari M, Carrozza D, Malavasi G, Venturi E, Avino G, Capponi PC, Iori M, Rubagotti S, Belluti S, Asti M, Ferrari E";;"Jul 2022";1658880000;;"Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto-enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto-enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto-enol form. A complete H/C NMR and UV-Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer." 14318;"Rabphilin-3A as a novel target to reverse α-synuclein-induced synaptic loss in Parkinson's disease.";"E. Ferrari";"Equipe 09, Team 09";35918045;"Pharmacological research";"Ferrari E, Scheggia D, Zianni E, Italia M, Brumana M, Palazzolo L, Parravicini C, Pilotto A, Padovani A, Marcello E, Eberini I, Calabresi P, Diluca M, Gardoni F";;"Aug 2022";1659398400;;"Toxic aggregates of α-synuclein (αsyn) are considered key drivers of Parkinson's disease (PD) pathology. In early PD, αsyn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying αsyn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract αsyn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with αsyn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of αsyn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/αsyn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in αsyn-injected mice. Notably, the same experimental approaches prevented αsyn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of αsyn aggregates in PD." 14316;"Clinical event rate in patients with and without left main disease undergoing isolated coronary artery bypass grafting: results from the European DuraGraft Registry.";"E. Ferrari";"Equipe 09, Team 09";35929787;"European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery";"Caliskan E, Misfeld M, Sandner S, Böning A, Aramendi J, Salzberg SP, Choi YH, Perrault LP, Tekin I, Cuerpo GP, Lopez-Menendez J, Weltert LP, Böhm J, Krane M, González-Santos JM, Tellez JC, Holubec T, Ferrari E, Emmert MY, ";;"Aug 2022";1659657600;;"Left main coronary artery disease (LMCAD) is considered an independent risk factor for clinical events after coronary artery bypass grafting (CABG). We have conducted a subgroup analysis of the multicentre European DuraGraft Registry to investigate clinical event rates at 1 year in patients with and without LMCAD undergoing isolated CABG in contemporary practice." 14314;"Synaptic neurofilaments and GluN1-NfL interaction in experimental models of α-synucleinopathies.";"E. Ferrari";"Equipe 09, Team 09";35940118;"Neuro-degenerative diseases";"Imarisio A, Ferrari E, Pilotto A, Di Luca M, Padovani A, Gardoni F";;"Aug 2022";1659916800;;"despite neurofilaments are mainly expressed in large caliber myelinated axons, recent evidence supports the existence of a specific synaptic pool, where neurofilament light chain (NfL) has been proposed to stabilize NMDAR at post-synaptic membrane through a direct interaction with the GluN1 subunit. Here, we assessed the expression and synaptic abundance of neurofilaments and their interaction with NMDAR in experimental α-synucleinopathy models." 14312;"β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration.";"E. Ferrari";"Equipe 09, Team 09";35954187;Cells;"Lunghi G, Carsana EV, Loberto N, Cioccarelli L, Prioni S, Mauri L, Bassi R, Duga S, Straniero L, Asselta R, Soldà G, Di Fonzo A, Frattini E, Magni M, Liessi N, Armirotti A, Ferrari E, Samarani M, Aureli M";;"Aug 2022";1660262400;;"β-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphingolipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson's disease. Despite this evidence, the molecular mechanism linking the impairment in β-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of β-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific β-glucocerebrosidase inhibitor conduritol B epoxide. Neurons deficient for β-glucocerebrosidase activity showed a lysosomal accumulation of glucosylceramide and the onset of neuronal damage. Moreover, we found that neurons react to the lysosomal impairment by the induction of their biogenesis and exocytosis. This latter event was responsible for glucosylceramide accumulation also at the plasma membrane level, with an alteration in lipid and protein composition of specific signaling microdomains. Collectively, our data suggest that β-glucocerebrosidase loss of function impairs the lysosomal compartment, establishing a lysosome-plasma membrane axis responsible for modifications in the plasma membrane architecture and possible alterations of intracellular signaling pathways, leading to neuronal damage." 14310;"Fibrillatory Wave Amplitude Evolution during Persistent Atrial Fibrillation Ablation: Implications for Atrial Substrate and Fibrillation Complexity Assessment.";"E. Ferrari";"Equipe 09, Team 09";35956135;"Journal of clinical medicine";"Squara F, Scarlatti D, Bun SS, Moceri P, Ferrari E, Meste O, Zarzoso V";;"Aug 2022";1660262400;;". Fibrillatory Wave Amplitude (FWA) has been described as a non-invasive marker of atrial fibrillation (AF) complexity, and it predicts catheter ablation outcome. However, the actual determinants of FWA remain incompletely understood. . To assess the respective implications of anatomical atrial substrate and AF spectral characteristics for FWA. . Persistent AF patients undergoing radiofrequency catheter ablation were included. FWA was measured on 1-min ECG by TQ concatenation in Lead I, V1, V2, and V5 at baseline and immediately before AF termination. FWA evolution during ablation was compared to that of AF dominant frequency (DF) measured by Independent Component Analysis on 12-lead ECG. FWA was compared to the extent of endocardial low-voltage areas (LVA I 30%), to the surface of healthy left atrial tissue, and to P-wave amplitude in sinus rhythm. The predictive value of FWA for AF recurrence during follow-up was assessed. . We included 29 patients. FWA remained stable along ablation procedure with comparable values at baseline and before AF termination (Lead I = 0.54; V1 = 0.858; V2 = 0.215; V5 = 0.14), whereas DF significantly decreased (5.67 ± 0.68 vs. 4.95 ± 0.58 Hz, p < 0.001). FWA was higher in LVA-I than in LVA-II, -III, and -IV in Lead I and V5 ( = 0.02 and = 0.01). FWA in V5 was strongly correlated with the surface of healthy left atrial tissue (R = 0.786; p < 0.001). FWA showed moderate to strong correlation to P-wave amplitude in all leads. Finally, FWA did not predict AF recurrence after a follow-up of 23.3 ± 9.8 months. . These findings suggest that FWA is unrelated to AF complexity but is mainly determined by the amount of viable atrial myocytes. Therefore, FWA should only be referred as a marker of atrial tissue pathology." 14308;"Latency and Crisis: Mutual Aid Activism in the Covid-19 Pandemic.";"E. Ferrari";"Equipe 09, Team 09";35966137;"Qualitative sociology";"Ferrari E";;"Aug 2022";1660521600;;"Activists have responded to the Covid-19 pandemic by organizing for mutual aid: creating collective action to meet people's material needs and build ties of solidarity. I examine the difficulties encountered by mutual aid activists during the pandemic through Alberto Melucci's notions of latency and collective identity. Through digital ethnographic observations of the Instagram accounts of mutual aid groups based in Philadelphia, USA, as well as interviews with the activists, I explore how mutual aid, conceptualized as latency work, was practiced by activists in the unprecedented conditions of the pandemic and how activists approached collective identity processes. I show that activists experienced a compression of latency and mobilization within the crisis context of the pandemic, which made it more difficult for them to pursue the construction of a collective identity. I also suggest that the effects of this compression were further exacerbated by the logic of immediacy that characterizes social network sites." 14306;"Delayed development of aneurysmal dilatations in patients with extracranial carotid artery dissections.";"E. Ferrari";"Equipe 09, Team 09";35977695;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"van Laarhoven CJHCM, Arnold M, Danilova M, Dreval M, Ferrari E, Goeggel Simonetti B, Gralla J, Heldner M, Kalashnikova L, Mancuso M, Metso TM, Steinsiepe VK, Strbian D, Tatlisumak T, de Kleijn DPV, de Borst GJ";;"Aug 2022";1660694400;;"Dissection of the carotid artery (CaAD) may result in aneurysm formation. The present study was undertaken to evaluate time of onset of dissecting extracranial carotid artery aneurysms (ECAA) following CaAD, and analyse independent risk factors for development of these aneurysms." 14304;"Postthrombotic syndrome and quality of life after deep vein thrombosis in patients treated with edoxaban versus warfarin.";"E. Ferrari";"Equipe 09, Team 09";35992565;"Research and practice in thrombosis and haemostasis";"Bistervels IM, Bavalia R, Beyer-Westendorf J, Ten Cate-Hoek AJ, Schellong SM, Kovacs MJ, Falvo N, Meijer K, Stephan D, Boersma WG, Ten Wolde M, Couturaud F, Verhamme P, Brisot D, Kahn SR, Ghanima W, Montaclair K, Hugman A, Carroll P, Pernod G, Sanchez O, Ferrari E, Roy PM, Sevestre-Pietri MA, Birocchi S, Wik HS, Hutten BA, Coppens M, Naue C, Grosso MA, Shi M, Lin Y, Quéré I, Middeldorp S, ";;"Aug 2022";1661126400;;"Postthrombotic syndrome (PTS) is a long-term complication after deep vein thrombosis (DVT) and can affect quality of life (QoL). Pathogenesis is not fully understood but inadequate anticoagulant therapy with vitamin K antagonists is a known risk factor for the development of PTS." 14302;"Nanosponges by the oxo-Michael polyaddition of cyclodextrins as sorbents of water pollutants: the o-toluidine case.";"E. Ferrari";"Equipe 09, Team 09";36001264;"Environmental science and pollution research international";"Pifferi V, Ferrari E, Manfredi A, Ferruti P, Alongi J, Ranucci E, Falciola L";;"Aug 2022";1661299200;;"Hydrophilic cyclodextrin nanosponges were prepared by the oxo-Michael polyaddition in an aqueous solution at pH > 10 of α-, β-, and γ-cyclodextrin with 1,4-bisacryloylpiperazine or 2,2-bisacrylamidoacetic acid. These nanosponges and, for comparison purposes, their precursor cyclodextrins were tested as sorbents of o-toluidine, a carcinogenic wastewater contaminant, by monitoring the depletion of o-toluidine from a 10 M (10 ppm) aqueous solutions. To this aim, an innovative analytical procedure was used: The voltammetric peak currents of o-toluidine in linear sweep voltammetry experiments were registered using multi-walled carbon nanotubes-modified glassy carbon electrodes. The experimental sorption curves fitted a mono-exponential kinetic model, and the residual o-toluidine was 0.16 ppm, one order of magnitude lower than those of all other sorbents reported so far. The sorption capacities ranged from 88 to 199 µmol g (10-21.3 mg g), equal to or higher than those of the parent cyclodextrins. All nanosponges were completely regenerated by extracting with methanol. After regeneration, the sorption capacity slightly improved, suggesting a rearrangement of the nanosponge network. Overall, it may be reasonably concluded that the cyclodextrin nanosponges reported in this paper warrant potential as o-toluidine exhaustive sorbents." 14300;"Skeletal status in children and adolescents with new-onset type 1 diabetes: a preliminary study based on bone densitometry and quantitative ultrasound.";"E. Ferrari";"Equipe 09, Team 09";36134673;"Pediatric endocrinology, diabetes, and metabolism";"Silvestri F, Infante M, Fabbri A, Ferrara C, Ferraguti G, Costantino F, Ferrari E, Bonci E, Turchetti A, Tiberti C, Tromba V";;"Sep 2022";1663804800;;"Type 1 diabetes (T1D) represents a risk factor for bone loss and impaired bone quality." 14298;"Rapid deployment and sutureless aortic valve replacement international registry: a step forward to define the ideal target patient population.";"E. Ferrari";"Equipe 09, Team 09";36135810;"European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery";"Pozzoli A, Demertzis S, Ferrari E";;"Sep 2022";1663804800;; 14296;"Rational Approach to Finding Genes Encoding Molecular Biomarkers: Focus on Breast Cancer.";"E. Ferrari";"Equipe 09, Team 09";36140706;Genes;"Schneider N, Reed E, Kamel F, Ferrari E, Soloviev M";;"Sep 2022";1663891200;;"Early detection of cancer facilitates treatment and improves patient survival. We hypothesized that molecular biomarkers of cancer could be rationally predicted based on even partial knowledge of transcriptional regulation, functional pathways and gene co-expression networks. To test our data mining approach, we focused on breast cancer, as one of the best-studied models of this disease. We were particularly interested to check whether such a 'guilt by association' approach would lead to pan-cancer markers generally known in the field or whether molecular subtype-specific 'seed' markers will yield subtype-specific extended sets of breast cancer markers. The key challenge of this investigation was to utilize a small number of well-characterized, largely intracellular, breast cancer-related proteins to uncover similarly regulated and functionally related genes and proteins with the view to predicting a much-expanded range of disease markers, especially that of extracellular molecular markers, potentially suitable for the early non-invasive detection of the disease. We selected 23 previously characterized proteins specific to three major molecular subtypes of breast cancer and analyzed their established transcription factor networks, their known metabolic and functional pathways and the existing experimentally derived protein co-expression data. Having started with largely intracellular and transmembrane marker 'seeds' we predicted the existence of as many as 150 novel biomarker genes to be associated with the selected three major molecular sub-types of breast cancer all coding for extracellularly targeted or secreted proteins and therefore being potentially most suitable for molecular diagnosis of the disease. Of the 150 such predicted protein markers, 114 were predicted to be linked through the combination of regulatory networks to basal breast cancer, 48 to luminal and 7 to Her2-positive breast cancer. The reported approach to mining molecular markers is not limited to breast cancer and therefore offers a widely applicable strategy of biomarker mining." 14294;"Fast Protocols for Characterizing Antibody-Peptide Binding.";"E. Ferrari";"Equipe 09, Team 09";36152282;"Methods in molecular biology (Clifton, N.J.)";"Cleaver S, Gardner M, Barlow A, Ferrari E, Soloviev M";;"Sep 2022";1663977600;;"Microarray assay formats gained popularity in the 1990s, first implemented in DNA-based arrays but later adopted for use with proteins, namely antibodies, peptides, low molecular weight (LMW) molecules, such as lipids, and even tissues. In nucleic acid-based affinity assays and arrays, but not in protein or peptide arrays, the specificity and affinity of complementary strand interactions can be deduced from or adjusted through modifications to the nucleotide sequence. Arrays of LMW molecules are characterized by largely uniform but low binding affinities. Multiplexed protein-based affinity assays, such as microarrays, might present an additional challenge due to heterogeneity of antigen properties and of their binding affinities. The use of peptides instead of proteins reduces physical heterogeneity of these reagents through either the widened peptide selection options or rational sequence engineering. However, rational engineering of binding affinities remains an unmet need, and peptide-binding affinities to the respective antipeptide antibodies could vary by orders of magnitude. Hence, multiplexing of such assays by using a microarray format and data analysis and interpretation requires some knowledge of their binding affinities. Low-throughput binding assays to characterize such peptide-antipeptide antibodies interactions are widely available, but scaling-up of traditional protein- and peptide-binding assays might present practical challenges. Here, we describe fast label-free practical approach especially suitable for estimating peptide-binding affinities. The method in question relies on commercially available biolayer interferometry-based equipment with a protocol which can be easily scaled-up, subject to user needs and equipment availability." 14292;"Importance of T, NK, CAR T and CAR NK Cell Metabolic Fitness for Effective Anti-Cancer Therapy: A Continuous Learning Process Allowing the Optimization of T, NK and CAR-Based Anti-Cancer Therapies.";"E. Verhoeyen";"Team 03, Equipe 03";35008348;Cancers;"Krug A, Martinez-Turtos A, Verhoeyen E";;"Jan 2022";1641859200;;"Chimeric antigen receptor (CAR) T and CAR NK cell therapies opened new avenues for cancer treatment. Although original successes of CAR T and CAR NK cells for the treatment of hematological malignancies were extraordinary, several obstacles have since been revealed, in particular their use for the treatment of solid cancers. The tumor microenvironment (TME) is competing for nutrients with T and NK cells and their CAR-expressing counterparts, paralyzing their metabolic effective and active states. Consequently, this can lead to alterations in their anti-tumoral capacity and persistence in vivo. High glucose uptake and the depletion of key amino acids by the TME can deprive T and NK cells of energy and building blocks, which turns them into a state of anergy, where they are unable to exert cytotoxic activity against cancer cells. This is especially true in the context of an immune-suppressive TME. In order to re-invigorate the T, NK, CAR T and CAR NK cell-mediated antitumor response, the field is now attempting to understand how metabolic pathways might change T and NK responses and functions, as well as those from their CAR-expressing partners. This revealed ways to metabolically rewire these cells by using metabolic enhancers or optimizing pre-infusion in vitro cultures of these cells. Importantly, next-generation CAR T and CAR NK products might include in the future the necessary metabolic requirements by improving their design, manufacturing process and other parameters. This will allow the overcoming of current limitations due to their interaction with the suppressive TME. In a clinical setting, this might improve their anti-cancer effector activity in synergy with immunotherapies. In this review, we discuss how the tumor cells and TME interfere with T and NK cell metabolic requirements. This may potentially lead to therapeutic approaches that enhance the metabolic fitness of CAR T and CAR NK cells, with the objective to improve their anti-cancer capacity." 14288;"Targeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity.";"E. Verhoeyen";"Team 03, Equipe 03";35589278;"Journal for immunotherapy of cancer";"Bernard PL, Delconte R, Pastor S, Laletin V, Costa Da Silva C, Goubard A, Josselin E, Castellano R, Krug A, Vernerey J, Devillier R, Olive D, Verhoeyen E, Vivier E, Huntington ND, Nunes J, Guittard G";;"May 2022";1652918400;;"The success and limitations of current immunotherapies have pushed research toward the development of alternative approaches and the possibility to manipulate other cytotoxic immune cells such as natural killer (NK) cells. Here, we targeted an intracellular inhibiting protein 'cytokine inducible SH2-containing protein' (CISH) in NK cells to evaluate the impact on their functions and antitumor properties." 14286;"IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.";"E. Verhoeyen, JE. Ricci, J. Chiche, S. Marchetti, H. Issaoui, R. Paul-Bellon";"Team 03, Equipe 03";36046811;Oncoimmunology;"Martinez-Turtos A, Paul R, Grima-Reyes M, Issaoui H, Krug A, Mhaidly R, Bossowski JP, Chiche J, Marchetti S, Verhoeyen E, Chevet E, Ricci JE";;"Sep 2022";1661990400;;"IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α." 14284;"The efficacy of a task model approach to ADL rehabilitation in stroke apraxia and action disorganisation syndrome: A randomised controlled trial.";"E. Jean-Baptiste";"Team 09, Equipe 09";35239707;"PloS one";"Howe J, Chua W, Sumner E, Drozdowska B, Laverick R, Bevins RL, Jean-Baptiste E, Russell M, Rotshtein P, Wing AM";;"Mar 2022";1646265600;;"Apraxia and action disorganization syndrome (AADS) after stroke can disrupt activities of daily living (ADL). Occupational therapy has been effective in improving ADL performance, however, inclusion of multiple tasks means it is unclear which therapy elements contribute to improvement. We evaluated the efficacy of a task model approach to ADL rehabilitation, comparing training in making a cup of tea with a stepping training control condition." 14282;"Automatic Measurement of Vascular Calcifications in Patients with Aorto-Iliac Occlusive Disease to Predict the Risk of Re-intervention After Endovascular Repair.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Team 09, Equipe 09";35271959;"Annals of vascular surgery";"Guidi L, Lareyre F, Chaudhuri A, Lê CD, Adam C, Carrier M, Hassen-Khodja R, Jean-Baptiste E, Raffort J";;"Mar 2022";1646870400;;"There is currently a lack of consensus and tools to easily measure vascular calcification using computed tomography angiography (CTA). The aim of this study was to develop a fully automatic software to measure calcifications and to evaluate the interest as predictive factor in patients with aorto-iliac occlusive disease." 14280;"Delivery of Complementary and Integrative Health Using Virtual Health Resources: A Scoping Review.";"E. Jean-Baptiste";"Team 09, Equipe 09";35819410;"Journal of integrative and complementary medicine";"Haun JN, Alman AC, Jean-Baptiste E, Melillo C, McMahon-Grenz J, Paykel JM";;"Jul 2022";1657584000;;" Complementary and integrative health (CIH) modalities promote overall health and well-being and can be beneficial for individuals with a range of conditions. Traditionally, CIH has been delivered in person. COVID-19 created a need to identify sustainable remote delivery options to assure access to CIH while practicing public health recommendations. This scoping review maps the opportunities and challenges to remotely delivered CIH. A scoping review was conducted between June 2020 and October 2020 using the following search engines: PubMed, Academic Search Premier, PsycINFO, CINAHL, Cochrane Reviews, and the Cochrane Clinical Trial Collections. Search results investigating remote CIH delivery were restricted to articles written in English, published after 1990. Of the 10,884 articles identified, after review for content and methods, 330 articles were included. Most articles were randomized controlled trials ( = 170), applied mindfulness ( = 203), and targeted mental and behavioral health conditions ( = 182). Interventions were primarily delivered through mobile applications ( = 151) and web-based platforms ( = 86). Most commonly reported barriers were adherence ( = 24), resource requirements (e.g., time and space) ( = 23), and technology-related issues ( = 21). Although most studies did not report facilitators ( = 217), most commonly reported facilitators were social and technologic supports, accessibility, usability, perceptions, and rewards. Participant outcomes measured were broad and included movement ( = 88), stress ( = 68), and pain ( = 54). Intervention characteristic outcomes most often measured were satisfaction and usability ( = 5). This scoping literature review identified many articles addressing remote delivery of CIH, but few reporting on the implementation of remotely delivered CIH. Findings suggest remotely delivered CIH, specifically mindfulness and meditation-based modalities, is a viable treatment option for a diverse range of health conditions. Feasibility studies and larger sample sizes are recommended to strengthen the scientific evidence." 14252;"Recent advances in understanding the role of HES6 in cancers.";"C. Bertolotto, R. Ballotti";"Equipe 01, Team 01";35673577;Theranostics;"Krossa I, Strub T, Martel A, Nahon-Esteve S, Lassalle S, Hofman P, Baillif S, Ballotti R, Bertolotto C";;"Jun 2022";1654646400;;"The NOTCH signaling system regulates a variety of cellular processes during embryonic development and homeostasis maintenance in different tissues and contexts. Hence, dysregulation of NOTCH signaling is associated with a plethora of human cancers, and there have been multiple efforts to target key components of this pathway. In this review, we briefly highlight the latest research advances in understanding HES6, a poorly studied component of the NOTCH pathway. We summarize the role of HES6 in cancers with a focus on uveal melanoma. Finally, we discuss the ongoing efforts to target the NOTCH-HES6 axis in cancers." 14250;"Cutaneous and uveal melanoma: two different cancers in therapeutic needs.";"C. Bertolotto";"Equipe 01, Team 01";35786627;"Comptes rendus biologies";"Bertolotto C";;"Jul 2022";1656979200;;"Melanocytes are located in various parts of the human body, such as the skin and the eye. Their transformation leads to melanoma, an aggressive and deadly neoplasm. Cutaneous and uveal melanomas show different characteristics, including significant differences in genetic alterations, metastatic sites and therapeutic response. In recent decades, great efforts have been made to obtain a more comprehensive understanding of genetics, genomics and molecular changes, enabling the identification of key cellular processes and signaling pathways in melanomas. Major breakthroughs were realized in the treatment of metastatic cutaneous melanoma, but most patients relapse. Currently, there is no approved systemic treatment for metastatic uveal melanoma. Thus, these two different cancers are in therapeutic need to overcome treatment failure and improve patient prognosis. In this review we discuss on one hand the mutation of MITF, the master gene of melanocyte homeostasis, which we identified as a new melanoma predisposition gene in cutaneous melanoma, and on the other hand the recent findings of intratumor heterogeneity and characterization of cell sub-populations in primary uveal melanomas. These studies offer new tools for early detection and therapeutic targets." 14248;"[Analysis of primary uveal melanomas using single cell RNA sequencing].";"C. Bertolotto";"Equipe 01, Team 01";36094248;"Medecine sciences : M/S";"Grandjean-Closson E, Heckmann C, Le Coz C, Louvet I, Neri M, Bertolotto C";;"Sep 2022";1662940800;; 14246;"Transient Post-Natal Exposure to Xenoestrogens Induces Long-Term Alterations in Cardiac Calcium Signaling.";"C. Mauduit, M. Benahmed";"Equipe 10, Team 10";35324727;Toxics;"Tabasso C, Frossard MP, Ducret C, Chehade H, Mauduit C, Benahmed M, Simeoni U, Siddeek B";;"Mar 2022";1648080000;;"Today, non-communicable disorders are widespread worldwide. Among them, cardiovascular diseases represent the main cause of death. At the origin of these diseases, exposure to challenges during developmental windows of vulnerability (peri-conception, in utero, and early infancy periods) have been incriminated. Among the challenges that have been described, endocrine disruptors are of high concern because of their omnipresence in the environment. Worrisomely, since birth, children are exposed to a significant number of endocrine disruptors. However, the role of such early exposure on long-term cardiac health is poorly described. In this context, based on a model of rats exposed postnatally and transiently to an estrogenic compound prototype (estradiol benzoate, EB), we aimed to delineate the effects on the adult heart of such transient early exposure to endocrine disruptors and identify the underlying mechanisms involved in the potential pathogenesis. We found that this transient post-natal exposure to EB induced cardiac hypertrophy in adulthood, with increased cardiomyocyte size. The evaluation of cardiac calcium signaling, through immunoblot approaches, highlighted decreased expression of the sarcoplasmic reticulum calcium ATPase 2 (SERCA2) and decreased Nuclear Factor of Activated T Cells (NFAT3) phosphorylation as a potential underlying mechanism of cardiac hypertrophy. Furthermore, the treatment of cardiomyocytes with EB in vitro induced a decrease in SERCA2 protein levels. Overall, our study demonstrates that early transient exposure to EB induces permanent cardiac alterations. Together, our data highlight SERCA2 down-regulation as a potential mechanism involved in the cardiac pathogenesis induced by EB. These results suggest programming of adult heart dysfunctions such as arrhythmia and heart failures by early exposure to endocrine disruptors and could open new perspectives for treatment and prevention." 14238;"Dermatoscopic and clinical features of congenital or congenital-type nail matrix nevi: A multicenter prospective cohort study by the International Dermoscopy Society.";"C. Chiaverini";"Equipe 12, Team 12";35104588;"Journal of the American Academy of Dermatology";"Pham F, Boespflug A, Duru G, Phan A, Poulalhon N, Weiler L, Tanaka M, Lallas A, Ogata D, Davaine AC, Bahadoran P, Balguerie X, Kamińska-Winciorek G, Tromme I, Correia O, Kim MB, Marghoob AA, Linda Martin , Guitera P, Meziane M, Miquel J, Mun JH, Argenziano G, Bessis D, Bourke J, Mijuskovic Z, Chiaverini C, Corven-Benoit C, Droitcourt C, Skowron F, Marque M, Zalaudek I, Rosendahl C, Moreno-Ramirez D, Vabres P, Haenssle H, Malvehy J, Puig S, Robert C, Schopf TR, Scope A, Dalle S, Thomas L";;"Feb 2022";1643673600;;"Congenital nail matrix nevi (NMN) are difficult to diagnose because they feature clinical characteristics suggestive of adult subungual melanoma. Nail matrix biopsy is difficult to perform, especially in children." 14236;"Case Report, Practices Survey and Literature Review of an Under-Recognized Pediatric Vascular Disorder: The BASCULE Syndrome.";"C. Chiaverini";"Equipe 12, Team 12";35463901;"Frontiers in pediatrics";"Baurens N, Briand C, Giovannini-Chami L, De Guillebon De Resnes JM, Hubiche T, Chiaverini C, Giordana P, Leftheriotis G, Bernardor J";;"Apr 2022";1650844800;;"Bier anemic spots, cyanosis, and urticaria-like eruption (BASCULE) syndrome is an underreported pediatric vascular disorder from the group of acrosyndromes. In children, these include paroxysmal acrosyndromes (Raynaud's phenomenon and chilblain-like lesions), permanent acrosyndromes (acrocyanosis), and transient acrosyndromes, in which their pathogeneses are associated with virus infections, Epstein-Barr virus, and, more recently, SARS-CoV-2, respectively." 14234;"Perialar intertrigo in children and adolescents: A multicenter prospective study of 41 cases.";"C. Chiaverini";"Equipe 12, Team 12";35699273;"Pediatric dermatology";"Sanchez A, Mahe E, Miquel J, Abasq C, Phan A, Mazereeuw-Hautier J, Lemille J, Maruani A, Bonniaud B, Plantin P, Mallet S, Martin H, Hubiche T, Chiaverini C, Lacour JP, ";;"Jun 2022";1655164800;;"We observed isolated cases of perialar intertrigo in children and teenagers that did not appear to correspond to any known clinical entity. The objective of this study was to describe the clinical features of this dermatosis and the clinical characteristics of the patients." 14232;"Dermatologic manifestations in paediatric neurofibromatosis type 2: a cross sectional descriptive multicentric study.";"C. Chiaverini";"Equipe 12, Team 12";35729665;"Orphanet journal of rare diseases";"Legoupil S, Bessis D, Picard F, Mallet S, Mazereeuw J, Phan A, Dupin-Deguine D, Kalamarides M, , Chiaverini C";;"Jun 2022";1655769600;;"Neurofibromatosis type 2 (NF2) is characterized by bilateral vestibular schwannoma (VS) more often in adults but a severe paediatric form with multiple neurological tumours is also described. In this population, a early diagnosis is important to prevent the onset of neurological complications but is difficult, particularly without a familial history. Cutaneous manifestations, which may precede VS or neurological tumours by several years, may contribute to an early diagnosis, but specific studies are lacking. The objective of this study was to characterize cutaneous manifestations of NF2 in a paediatric population." 14230;"Quality of life of children with capillary malformations of the lower limbs: Evolution and associated factors. Data from the French national paediatric cohort, CONAPE.";"C. Chiaverini";"Equipe 12, Team 12";35810006;"Annales de dermatologie et de venereologie";"Robert J, Marchand A, Mazereeuw-Hautier J, Boccara O, Martin L, Chiaverini C, Beneton N, Vabres P, Balguerie X, Plantin P, Bessis D, Barbarot S, Dadban A, Droitcourt C, Samimi M, Morel B, Caille A, Maruani A, Leducq S, ";;"Jul 2022";1657324800;; 14228;"Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice.";"C. Chiaverini";"Equipe 12, Team 12";35854650;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Lasek A, Bellon N, Mallet S, Puzenat E, Bursztejn AC, Abasq C, Mazereeuw-Hautier J, Chiaverini C, Hubiche T, Raison Peyron N, Du Thanh A, Barbarot S, Aubert H, Reguiai Z, Droitcourt C, Fievet C, Bellissen A, Bachelerie M, Nosbaum A, Leymarie A, Armingaud P, Masson Regnault M, Mahé E, , ";;"Jul 2022";1658275200;;"Dupilumab is the first biotherapy available for the treatment of moderate-to-severe childhood atopic dermatitis (AD)." 14226;"Folliculitis decalvans and dystrophic epidermolysis bullosa: a significant association.";"C. Chiaverini";"Equipe 12, Team 12";35904062;"The British journal of dermatology";"Matard B, Bourrat E, Cavalié M, Chiaverini C, Reygagne P";;"Jul 2022";1659052800;;"This work reports 30 cases of folliculitis decalvans (FD) in patients with dystrophic epidermolysis bullosa (DEB) among a cohort of 125 DEB patients seen between 2010 and 2021 in 2 French expert centers for the management of inherited epidermolysis bullosa. Such an association between two rare diseases cannot be fortuitous and implies a physiopathological link that we discuss in this paper. This association is a new significant fact to add to the reflexion on FD causes, suggesting that skin abnormality of DEB could act as a factor of a specific skin barrier alteration which could favor FD. Scarring alopecia with tufted folliculitis and pustules on inflamed skin at the vertex of a woman with dominant dystrophic epidermolysis bullosa." 14224;"Perception of Oral Health-Related Quality of Life in Children with Epidermolysis Bullosa: A Quantitative and Qualitative Study.";"C. Chiaverini";"Equipe 12, Team 12";35993264;"JDR clinical and translational research";"Marty M, Chiaverini C, Milon C, Costa-Mendes L, Kémoun P, Mazereeuw-Hautier J, Joseph C";;"Aug 2022";1661126400;;"The results of this study confirm the difficulties experienced by patients in the oral sphere. They also show that patients are able to adapt and that their demands go beyond functional rehabilitation. This work should encourage dental practitioners to be part of the overall management of the disease, involving regular checkups, preventive dental measures, and oral hygiene education. Therefore, more effective communication is required, not only between the dental and dermatological teams but also with the parents and caregivers." 14222;"Selecting a multiplex PCR panel for accurate molecular diagnosis of intestinal protists: a comparative study of Allplex (Seegene), G-DiaParaTrio (Diagenode), and RIDAGENE (R-Biopharm) assays and microscopic examination.";"C. Pomares";"Equipe 06, Team 06";35138245;"Parasite (Paris, France)";"Argy N, Nourrisson C, Aboubacar A, Poirier P, Valot S, Laude A, Desoubeaux G, Pomares C, Machouart M, Le Govic Y, Dalle F, Botterel F, Bourgeois N, Cateau E, Leterrier M, Le Pape P, Morio F, Houze S";;"Feb 2022";1644364800;;"Commercial multiplex PCR assay panels were developed to overcome the limitations of microscopic examination for parasitological diagnosis on stool samples. However, given the increased supply of this diagnostic approach, these assays must be evaluated to position them in a diagnostic algorithm. Analytical performances of the multiplex PCR assay G-DiaParaTrio, Allplex GI parasite and RIDAGENE parasitic stool panel for detecting Blastocystis sp., Entamoeba histolytica, Giardia duodenalis, Cryptosporidium spp., Dientamoeba fragilis, and Cyclospora cayetanensis, were assessed through a retrospective comparative study on 184 stool samples initially sent for parasitological investigation. The composite reference method for parasitological diagnosis was microscopic observation and Entamoeba histolytica-specific adhesion detection when necessary. Multiplex PCR assays were performed on extracted DNA from each stool, following the manufacturer's recommendations. Discrepant results with the composite reference method were investigated with species-specific PCR to approach a final parasitological diagnosis. Overall sensitivity/specificity for the multiplex PCR assays was 93.2%/100% for G-DiaParaTrio, 96.5%/98.3% for Allplex GI parasite and 89.6%/98.3% for RIDAGENE, whereas the composite reference method presented an overall sensitivity/specificity of 59.6%/99.8%. These results confirmed the added diagnostic value of the multiplex PCR approach for gastrointestinal protists. Nevertheless, the PCR procedure and the analytical performance for each protist of interest, variable depending on the multiplex PCR assay, must be considered when implementing a PCR-based diagnostic approach." 14220;"Corrigendum to: Toxoplasmosis Outbreak Associated With Toxoplasma gondii-Contaminated Venison-High Attack Rate, Unusual Clinical Presentation, and Atypical Genotype.";"C. Pomares";"Equipe 06, Team 06";35169828;"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America";"Schumacher AC, Elbadawi LI, DeSalvo T, Straily A, Ajzenberg D, Letzer D, Moldenhauer E, Handly TL, Hill D, Dardé ML, Pomares C, Passebosc-Faure K, Bisgard K, Gomez CA, Press C, Smiley S, Montoya JG, Kazmierczak JJ";;"Feb 2022";1644969600;; 14218;"Could the re-emerging practice of wild boar hunting linked to the recent economic crisis lead to new outbreaks of trichinellosis in Lebanon?";"C. Pomares, P. Marty";"Equipe 06, Team 06";35225786;"Parasite (Paris, France)";"Khalil G, Marty P, Hage K, Sfeir S, El Hage J, Bou Assi T, Rassam M, Pomares C, Mikhael E";;"Feb 2022";1646006400;;"Documented trichinellosis outbreaks in Lebanon date back to the late 19th century. The first published outbreaks were attributed to the consumption of wild boar meat, while those that followed incriminated pork. The practice of hunting wild boar is currently re-emerging in Lebanon given the recent economic crisis that has limited the purchase of livestock meat." 14216;"Toxoplasmosis in patients with an autoimmune disease and immunosuppressive agents: A multicenter study and literature review.";"C. Pomares";"Equipe 06, Team 06";35939518;"PLoS neglected tropical diseases";"Durieux MF, Lopez JG, Banjari M, Passebosc-Faure K, Brenier-Pinchart MP, Paris L, Gargala G, Berthier S, Bonhomme J, Chemla C, Villena I, Flori P, Fréalle E, L'Ollivier C, Lussac-Sorton F, Montoya JG, Cateau E, Pomares C, Simon L, Quinio D, Robert-Gangneux F, Yera H, Labriffe M, Fauchais AL, Dardé ML";;"Aug 2022";1659916800;;"Cases of Toxoplasma reactivation or more severe primary infection have been reported in patients receiving immunosuppressive (IS) treatment for autoimmune diseases (AID). The purpose of this study was to describe features of toxoplasmosis occurring in patients with AID treated by IS therapy, excluded HIV-positive and transplant patients." 14210;"Humoral and cellular responses after a third dose of SARS-CoV-2 BNT162b2 vaccine in patients with lymphoid malignancies.";"B. Bailly-Maitre, M. Carles";"Equipe 13, Team 13, Equipe 06, Team 06";35165284;"Nature communications";"Re D, Seitz-Polski B, Brglez V, Carles M, Graça D, Benzaken S, Liguori S, Zahreddine K, Delforge M, Bailly-Maitre B, Verrière B, Chamorey E, Barrière J";;"Feb 2022";1644883200;;"Patients with hematological malignancies have impaired immune response after two doses of BNT162b2 (Pfizer/BioNTech) vaccine against SARS-CoV-2. Here, in this observational study (registration number HDH F20210324145532), we measure SARS-CoV-2 anti-Spike antibodies, neutralizing antibodies and T-cell responses after immune stimulation with a third dose (D3) of the same vaccine in patients with chronic lymphocytic leukemia (n = 13), B cell non-Hodgkin lymphoma (n = 14), and multiple myeloma (n = 16)). No unexpected novel side effects are reported. Among 25 patients with positive anti-S titers before D3, 23 (92%) patients increase their anti-S and neutralizing antibody titer after D3. All 18 (42%) initially seronegative patients remain negative. D3 increases the median IFN-γ secretion in the whole cohort and induces IFN-γ secretion in a fraction of seronegative patients. Our data thus support the use of a third vaccine dose amongst patients with lymphoid malignancies, even though some of them will still have vaccine failure." 14208;"A plant receptor domain with functional analogies to animal malectin disables ER stress responses upon infection.";"B. Bailly-Maitre";"Equipe 13, Team 13";35243239;iScience;"Giordano L, Allasia V, Cremades A, Hok S, Panabières F, Bailly-Maître B, Keller H";;"Mar 2022";1646352000;;"Malectins from the oligosaccharyltransferase (OST) complex in the endoplasmic reticulum (ER) of animal cells are involved in ER quality control and contribute to the Unfolded Protein Response (UPR). Malectins are not found in plant cells, but malectin-like domains (MLDs) are constituents of many membrane-bound receptors. In , the MLD-containing receptor IOS1 promotes successful infection by filamentous plant pathogens. We show that the MLD of its exodomain retains IOS1 in the ER of plant cells and attenuates the infection-induced UPR. Expression of the MLD in the knockout background is sufficient to complement infection-related phenotypes of the mutant, such as increased UPR and reduced disease susceptibility. IOS1 interacts with the ER membrane-associated ribophorin HAP6 from the OST complex, and mutants show decreased pathogen-responsive UPR and increased disease susceptibility. Altogether, this study revealed a previously uncharacterized role of a plant receptor domain in the regulation of ER stress during infection." 14206;"[Does metabolism protect our immune system?]";"B. Bailly-Maitre, L. Yvan-Charvet";"Equipe 13, Team 13";35766844;"Medecine sciences : M/S";"Yvan-Charvet L, Bailly-Maitre B";;"Jun 2022";1656460800;; 14204;"Esophageal Cancer in Patients Undergoing Bariatric Surgery: What Is the Real Burden?";"A. IANNELLI";"Team 08, Equipe 08";35000067;"Obesity surgery";"Iannelli A, Bouam S, Schneck AS, Alifano M";;"Jan 2022";1641686400;; 14202;"Reply to Comment on Sleeve Gastrectomy Versus Roux-en-Y Gastric Bypass in the Elderly: 1-Year Preliminary Outcomes in a Randomized Trial (BASE Trial).";"A. IANNELLI";"Team 08, Equipe 08";35088250;"Obesity surgery";"Facchiano E, Iannelli A, Lucchese M";;"Jan 2022";1643328000;; 14200;"[Bariatric surgery: epidemiological data and challenges].";"A. IANNELLI";"Team 08, Equipe 08";35289520;"La Revue du praticien";"Lazzati A, Iannelli A";;"Mar 2022";1647302400;; 14198;"Impact of SARS-CoV-2 Lockdown on the Preoperative Care Program of Patients Scheduled for Bariatric Surgery.";"A. IANNELLI";"Team 08, Equipe 08";35406101;Nutrients;"Schiavo L, Calabrese P, Aliberti SM, Tramontano S, Iannelli A, Pilone V";;"Apr 2022";1649721600;;"To evaluate the effect of the SARS-CoV-2 lockdown on dietary habits, body weight, left hepatic lobe volume, use of micronutrient supplements, micronutrient status, frequency of physical activity, and evolution of comorbidities in patients undergoing preoperative care for BS." 14196;"Four-week omega-3 polyunsaturated fatty acids supplementation for liver left lateral section volume reduction in individuals with morbid obesity undergoing bariatric surgery: A double blind, multicenter, randomized placebo-controlled trial.";"A. IANNELLI";"Team 08, Equipe 08";35417778;"International journal of surgery (London, England)";"Iannelli A, Fontas E, Grec L, Nocca D, Robert M, Schiavo L, Schneck AS";;"Apr 2022";1649808000;;"Liver steatosis in morbidly obese individuals undergoing bariatric surgery increases liver volume and may complicate the surgical procedure. This study aimed to assess whether a 4-week supplementation with omega-3 polyunsaturated fatty acids (PUFA) is effective in reducing liver left lateral section (LLLS) volume." 14194;"Role of Branched-Chain Amino Acid Metabolism in Type 2 Diabetes, Obesity, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease.";"A. IANNELLI";"Team 08, Equipe 08";35457142;"International journal of molecular sciences";"Cuomo P, Capparelli R, Iannelli A, Iannelli D";;"Apr 2022";1650672000;;"Branched-chain amino acids (BCAAs) include leucine, isoleucine, and valine. Mammalians cannot synthesize these amino acids de novo and must acquire them through their diet. High levels of BCAAs are associated with insulin resistance; type 2 diabetes; obesity; and non-metabolic diseases, including several forms of cancer. BCAAs-in particular leucine-activate the rapamycin complex1 mTORC1, which regulates cell growth and metabolism, glucose metabolism and several more essential physiological processes. Diets rich in BCAAs are associated with metabolic diseases (listed above), while diets low in BCAAs are generally reported to promote metabolic health. As for the dysregulation of the metabolism caused by high levels of BCAAs, recent studies propose that the accumulation of acyl-carnitine and diacyl-CoA in muscles alters lipid metabolism. However, this suggestion is not broadly accepted. On clinical grounds, pre- and post-operative metabolic profiles of candidate patients for bariatric surgery are being used to select the optimal procedure for each individual patient." 14192;"Changes in Food Choice, Taste, Desire, and Enjoyment 1 Year after Sleeve Gastrectomy: A Prospective Study.";"A. IANNELLI";"Team 08, Equipe 08";35631200;Nutrients;"Schiavo L, Aliberti SM, Calabrese P, Senatore AM, Severino L, Sarno G, Iannelli A, Pilone V";;"May 2022";1653696000;;"Obesity is a well-recognized global health problem, and bariatric surgery (BS)-induced weight reduction has been demonstrated to improve survival and obesity-related conditions. Sleeve gastrectomy (SG) is actually one of the most performed bariatric procedures. The underlying mechanisms of weight loss and its maintenance after SG are not yet fully understood. However, changes to the taste function could be a contributing factor. Data on the extent of the phenomenon are limited. The primary objective was to assess, through validated questionnaires, the percentage of patients who report an altered perception of post-SG taste and compare the frequency of intake of the different food classes before SG and after 1 year follow-up. The secondary objective was to evaluate the total body weight change." 14190;"Clinical and Economic Impact of Bariatric Surgery Post Liver Transplantation: a Nationwide, Population-Based Retrospective Study.";"A. IANNELLI";"Team 08, Equipe 08";35668279;"Obesity surgery";"Chierici A, Bulsei J, Castaldi A, Petrucciani N, Drai C, Schneck AS, Chevalier N, Fontas E, Iannelli A";;"Jun 2022";1654473600;;"Prevalence of obesity in liver transplant recipients is increasing with the overall epidemic augmentation of severe obesity, the effects of immunosuppressive drugs, and lifestyle changes which are responsible for de novo obesity development or aggravation of pre-existing obesity. The aim of this study is to analyze the differences in overall mortality, re-hospitalization rate, and hospitalization-related costs between patients undergoing bariatric surgery after liver transplantation and patients undergoing bariatric surgery alone." 14188;"Bioabsorbable Glycolide Copolymer is Effective in Reducing Staple Line Bleeding in Sleeve Gastrectomy.";"A. IANNELLI";"Team 08, Equipe 08";35696051;"Obesity surgery";"Iannelli A, Chierici A, Castaldi A, Drai C, Schneck AS";;"Jun 2022";1655078400;;"Postoperative bleeding from the staple line after sleeve gastrectomy occurs in 2-8% of patients and it is associated with increased length and cost of hospitalization and may demand reoperation to gain hemostasis. Reinforced staplers are used by bariatric surgeons to reduce the incidence of postoperative leak but can have a role in avoiding bleeding. The aim of this study is to analyze the effects of reinforcement on the whole gastric staple line during sleeve gastrectomy on postoperative bleeding." 14186;"Defining Benchmark Outcomes for Distal Pancreatectomy: Results of a French Multicentric Study.";"A. IANNELLI";"Team 08, Equipe 08";35762617;"Annals of surgery";"Durin T, Marchese U, Sauvanet A, Dokmak S, Cherkaoui Z, Fuks D, Laurent C, André M, Ayav A, Magallon C, Turrini O, Sulpice L, Robin F, Bachellier P, Addeo P, Souche FR, Bardol T, Perinel J, Adham M, Tzedakis S, Birnbaum DJ, Facy O, Gagniere J, Gaujoux S, Tribillon E, Roussel E, Schwarz L, Barbier L, Doussot A, Regenet N, Iannelli A, Regimbeau JM, Piessen G, Lenne X, Truant S, El Amrani M";;"Jun 2022";1656374400;;"Defining robust and standardized outcome references for distal pancreatectomy (DP) by using Benchmark analysis." 14184;"Challenges in Bariatric Surgery: Outcomes in Patients Having Three or More Bariatric Procedures.";"A. IANNELLI";"Team 08, Equipe 08";35997931;"Obesity surgery";"Raglione D, Chierici A, Castaldi A, Drai C, de Fatico S, Mazahreh TS, Schiavo L, Schneck AS, Iannelli A";;"Aug 2022";1661212800;;"Over the last two decades, a progressive increase in failure rate of bariatric surgery (BS) has occurred in conjunction with an exponential increase in BS worldwide. Bariatric surgeons are confronted with challenging situations in patients with a complex bariatric history. In this study, we aim to evaluate the feasibility and outcomes of revisional BS in patients with at least two or more previous bariatric procedures." 14182;"Infectious complications of portal biliopathy leading to liver transplantation.";"R. ANTY, A. TRAN";"Equipe 08, Team 08";35151912;"Clinics and research in hepatology and gastroenterology";"Levi-Strauss T, Vanbiervliet G, Chevallier P, Anty R, Tran A, Ouizeman DJ";;"Feb 2022";1644710400;; 14180;"Spontaneous Bacterial Peritonitis: The Incremental Value of a Fast and Direct Bacterial Identification from Ascitic Fluids Inoculated in Blood Culture Bottles by MALDI-TOF MS for a Better Management of Patients.";"R. Ruimy, R. Lotte, A. TRAN";"Equipe 06, Team 06, Equipe 08, Team 08";35744706;Microorganisms;"Lotte R, Courdurié A, Gaudart A, Emery A, Chevalier A, Tran A, Payen M, Ruimy R";;"Jun 2022";1656028800;;"Spontaneous bacterial peritonitis (SBP) is a severe infection that requires fast and accurate antibiotic therapy to improve the patient outcome. Direct bacterial identification using MALDI-TOF mass spectrometry from ascitic fluid inoculated in blood culture bottles (BCBs) could therefore improve patients' management. We evaluated the impact of the implementation of this method for the treatment of patients. Our identification protocol was performed on 136 positive BCBs collected from 61 patients between December 2018 and December 2020. The therapeutic impact of our protocol was evaluated using a before (2015-2016) and after (2019-2020) case-control study in two populations of 41 patients diagnosed with SBP and treated with antibiotics. The decrease in time to first identification and the optimization of antibiotic therapy following communication of the identification result were evaluated. Our protocol allowed us to identify 78% of bacteria in ascitic fluids. The transmission of the direct identification allowed the introduction or adaption of the antibiotic therapy early in 37% of SBP, with a mean decrease in time to first antibiotic change of 17 h. Our direct identification protocol for positive inoculated ascitic fluids is fast, reliable and inexpensive. Its routine integration into a microbiology laboratory allows the early introduction of appropriate antibiotic therapy and improves the management of patients with SBP." 14089;"Dephosphorylation of human insulin-like growth factor I (IGF-I) receptors by membrane-associated tyrosine phosphatases.";"P. Peraldi";"Equipe 05";1322128;"The Biochemical journal";"Peraldi P, Hauguel-de Mouzon S, Alengrin F, Van Obberghen E";;"Jul 1992";709948800;;"The insulin-like growth factor-I (IGF-I) receptor exhibits structural and functional similarities to the insulin receptor. Although the regulation of the insulin-receptor tyrosine kinase has been extensively investigated, the mechanisms involved in phosphorylation/dephosphorylation of the IGF-I receptor have received only little attention. To obtain a better understanding of the mode of IGF-I action, we have investigated the effects of protein phosphotyrosine phosphatases (PTPases) on the phosphorylation status of the IGF-I receptor. The dephosphorylation of the human IGF-I receptor by membrane-associated tyrosine phosphatases was studied by an immuno-enzymic assay based on the recognition of phosphotyrosine residues by anti-phosphotyrosine antibodies. Using intact IGF-I receptors as substrates, we show that they could be completely dephosphorylated by different cellular PTPases. Three pieces of evidence indicate that receptor dephosphorylation takes place on phosphotyrosine, i.e. the inhibition profile of phosphatase activity by zinc and vanadate, its absolute requirement for thiol compounds and the diminution of [32P]phosphotyrosine labelling of the beta subunit assessed by SDS/PAGE and phosphoamino acid analysis. Tyrosine kinase activity and autophosphorylation of the IGF-I receptor were decreased in a dose-dependent manner by PTPases, indicating that partial dephosphorylation of the receptor was associated with a decrease in its intrinsic activity. The sensitivity of the activated human IGF-I receptor to dephosphorylation on tyrosine leads to the speculation that IGF-I receptor activity might be regulated by mechanisms such as those described for the insulin receptor. Further investigation of the pathways of IGF-I receptor dephosphorylation will contribute to define the role(s) of PTPases in the overall mechanism of IGF-I signalling." 14088;"Alteration of phosphotyrosine phosphatase activity in tissues from diabetic and pregnant rats.";"P. Peraldi";"Equipe 05";8419148;Endocrinology;"Hauguel-de Mouzon S, Peraldi P, Alengrin F, Van Obberghen E";;"Jan 1993";725846400;;"Membrane-associated tyrosine phosphatase activities were studied in two distinct states of insulin resistance: diabetes and pregnancy. Using a novel immunoenzymatic assay with intact insulin-like growth factor-I (IGF-I) and insulin receptors as substrates, we show that phosphotyrosine-protein phosphatases (PTP-ases) from normal rat tissues induce a decrease in tyrosine phosphorylation of both receptors. Membrane fractions from kidney, brain, and liver contain the highest PTP-ase activity toward the insulin receptor. After 20-day streptozotocin-induced diabetes, PTP-ase activities are increased by 70% in the placenta, reduced by 40-50% in liver and skeletal muscle, and remained unchanged in the nonclassical insulin target tissues, kidney and brain. In general, the dephosphorylation of IGF-I receptor follows a pattern similar to that of insulin receptor except in red skeletal muscle in which it is not modified. Pregnancy also induces alterations of liver PTP-ases similar to those elicited by diabetes with a 50% reduction of insulin and IGF-I receptor dephosphorylation. This effect of pregnancy is further potentiated by diabetes. The alterations in the activity of hepatic PTP-ases from diabetic and pregnant rats are associated with a decreased autophosphorylation of the insulin receptor, suggesting that the diminution of phosphatase activity might be associated to the state of receptor phosphorylation and activation. Our data demonstrate that alterations of PTP-ases in insulin target tissues are found in two insulin-resistant states, one characterized by hyperinsulinemia, pregnancy and one by insulinopenia, streptozotocin-diabetes. These observations suggest a possible relationship between the defective activity of receptor tyrosine kinases and membrane-associated phosphatases from insulin responsive tissues." 14084;"Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90-kDa ribosomal S6 kinase in PC12 cells. Distinct effects of the neurotrophic factor, nerve growth factor, and the mitogenic factor, epidermal growth factor.";"P. Peraldi";"Equipe 05";8387505;"The Journal of biological chemistry";"Nguyen TT, Scimeca JC, Filloux C, Peraldi P, Carpentier JL, Van Obberghen E";;"May 1993";736560000;;"We recently characterized the association of the 44-kDa mitogen-activated protein kinase, also known as extracellular-regulated kinase 1 (ERK1), with the 90-kDa ribosomal S6 kinase (pp90rsk), one of its putative substrates in intact PC12 cells. Using antibodies to ERK1 that precipitate a functional ERK1.pp90rsk phosphoprotein complex, we demonstrate here the regulation of both kinases by various stimuli. In mouse fibroblasts expressing human insulin receptors, insulin and vanadate swiftly stimulated ERK1 activity within 5 min. While the hormonal effect was short-lived, vanadate led to a first peak followed by a progressively increasing second phase. In PC12 cells, epidermal growth factor, which is a growth promoting factor, provokes a rapid but evanescent activation of ERK1. In contrast, nerve growth factor (NGF), which acts as a neuronal differentiation factor for PC12 cells, induced a swift monophasic response followed by a sustained second phase. This strikingly different pattern of ERK1 stimulation by NGF and epidermal growth factor was associated to a contrasting effect on ERK1 cellular translocation. Thus, NGF induced a nuclear translocation of ERK1, while epidermal growth factor was without noticeable effect on ERK1 localization. In both cell systems all effectors tested stimulated ERK1 phosphorylation on both threonine and tyrosine residues in an 1:1 ratio. During ERK1 inactivation, phosphothreonine and phosphotyrosine were dephosphorylated in a similar fashion. Concurrent with ERK1 activation was the de novo appearance of phosphothreonine and an increase in phosphoserine on pp90rsk. The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases. Finally, we would like to suggest that the differentiating action of NGF in PC12 cells might be due, at least in part, to the conjunction of its sustained and robust stimulation of ERK1 and pp90rsk, and of its induction of ERK1 nuclear translocation." 14081;"Insulin and tumor-promoting agent regulate an inhibitor of the 44-kDa mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1 in fibroblasts.";"P. Peraldi";"Equipe 05";8281932;"European journal of biochemistry";"Peraldi P, Van Obberghen E";;"Dec 1993";755913600;;"We have examined the negative regulation of the 44-kDa mitogen-activated protein kinase (MAP kinase), also known as extracellular signal-regulated protein kinase 1 (ERK1), in NIH3T3 cells transfected with an expression plasmid encoding the human insulin receptor (NHIR cells). In these cells ERK1 activation is induced by two distinct stimuli, insulin and tumor-promoting agent (TPA). While insulin was found to be more potent than TPA for ERK1 activation, both stimuli produced the same transient activation pattern with a rapid peak (reached within 5 min) followed by a fast decrease within 20 min. By performing reconstitution experiments with immunoprecipitated ERK1 and lysates from NHIR cells, we showed that extracts from untreated cells exhibit an ERK1 inhibitory activity. Interestingly, this inhibitor was found to be regulated by insulin and TPA with a profile that is the mirror image of ERK1 activity. This repressing activity was sensitive to tyrosine phosphatase inhibitors, such as sodium orthovanadate and zinc acetate, but it was not affected by serine/threonine phosphatase inhibitors, such as sodium fluoride and okadaic acid. Moreover, it was possible to observe in extracts of NHIR cells an activity dephosphorylating ERK1. The time course of this phosphatase activity was comparable to that of the ERK1 inhibition, suggesting that the repressing activity could reflect a dephosphorylating action. Interestingly, phosphatase 2A treatment of extracts from 5-min TPA-treated cells (where the ERK1 inhibitor was weak) was able to induce an increase in the ERK1 repressing activity. This suggests that serine/threonine dephosphorylation of ERK1 inhibitor leads to an increase in its activity. In summary, we have shown that NHIR cells contain a regulatable ERK1 inhibitor, which is likely to be due to tyrosine phosphatase(s). We would like to suggest that such activities are key components in the fine-tuning of the MAP kinase cascade." 14083;"Regulation of extracellular signal-regulated protein kinase-1 (ERK-1; pp44/mitogen-activated protein kinase) by epidermal growth factor and nerve growth factor in PC12 cells: implication of ERK1 inhibitory activities.";"P. Peraldi";"Equipe 05";8389283;Endocrinology;"Peraldi P, Scimeca JC, Filloux C, Van Obberghen E";;"Jun 1993";738892800;;"In PC12 cells, extracellular signal-regulated kinase-1 (ERK1 or pp44/mitogen-activated protein kinase) is stimulated in response to epidermal growth factor (EGF) and nerve growth factor (NGF). This stimulation is rapid and short-lived after EGF activation. In contrast, NGF promotes a swift, but persistent, ERK1 stimulation. We took advantage of this difference in activation pattern to study the negative regulation of ERK1. Using antibodies to the C-terminus of ERK1, we performed in vitro reconstitution experiments with immunoprecipitated ERK1 from stimulated cells and extracts from PC12 cells incubated with EGF or NGF for various periods of times. Using this approach, we showed that extracts from unstimulated cells reduce ERK1 activity. Upon exposure of cells to NGF or EGF, we found that the inhibitory activity had a pattern opposite that of ERK1 phosphorylation and activity. Indeed, the highest ERK1 activation was associated with the lowest ERK1-repressing activity and vice versa. This ERK1 inhibitory activity was found to be sensitive mainly to sodium orthovanadate and to a lesser extent to zinc acetate. Interestingly, okadaic acid decreased ERK1-repressing activity from unstimulated cells when tested with ERK1 from 5-min NGF-treated cells, but not with ERK1 from 5-min EGF-treated cells. Hence, ERK1 appears to be regulated differently after stimulation of cells with EGF compared to NGF. We show that cell extracts promote ERK1 dephosphorylation. Indeed, we were able to detect a phosphatase activity toward in vivo phosphorylated ERK1 that was regulated differently after NGF and EGF treatments of the cells, and that has a profile of regulation similar to that of the ERK1 inhibitory activity. This regulatable phosphatase activity was also observed using in vitro phosphorylated ERK1. Taken together, our data provide evidence that ERK1 is negatively controlled by a phosphatase(s) that can undergo differential modulation depending on the stimuli used." 14079;"Insulin receptor dephosphorylation by phosphotyrosine phosphatases obtained from insulin-resistant obese mice.";"P. Peraldi";"Equipe 05";8150231;Diabetologia;"Olichon-Berthe C, Hauguel-De Mouzon S, Péraldi P, Van Obberghen E, Le Marchand-Brustel Y";;"Jan 1994";757382400;;"To study the possible involvement of phosphotyrosine phosphatases in insulin resistance, the ability of cytosolic and membrane preparations to dephosphorylate insulin receptors was examined in lean and goldthioglucose-treated insulin-resistant and obese mice. Preparations were obtained from liver, heart, diaphragm and hindleg muscle and their phosphotyrosine phosphatase activities were measured using an immunoenzymatic assay with phosphorylated insulin receptors as substrate. Liver cytosolic and particulate phosphotyrosine phosphatases were more potent than preparations from other tissues and were able to almost completely dephosphorylate the insulin receptor in a dose- and time-dependent manner. No change was observed in cytosolic and membrane-associated phosphotyrosine phosphatases in liver, diaphragm, and heart of obese mice compared with lean mice. In contrast, cytosolic, but not membrane-associated, phosphotyrosine phosphatase activity was decreased in hindleg muscles of obese mice. These results suggest that the regulation of phosphotyrosine phosphatases is tissue-specific. In addition, alterations in total phosphotyrosine phosphatase activity do not appear to play an important role in insulin resistance in all tissues of obese mice, although specific changes cannot be excluded." 14078;"Cyclic AMP activates the mitogen-activated protein kinase cascade in PC12 cells.";"P. Peraldi";"Equipe 05";7907091;"The Journal of biological chemistry";"Frödin M, Peraldi P, Van Obberghen E";;"Feb 1994";762134400;;"Mitogen-activated protein (MAP) kinases are activated in response to a large variety of extracellular signals, including growth factors, hormones, and neurotransmitters, which activate distinct intracellular signaling pathways. Their activation by the cAMP-dependent pathway, however, has not been reported. In rat pheochromocytoma PC12 cells, we demonstrate here a stimulation of the MAP kinase isozyme extracellular signal-regulated kinase 1 (ERK1) following elevation of intracellular cAMP after exposure of the cells to isobutylmethylxanthine, cholera toxin, forskolin, or cAMP-analogues. cAMP acted synergistically with phorbol ester, an activator of protein kinase C, in the stimulation of ERK1. In accordance with this observation, the peptide neurotransmitter pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), which stimulates cAMP production as well as phosphatidylinositol breakdown in PC12 cells, was an efficient activator of ERK1. In combination with various growth factors, cAMP acted in a more than additive manner on ERK1 activity. Elevation of intracellular cAMP increased in vivo 32P-labeling of ERK1, suggesting that cAMP stimulated ERK1 by activating MAP kinase kinase, an immediate upstream activator of ERK1 in the MAP kinase cascade. Supporting this view, forskolin and a cAMP analogue were found to increase the activity of MAP kinase kinase in PC12 cells, alone as well as in combination with phorbol ester. PACAP38 also stimulated in vivo 32P-labeling of ERK1 and MAP kinase kinase activity. Finally, cAMP or PACAP38 increased by 3-fold nerve growth factor-stimulated neurite formation in PC12 cells, which may be correlated with the potentiating effect of these agents on nerve growth factor-stimulated ERK1 activity." 14075;"Protein-tyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase.";"P. Peraldi";"Equipe 05";8197172;"Proceedings of the National Academy of Sciences of the United States of America";"Peraldi P, Zhao Z, Filloux C, Fischer EH, Van Obberghen E";;"May 1994";769737600;;"Protein-tyrosine-phosphatase 2C (PTP2C, also named SHPTP2, SHPTP3, or PTP1D) is a cytosolic enzyme with two Src homology 2 domains. We have investigated its regulation by phosphorylation in PC12 rat pheochromocytoma cells. In untreated cells, PTP2C was phosphorylated predominantly on serine residues. A 5-min treatment with epidermal growth factor (EGF) induced an increase in phosphorylation on threonine and, to a lesser degree, on serine. After 45 min of exposure to EGF, PTP2C phosphorylation returned to basal levels. Using an in vitro kinase assay, we found that the 44-kDa mitogen-activated protein kinase, p44mapk, phosphorylated PTP2C on serine and threonine residues. This phosphorylation resulted in a pronounced inhibition of PTP2C enzyme activity measured with phosphorylated EGF receptors as substrate. Moreover, in intact PC12 cells, PTP2C was also inhibited following a short EGF treatment, but its activity returned to normal when the exposure to EGF was maintained for 45 min. The profile of this response to EGF can be inversely correlated to that of the stimulatory action of EGF on p44mapk. These data suggest that the EGF-induced regulation of PTP2C activity is mediated by p44mapk. These findings provide evidence for an additional role of the mitogen-activated protein kinase cascade--namely, the regulation of a PTP." 14073;"Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP.";"P. Peraldi";"Equipe 05";7835430;"FEBS letters";"Peraldi P, Frödin M, Barnier JV, Calleja V, Scimeca JC, Filloux C, Calothy G, Van Obberghen E";;"Jan 1995";789609600;;"In PC12 cells, cAMP stimulates the MAP kinase pathway by an unknown mechanism. Firstly, we examined the role of calcium ion mobilization and of protein kinase C in cAMP-stimulated MAP kinase activation. We show that cAMP stimulates p44mapk independently of these events. Secondly, we studied the role of B-Raf in this process. We observed that NGF, PMA and cAMP induce the phosphorylation of B-Raf as well as an upward shift in its electrophoretic mobility. We show that B-Raf is activated following NGF and PMA treatment of PC12 cells, and that it can phosphorylate and activate MEK-1. However, cAMP inhibits B-Raf autokinase activity as well as its ability to phosphorylate and activate MEK-1. This inhibition is likely to be due to a direct effect since we found that PKA phosphorylates B-Raf in vitro. Further, we show that B-Raf binds to p21ras, but more important, this binding to p21ras is virtually abolished with B-Raf from PC12 cells treated with CPT-cAMP. Hence, these data indicate that the PKA-mediated phosphorylation of B-Raf hampers its interaction with p21ras, which is responsible for the PKA-mediated decrease in B-Raf activity. Finally, our work suggests that in PC12 cells, cAMP stimulates MAP kinase through the activation of an unidentified MEK kinase and/or the inhibition of a MEK phosphatase." 14066;"Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase.";"P. Peraldi";"Equipe 05";8662983;"The Journal of biological chemistry";"Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM";;"May 1996";833500800;;"Tumor necrosis factor (TNF)-alpha plays a central role in the state of insulin resistance associated with obesity. It has previously been shown that one important mechanism by which TNF-alpha interferes with insulin signaling is through the serine phosphorylation of insulin receptor substrate-1 (IRS-1), which can then function as an inhibitor of the tyrosine kinase activity of the insulin receptor (IR). However, the receptors and the signaling pathway used by TNF-alpha that mediate the inhibition of IR activity are unknown. We show here that human TNF-alpha, which binds only to the murine p55 TNF receptor (TNFR), is as effective at inhibiting insulin-dependent tyrosine phosphorylation of IR and IRS-1 in adipocytes and myeloid 32D cells as murine TNF-alpha, which binds to both p55 TNFR and p75 TNFR. Likewise, antibodies that are specific agonists for p55 TNFR or p75 TNFR demonstrate that stimulation of p55 TNFR is sufficient to inhibit insulin signaling, though a small effect can also be seen with antibodies to p75 TNFR. Exogenous sphingomyelinase and ceramides, known to be formed by activation of p55 TNFR, inhibit IR and IRS-1 tyrosine phosphorylation and convert IRS-1 into an inhibitor of IR tyrosine kinase in vitro. Myeloid 32D cells expressing IR and IRS-1 are sensitive to this inhibition, but cells expressing IR and IRS-2 are resistant, pointing to an important difference in the biological function between IRS-1 and IRS-2. These data strongly suggest that TNF-alpha inhibits insulin signaling via stimulation of p55 TNFR and sphingomyelinase activity, which results in the production of an inhibitory form of IRS-1." 14067;"IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.";"P. Peraldi";"Equipe 05";8571133;"Science (New York, N.Y.)";"Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM";;"Feb 1996";823219200;;"Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling." 14062;"[TNF-alpha: molecular tie between obesity and insulin resistance].";"P. Peraldi";"Equipe 05";9296970;"Journees annuelles de diabetologie de l'Hotel-Dieu";"Peraldi P, Spiegelman BM";;"Jan 1997";852076800;; 14063;"[Bad clinical results of cemented caps with metal-backed acetabular components. 124 cases with 21 months follow-up].";"P. Peraldi";"Equipe 05";9587621;"Revue de chirurgie orthopedique et reparatrice de l'appareil moteur";"Peraldi P, Vandenbussche E, Augereau B";;"Jan 1997";852076800;;"The authors reviewed with short term follow-up 124 total hip arthroplasties using a cemented metal-backed acetabular component. The purpose of the study was to evaluate clinical and radiological results because of early periacetabular radiolucent lines reported by Ritter." 14060;"[Acetabulum deformations after implantation of a cemented cup with or without metal-back component. An in vitro comparative study of monopodal load].";"P. Peraldi";"Equipe 05";9452792;"Revue de chirurgie orthopedique et reparatrice de l'appareil moteur";"Vandenbussche E, Peraldi P, Massin P, Augereau B, Lavaste F";;"Jan 1997";852076800;;"The purpose of this study was to find a biomechanical explanation for a clinical failure of metal backed acetabular components. Periacetabular deformations were measured on fresh cadaver bones equipped with strain-gauge rosettes." 14058;"The effect of cyclic adenosine monophosphate on the mitogen-activated protein kinase pathway depends on both the cell type and the type of tyrosine kinase-receptor.";"P. Peraldi";"Equipe 05";9048617;Endocrinology;"Calleja V, Ruiz Enríquez P, Filloux C, Peraldi P, Baron V, Van Obberghen E";;"Mar 1997";857174400;;"The mitogen-activated protein kinase (MAP kinase) is a key participant in growth factor-stimulated intracellular events such as proliferation and differentiation. We and others have previously described a cross-talk between the MAP kinase pathway and the cAMP pathway. Indeed, in several cell lines and, in particular in fibroblasts, an increase in the level of cAMP produced an inhibition of MAP kinase together with decreased cell proliferation. In contrast, in PC12 cells, cAMP induced an increase in the NGF-induced activation of MAP kinase concomitantly with augmented NGF-induced differentiation. Therefore, it has been proposed that the cellular context is important for the nature of the cAMP effects on growth factor-stimulated MAP kinase activity. Here we show that the type of tyrosine kinase receptor stimulated also participates in the nature of the cAMP effect. Thus, in NIH3T3 fibroblasts expressing NGF receptors (NIH3T3/trk cells) we found that cAMP potentiates NGF-stimulated ERK1 and MEK1 activities, whereas in NIH3T3 fibroblasts expressing insulin receptors (NIH3T3/IR cells) we saw no effect of cAMP on the activation of insulin-stimulated ERK1 and MEK1. In PC12 cells and in Rat1 fibroblasts expressing insulin receptors (PC12/IR and Rat1/IR cells) we observed, respectively, a potentiation and an inhibition of insulin-stimulated ERK1 activity. In addition, cAMP does not seem to modify the basal nor growth factor-stimulated She or IRS-1 tyrosine phosphorylation in the different cell lines studied. Finally, we observed that cAMP inhibited serum- and insulin-induced, but not NGF-induced, cell proliferation in NIH3T3 cells. However, cAMP potentiated insulin-stimulated cell differentiation in PC12/IR cells. These results led us to conclude that the cAMP effect on cell proliferation in NIH3T3 fibroblasts and PC12/IR cells appears to be correlated, in part, with the effect of cAMP on the MAP kinase pathway, but by itself this pathway cannot fully account for these observations." 14056;"Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling.";"P. Peraldi";"Equipe 05";9312188;"The Journal of clinical investigation";"Peraldi P, Xu M, Spiegelman BM";;"Oct 1997";876096000;;"TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity. This cytokine induces insulin resistance, at least in part, through inhibition of the tyrosine kinase activity of the insulin receptor. Recently, a new class of compounds, the antidiabetic thiazolidinediones (TZDs), has been shown to improve insulin resistance in obesity and non-insulin-dependent diabetes mellitus in both rodents and man. Here we show that TZDs have powerful effects on the ability of TNF-alpha to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relatively high doses (25 ng/ml). That this effect of TZDs operates through activation of the nuclear receptor PPARgamma/ RXR complex is shown by the fact that similar effects are observed with other PPARgamma/RXR ligands such as 15 deoxy Delta12,14PGJ2 and LG268. The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions." 14054;"Studies of the mechanism of inhibition of insulin signaling by tumor necrosis factor-alpha.";"P. Peraldi";"Equipe 05";9415053;"The Journal of endocrinology";"Peraldi P, Spiegelman BM";;"Jan 1998";883612800;; 14050;"TNF-alpha and insulin resistance: summary and future prospects.";"P. Peraldi";"Equipe 05";9609126;"Molecular and cellular biochemistry";"Peraldi P, Spiegelman B";;"Jun 1998";896832000;;"While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-alpha) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-alpha in insulin resistance during obesity and how TNF-alpha interferes with insulin signaling." 14049;"SOCS-3 is an insulin-induced negative regulator of insulin signaling.";"P. Peraldi";"Equipe 05";10821852;"The Journal of biological chemistry";"Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E";;"May 2000";959126400;;"The SOCS proteins are induced by several cytokines and are involved in negative feedback loops. Here we demonstrate that in 3T3-L1 adipocytes, insulin, a hormone whose receptor does not belong to the cytokine receptor family, induces SOCS-3 expression but not CIS or SOCS-2. Using transfection of COS-7 cells, we show that insulin induction of SOCS-3 is enhanced upon Stat5B expression. Moreover, Stat5B from insulin-stimulated cells binds directly to a Stat element present in the SOCS-3 promoter. Once induced, SOCS-3 inhibits insulin activation of Stat5B without modifying the insulin receptor tyrosine kinase activity. Two pieces of evidence suggest that this negative regulation likely results from competition between SOCS-3 and Stat5B binding to the same insulin receptor motif. First, using a yeast two-hybrid system, we show that SOCS-3 binds to the insulin receptor at phosphotyrosine 960, which is precisely where Stat5B binds. Second, using confocal microscopy, we show that insulin induces translocation of SOCS-3 from an intracellular compartment to the cell membrane, leading to colocalization of SOCS-3 with the insulin receptor. This colocalization is dependent upon phosphorylation of insulin receptor tyrosine 960. Indeed, in cells expressing an insulin receptor mutant in which tyrosine 960 has been mutated to phenylalanine, insulin does not modify the cellular localization of SOCS-3. We have thus revealed an insulin target gene of which the expression is potentiated upon Stat5B activation. By inhibiting insulin-stimulated Stat5B, SOCS-3 appears to function as a negative regulator of insulin signaling." 14048;"Insulin induces suppressor of cytokine signaling-3 tyrosine phosphorylation through janus-activated kinase.";"P. Peraldi";"Equipe 05";11325969;"The Journal of biological chemistry";"Peraldi P, Filloux C, Emanuelli B, Hilton DJ, Van Obberghen E";;"Apr 2001";988416000;;"Suppressor of cytokine signaling (SOCS) proteins were originally described as cytokine-induced molecules involved in negative feedback loops. We have shown that SOCS-3 is also a component of the insulin signaling network (). Indeed, insulin leads to SOCS-3 expression in 3T3-L1 adipocytes. Once produced, SOCS-3 binds to phosphorylated tyrosine 960 of the insulin receptor and inhibits insulin signaling. Now we show that in 3T3-L1 adipocytes and in transfected COS-7 cells insulin leads to SOCS-3 tyrosine phosphorylation. This phosphorylation takes place on Tyr(204) and is dependent upon a functional SOCS-3 SH2 domain. Purified insulin receptor directly phosphorylates SOCS-3. However, in intact cells, a mutant of the insulin receptor, IRY960F, unable to bind SOCS-3, was as efficient as the wild type insulin receptor to phosphorylate SOCS-3. Importantly, IRY960F is as potent as the wild type insulin receptor to activate janus-activated kinase (Jak) 1 and Jak2. Furthermore, expression of a dominant negative form of Jak2 inhibits insulin-induced SOCS-3 tyrosine phosphorylation. As transfected Jaks have been shown to cause SOCS-3 phosphorylation, we propose that insulin induces SOCS-3 phosphorylation through Jak activation. Our data indicate that SOCS-3 belongs to a class of tyrosine-phosphorylated insulin signaling molecules, the phosphorylation of which is not dependent upon a direct coupling with the insulin receptor but relies on the Jaks." 14046;"SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice.";"P. Peraldi";"Equipe 05";11604392;"The Journal of biological chemistry";"Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van Obberghen E";;"Oct 2001";1003363200;;"SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-alpha (TNF-alpha), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-alpha induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-alpha target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance." 14044;"Cloning of hOST-PTP: the only example of a protein-tyrosine-phosphatase the function of which has been lost between rodent and human.";"P. Peraldi";"Equipe 05";15358244;"Biochemical and biophysical research communications";"Cousin W, Courseaux A, Ladoux A, Dani C, Peraldi P";;"Sep 2004";1094860800;;"Protein-tyrosine-phosphatases (PTP-ases), in concert with protein tyrosine kinases, control various biological activities such as cell growth and differentiation. In rodents, around 40 PTP-ases have been described. Functional orthologue for each of these PTP-ases have been identified in human, except for OST-PTP. OST-PTP is a transmembrane PTP-ase with a restricted tissue distribution. In silico analysis on public sequence databases reveals a human OST-PTP gene orthologue that encompasses 21 kb on chromosome 1q32.1. Using RT-PCR we isolated a 4 kb hOST-PTP transcript. hOST-PTP cDNA sequence exhibits numerous disablements indicating that it does not code for a PTP-ase but is rather a pseudogene with unique features. Indeed, (i) it has no ""functional"" parent in the human genome, (ii) it has retained an ""intron-exon"" structure, and (iii) it is transcribed in a regulated manner. Interestingly, we found two ESTs, from domesticated pig and from cow that exhibit ORF that would predict a functional OST-PTP orthologue in Artiodactyls. Taken together, these results indicate that OST-PTP is the only PTP-ase the function of which has been lost during the evolution process between rodents and human." 14042;"The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells.";"P. Peraldi";"Equipe 05";15561930;Diabetes;"Emanuelli B, Glondu M, Filloux C, Peraldi P, Van Obberghen E";;"Nov 2004";1101340800;;"Defects in insulin secretion, resulting from loss of function or destruction of pancreatic beta-cells, trigger diabetes. Interleukin (IL)-1beta is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs beta-cell survival and function. Because effective insulin signaling is required for the optimal beta-cell function, we assessed the effect of IL-1beta on the insulin pathway in a rat pancreatic beta-cell line. We show that IL-1beta decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1beta-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1beta inhibitory effect on insulin signaling in these cells. We show that IL-1beta increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1beta treatment in RINm5F cells. We propose that IL-1beta decreases insulin action in beta-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced beta-cell survival." 14040;"Inhibition of the anti-adipogenic Hedgehog signaling pathway by cyclopamine does not trigger adipocyte differentiation.";"P. Peraldi";"Equipe 05";16949046;"Biochemical and biophysical research communications";"Cousin W, Dani C, Peraldi P";;"Sep 2006";1157414400;;"Dysregulation of Hedgehog signaling can lead to several pathologies such as congenital defects and cancer. Here, we show that Hedgehog signaling is active in undifferentiated 3T3-L1 cells and decreases during adipocyte differentiation. Interestingly, this is paralleled by a decrease in Indian Hedgehog expression. We then tested if this down-regulation was sufficient to induce adipocyte differentiation. To this end, we demonstrate that the well-characterized Hedgehog inhibitor cyclopamine induced a decrease in Hedgehog signaling, similar to the one observed during adipocyte differentiation. However, cyclopamine did not induce nor potentiate adipocyte differentiation, as monitored by triglyceride staining and by the expression of several adipocyte markers: aP2, adipsin, C/EBPalpha, and Pref-1. Moreover, cyclopamine cannot substitute for other components of the differentiation medium: insulin, dexamethasone or IBMX. These results indicate that although Hedgehog signaling decreases during adipocyte differentiation, this down-regulation is not sufficient to trigger adipocyte differentiation. This suggests that Hedgehog signaling is an inadequate pharmacological target for patient suffering from syndromes associated with a decrease in fat mass, such as the ones observed in lipodystrophies." 14037;"Hedgehog and adipogenesis: fat and fiction.";"P. Peraldi";"Equipe 05";17933451;Biochimie;"Cousin W, Fontaine C, Dani C, Peraldi P";;"Oct 2007";1192492800;;"Morphogenes, abundantly described during embryogenesis have recently emerged as crucial modulators of cell differentiation processes. Hedgehog signaling, the dysregulation of which causing several pathologies such as congenital defects and cancer, is involved in several cell differentiation processes including adipogenesis. This review presents an overview of the relations between Hedgehog signaling, adipocyte differentiation and fat mass. While the anti-adipogenic role of Hedgehog signaling seems to be established, the effect of Hedgehog inhibition on adipocyte differentiation in vitro remains debated. Finally, Hedgehog potential as a pharmacological target to treat fat mass disorders is discussed." 14036;"Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells.";"P. Peraldi";"Equipe 05";18258719;"Stem cells (Dayton, Ohio)";"Fontaine C, Cousin W, Plaisant M, Dani C, Peraldi P";;"Feb 2008";1202515200;;"Human stem cells are powerful tools by which to investigate molecular mechanisms of cell growth and differentiation under normal and pathological conditions. Hedgehog signaling, the dysregulation of which causes several pathologies, such as congenital defects and cancer, is involved in several cell differentiation processes and interferes with adipocyte differentiation of rodent cells. The present study was aimed at investigating the effect of Hedgehog pathway modulation on adipocyte phenotype using different sources of human mesenchymal cells, such as bone marrow stromal cells and human multipotent adipose-derived stem cells. We bring evidence that Hedgehog signaling decreases during human adipocyte differentiation. Inhibition of this pathway is not sufficient to trigger adipogenesis, but activation of Hedgehog pathway alters adipocyte morphology as well as insulin sensitivity. Analysis of glycerol-3-phosphate dehydrogenase activity and expression of adipocyte marker genes indicate that activation of Hedgehog signaling by purmorphamine impairs adipogenesis. In sharp contrast to reports in rodent cells, the maturation process, but not the early steps of human mesenchymal stem cell differentiation, is affected by Hedgehog activation. Hedgehog interferes with adipocyte differentiation by targeting CCAAT enhancer-binding protein alpha and peroxisome proliferator-activated receptor (PPAR) gamma2 expression, whereas PPARgamma1 level remains unaffected. Although Hedgehog pathway stimulation does not modify the total number of adipocytes, adipogenesis appears dramatically impaired, with reduced lipid accumulation, a decrease in adipocyte-specific markers, and acquisition of an insulin-resistant phenotype. This study indicates that a decrease in Hedgehog signaling is necessary but not sufficient to trigger adipocyte differentiation and unveils a striking difference in the adipocyte differentiation process between rodent and human mesenchymal stem cells." 14034;"Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes.";"P. Peraldi";"Equipe 05";18271953;"BMC cell biology";"Zaragosi LE, Wdziekonski B, Fontaine C, Villageois P, Peraldi P, Dani C";;"Feb 2008";1203033600;;"Multipotent stem cells exist within adipose tissue throughout life. An abnormal recruitment of these adipose precursor cells could participate to hyperplasia of adipose tissue observed in severe obesity or to hypoplasia of adipose tissue observed in lipodystrophy. Therefore, pharmacological molecules that control the pool of stem cells in adipose tissue are of great interest. Glycogen Synthase Kinase (GSK) 3 has been previously described as involved in differentiation of preadipose cells and might be a potential therapeutic target to modulate proliferation and differentiation of adipocyte precursors. However, the impact of GSK3 inhibition on human adipose-derived stem cells remained to be investigated. The aim of this study was to investigate GSK3 as a possible target for pharmacological inhibition of stem cell adipogenesis. To reach this goal, we studied the effects of pharmacological inhibitors of GSK3, i.e. lithium chloride (LiCl) and BIO on proliferation and adipocyte differentiation of multipotent stem cells derived from human adipose tissue." 14032;"Activation of hedgehog signaling inhibits osteoblast differentiation of human mesenchymal stem cells.";"P. Peraldi";"Equipe 05";19096040;"Stem cells (Dayton, Ohio)";"Plaisant M, Fontaine C, Cousin W, Rochet N, Dani C, Peraldi P";;"Dec 2008";1229731200;;"Mesenchymal stem cells within the bone are responsible for the generation of osteoblasts, chondrocytes, and adipocytes. In rodents, Indian hedgehog has been shown to play a role in osteoblast differentiation. However, evidence for a direct function of hedgehog (Hh) in human osteoblastic differentiation is missing. Using different models of human mesenchymal stem cells we show that Hh signaling decreases during osteoblast differentiation. This is associated with a decrease in Smoothened expression, a key partner that triggers Hh signaling, and in the number of cells displaying a primary cilium, an organelle necessary for Hh signaling. Remarkably, treatment of human mesenchymal stem cells with sonic hedgehog or two molecules able to activate Hh signaling inhibits osteoblast differentiation. This inhibition is visualized through a decrease in mineralization and in the expression of osteoblastic genes. In particular, activation of Hh signaling induces a decrease in Runx2 expression, a key transcriptional factor controlling the early stage of osteoblast differentiation. Consistently, the activation of Hh signaling during the first days of differentiation is sufficient to inhibit osteoblast differentiation, whereas differentiated osteoblasts are not affected by Hh signaling. In summary, we show here, using various inducers of Hh signaling and mesenchymal stem cells of two different origins, that Hh signaling inhibits human osteoblast differentiation, in sharp contrast to what has been described in rodent cells. This species difference should be taken into account for screening for pro-osteogenic molecules." 14029;"Lopinavir co-induces insulin resistance and ER stress in human adipocytes.";"P. Peraldi";"Equipe 05";19501568;"Biochemical and biophysical research communications";"Djedaini M, Peraldi P, Drici MD, Darini C, Saint-Marc P, Dani C, Ladoux A";;"Jun 2009";1244505600;;"HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, their use has been associated with occurence of metabolic abnormalities the causes of which are not well understood. We report here that lopinavir, one of the most prescribed PI, dose-dependently co-induced insulin resistance and ER stress in human adipocytes obtained from differentiation of precursor cells. Insulin resistance was subsequent to IRS1 phosphorylation defects and resulted in a concentration-dependent decrease of glucose uptake. The major ER stress pathway involved was the phosphorylation of eIF2-alpha. Salubrinal, a selective eIF2-alpha dephosphorylation inhibitor, induced insulin resistance by targeting IRS1 phosphorylation at serine 312 and acted synergistically with LPV when both drugs were used in combination. This study points out the key role of eIF2-alpha phosphorylation in the development of PI-associated insulin resistance and ER stress. Thus, this protein represents a promising therapeutic target for development of new PIs devoid of adverse metabolic effects." 14028;"Regulators of human adipose-derived stem cell self-renewal.";"P. Peraldi";"Equipe 05";23671796;"American journal of stem cells";"Villageois P, Wdziekonski B, Zaragosi LE, Plaisant M, Mohsen-Kanson T, Lay N, Ladoux A, Peraldi P, Dani C";;"May 2013";1368576000;;"Adipose tissue is an alternative source of mesenchymal stem cells and human adipose-derived stem cells (ASCs) display an attractive and substantial therapeutic potential when transplanted in animal models. To this end, an understanding of ASC biology is necessary and the knowledge of mechanisms that maintain ASCs in an undifferentiated state with no loss of differentiation potential during ex vivo expansion represents a crucial step. However, these mechanisms remain to be identified because appropriate human cellular models are scant. In this review we will describe a cellular model isolated from human adipose tissue displaying all the features of stem cells. Then, we will focus on the identification of intrinsic and extrinsic factors regulating the balance between human ASC proliferation and differentiation. We will point out the role of factors secreted by undifferentiated ASCs, such a FGF2, activin A, BMP4, Hedgehog molecules and secreted by adipose tissue macrophages. Finally, we will outline the role of miRNAs in these processes." 14026;"The primary cilium undergoes dynamic size modifications during adipocyte differentiation of human adipose stem cells.";"P. Peraldi";"Equipe 05";25637533;"Biochemical and biophysical research communications";"Forcioli-Conti N, Lacas-Gervais S, Dani C, Peraldi P";;"Feb 2015";1422748800;;"The primary cilium is an organelle present in most of the cells of the organism. Ciliopathies are genetic disorders of the primary cilium and can be associated with obesity. We have studied the primary cilium during adipocyte differentiation of human adipose stem cells (hASC). We show here that the size of the primary cilium follows several modifications during adipocyte differentiation. It is absent in growing cells and appears in confluent cells. Interestingly, during the first days of differentiation, the cilium undergoes a dramatic elongation that can be mimicked by dexamethasone alone. Thereafter, its size decreases. It can still be detected in cells that begin to accumulate lipids but is absent in cells that are filled with lipids. The cilium elongation does not seem to affect the localization of proteins associated with the cilium such as Kif3-A or Smoothened. However, Hedgehog signaling, an anti-adipogenic pathway dependent on the primary cilium, is inhibited after three days of differentiation, concomitantly with the cilium size increase. Together, these results shed new light on the primary cilium and could provide us with new information on adipocyte differentiation under normal and pathological conditions." 14023;"The size of the primary cilium and acetylated tubulin are modulated during adipocyte differentiation: Analysis of HDAC6 functions in these processes.";"P. Peraldi";"Equipe 05";26363102;Biochimie;"Forcioli-Conti N, Estève D, Bouloumié A, Dani C, Peraldi P";;"Sep 2015";1442102400;;"The primary cilium is an organelle present in most of the cells of the organism. Ciliopathies, such as the Bardet Biedl and the Alstrom syndromes are associated with obesity. We, and others, have shown that the primary cilium undergoes size modifications during adipocyte differentiation of human adipose stromal cells. We show here that the levels of acetylated α-tubulin, a constituent of the primary cilium, and the expression of HDAC6, the enzyme that deacetylates α-tubulin and is responsible for the loss of the cilium during mitosis, are modulated during adipogenesis. Moreover, during adipocyte differentiation cells that express higher level of HDAC6 are the first to lose their primary cilium. We have investigated the function of HDAC6 on adipocyte differentiation and on the primary cilium. We observe that inhibition of HDAC6 activity leads to a decrease in adipocyte differentiation. This is associated with an inhibition of the initial elongation of the cilium. Interestingly, overexpression of HDAC6 inhibits adipocyte differentiation and blunts the elongation of the primary cilium. In both situations, inhibition of adipocyte differentiation was not associated with an inhibition of the glucocorticoid receptor activity. This indicates that HDAC6 controls adipogenesis through the levels of acetylated α-tubulin. Moreover, we show that although HDAC6 expression increases during adipocyte differentiation it is not sufficient to provoke the loss of the cilium. This suggests the existence of a novel mechanism for the loss of the cilium. Together, these data indicate that HDAC6, and acetylated α-tubulin, are important regulator of adipocyte differentiation." 14022;"Brown-like adipose progenitors derived from human induced pluripotent stem cells: Identification of critical pathways governing their adipogenic capacity.";"P. Peraldi";"Equipe 05";27577850;"Scientific reports";"Hafner AL, Contet J, Ravaud C, Yao X, Villageois P, Suknuntha K, Annab K, Peraldi P, Binetruy B, Slukvin II, Ladoux A, Dani C";;"Sep 2016";1472688000;;"Human induced pluripotent stem cells (hiPSCs) show great promise for obesity treatment as they represent an unlimited source of brown/brite adipose progenitors (BAPs). However, hiPSC-BAPs display a low adipogenic capacity compared to adult-BAPs when maintained in a traditional adipogenic cocktail. The reasons of this feature are unknown and hamper their use both in cell-based therapy and basic research. Here we show that treatment with TGFβ pathway inhibitor SB431542 together with ascorbic acid and EGF were required to promote hiPSCs-BAP differentiation at a level similar to adult-BAP differentiation. hiPSC-BAPs expressed the molecular identity of adult-UCP1 expressing cells (PAX3, CIDEA, DIO2) with both brown (ZIC1) and brite (CD137) adipocyte markers. Altogether, these data highlighted the critical role of TGFβ pathway in switching off hiPSC-brown adipogenesis and revealed novel factors to unlock their differentiation. As hiPSC-BAPs display similarities with adult-BAPs, it opens new opportunities to develop alternative strategies to counteract obesity." 14020;"[Adipose progenitors, myofibroblasts and fibrosis: is it all in the cilium?]";"N. Arrighi, P. Peraldi";"Equipe 01, Team 01, Equipe 05";30067208;"Medecine sciences : M/S";"Arrighi N, Dani C, Peraldi P";;"Aug 2018";1533168000;; 14018;"Platelet-rich plasma respectively reduces and promotes adipogenic and myofibroblastic differentiation of human adipose-derived stromal cells via the TGFβ signalling pathway.";"P. Peraldi";"Equipe 05";28592806;"Scientific reports";"Chignon-Sicard B, Kouidhi M, Yao X, Delerue-Audegond A, Villageois P, Peraldi P, Ferrari P, Rival Y, Piwnica D, Aubert J, Dani C";;"Jun 2017";1496966400;;"Autologous fat grafting is a gold standard therapy for soft tissue defects, but is hampered by unpredictable postoperative outcomes. Fat graft enrichment with adipose-derived stromal cell (ASCs) was recently reported to enhance graft survival. Platelet-rich plasma (PRP) has also emerged as a biologic scaffold that promotes fat graft viability. Combined ASC/PRP fat grafting enrichment is thus a promising new regenerative medicine approach. The effects of PRP on ASC proliferation are well documented, but the impact of PRP on ASC differentiation has yet to be investigated in depth to further elucidate the PRP clinical effects. Here we analyzed the human ASC fate upon PRP treatment. PRP was found to sharply reduce the potential of ASCs to undergo differentiation into adipocytes. Interestingly, the PRP anti-adipogenic effect was accompanied by the generation of myofibroblast-like cells. Among the various factors released from PRP, TGFβ pathway activators played a critical role in both the anti-adipogenic and pro-myofibroblastic PRP effects. Overall, these data suggest that PRP participates in maintaining a pool of ASCs and in the repair process by promoting ASC differentiation into myofibroblast-like cells. TGFβ may provide an important target pathway to improve PRP clinical outcomes." 14016;"Distinct Shades of Adipocytes Control the Metabolic Roles of Adipose Tissues: From Their Origins to Their Relevance for Medical Applications.";"P. Peraldi";"Equipe 05";33466493;Biomedicines;"Ladoux A, Peraldi P, Chignon-Sicard B, Dani C";;"Jan 2021";1611100800;;"Adipose tissue resides in specific depots scattered in peripheral or deeper locations all over the body and it enwraps most of the organs. This tissue is always in a dynamic evolution as it must adapt to the metabolic demand and constraints. It exhibits also endocrine functions important to regulate energy homeostasis. This complex organ is composed of depots able to produce opposite functions to monitor energy: the so called white adipose tissue acts to store energy as triglycerides preventing ectopic fat deposition while the brown adipose depots dissipate it. It is composed of many cell types. Different types of adipocytes constitute the mature cells specialized to store or burn energy. Immature adipose progenitors (AP) presenting stem cells properties contribute not only to the maintenance but also to the expansion of this tissue as observed in overweight or obese individuals. They display a high regeneration potential offering a great interest for cell therapy. In this review, we will depict the attributes of the distinct types of adipocytes and their contribution to the function and metabolic features of adipose tissue. We will examine the specific role and properties of distinct depots according to their location. We will consider their cellular heterogeneity to present an updated picture of this sophisticated tissue. We will also introduce new trends pointing out a rational targeting of adipose tissue for medical applications." 14014;"The FibromiR miR-214-3p Is Upregulated in Duchenne Muscular Dystrophy and Promotes Differentiation of Human Fibro-Adipogenic Muscle Progenitors.";"N. Arrighi, P. Peraldi";"Equipe 01, Team 01, Equipe 05";34360002;Cells;"Arrighi N, Moratal C, Savary G, Fassy J, Nottet N, Pons N, Clément N, Fellah S, Larrue R, Magnone V, Lebrigand K, Pottier N, Dechesne C, Vassaux G, Dani C, Peraldi P, Mari B";;"Aug 2021";1628294400;;"Fibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFβ1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several ""FibromiRs"", was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFβ1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFβ1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR » miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFβ axis, opening new avenues for the treatment of DMD." 14012;"Identification of Human Breast Adipose Tissue Progenitors Displaying Distinct Differentiation Potentials and Interactions with Cancer Cells.";"P. Peraldi";"Equipe 05";36009475;Biomedicines;"Peraldi P, Loubat A, Chignon-Sicard B, Dani C, Ladoux A";;"Aug 2022";1661472000;;"Breast adipose tissue (AT) participates in the physiological evolution and remodeling of the mammary gland due to its high plasticity. It is also a favorable microenvironment for breast cancer progression. However, information on the properties of human breast adipose progenitor cells (APCs) involved in breast physiology or pathology is scant. We performed differential enzymatic dissociation of human breast AT lobules. We isolated and characterized two populations of APCs. Here we report that these distinct breast APC populations selectively expressed markers suitable for characterization. The population preferentially expressing (MSCA1) showed higher adipogenic potential. The population expressing higher levels of and acquired myofibroblast characteristics upon TGF-β treatment and a myo-cancer-associated fibroblast profile in the presence of breast cancer cells. This population expressed the immune checkpoint CD274 (PD-L1) and facilitated the expansion of breast cancer mammospheres compared with the adipogenic population. Indeed, the breast, as with other fat depots, contains distinct types of APCs with differences in their ability to specialize. This indicates that they were differentially involved in breast remodeling. Their interactions with breast cancer cells revealed differences in the potential for tumor dissemination and estrogen receptor expression, and these differences might be relevant to improve therapies targeting the tumor microenvironment." 14010;"Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways.";"C. Hinault, F. BOST, N. Chevalier";"Equipe 05, Team 05";35887249;"International journal of molecular sciences";"Charazac A, Hinault C, Dolfi B, Hautier S, Decondé Le Butor C, Bost F, Chevalier N";;"Jul 2022";1658880000;;"Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health-such as obesity, fertility disorders and cancers-by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10 M to 10 M; cytotoxicity and proliferation were monitored using the IncuCyte technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10 M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10 M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10 M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens." 14007;"Harsh intertidal environment enhances metabolism and immunity in oyster (Crassostrea gigas) spat.";"N. Mazure";"Equipe 05, Team 05";35988349;"Marine environmental research";"Corporeau C, Petton S, Vilaça R, Delisle L, Quéré C, Le Roy V, Dubreuil C, Lacas-Gervais S, Guitton Y, Artigaud S, Bernay B, Pichereau V, Huvet A, Petton B, Pernet F, Fleury E, Madec S, Brigaudeau C, Brenner C, Mazure NM";;"Aug 2022";1661040000;;"The Pacific oyster Crassostrea gigas is established in the marine intertidal zone, experiencing rapid and highly dynamic environmental changes throughout the tidal cycle. Depending on the bathymetry, oysters face oxygen deprivation, lack of nutrients, and high changes in temperature during alternation of the cycles of emersion/immersion. Here we showed that intertidal oysters at a bathymetry level of 3 and 5 m delayed by ten days the onset of mortality associated with Pacific Oyster Mortality Syndrome (POMS) as compared to subtidal oysters. Intertidal oysters presented a lower growth but similar energetic reserves to subtidal oysters but induced proteomic changes indicative of a boost in metabolism, inflammation, and innate immunity that may have improved their resistance during infection with the Ostreid herpes virus. Our work highlights that intertidal harsh environmental conditions modify host-pathogen interaction and improve oyster health. This study opens new perspectives on oyster farming for mitigation strategies based on tidal height." 13986;"The Stress-Responsive microRNA-34a Alters Insulin Signaling and Actions in Adipocytes through Induction of the Tyrosine Phosphatase PTP1B.";"B. Angot, JF. Tanti, J. Jager, M. Ohanna, M. Cormont";"Equipe 07, Team 07, Equipe 11, Team 11";36010657;Cells;"Cornejo PJ, Vergoni B, Ohanna M, Angot B, Gonzalez T, Jager J, Tanti JF, Cormont M";;"Aug 2022";1661472000;;"Metabolic stresses alter the signaling and actions of insulin in adipocytes during obesity, but the molecular links remain incompletely understood. Members of the microRNA-34 (miR-34 family play a pivotal role in stress response, and previous studies showed an upregulation of miR-34a in adipose tissue during obesity. Here, we identified miR-34a as a new mediator of adipocyte insulin resistance. We confirmed the upregulation of miR-34a in adipose tissues of obese mice, which was observed in the adipocyte fraction exclusively. Overexpression of miR-34a in 3T3-L1 adipocytes or in fat pads of lean mice markedly reduced Akt activation by insulin and the insulin-induced glucose transport. This was accompanied by a decreased expression of VAMP2, a target of miR-34a, and an increased expression of the tyrosine phosphatase PTP1B. Importantly, PTP1B silencing prevented the inhibitory effect of miR-34a on insulin signaling. Mechanistically, miR-34a decreased the NAD level through inhibition of and , resulting in an inhibition of Sirtuin-1, which promoted an upregulation of PTP1B. Furthermore, the mRNA expression of and was decreased in adipose tissue of obese mice. Collectively, our results identify miR-34a as a new inhibitor of insulin signaling in adipocytes, providing a potential pathway to target to fight insulin resistance." 13972;"A new ChEMBL dataset for the similarity-based target fishing engine FastTargetPred: Annotation of an exhaustive list of linear tetrapeptides.";"P. Auberger";"Equipe 02, Team 02";35496477;"Data in brief";"Tanwar S, Auberger P, Gillet G, DiPaola M, Tsaioun K, Villoutreix BO";;"May 2022";1651449600;;"Drug discovery often requires the identification of off-targets as the binding of a compound to targets other than the intended target(s) can be beneficial in some cases or detrimental in other situations (e.g., binding to anti-targets). Such investigations are also of importance during the early stage of a project, for example when the target is not known (e.g., phenotypic screening). Target identification can be performed , but various methods have also been developed in recent years to facilitate target identification and help generate ideas. FastTargetPred is one such approach, it is a freely available Python/C program that attempts to predict putative macromolecular targets (i.e., target fishing) for a single input small molecule query or an entire compound collection using established chemical similarity search approaches. Indeed, the putative macromolecular target(s) of a small chemical compound can be predicted by identifying ligands that are known experimentally to bind to some targets and that are structurally similar to the input query chemical compound. Therefore, this type of target fishing approach relies on a large collection of experimentally validated macromolecule-chemical compound binding data. The small chemical compounds can be described as molecular fingerprints encoding their structural characteristics as a vector. The published version of FastTargetPred used ligand-target binding data extracted from the release 25 (2019) of the ChEMBL database. Here we provide a new dataset for FastTargetPred extracted from the last ChEMBL release, namely, at the time of writing, ChEMBL29 (2021). Four fingerprints were computed (ECFP4, ECFP6, MACCS and PL) for the extracted compound dataset (714,780 unique ChEMBL29 compounds while the entire ChEMBL29 database contained about 2.1 million compounds). However, it was not possible to compute fingerprints for 19 molecules because of their unusual chemistry (complex macrocycles). These data files were then prepared so as to be compatible with FastTargetPred requirements. The 714,761 ChEMBL chemical compounds with computed fingerprints hit 6,477 macromolecular targets based on the selected criteria. For these ChEMBL compounds a ChEMBL target ID is reported and these target IDs were matched with the corresponding UniProt IDs. Thus, when available, the UniProt ID is provided, the protein UniProt name, the gene name, the organism as well as annotated involvement in diseases, gene ontology data, and cross-references to the Reactome pathway database. As short peptides can be of interest for drug discovery and chemical biology endeavours, we were interested in attempting to predict putative macromolecular targets for a previously reported exhaustive combination of peptides containing four natural amino acids (i.e., 20 × 20 × 20 × 20 = 160,000 linear tetrapeptides) using FastTargetPred and the presently generated ChEMBL29 dataset. With the parameters used, putative targets are reported for 63,944 unique query peptides. These target predictions are provided in two different searchable files with hyperlinks to the ChEMBL, UniProt and Reactome databases." 13970;"Reprogramming monocyte-derived macrophages through caspase inhibition.";"A. Jacquel, C. Savy, G. Robert, P. Auberger, P. Chaintreuil, T. Cluzeau";"Equipe 02, Team 02, Equipe 06, Team 06";35251769;Oncoimmunology;"Chaintreuil P, Laplane L, Esnault F, Ghesquier V, Savy C, Furstoss N, Arcangeli ML, Cluzeau T, Robert G, Droin N, Solary E, Auberger P, Jacquel A";;"Mar 2022";1646611200;;"Macrophages are widely distributed innate immune cells that play an indispensable role in a variety of physiologic and pathologic processes, including organ development, host defense, acute and chronic inflammation, solid and hematopoietic cancers. Beyond their inextricable role as conveyors of programmed cell death, we have previously highlighted that caspases exert non-apoptotic functions, especially during the differentiation of monocyte-derived cells in response to CSF-1. Here, we found that non-canonic cleavages of caspases, reflecting their activation, are maintained during IL-4-induced monocyte-derived macrophages polarization. Moreover, Emricasan, a pan-caspase inhibitor that demonstrated promising preclinical activity in various diseases and safely entered clinical testing for the treatment of liver failure, prevents the generation and the anti-inflammatory polarization of monocyte-derived macrophages . Interestingly, caspase inhibition also triggered the reprogramming of monocyte-derived cells evidenced by RNA sequencing. Taken together, our findings position Emricasan as a potential alternative to current therapies for reprogramming macrophages in diseases driven by monocyte-derived macrophages." 13968;"P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.";"A. Jacquel, P. Auberger, P. Chaintreuil";"Equipe 02, Team 02";35668193;"Nature cancer";"Lin KH, Rutter JC, Xie A, Killarney ST, Vaganay C, Benaksas C, Ling F, Sodaro G, Meslin PA, Bassil CF, Fenouille N, Hoj J, Washart R, Ang HX, Cerda-Smith C, Chaintreuil P, Jacquel A, Auberger P, Forget A, Itzykson R, Lu M, Lin J, Pierobon M, Sheng Z, Li X, Chilkoti A, Owzar K, Rizzieri DA, Pardee TS, Benajiba L, Petricoin E, Puissant A, Wood KC";;"Jun 2022";1654473600;;"Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML." 13966;"Acadesine Circumvents Azacitidine Resistance in Myelodysplastic Syndrome and Acute Myeloid Leukemia.";"A. Jacquel, C. Savy, G. Robert, L. Blot, P. Auberger, PS. ROHRLICH, T. Cluzeau";"Equipe 02, Team 02, Equipe 12, Team 12, Equipe 04, Team 04";31881723;"International journal of molecular sciences";"Cluzeau T, Furstoss N, Savy C, El Manaa W, Zerhouni M, Blot L, Calleja A, Dufies M, Dubois A, Ginet C, Mounier N, Garnier G, Raynaud S, Rohrlich PS, Peterlin P, Stamatoullas A, Chermat F, Fenaux P, Jacquel A, Robert G, Auberger P";;"Dec 2019";1577577600;;"Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities." 13964;"The Rho GTPase activators CNF1 and DNT bacterial toxins have mucosal adjuvant properties.";"P. Munro";"Equipe 06, Team 06";15780436;Vaccine;"Munro P, Flatau G, Anjuère F, Hofman V, Czerkinsky C, Lemichez E";;"Mar 2005";1111536000;;"Cytotoxic necrotizing factor 1 (CNF1) from uropathogenic Escherichia coli belongs to a family of factors activating Rho GTPases. We report the in vivo effects of CNF1 in mice co-fed toxin and the soluble protein antigen ovalbumin (OVA). Similar to cholera toxin, CNF1 elicits adjuvanticity anti-OVA responses, both systemic and mucosal. In contrast, the catalytic inactive mutant CNF1-C866S demonstrated no effects. Using dermonecrotic toxin (DNT), a closely related Rho activating toxin from Bordetella, we discovered that the adjuvant property is within the DNT catalytic domain. Manipulation of Rho proteins thus provides a possible new approach for the development of effective mucosal immunoadjuvants." 13962;"Bacteria and the ubiquitin pathway.";"P. Munro";"Equipe 06, Team 06";17157551;"Current opinion in microbiology";"Munro P, Flatau G, Lemichez E";;"Dec 2006";1165968000;;"Ubiquitylation participates in a repertoire of reversible post-translational modifications that modulate the function, localization and half-life of proteins by regulating their association with various ubiquitin-binding proteins. In response to pathogen infection, bacterial effectors impact ubiquitin and ubiquitin-like modifications of key proteins in immune and anti-apoptotic signaling cascades. Certain bacteria corrupt the ubiquitylation machinery in order to regulate their virulence factors spatially and temporally or to trigger internalization of bacteria into host cells. Several new examples of how bacterial factors target ubiquitin and ubiquitin-like regulation emphasize the importance of modulating ubiquitin signaling to establish either long-lasting or devastating relationships of bacteria with their hosts." 13960;"Luciferase-expressing Leishmania infantum allows the monitoring of amastigote population size, in vivo, ex vivo and in vitro.";"C. Pomares, G. MICHEL, P. Munro, P. Marty";"Equipe 06, Team 06";21931877;"PLoS neglected tropical diseases";"Michel G, Ferrua B, Lang T, Maddugoda MP, Munro P, Pomares C, Lemichez E, Marty P";;"Sep 2011";1316563200;;"Here we engineered transgenic Leishmania infantum that express luciferase, the objectives being to more easily monitor in real time their establishment either in BALB/c mice--the liver and spleen being mainly studied-or in vitro. Whatever stationary phase L. infantum promastigotes population--wild type or engineered to express luciferase-the parasite burden was similar in the liver and the spleen at day 30 post the intravenous inoculation of BALB/c mice. Imaging of L. infantum hosting BALB/C mice provided sensitivity in the range of 20,000 to 40,000 amastigotes/mg tissue, two tissues-liver and spleen-being monitored. Once sampled and processed ex vivo for their luciferin-dependent bioluminescence the threshold sensitivity was shown to range from 1,000 to 6,000 amastigotes/mg tissue. This model further proved to be valuable for in vivo measurement of the efficiency of drugs such as miltefosine and may, therefore, additionally be used to evaluate vaccine-induced protection." 13958;"The Staphylococcus aureus epidermal cell differentiation inhibitor toxin promotes formation of infection foci in a mouse model of bacteremia.";"P. Munro";"Equipe 06, Team 06";20479081;"Infection and immunity";"Munro P, Benchetrit M, Nahori MA, Stefani C, Clément R, Michiels JF, Landraud L, Dussurget O, Lemichez E";;"May 2010";1274227200;;"Inactivation of the host GTPase RhoA by staphylococcal epidermal cell differentiation inhibitor (EDIN) exotoxins triggers the formation of large transcellular tunnels, named macroapertures, in endothelial cells. We used bioluminescent strains of Staphylococcus aureus to monitor the formation of infection foci during the first 24 h of hematogenous bacterial dissemination. Clinically derived EDIN-expressing S. aureus strains S25 and Xen36 produced many disseminated foci. EDIN had no detectable impact on infection foci in terms of histopathology or the intensity of emitted light. Moreover, EDIN did not modify the course of bacterial clearance from the bloodstream. In contrast, we show that EDIN expression promotes a 5-fold increase in the number of infection foci produced by Xen36. This virulence activity of EDIN requires RhoA ADP-ribosyltranferase activity. These results suggest that EDIN is a risk factor for S. aureus dissemination through the vasculature by virtue of its ability to promote the formation of infection foci in deep-seated tissues." 13956;"Intranasal immunization with tetanus toxoid and CNF1 as a new mucosal adjuvant protects BALB/c mice against lethal challenge.";"P. Munro";"Equipe 06, Team 06";18035455;Vaccine;"Munro P, Flatau G, Lemichez E";;"Nov 2007";1195862400;;"Although often requiring the development of efficient adjuvants, needle-free mucosal delivery of vaccine is of major interest as a strategy of mass immunization against infectious diseases. We report that mucosal immunization against tetanus toxoid through nasal route, together with active cytotoxic necrotizing factor 1 (CNF1), elicits a specific and long lasting anti-tetanus toxin response, comprising seric IgG and IgA, as well as mucosal IgA. Immunized mice were protected against a challenge with lethal doses of tetanus toxin (10 x LD(50)). The Rho GTPase activating toxin CNF1 is thus an attractive mucosal adjuvant candidate for nasal vaccines." 13954;"Specificity of immunomodulator secretion in urinary samples in response to infection by alpha-hemolysin and CNF1 bearing uropathogenic Escherichia coli.";"P. Munro";"Equipe 06, Team 06";17382555;Cytokine;"Real JM, Munro P, Buisson-Touati C, Lemichez E, Boquet P, Landraud L";;"Mar 2007";1174953600;;"Escherichia coli are the most common etiological agents of urinary tract infections (UTIs). Uropathogenic E. coli (UPECs) produce specific toxins including the cytotoxic necrotizing factor-1 (CNF1) and the alpha-hemolysin (alpha-Hly). CNF1 triggers, through Rho protein activation, a specific gene response of host cells, which results in the production for instance of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and the macrophage inflammatory protein-3alpha (MIP-3alpha). The alpha hemolysin alpha-Hly also triggers the production of inflammatory mediators. Cnf1 is always associated with alpha-hly in a pathogenicity island conserved among UPECs. Using two complementary approaches we have investigated whether alpha-hly and cnf1 bearing UPECs are associated with a specific type of UTI both in term of pathology and host response. Here we report that UPECs bearing alpha-hly/cnf1 have a prevalence of 50% in UPECs isolated from hemorrhagic UTIs, as compared to 30% in the overall UPEC population. In addition, we observed that MCP-1, and IL-8 to a lower extent, is produced in urine at higher concentrations in UTIs caused by UPECs carrying alpha-hly/cnf1." 13857;"Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation.";"S. Tartare-Deckert";"Equipe 11, Team 11";35322197;Oncogene;"Sala M, Allain N, Moreau M, Jabouille A, Henriet E, Abou-Hammoud A, Uguen A, Di-Tommaso S, Dourthe C, Raymond AA, Dupuy JW, Gerard E, Dugot-Senant N, Rousseau B, Merlio JP, Pham-Ledart A, Vergier B, Tartare-Deckert S, Moreau V, Saltel F";;"Mar 2022";1648080000;;"Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism." 13855;"Risk for nevus transformation and melanoma proliferation and invasion during natalizumab treatment: four years of dermoscopic follow-up with immunohistological studies and proliferation and invasion assays.";"S. Tartare-Deckert, T. Passeron";"Equipe 11, Team 11, Equipe 12, Team 12";24919481;"JAMA dermatology";"Pharaon M, Tichet M, Lebrun-Frénay C, Tartare-Deckert S, Passeron T";;"Jun 2014";1402617600;; 13853;"Scarring after chemical tattoo removal: a retrospective study.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";35766080;"European journal of dermatology : EJD";"Kenani Z, Le Duff F, Hachem JP, Le Pillouer-Prost A, Martin-Chico R, Patarin M, Laubach H, Ducamp I, Cante V, Perillat Y, Toubel G, Passeron T, Bahadoran P";;"Jun 2022";1656460800;; 13851;"Unravelling the sex-specific diversity and functions of adrenal gland macrophages.";"J. GILLERON, L. Yvan-Charvet, N. Vaillant";"Equipe 07, Team 07, Equipe 13, Team 13";35705045;"Cell reports";"Dolfi B, Gallerand A, Firulyova MM, Xu Y, Merlin J, Dumont A, Castiglione A, Vaillant N, Quemener S, Gerke H, Stunault MI, Schrank PR, Kim SH, Zhu A, Ding J, Gilleron J, Magnone V, Barbry P, Dombrowicz D, Duranton C, Wakkach A, Blin-Wakkach C, Becher B, Pagnotta S, Argüello RJ, Rantakari P, Chakarov S, Ginhoux F, Zaitsev K, Kim KW, Yvan-Charvet L, Guinamard RR, Williams JW, Ivanov S";;"Jun 2022";1655251200;;"Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We define the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and use genetic models to explore the developmental mechanisms yielding macrophage diversity. We define populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identify a female-specific subset with low major histocompatibility complex (MHC) class II expression. In adulthood, monocyte recruitment dominates adrenal gland macrophage maintenance in female mice. Adrenal gland macrophage sub-tissular distribution follows a sex-dimorphic pattern, with MHC class II macrophages located at the cortico-medullary junction. Macrophage sex dimorphism depends on the presence of the cortical X-zone. Adrenal gland macrophage depletion results in altered tissue homeostasis, modulated lipid metabolism, and decreased local aldosterone production during stress exposure. Overall, these data reveal the heterogeneity of adrenal gland macrophages and point toward sex-restricted distribution and functions of these cells." 13849;"Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis.";"A. TRAN, A. IANNELLI, S. PATOURAUX, P. GUAL, R. ANTY";"Equipe 08, Team 08";35358616;"Journal of hepatology";"Beaulant A, Dia M, Pillot B, Chauvin MA, Ji-Cao J, Durand C, Bendridi N, Chanon S, Vieille-Marchiset A, Da Silva CC, Patouraux S, Anty R, Iannelli A, Tran A, Gual P, Vidal H, Gomez L, Paillard M, Rieusset J";;"Mar 2022";1648684800;;"Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions; however, whether MAM dysfunction plays a causal role in hepatic insulin resistance and steatosis is not clear. Thus, we aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment." 13847;"Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation.";"A. TRAN, A. IANNELLI, S. PATOURAUX, P. GUAL, R. ANTY, S. BONNAFOUS";"Equipe 08, Team 08";35884801;Biomedicines;"Laurain A, Rubera I, Razzouk-Cadet M, Bonnafous S, Albuquerque M, Paradis V, Patouraux S, Duranton C, Lesaux O, Lefthériotis G, Tran A, Anty R, Gual P, Iannelli A, Favre G";;"Jul 2022";1658880000;;"Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh-Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = -0.57, = 0.001, n = 29) and FIB-4 (r = -0.47, = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; < 0.0001, n = 20). ALBI, MELD, and Pugh-Child scores correlated negatively with [PPi]pl (r = -0.60, = 0.0005; r = -0.56, = 0.002; r = -0.41, = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, = 0.02, n = 16; r = 0.58, = 0.009, n = 20; r = 0.41, = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, = 0.02, n = 16; r = 0.67, = 0.002, n = 20; r = 0.61, = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37-44] vs. 35 [30-40], = 0.009) and [PPi]pl was normalized (1.40 [1.07-1.86] vs. 0.68 [0.53-0.80] µmol/L, = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters." 13845;"Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD.";"A. TRAN, P. GUAL, S. BONNAFOUS";"Equipe 08, Team 08";35768000;"Developmental cell";"Donne R, Saroul-Ainama M, Cordier P, Hammoutene A, Kabore C, Stadler M, Nemazanyy I, Galy-Fauroux I, Herrag M, Riedl T, Chansel-Da Cruz M, Caruso S, Bonnafous S, Öllinger R, Rad R, Unger K, Tran A, Couty JP, Gual P, Paradis V, Celton-Morizur S, Heikenwalder M, Revy P, Desdouets C";;"Jun 2022";1656460800;;"Non-alcoholic steatotic liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD has a major effect on the intrinsic proliferative properties of hepatocytes. Here, we investigated the mechanisms underlying the activation of DNA damage response during NAFLD. Proliferating mouse NAFLD hepatocytes harbor replication stress (RS) with an alteration of the replication fork's speed and activation of ATR pathway, which is sufficient to cause DNA breaks. Nucleotide pool imbalance occurring during NAFLD is the key driver of RS. Remarkably, DNA lesions drive cGAS/STING pathway activation, a major component of cells' intrinsic immune response. The translational significance of this study was reiterated by showing that lipid overload in proliferating HepaRG was sufficient to induce RS and nucleotide pool imbalance. Moreover, livers from NAFLD patients displayed nucleotide pathway deregulation and cGAS/STING gene alteration. Altogether, our findings shed light on the mechanisms by which damaged NAFLD hepatocytes might promote disease progression." 13840;"The Damaging Effects of Long UVA (UVA1) Rays: A Major Challenge to Preserve Skin Health and Integrity.";"T. Passeron";"Equipe 12, Team 12";35897826;"International journal of molecular sciences";"Bernerd F, Passeron T, Castiel I, Marionnet C";;"Jul 2022";1658966400;;"Within solar ultraviolet (UV) light, the longest UVA1 wavelengths, with significant and relatively constant levels all year round and large penetration properties, produce effects in all cutaneous layers. Their effects, mediated by numerous endogenous chromophores, primarily involve the generation of reactive oxygen species (ROS). The resulting oxidative stress is the major mode of action of UVA1, responsible for lipid peroxidation, protein carbonylation, DNA lesions and subsequent intracellular signaling cascades. These molecular changes lead to mutations, apoptosis, dermis remodeling, inflammatory reactions and abnormal immune responses. The altered biological functions contribute to clinical consequences such as hyperpigmentation, inflammation, photoimmunosuppression, sun allergies, photoaging and photocancers. Such harmful impacts have also been reported after the use of UVA1 phototherapy or tanning beds. Furthermore, other external aggressors, such as pollutants and visible light (Vis), were shown to induce independent, cumulative and synergistic effects with UVA1 rays. In this review, we synthetize the biological and clinical effects of UVA1 and the complementary effects of UVA1 with pollutants or Vis. The identified deleterious biological impact of UVA1 contributing to clinical consequences, combined with the predominance of UVA1 rays in solar UV radiation, constitute a solid rational for the need for a broad photoprotection, including UVA1 up to 400 nm." 13838;"Allogeneic hematopoietic stem cell transplantation for adult HLH: a retrospective study by the chronic malignancies and inborn errors working parties of EBMT.";"PS. ROHRLICH";"Equipe 04, Team 04";35332305;"Bone marrow transplantation";"Machowicz R, Suarez F, Wiktor-Jedrzejczak W, Eikema DJ, de Wreede LC, Blok HJ, Isaksson C, Einsele H, Poiré X, van Dorp S, Nikolousis E, Johansson JE, Kobbe G, Zecca M, Arnold R, Gerbitz A, Finke J, Díez-Martín JL, Bonifazi F, McQuaker G, Lenhoff S, Rohrlich PS, Theobald M, Ljungman P, Collin M, Albert MH, Ehninger G, Carlson K, Halaburda K, Lehmberg K, Schönland S, Yakoub-Agha I, Gennery AR, Lankester AC, Kröger N";;"Mar 2022";1648166400;;"Hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) is a rare syndrome of potentially fatal, uncontrolled hyperinflammation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in primary, recurrent or progressive HLH, but information about its outcomes in the adult population is limited. We obtained data about 87 adult (≥18 years of age) patients retrospectively reported to the EBMT. The median survival time was 13.9 months. The three and five-year overall survival (OS) was 44% (95% CI 33-54%). Among 39 patients with a follow-up longer than 15 months, only three died. Relapse rate was 21% (95% CI 13-30%), while NRM reached 36% (95% CI 25-46%). Younger patients (<30 years of age) had better prognosis, with an OS of 59% (95% CI 45-73%) at three and five years vs 23% (95% CI 8-37%) for older ones. No difference in survival between reduced and myeloablative conditioning was found. To our knowledge, this is the largest report of adult HLH patients who underwent allo-HSCT. Patients who survive the first period after this procedure can expect a long disease-free survival. Both reduced intensity and myeloablative conditioning have therapeutic potential in adult HLH." 13836;"Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC).";"PS. ROHRLICH, G. MICHEL";"Equipe 04, Team 04, Equipe 06, Team 06";35507103;"Journal of cancer research and clinical oncology";"Grain A, Rialland-Battisti F, Chevallier P, Blin N, Dalle JH, Michel G, Dhédin N, Peffault de Latour R, Pochon C, Yakoub-Agha I, Bertrand Y, Sirvent A, Jubert C, Forcade E, Berceanu A, Gandemer V, Schneider P, Bay JO, Rohrlich PS, Brissot E, Paillard C, Plantaz D, Nguyen Quoc S, Gonzales F, Maillard N, Planche L, Baruchel A";;"May 2022";1651622400;;"In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences." 13834;"Erratum for Brahimi-Horn et al., ""Local Mitochondrial-Endolysosomal Microfusion Cleaves the Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia"".";"N. Mazure";"Equipe 05, Team 05";35049340;"Molecular and cellular biology";"Brahimi-Horn MC, Lacas-Gervais S, Adaixo R, Ilc K, Rouleau M, Notte A, Dieu M, Michiels C, Voeltzel T, Maguer-Satta V, Pelletier J, Ilie M, Hofman P, Manoury B, Schmidt A, Hiller S, Pouysségur J, Mazure NM";;"Jan 2022";1642636800;; 13832;"VEGF-A-related genetic variants protect against Alzheimer's disease.";"M. Stathopoulou";"Equipe 10, Team 10";35347084;Aging;"Petrelis AM, Stathopoulou MG, Kafyra M, Murray H, Masson C, Lamont J, Fitzgerald P, Dedoussis G, Yen FT, Visvikis-Siest S";;"Mar 2022";1648512000;;"The Apolipoprotein E () genotype has been shown to be the strongest genetic risk factor for Alzheimer's disease (AD). Moreover, both the lipolysis-stimulated lipoprotein receptor (LSR) and the vascular endothelial growth factor A (VEGF-A) are involved in the development of AD. The aim of the study was to develop a prediction model for AD including single nucleotide polymorphisms (SNP) of , and VEGF-A-related variants. The population consisted of 323 individuals (143 AD cases and 180 controls). Genotyping was performed for: the common polymorphism (rs429358 and rs7412), two variants (rs34259399 and rs916147) and 10 VEGF-A-related SNPs (rs6921438, rs7043199, rs6993770, rs2375981, rs34528081, rs4782371, rs2639990, rs10761741, rs114694170, rs1740073), previously identified as genetic determinants of VEGF-A levels in GWAS studies. The prediction model included direct and epistatic interaction effects, age and sex and was developed using the elastic net machine learning methodology. An optimal model including the direct effect of the allele, age and eight epistatic interactions between and , and VEGF-A-related variants was developed with an accuracy of 72%. Two epistatic interactions (rs7043199*rs6993770 and rs2375981*rs34528081) were the strongest protective factors against AD together with the absence of allele. Based on pathway analysis, the involved variants and related genes are implicated in neurological diseases. In conclusion, this study demonstrated links between , and VEGF-A-related variants and the development of AD and proposed a model of nine genetic variants which appears to strongly influence the risk for AD." 13824;"Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression.";"JE. Ricci, J. Chiche, R. Paul-Bellon, S. Marchetti";"Equipe 03, Team 03";35857457;"Science advances";"Grima-Reyes M, Vandenberghe A, Nemazanyy I, Meola P, Paul R, Reverso-Meinietti J, Martinez-Turtos A, Nottet N, Chan WK, Lorenzi PL, Marchetti S, Ricci JE, Chiche J";;"Jul 2022";1658275200;;"Depletion of circulating asparagine with l-asparaginase (ASNase) is a mainstay of leukemia treatment and is under investigation in many cancers. Expression levels of asparagine synthetase (ASNS), which catalyzes asparagine synthesis, were considered predictive of cancer cell sensitivity to ASNase treatment, a notion recently challenged. Using [U-C]-l-glutamine in vitro and in vivo in a mouse model of B cell lymphomas (BCLs), we demonstrated that supraphysiological or physiological concentrations of asparagine prevent de novo asparagine biosynthesis, regardless of ASNS expression levels. Overexpressing ASNS in ASNase-sensitive BCL was insufficient to confer resistance to ASNase treatment in vivo. Moreover, we showed that ASNase's glutaminase activity enables its maximal anticancer effect. Together, our results indicate that baseline ASNS expression (low or high) cannot dictate BCL dependence on de novo asparagine biosynthesis and predict BCL sensitivity to dual ASNase activity. Thus, except for ASNS-deficient cancer cells, ASNase's glutaminase activity should be considered in the clinic." 13822;"Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network.";"JE. Ricci";"Equipe 03, Team 03";35883457;Biomolecules;"Ichim G, Gibert B, Adriouch S, Brenner C, Davoust N, Desagher S, Devos D, Dokudovskaya S, Dubrez L, Estaquier J, Gillet G, Guénal I, Juin PP, Kroemer G, Legembre P, Levayer R, Manon S, Mehlen P, Meurette O, Micheau O, Mignotte B, Nguyen-Khac F, Popgeorgiev N, Poyet JL, Priault M, Ricci JE, Riquet FB, Susin SA, Suzanne M, Vacher P, Walter L, Mollereau B";;"Jul 2022";1658880000;;"Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in , apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy." 13820;"Diabetes-Induced Changes in Macrophage Biology Might Lead to Reduced Risk for Abdominal Aortic Aneurysm Development.";"J. Neels, J. Murdaca, F. Lareyre, G. Chinetti, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";35208203;Metabolites;"Chinetti G, Carboni J, Murdaca J, Moratal C, Sibille B, Raffort J, Lareyre F, Baptiste EJ, Hassen-Khodja R, Neels JG";;"Feb 2022";1645747200;;"Type 2 diabetes patients are less likely to develop an abdominal aortic aneurysm (AAA). Since macrophages play a crucial role in AAA development, we hypothesized that this decrease in AAA risk in diabetic patients might be due to diabetes-induced changes in macrophage biology. To test this hypothesis, we treated primary macrophages obtained from healthy human volunteers with serum from non-diabetic vs. diabetic AAA patients and observed differences in extracellular acidification and the expression of genes involved in glycolysis and lipid oxidation. These results suggest an increase in metabolism in macrophages treated with serum from diabetic AAA patients. Since serum samples used did not differ in glucose content, these changes are not likely to be caused by differences in glycemia. Macrophage functions have been shown to be linked to their metabolism. In line with this, our data suggest that this increase in macrophage metabolism is accompanied by a shift towards an anti-inflammatory state. Together, these results support a model where diabetes-induced changes in metabolism in macrophages might lead to a reduced risk for AAA development." 13816;"REDD1 is a gatekeeper of murine hematopoietic stem cell functions during stress responses.";"G. Robert, A. Jacquel, P. Auberger";"Equipe 02, Team 02";35641638;Leukemia;"Barroca V, Henry E, Dechamps N, Renou L, Chaintreuil P, Kulkarni R, Devanand S, Jacquel A, Robert G, Auberger P, Pflumio F, Arcangeli ML";;"May 2022";1653955200;; 13814;"Novel T Follicular Helper-like T-Cell Lymphoma Therapies: From Preclinical Evaluation to Clinical Reality.";"JE. Ricci, E. Verhoeyen";"Equipe 03, Team 03";35625998;Cancers;"Krug A, Tari G, Saidane A, Gaulard P, Ricci JE, Lemonnier F, Verhoeyen E";;"May 2022";1653696000;;"The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy but gives very unsatisfying results for these patients. Enormous progress in the last decade in terms of understanding the implicated genetic mutations leading to signaling and epigenetic pathway deregulation in Tfh PTCL allowed the research community to propose new therapeutic approaches. These findings point towards new biomarkers and new therapies, including hypomethylating agents, such as azacytidine, and inhibitors of the TCR-hyperactivating molecules in Tfh PTCL. Additionally, metabolic interference, inhibitors of the NF-κB and PI3K-mTOR pathways and possibly novel immunotherapies, such as antibodies and chimeric antigen receptors (CAR) directed against Tfh malignant T-cell surface markers, are discussed in this review among other new treatment options." 13794;"Secretion of IL1 by Dedifferentiated Melanoma Cells Inhibits JAK1-STAT3-Driven Actomyosin Contractility of Lymph Node Fibroblastic Reticular Cells.";"C. Girard, M. Deckert, S. Tartare-Deckert, T. Passeron, V. PROD'HOMME";"Equipe 11, Team 11, Equipe 12, Team 12";35502542;"Cancer research";"Rovera C, Berestjuk I, Lecacheur M, Tavernier C, Diazzi S, Pisano S, Irondelle M, Mallavialle A, Albrengues J, Gaggioli C, Girard CA, Passeron T, Deckert M, Tartare-Deckert S, Prod'homme V";;"May 2022";1651536000;;"Fibroblastic reticular cells (FRC) are immunologically specialized myofibroblasts that control the elasticity of the lymph node, in part through their contractile properties. Swelling of tumor-draining lymph nodes is a hallmark of lymphophilic cancers such as cutaneous melanoma. Melanoma displays high intratumoral heterogeneity with the coexistence of melanoma cells with variable differentiation phenotypes from melanocytic to dedifferentiated states. Factors secreted by melanoma cells promote premetastatic lymph node reprograming and tumor spreading. Elucidating the impact of the melanoma secretome on FRC could help identify approaches to prevent metastasis. Here we show that melanocytic and dedifferentiated melanoma cells differentially impact the FRC contractile phenotype. Factors secreted by dedifferentiated cells, but not by melanocytic cells, strongly inhibited actomyosin-dependent contractile forces of FRC by decreasing the activity of the RHOA-RHO-kinase (ROCK) pathway and the mechano-responsive transcriptional coactivator Yes1 associated transcriptional regulator (YAP). Transcriptional profiling and biochemical analyses indicated that actomyosin cytoskeleton relaxation in FRC is driven by inhibition of the JAK1-STAT3 pathway. This FRC relaxation was associated with increased FRC proliferation and activation and with elevated tumor invasion in vitro. The secretome of dedifferentiated melanoma cells also modulated the biomechanical properties of distant lymph node in premetastatic mouse models. Finally, IL1 produced by dedifferentiated cells was involved in the inhibition of FRC contractility. These data highlight the role of the JAK1-STAT3 and YAP pathways in spontaneous contractility of resting FRC. They also suggest that dedifferentiated melanoma cells specifically target FRC biomechanical properties to favor tumor spreading in the premetastatic lymph node niche. Targeting this remote communication could be an effective strategy to prevent metastatic spread of the disease." 13124;"Emerging Role of Deubiquitinating Enzymes (DUBs) in Melanoma Pathogenesis.";"M. Deckert, M. Ohanna, P. Biber";"Equipe 11, Team 11";35884430;Cancers;"Ohanna M, Biber P, Deckert M";;"07 2022";1656633600;;"Metastatic melanoma is the leading cause of death from skin cancer. Therapies targeting the BRAF oncogenic pathway and immunotherapies show remarkable clinical efficacy. However, these treatments are limited to subgroups of patients and relapse is common. Overall, the majority of patients require additional treatments, justifying the development of new therapeutic strategies. Non-genetic and genetic alterations are considered to be important drivers of cellular adaptation mechanisms to current therapies and disease relapse. Importantly, modification of the overall proteome in response to non-genetic and genetic events supports major cellular changes that are required for the survival, proliferation, and migration of melanoma cells. However, the mechanisms underlying these adaptive responses remain to be investigated. The major contributor to proteome remodeling involves the ubiquitin pathway, ubiquitinating enzymes, and ubiquitin-specific proteases also known as DeUBiquitinases (DUBs). In this review, we summarize the current knowledge regarding the nature and roles of the DUBs recently identified in melanoma progression and therapeutic resistance and discuss their potential as novel sources of vulnerability for melanoma therapy." 13115;"Prevention of Polymorphic Light Eruption Afforded by a Very High Broad-Spectrum Protection Sunscreen Containing Ectoin.";"T. Passeron";"Equipe 12, Team 12";35716331;"Dermatology and therapy";"Duteil L, Queille-Roussel C, Aladren S, Bustos X, Trullas C, Granger C, Krutmann J, Passeron T";;"Jun 2022";1655510400;;"Polymorphic light eruption (PLE) is the most common idiopathic, acquired photodermatosis. The pathophysiology of PLE is not yet fully understood but seems to involve immunological mechanisms, UVA-induced oxidative stress, and the subsequent elicitation of a cellular stress response affecting keratinocyte gene expression and skin immune function. In the present study, a high broad-spectrum sunscreen medical device (MD), containing a very high protection complex of UVB and UVA filters and ectoin, was investigated for its ability to protect against UVA-induced PLE." 12996;"Hypoxia decreases insulin signaling pathways in adipocytes.";"C. Regazzetti, F. BOST, M. Cormont, S. Giorgetti-Peraldi";"Equipe 12, Team 12, Equipe 05, Team 05";18984735;Diabetes;"Regazzetti C, Peraldi P, Grémeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S";;"11 2008";1225497600;;"Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated whether this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on the insulin signaling pathway in adipocytes." 12994;"Insulin induces REDD1 expression through hypoxia-inducible factor 1 activation in adipocytes.";"C. Regazzetti, F. BOST, JF. Tanti, S. Giorgetti-Peraldi";"Equipe 12, Team 12, Equipe 05, Team 05, Equipe 07, Team 07";19996311;"The Journal of biological chemistry";"Regazzetti C, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S";;"12 2009";1259625600;;"REDD1 (regulated in development and DNA damage responses) is essential for the inhibition of mTORC1 (mammalian target of rapamycin complex) signaling pathway in response to hypoxia. REDD1 expression is regulated by many stresses such as hypoxia, oxidative stress, and energy depletion. However, the regulation of REDD1 expression in response to insulin remains unknown. In the present study, we demonstrate that in murine and in human adipocytes, insulin stimulates REDD1 expression. Insulin-induced REDD1 expression occurs through phosphoinositide 3-kinase/mTOR-dependent pathways. Moreover, using echinomycin, a hypoxia-inducible factor 1 (HIF-1) inhibitor, and HIF-1alpha small interfering RNA, we demonstrate that insulin stimulates REDD1 expression only through the transcription factor HIF-1. In conclusion, our study shows that insulin stimulates REDD1 expression in adipocytes." 12992;"Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1.";"C. Regazzetti, F. BOST, G. Robert, JF. Tanti, P. Auberger, S. Giorgetti-Peraldi";"Equipe 12, Team 12, Equipe 05, Team 05, Equipe 02, Team 02, Equipe 07, Team 07";21540236;"Cancer research";"Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F";;"05 2011";1304208000;;"Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment." 12990;"Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes.";"C. Regazzetti, JF. Tanti, S. Giorgetti-Peraldi";"Equipe 12, Team 12, Equipe 07, Team 07";23272222;"PloS one";"Regazzetti C, Dumas K, Le Marchand-Brustel Y, Peraldi P, Tanti JF, Giorgetti-Peraldi S";;"12 2012";1354320000;;"REDD1 (Regulated in development and DNA damage response 1) is a hypoxia and stress response gene and is a negative regulator of mTORC1. Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by insulin. In human and murine adipocytes, insulin transiently stimulates REDD1 expression through a MEK dependent pathway. In HEK-293 cells, expression of a constitutive active form of MEK stabilizes REDD1 and protects REDD1 from proteasomal degradation mediated by CUL4A-DDB1 ubiquitin ligase complex. In 3T3-L1 adipocytes, silencing of REDD1 with siRNA induces an increase of mTORC1 activity as well as an inhibition of insulin signaling pathway and lipogenesis. Rapamycin, a mTORC1 inhibitor, restores the insulin signaling after downregulation of REDD1 expression. This observation suggests that REDD1 positively regulates insulin signaling through the inhibition of mTORC1 activity. In conclusion, our results demonstrate that insulin increases REDD1 expression, and that REDD1 participates in the biological response to insulin." 12988;"Hypoxia inhibits Cavin-1 and Cavin-2 expression and down-regulates caveolae in adipocytes.";"A. TRAN, C. Regazzetti, JF. Tanti, M. Cormont, P. GUAL, S. Giorgetti-Peraldi, S. BONNAFOUS";"Equipe 08, Team 08, Equipe 12, Team 12, Equipe 07, Team 07";25521582;Endocrinology;"Regazzetti C, Dumas K, Lacas-Gervais S, Pastor F, Peraldi P, Bonnafous S, Dugail I, Le Lay S, Valet P, Le Marchand-Brustel Y, Tran A, Gual P, Tanti JF, Cormont M, Giorgetti-Peraldi S";;"12 2014";1417392000;;"During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance." 12986;"Micro holes for delivering melanocytes into the skin: an ex vivo approach.";"C. Regazzetti, T. Passeron";"Equipe 12, Team 12";27172992;"Pigment cell & melanoma research";"Regazzetti C, Alcor D, Chignon-Sicard B, Passeron T";;"May 2016";1463184000;; 12984;"Implication of REDD1 in the activation of inflammatory pathways.";"C. Regazzetti, JF. Tanti, M. Cormont, S. Giorgetti-Peraldi";"Equipe 12, Team 12, Equipe 07, Team 07";28765650;"Scientific reports";"Pastor F, Dumas K, Barthélémy MA, Regazzetti C, Druelle N, Peraldi P, Cormont M, Tanti JF, Giorgetti-Peraldi S";;"08 2017";1501545600;;"In response to endotoxemia, the organism triggers an inflammatory response, and the visceral adipose tissue represents a major source of proinflammatory cytokines. The regulation of inflammation response in the adipose tissue is thus of crucial importance. We demonstrated that Regulated in development and DNA damage response-1 (REDD1) is involved in inflammation. REDD1 expression was increased in response to lipopolysaccharide (LPS) in bone marrow derived macrophages (BMDM) and in epidydimal adipose tissue. Loss of REDD1 protected the development of inflammation, since the expression of proinflammatory cytokines (TNFα, IL-6, IL-1β) was decreased in adipose tissue of REDD1 mice injected with LPS compared to wild-type mice. This decrease was associated with an inhibition of the activation of p38MAPK, JNK, NF-κB and NLRP3 inflammasome leading to a reduction of IL-1β secretion in response to LPS and ATP in REDD1 BMDM. Although REDD1 is an inhibitor of mTORC1, loss of REDD1 decreased inflammation independently of mTORC1 activation but more likely through oxidative stress regulation. Absence of REDD1 decreases ROS associated with a dysregulation of Nox-1 and GPx3 expression. Absence of REDD1 in macrophages decreases the development of insulin resistance in adipocyte-macrophage coculture. Altogether, REDD1 appears to be a key player in the control of inflammation." 12957;"Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses.";"R. Ballotti, S. Rocchi, T. Botton";"Equipe 01, Team 01, Equipe 12, Team 12";31618628;"Cell reports";"Botton T, Talevich E, Mishra VK, Zhang T, Shain AH, Berquet C, Gagnon A, Judson RL, Ballotti R, Ribas A, Herlyn M, Rocchi S, Brown KM, Hayward NK, Yeh I, Bastian BC";;"Oct 2019";1571270400;;"BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions." 12917;"Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";34088741;"Journal for immunotherapy of cancer";"Gérard A, Doyen J, Cremoni M, Bailly L, Zorzi K, Ruetsch-Chelli C, Brglez V, Picard-Gauci A, Troin L, Esnault VLM, Passeron T, Montaudié H, Seitz-Polski B";;"Jun 2021";1622851200;;"Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma." 12904;"Identification by mutation of the tyrosine residues in the insulin receptor substrate-1 affecting association with the tyrosine phosphatase 2C and phosphatidylinositol 3-kinase.";"S. Tartare-Deckert, S. Rocchi";"Equipe 11, Team 11, Equipe 12, Team 12";7588273;Endocrinology;"Rocchi S, Tartare-Deckert S, Mothe I, Van Obberghen E";;"Dec 1995";817776000;;"The insulin receptor substrate-1 (IRS-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Phosphorylated IRS-1 acts as a docking protein for Src homology-2 (SH2) domain-containing proteins involved in insulin signaling. These include in vivo the regulatory subunit p85 of the phosphatidylinositol 3-kinase (PI3-K) and the phosphotyrosine phosphatase-2C (PTP2C). In this report, we examined which tyrosine residues of IRS-1 are required for the interactions of IRS-1 with PI3-K and PTP2C. To address this issue, we constructed different rat IRS-1 mutants containing mutations in the tyrosine residues that interact with the SH2 domains of PI3-K and PTP2C in vitro. Each of the IRS-1 mutants obtained have been transiently expressed in 293 EBNA cells to study their ability to interact with PI3-K and PTP2C in vivo. Our results demonstrate that mutation of tyrosine 608 affects the PI3-K activity associated with IRS-1, suggesting that this tyrosine is likely to be a principal site of interaction with the SH2 domains of p85 in response to insulin. Furthermore, we found that mutation of tyrosines 1172 and 1222 totally prevents the insulin-induced association of IRS-1 with the SH2 domains of PTP2C, demonstrating that both tyrosines 1172 and 1222 are key elements in the binding sites for the SH2 domains of PTP2C. Finally, we found that the ability of purified PTP2C to dephosphorylate IRS-1 is dependent on the association of PTP2C with phosphorylated IRS-1." 12902;"Interaction of SH2-containing protein tyrosine phosphatase 2 with the insulin receptor and the insulin-like growth factor-I receptor: studies of the domains involved using the yeast two-hybrid system.";"S. Tartare-Deckert, S. Rocchi";"Equipe 11, Team 11, Equipe 12, Team 12";8895367;Endocrinology;"Rocchi S, Tartare-Deckert S, Sawka-Verhelle D, Gamha A, van Obberghen E";;"Nov 1996";846806400;;"Activated insulin and insulin-like growth factor-I receptors transmit downstream signals via the insulin receptor substrate (IRS-1 and IRS-2) and a series of proteins containing Src homology-2 (SH2) domains, including SH2-containing protein tyrosine phosphatase 2 (SHP-2). In the present study, we analyzed in the yeast two-hybrid system the interaction between both receptors and SHP-2. We found that a catalytically inactive SHP-2 is able to bind to tyrosine-phosphorylated IR beta-subunit and IGF-I R beta-subunit. However, with wild-type SHP-2, we were unable to detect an interaction with these receptors, which is likely to be due to dephosphorylation of the receptors by the phosphatase. Further, our results demonstrate that tyrosine 1322 of the IR, and the corresponding tyrosine 1316 of the IGF-I R are implicated in the interaction with the SHP-2 SH2 domain. At the level of SHP-2, it would appear that both SH2 domains of SHP-2 are necessary for optimal association with either receptor. Finally, using several insulin and IGF-I receptor mutants, we found that the kinase regulatory autophosphorylation sites play an important role in the interaction of these receptors with the SHP-2 SH2 domain. These sites are also necessary for the interaction with full-length IRS-1. We conclude that 1) the IR and IGF-I R directly interact with SHP-2; 2) the C-terminus autophosphorylation of these receptors sites are involved in this process; and 3) the receptors' kinase autophosphorylation sites are necessary for the interaction with SHP-2 and also with IRS-1." 12896;"Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis.";"P. GUAL, S. Rocchi";"Equipe 08, Team 08, Equipe 12, Team 12";10734310;Oncogene;"Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM";;"Mar 2000";954288000;;"A distinctive property of Hepatocyte Growth Factor (HGF) is its ability to induce differentiation of tubular structures from epithelial and endothelial cells (branching tubulogenesis). The HGF receptor directly activates PI3 kinase, Ras and STAT signalling pathways and phosphorylates the adaptator GRB2 Associated Binder-1 (Gab1). Gab1 is also phosphorylated in response to Epidermal Growth Factor (EGF) but is unable to induce tubule formation. Comparison of 32P-peptide maps of Gab1 from EGF- versus HGF-treated cells, demonstrates that the same sites are phosphorylated in vivo. However, while both EGF and HGF induce rapid tyrosine phosphorylation of Gab1 with a peak at 15 min, the phosphorylation persists for over 1 h, only in response to HGF. Nine tyrosines are phosphorylated by both receptors. Three of them (Y307, Y373, Y407) bind phospholipase C-gamma (PLC-gamma). Interestingly, the overexpression of a Gab1 mutant unable to bind PLC-gamma (Gab1 Y307/373/407F) did not alter HGF-stimulated cell scattering, only partially reduced the growth stimulation but completely abolished HGF-mediated tubulogenesis. It is concluded that sustained recruitment of PLCgamma to Gab1 plays an important role in branching tubulogenesis." 12897;"Potential involvement of FRS2 in insulin signaling.";"S. Rocchi";"Equipe 12, Team 12";10650943;Endocrinology;"Delahaye L, Rocchi S, Van Obberghen E";;"Jan 2000";949104000;;"Shp-2 is implicated in several tyrosine kinase receptor signaling pathways. This phosphotyrosine phosphatase is composed of a catalytic domain in its C-terminus and two SH2 domains in its N-terminus. Shp-2 becomes activated upon binding through one or both SH2 domains to tyrosine phosphorylated molecules such as Shc or insulin receptor substrates. We were interested in finding a new molecule(s), tyrosine phosphorylated by the insulin receptor (IR), that could interact with Shp-2. To do so, we screened a human placenta complementary DNA (cDNA) library with the SH2 domain-containing part of Shp-2 using a modified yeast two-hybrid system. In this system we induce or repress the expression of a constitutive active IR beta-subunit. When expressed, IR phosphorylates proteins produced from the library that can then associate with Shp-2. Using this approach, we isolated FRS2 as a potential target for tyrosine phosphorylation by the IR. After cloning the entire cDNA, we found that 1) in the yeast two-hybrid system, FRS2 interacts with Shp-2 in a fashion dependent on the presence of the IR; and 2) in the PC12/IR cell-line, insulin leads to an increase in FRS2 association with the phosphatase. We next wanted to determine whether FRS2 could be a direct substrate for IR. In an in vitro kinase assay we found that wheat-germ agglutinin-purified IR phosphorylates glutathione-S-transferase-FRS2 fusion protein. Finally, in intact cells we show that insulin stimulates tyrosine phosphorylation of endogenous FRS2. In summary, by screening a two-hybrid cDNA library, we have isolated FRS2 as a possible substrate for IR. We found that IR can directly phosphorylate FRS2. Moreover, in intact cells insulin stimulates tyrosine phosphorylation of FRS2 and its subsequent association with Shp-2. Taken together these results suggest that FRS2 could participate in insulin signaling by recruiting Shp-2 and, hence, could function as a docking molecule similar to insulin receptor substrate proteins." 12894;"Adrenocorticotrophic hormone stimulates phosphotyrosine phosphatase SHP2 in bovine adrenocortical cells: phosphorylation and activation by cAMP-dependent protein kinase.";"S. Rocchi";"Equipe 12, Team 12";11085942;"The Biochemical journal";"Rocchi S, Gaillard I, van Obberghen E, Chambaz EM, Vilgrain I";;"Nov 2000";974851200;;"During activation of adrenocortical cells by adrenocorticotrophic hormone (ACTH), tyrosine dephosphorylation of paxillin is stimulated and this correlates with protrusion of filopodial structures and a decreased number of focal adhesions. These effects are inhibited by Na(3)VO(4), a phosphotyrosine phosphatase inhibitor [Vilgrain, Chinn, Gaillard, Chambaz and Feige (1998) Biochem. J. 332, 533-540]. However, the tyrosine phosphatases involved in these processes remain to be identified. In this study, we provide evidence that the Src homology domain (SH)2-containing phosphotyrosine phosphatase (SHP)2, but not SHP1, is expressed in adrenocortical cells and is phosphorylated upon ACTH challenge. ACTH (10(-8) M) treatment of (32)P-labelled adrenocortical cells resulted in an increase in phosphorylated SHP2. By probing SHP2-containing immunoprecipitates with an antibody to phosphoserine we found that SHP2 was phosphorylated on serine in ACTH-treated cells in a dose- and time-dependent manner. Furthermore, using an in vitro kinase assay, we showed that SHP2 was a target for cAMP-dependent protein kinase (PKA). Serine was identified as the only target amino acid phosphorylated in SHP2. Phosphorylation of SHP2 by PKA resulted in a dramatic stimulation of phosphatase activity measured either with insulin receptor substrate-1 or with the synthetic peptide [(32)P]poly(Glu/Tyr) as substrate. In an in-gel assay of SHP2-containing immunoprecipitates, phosphorylated in vitro by PKA or isolated from adrenocortical cells treated with 10 nM ACTH, a pronounced activation of SHP2 activity was shown. These observations clearly support the idea that a PKA-mediated signal transduction pathway contributes to SHP2 regulation in adrenocortical cells and point to SHP2 as a possible mediator of the effects of ACTH." 12890;"Focal adhesion kinase pp125FAK interacts with the large conductance calcium-activated hSlo potassium channel in human osteoblasts: potential role in mechanotransduction.";"S. Rocchi";"Equipe 12, Team 12";14584897;"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research";"Rezzonico R, Cayatte C, Bourget-Ponzio I, Romey G, Belhacene N, Loubat A, Rocchi S, Van Obberghen E, Girault JA, Rossi B, Schmid-Antomarchi H";;"Oct 2003";1067558400;;"Molecular events of mechanotransduction in osteoblasts are poorly defined. We show that the mechanosensitive BK channels open and recruit the focal adhesion kinase FAK in osteoblasts on hypotonic shock. This could convert mechanical signals in biochemical events, leading to osteoblast activation." 12888;"Peroxisome proliferator-activated receptor gamma, the ultimate liaison between fat and transcription.";"S. Rocchi";"Equipe 12, Team 12";11242474;"The British journal of nutrition";"Rocchi S, Auwerx J";;"Mar 2001";984182400;;"The peroxisome proliferator-activated receptor gamma (PPARgamma) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARgamma in obesity and diabetes." 12886;"Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator.";"S. Rocchi";"Equipe 12, Team 12";10574507;"Annals of medicine";"Rocchi S, Auwerx J";;"Nov 1999";943574400;;"The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that controls the expression of a large array of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by prostaglandin J2 and fatty acid derivatives, which are its natural ligands. In addition, thiazolidinediones and nonsteroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. Several studies have recently shown that this nuclear receptor has a role expanding beyond metabolism (diabetes and obesity) with functions in cell cycle control, carcinogenesis, inflammation and atherosclerosis. This review addresses the role of PPARgamma in these processes." 12882;"SRC-1 and TIF2 control energy balance between white and brown adipose tissues.";"S. Rocchi";"Equipe 12, Team 12";12507421;Cell;"Picard F, Géhin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P, Auwerx J";;"Jan 2003";1041379200;;"We have explored the effects of two members of the p160 coregulator family on energy homeostasis. TIF2-/- mice are protected against obesity and display enhanced adaptive thermogenesis, whereas SRC-1-/- mice are prone to obesity due to reduced energy expenditure. In white adipose tissue, lack of TIF2 decreases PPARgamma activity and reduces fat accumulation, whereas in brown adipose tissue it facilitates the interaction between SRC-1 and PGC-1alpha, which induces PGC-1alpha's thermogenic activity. Interestingly, a high-fat diet increases the TIF2/SRC-1 expression ratio, which may contribute to weight gain. These results reveal that the relative level of TIF2/SRC-1 can modulate energy metabolism." 12884;"A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.";"S. Rocchi";"Equipe 12, Team 12";11684010;"Molecular cell";"Rocchi S, Picard F, Vamecq J, Gelman L, Potier N, Zeyer D, Dubuquoy L, Bac P, Champy MF, Plunket KD, Leesnitzer LM, Blanchard SG, Desreumaux P, Moras D, Renaud JP, Auwerx J";;"Oct 2001";1004486400;;"FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways." 12880;"Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS).";"C. Bertolotto, JF. PEYRON, K. Bille, M. Ohanna, R. Ballotti, S. Giuliano, S. Rocchi, V. Imbert";"Equipe 01, Team 01, Equipe 04, Equipe 11, Team 11, Equipe 12, Team 12, Team 04";21646373;"Genes & development";"Ohanna M, Giuliano S, Bonet C, Imbert V, Hofman V, Zangari J, Bille K, Robert C, Bressac-de Paillerets B, Hofman P, Rocchi S, Peyron JF, Lacour JP, Ballotti R, Bertolotto C";;"06 2011";1306886400;;"Melanoma cells can enter the process of senescence, but whether they express a secretory phenotype, as reported for other cells, is undetermined. This is of paramount importance, because this secretome can alter the tumor microenvironment and the response to chemotherapeutic drugs. More generally, the molecular events involved in formation of the senescent-associated secretome have yet to be determined. We reveal here that melanoma cells experiencing senescence in response to diverse stimuli, including anti-melanoma drugs, produce an inflammatory secretory profile, where the chemokine ligand-2 (CCL2) acts as a critical effector. Thus, we reveal how senescence induction might be involved in therapeutic failure in melanoma. We further provide a molecular relationship between senescence induction and secretome formation by revealing that the poly(ADP-ribose) polymerase-1 (PARP-1)/nuclear factor-κB (NF-κB) signaling cascade, activated during senescence, drives the formation of a secretome endowed with protumoral and prometastatic properties. Our findings also point to the existence of the PARP-1 and NF-κB-associated secretome, termed the PNAS, in nonmelanoma cells. Most importantly, inhibition of PARP-1 or NF-κB prevents the proinvasive properties of the secretome. Collectively, identification of the PARP-1/NF-κB axis in secretome formation opens new avenues for therapeutic intervention against cancers." 12878;"FALDH reverses the deleterious action of oxidative stress induced by lipid peroxidation product 4-hydroxynonenal on insulin signaling in 3T3-L1 adipocytes.";"S. Rocchi";"Equipe 12, Team 12";18174527;Diabetes;"Demozay D, Mas JC, Rocchi S, Van Obberghen E";;"01 2008";1199145600;;"Oxidative stress is associated with insulin resistance and is thought to contribute to progression toward type 2 diabetes. Oxidation induces cellular damages through increased amounts of reactive aldehydes from lipid peroxidation. The aim of our study was to investigate 1) the effect of the major lipid peroxidation end product, 4-hydroxynonenal (HNE), on insulin signaling in 3T3-L1 adipocytes, and 2) whether fatty aldehyde dehydrogenase (FALDH), which detoxifies HNE, protects cells and improves insulin action under oxidative stress conditions." 12876;"SRC-1 and TIF2 control energy balance between white and brown adipose tissues.";"S. Rocchi";"Equipe 12, Team 12";12507421;Cell;"Picard F, Géhin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P, Auwerx J";;"Jan 2003";1041379200;;"We have explored the effects of two members of the p160 coregulator family on energy homeostasis. TIF2-/- mice are protected against obesity and display enhanced adaptive thermogenesis, whereas SRC-1-/- mice are prone to obesity due to reduced energy expenditure. In white adipose tissue, lack of TIF2 decreases PPARgamma activity and reduces fat accumulation, whereas in brown adipose tissue it facilitates the interaction between SRC-1 and PGC-1alpha, which induces PGC-1alpha's thermogenic activity. Interestingly, a high-fat diet increases the TIF2/SRC-1 expression ratio, which may contribute to weight gain. These results reveal that the relative level of TIF2/SRC-1 can modulate energy metabolism." 12874;"Focal adhesion kinase pp125FAK interacts with the large conductance calcium-activated hSlo potassium channel in human osteoblasts: potential role in mechanotransduction.";"S. Rocchi";"Equipe 12, Team 12";14584897;"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research";"Rezzonico R, Cayatte C, Bourget-Ponzio I, Romey G, Belhacene N, Loubat A, Rocchi S, Van Obberghen E, Girault JA, Rossi B, Schmid-Antomarchi H";;"Oct 2003";1067558400;;"Molecular events of mechanotransduction in osteoblasts are poorly defined. We show that the mechanosensitive BK channels open and recruit the focal adhesion kinase FAK in osteoblasts on hypotonic shock. This could convert mechanical signals in biochemical events, leading to osteoblast activation." 12872;"Fatty aldehyde dehydrogenase: potential role in oxidative stress protection and regulation of its gene expression by insulin.";"S. Rocchi";"Equipe 12, Team 12";14638678;"The Journal of biological chemistry";"Demozay D, Rocchi S, Mas JC, Grillo S, Pirola L, Chavey C, Van Obberghen E";;"11 2003";1067644800;;"Phosphatidylinositol 3-kinase signaling regulates the expression of several genes involved in lipid and glucose homeostasis; deregulation of these genes may contribute to insulin resistance and progression toward type 2 diabetes. By employing RNA arbitrarily primed-PCR to search for novel phosphatidylinositol 3-kinase-regulated genes in response to insulin in isolated rat adipocytes, we identified fatty aldehyde dehydrogenase (FALDH), a key component of the detoxification pathway of aldehydes arising from lipid peroxidation events. Among these latter events are oxidative stresses associated with insulin resistance and diabetes. Upon insulin injection, FALDH mRNA expression increased in rat liver and white adipose tissue and was impaired in two models of insulin-resistant mice, db/db and high fat diet mice. FALDH mRNA levels were 4-fold decreased in streptozotocin-treated rats, suggesting that FALDH deregulation occurs both in hyperinsulinemic insulin-resistant state and hypoinsulinemic type 1 diabetes models. Moreover, insulin treatment increases FALDH activity in hepatocytes, and expression of FALDH was augmented during adipocyte differentiation. Considering the detoxifying role of FALDH, its deregulation in insulin-resistant and type 1 diabetic models may contribute to the lipid-derived oxidative stress. To assess the role of FALDH in the detoxification of oxidized lipid species, we evaluated the production of reactive oxygen species in normal versus FALDH-overexpressing adipocytes. Ectopic expression of FALDH significantly decreased reactive oxygen species production in cells treated by 4-hydroxynonenal, the major lipid peroxidation product, suggesting that FALDH protects against oxidative stress associated with lipid peroxidation. Taken together, our observations illustrate the importance of FALDH in insulin action and its deregulation in states associated with altered insulin signaling." 12870;"Transcription factors and nuclear receptors interact with the SWI/SNF complex through the BAF60c subunit.";"S. Rocchi";"Equipe 12, Team 12";14701856;"The Journal of biological chemistry";"Debril MB, Gelman L, Fayard E, Annicotte JS, Rocchi S, Auwerx J";;"12 2003";1070236800;;"Transcriptional activity relies on coregulators that modify chromatin structure or serve as bridging factors between transcription factors and the basal transcription machinery. We identified a new coregulator of peroxisome proliferator-activated receptor gamma, BRG1/Brm-associated factor of 60 kDa, subunit c2 (BAF60c2), in a yeast two-hybrid screen of a human adipose tissue cDNA library. BAF60c2 represents a new isoform of BAF60c, a component of the SWI/SNF (mating type switching/sucrose non-fermenting) chromatin remodeling complex. This new isoform as well as the previously identified protein, renamed BAF60c1, is localized primarily in the cell nucleus and is expressed in a wide variety of tissues. Both BAF60c isoforms bind to several nuclear receptors and transcription factors of various families. BAF60c proteins interact in a ligand-independent manner with peroxisome proliferator-activated receptor gamma and enhance its transcriptional activity. Both isoforms are enriched in the central nervous system and also modulate the transcriptional activity of retinoic acid-related orphan receptor alpha1. In conclusion, BAF60c represents a new coregulator that constitutes an important anchoring point by which the SWI/SNF complex is recruited to nuclear receptors and other transcription factors." 12868;"A short series of antidiabetic sulfonylureas exhibit multiple ligand PPARgamma-binding patterns.";"S. Rocchi";"Equipe 12, Team 12";18280694;"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie";"Arrault A, Rocchi S, Picard F, Maurois P, Pirotte B, Vamecq J";;"Feb 2008";1203379200;;"The present work explores the PPARgamma-activating properties of a series of eight sulfonylureas, using transfection experiments with 293T cells, and rosiglitazone as a reference PPARgamma agonist. In the same time, results from these in vitro experiments are compared to those generated by a sound in silico PPARgamma-ligand docking procedure combined to a simple and astute strategy analysis. The latter consists of building up a dendrogram (decision tree-like diagram) by applying three successive criteria, namely stability, conformational shape and H-binding strength of the docked sulfonylurea or rosiglitazone. This original dendrogram approach avers to be a successful way to account for our biochemical data. It discriminates also various PPARgamma-binding patterns from our small series of compounds. The recognition of these patterns is extremely important because of the extraordinary potentialities of PPARgamma ligands as therapeutic agents in diabetes, cancer, cardiovascular and neurological disorders." 12866;"The PPARgamma agonist FMOC-L-leucine protects both mature and immature brain.";"S. Rocchi";"Equipe 12, Team 12";18343627;"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie";"Maurois P, Rocchi S, Pages N, Bac P, Stables JP, Gressens P, Vamecq J";;"12 2007";1196467200;;"(N-[9-fluorenylmethoxycarbonyl]-)-L-leucine (FMOC-L-leucine) and rosiglitazone, two ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), were evaluated in mature (adult mice) and immature (pups) brain injury models. In adult magnesium-deficient mice, a model responsive to both neuroprotective and anti-seizure compounds, FMOC-L-leucine, but not rosiglitazone, protected against audiogenic seizures. The protection afforded by FMOC-L-leucine was alleviated by the PPARgamma antagonist GW9662 (1-2 mg/kg) and was induced in 50% animals by 4.8+/-1.2 mg/kg. At this dose, FMOC-L-leucine modified audiogenic seizure phase durations in convulsing mice differently than prototype antiepileptic drugs did. FMOC-L-leucine (up to 100 mg/kg) was inactive in the 6 Hz seizure test, an adult animal model largely responsive to anti-seizure drugs. In a model of neonatal brain injury, FMOC-L-leucine (4 microg/kg) was neuroprotective against cerebral ibotenate toxicity. It reduced significantly the size of lesions in grey but not in white matter, while rosiglitazone (10 microg/kg) was inactive. Taken as a whole, the present data support neuroprotective potentialities of FMOC-L-leucine towards both mature and immature brain. The PPAR-based protection of immature brain is more important as it is known that classic adult brain protectants (GABA(A) activators, N-methyl-D-aspartate and sodium channel blockers) may be toxic for immature brain. The PPARgamma agonist FMOC-L-leucine is likely to be devoid of these classic protective mechanisms because of its inactivity in the 6 Hz seizure test, its activity in the audiogenic test being explained by neuroprotective rather than intrinsic anti-seizure mechanisms. Targeting PPARs might be thus a promising way to protect immature brain." 12864;"PPARs: Interference with Warburg' Effect and Clinical Anticancer Trials.";"S. Rocchi";"Equipe 12, Team 12";22654896;"PPAR research";"Vamecq J, Colet JM, Vanden Eynde JJ, Briand G, Porchet N, Rocchi S";;"05 2012";1335830400;;"The metabolic/cell signaling basis of Warburg's effect (""aerobic glycolysis"") and the general metabolic phenotype adopted by cancer cells are first reviewed. Several bypasses are adopted to provide a panoramic integrated view of tumoral metabolism, by attributing a central signaling role to hypoxia-induced factor (HIF-1) in the expression of aerobic glycolysis. The cancer metabolic phenotype also results from alterations of other routes involving ras, myc, p53, and Akt signaling and the propensity of cancer cells to develop signaling aberrances (notably aberrant surface receptor expression) which, when present, offer unique opportunities for therapeutic interventions. The rationale for various emerging strategies for cancer treatment is presented along with mechanisms by which PPAR ligands might interfere directly with tumoral metabolism and promote anticancer activity. Clinical trials using PPAR ligands are reviewed and followed by concluding remarks and perspectives for future studies. A therapeutic need to associate PPAR ligands with other anticancer agents is perhaps an important lesson to be learned from the results of the clinical trials conducted to date." 12862;"Aurora B is regulated by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway and is a valuable potential target in melanoma cells.";"C. Bertolotto, K. Bille, M. Ohanna, P. Bahadoran, R. Ballotti, S. Giuliano, S. Rocchi";"Equipe 01, Team 01, Equipe 11, Team 11, Equipe 12, Team 12";22767597;"The Journal of biological chemistry";"Bonet C, Giuliano S, Ohanna M, Bille K, Allegra M, Lacour JP, Bahadoran P, Rocchi S, Ballotti R, Bertolotto C";;"07 2012";1341100800;;"Metastatic melanoma is a deadly skin cancer and is resistant to almost all existing treatment. Vemurafenib, which targets the BRAFV600E mutation, is one of the drugs that improves patient outcome, but the patients next develop secondary resistance and a return to cancer. Thus, new therapeutic strategies are needed to treat melanomas and to increase the duration of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor response. The ERK pathway controls cell proliferation, and Aurora B plays a pivotal role in cell division. Here, we confirm that Aurora B is highly expressed in metastatic melanoma cells and that Aurora B inhibition triggers both senescence-like phenotypes and cell death in melanoma cells. Furthermore, we show that the BRAF/ERK axis controls Aurora B expression at the transcriptional level, likely through the transcription factor FOXM1. Our results provide insight into the mechanism of Aurora B regulation and the first molecular basis of Aurora B regulation in melanoma cells. The inhibition of Aurora B expression that we observed in vemurafenib-sensitive melanoma cells was rescued in cells resistant to this drug. Consistently, these latter cells remain sensitive to the effect of the Aurora B inhibitor. Noteworthy, wild-type BRAF melanoma cells are also sensitive to Aurora B inhibition. Collectively, our findings, showing that Aurora B is a potential target in melanoma cells, particularly in those vemurafenib-resistant, may open new avenues to improve the treatment of metastatic melanoma." 12860;"Guidelines for the use and interpretation of assays for monitoring autophagy.";"F. BOST, N. Mazure, P. Auberger, P. GUAL, S. Rocchi";"Equipe 05, Team 05, Equipe 02, Team 02, Equipe 08, Team 08, Equipe 12, Team 12";22966490;Autophagy;"Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, Ahn HJ, Ait-Mohamed O, Ait-Si-Ali S, Akematsu T, Akira S, Al-Younes HM, Al-Zeer MA, Albert ML, Albin RL, Alegre-Abarrategui J, Aleo MF, Alirezaei M, Almasan A, Almonte-Becerril M, Amano A, Amaravadi R, Amarnath S, Amer AO, Andrieu-Abadie N, Anantharam V, Ann DK, Anoopkumar-Dukie S, Aoki H, Apostolova N, Arancia G, Aris JP, Asanuma K, Asare NY, Ashida H, Askanas V, Askew DS, Auberger P, Baba M, Backues SK, Baehrecke EH, Bahr BA, Bai XY, Bailly Y, Baiocchi R, Baldini G, Balduini W, Ballabio A, Bamber BA, Bampton ET, Bánhegyi G, Bartholomew CR, Bassham DC, Bast RC, Batoko H, Bay BH, Beau I, Béchet DM, Begley TJ, Behl C, Behrends C, Bekri S, Bellaire B, Bendall LJ, Benetti L, Berliocchi L, Bernardi H, Bernassola F, Besteiro S, Bhatia-Kissova I, Bi X, Biard-Piechaczyk M, Blum JS, Boise LH, Bonaldo P, Boone DL, Bornhauser BC, Bortoluci KR, Bossis I, Bost F, Bourquin JP, Boya P, Boyer-Guittaut M, Bozhkov PV, Brady NR, Brancolini C, Brech A, Brenman JE, Brennand A, Bresnick EH, Brest P, Bridges D, Bristol ML, Brookes PS, Brown EJ, Brumell JH, Brunetti-Pierri N, Brunk UT, Bulman DE, Bultman SJ, Bultynck G, Burbulla LF, Bursch W, Butchar JP, Buzgariu W, Bydlowski SP, Cadwell K, Cahová M, Cai D, Cai J, Cai Q, Calabretta B, Calvo-Garrido J, Camougrand N, Campanella M, Campos-Salinas J, Candi E, Cao L, Caplan AB, Carding SR, Cardoso SM, Carew JS, Carlin CR, Carmignac V, Carneiro LA, Carra S, Caruso RA, Casari G, Casas C, Castino R, Cebollero E, Cecconi F, Celli J, Chaachouay H, Chae HJ, Chai CY, Chan DC, Chan EY, Chang RC, Che CM, Chen CC, Chen GC, Chen GQ, Chen M, Chen Q, Chen SS, Chen W, Chen X, Chen X, Chen X, Chen YG, Chen Y, Chen Y, Chen YJ, Chen Z, Cheng A, Cheng CH, Cheng Y, Cheong H, Cheong JH, Cherry S, Chess-Williams R, Cheung ZH, Chevet E, Chiang HL, Chiarelli R, Chiba T, Chin LS, Chiou SH, Chisari FV, Cho CH, Cho DH, Choi AM, Choi D, Choi KS, Choi ME, Chouaib S, Choubey D, Choubey V, Chu CT, Chuang TH, Chueh SH, Chun T, Chwae YJ, Chye ML, Ciarcia R, Ciriolo MR, Clague MJ, Clark RS, Clarke PG, Clarke R, Codogno P, Coller HA, Colombo MI, Comincini S, Condello M, Condorelli F, Cookson MR, Coombs GH, Coppens I, Corbalan R, Cossart P, Costelli P, Costes S, Coto-Montes A, Couve E, Coxon FP, Cregg JM, Crespo JL, Cronjé MJ, Cuervo AM, Cullen JJ, Czaja MJ, D'Amelio M, Darfeuille-Michaud A, Davids LM, Davies FE, De Felici M, de Groot JF, de Haan CA, De Martino L, De Milito A, De Tata V, Debnath J, Degterev A, Dehay B, Delbridge LM, Demarchi F, Deng YZ, Dengjel J, Dent P, Denton D, Deretic V, Desai SD, Devenish RJ, Di Gioacchino M, Di Paolo G, Di Pietro C, Díaz-Araya G, Díaz-Laviada I, Diaz-Meco MT, Diaz-Nido J, Dikic I, Dinesh-Kumar SP, Ding WX, Distelhorst CW, Diwan A, Djavaheri-Mergny M, Dokudovskaya S, Dong Z, Dorsey FC, Dosenko V, Dowling JJ, Doxsey S, Dreux M, Drew ME, Duan Q, Duchosal MA, Duff K, Dugail I, Durbeej M, Duszenko M, Edelstein CL, Edinger AL, Egea G, Eichinger L, Eissa NT, Ekmekcioglu S, El-Deiry WS, Elazar Z, Elgendy M, Ellerby LM, Eng KE, Engelbrecht AM, Engelender S, Erenpreisa J, Escalante R, Esclatine A, Eskelinen EL, Espert L, Espina V, Fan H, Fan J, Fan QW, Fan Z, Fang S, Fang Y, Fanto M, Fanzani A, Farkas T, Farré JC, Faure M, Fechheimer M, Feng CG, Feng J, Feng Q, Feng Y, Fésüs L, Feuer R, Figueiredo-Pereira ME, Fimia GM, Fingar DC, Finkbeiner S, Finkel T, Finley KD, Fiorito F, Fisher EA, Fisher PB, Flajolet M, Florez-McClure ML, Florio S, Fon EA, Fornai F, Fortunato F, Fotedar R, Fowler DH, Fox HS, Franco R, Frankel LB, Fransen M, Fuentes JM, Fueyo J, Fujii J, Fujisaki K, Fujita E, Fukuda M, Furukawa RH, Gaestel M, Gailly P, Gajewska M, Galliot B, Galy V, Ganesh S, Ganetzky B, Ganley IG, Gao FB, Gao GF, Gao J, Garcia L, Garcia-Manero G, Garcia-Marcos M, Garmyn M, Gartel AL, Gatti E, Gautel M, Gawriluk TR, Gegg ME, Geng J, Germain M, Gestwicki JE, Gewirtz DA, Ghavami S, Ghosh P, Giammarioli AM, Giatromanolaki AN, Gibson SB, Gilkerson RW, Ginger ML, Ginsberg HN, Golab J, Goligorsky MS, Golstein P, Gomez-Manzano C, Goncu E, Gongora C, Gonzalez CD, Gonzalez R, González-Estévez C, González-Polo RA, Gonzalez-Rey E, Gorbunov NV, Gorski S, Goruppi S, Gottlieb RA, Gozuacik D, Granato GE, Grant GD, Green KN, Gregorc A, Gros F, Grose C, Grunt TW, Gual P, Guan JL, Guan KL, Guichard SM, Gukovskaya AS, Gukovsky I, Gunst J, Gustafsson AB, Halayko AJ, Hale AN, Halonen SK, Hamasaki M, Han F, Han T, Hancock MK, Hansen M, Harada H, Harada M, Hardt SE, Harper JW, Harris AL, Harris J, Harris SD, Hashimoto M, Haspel JA, Hayashi S, Hazelhurst LA, He C, He YW, Hébert MJ, Heidenreich KA, Helfrich MH, Helgason GV, Henske EP, Herman B, Herman PK, Hetz C, Hilfiker S, Hill JA, Hocking LJ, Hofman P, Hofmann TG, Höhfeld J, Holyoake TL, Hong MH, Hood DA, Hotamisligil GS, Houwerzijl EJ, Høyer-Hansen M, Hu B, Hu CA, Hu HM, Hua Y, Huang C, Huang J, Huang S, Huang WP, Huber TB, Huh WK, Hung TH, Hupp TR, Hur GM, Hurley JB, Hussain SN, Hussey PJ, Hwang JJ, Hwang S, Ichihara A, Ilkhanizadeh S, Inoki K, Into T, Iovane V, Iovanna JL, Ip NY, Isaka Y, Ishida H, Isidoro C, Isobe K, Iwasaki A, Izquierdo M, Izumi Y, Jaakkola PM, Jäättelä M, Jackson GR, Jackson WT, Janji B, Jendrach M, Jeon JH, Jeung EB, Jiang H, Jiang H, Jiang JX, Jiang M, Jiang Q, Jiang X, Jiang X, Jiménez A, Jin M, Jin S, Joe CO, Johansen T, Johnson DE, Johnson GV, Jones NL, Joseph B, Joseph SK, Joubert AM, Juhász G, Juillerat-Jeanneret L, Jung CH, Jung YK, Kaarniranta K, Kaasik A, Kabuta T, Kadowaki M, Kagedal K, Kamada Y, Kaminskyy VO, Kampinga HH, Kanamori H, Kang C, Kang KB, Kang KI, Kang R, Kang YA, Kanki T, Kanneganti TD, Kanno H, Kanthasamy AG, Kanthasamy A, Karantza V, Kaushal GP, Kaushik S, Kawazoe Y, Ke PY, Kehrl JH, Kelekar A, Kerkhoff C, Kessel DH, Khalil H, Kiel JA, Kiger AA, Kihara A, Kim DR, Kim DH, Kim DH, Kim EK, Kim HR, Kim JS, Kim JH, Kim JC, Kim JK, Kim PK, Kim SW, Kim YS, Kim Y, Kimchi A, Kimmelman AC, King JS, Kinsella TJ, Kirkin V, Kirshenbaum LA, Kitamoto K, Kitazato K, Klein L, Klimecki WT, Klucken J, Knecht E, Ko BC, Koch JC, Koga H, Koh JY, Koh YH, Koike M, Komatsu M, Kominami E, Kong HJ, Kong WJ, Korolchuk VI, Kotake Y, Koukourakis MI, Kouri Flores JB, Kovács AL, Kraft C, Krainc D, Krämer H, Kretz-Remy C, Krichevsky AM, Kroemer G, Krüger R, Krut O, Ktistakis NT, Kuan CY, Kucharczyk R, Kumar A, Kumar R, Kumar S, Kundu M, Kung HJ, Kurz T, Kwon HJ, La Spada AR, Lafont F, Lamark T, Landry J, Lane JD, Lapaquette P, Laporte JF, László L, Lavandero S, Lavoie JN, Layfield R, Lazo PA, Le W, Le Cam L, Ledbetter DJ, Lee AJ, Lee BW, Lee GM, Lee J, Lee JH, Lee M, Lee MS, Lee SH, Leeuwenburgh C, Legembre P, Legouis R, Lehmann M, Lei HY, Lei QY, Leib DA, Leiro J, Lemasters JJ, Lemoine A, Lesniak MS, Lev D, Levenson VV, Levine B, Levy E, Li F, Li JL, Li L, Li S, Li W, Li XJ, Li YB, Li YP, Liang C, Liang Q, Liao YF, Liberski PP, Lieberman A, Lim HJ, Lim KL, Lim K, Lin CF, Lin FC, Lin J, Lin JD, Lin K, Lin WW, Lin WC, Lin YL, Linden R, Lingor P, Lippincott-Schwartz J, Lisanti MP, Liton PB, Liu B, Liu CF, Liu K, Liu L, Liu QA, Liu W, Liu YC, Liu Y, Lockshin RA, Lok CN, Lonial S, Loos B, Lopez-Berestein G, López-Otín C, Lossi L, Lotze MT, Lőw P, Lu B, Lu B, Lu B, Lu Z, Luciano F, Lukacs NW, Lund AH, Lynch-Day MA, Ma Y, Macian F, MacKeigan JP, Macleod KF, Madeo F, Maiuri L, Maiuri MC, Malagoli D, Malicdan MC, Malorni W, Man N, Mandelkow EM, Manon S, Manov I, Mao K, Mao X, Mao Z, Marambaud P, Marazziti D, Marcel YL, Marchbank K, Marchetti P, Marciniak SJ, Marcondes M, Mardi M, Marfe G, Mariño G, Markaki M, Marten MR, Martin SJ, Martinand-Mari C, Martinet W, Martinez-Vicente M, Masini M, Matarrese P, Matsuo S, Matteoni R, Mayer A, Mazure NM, McConkey DJ, McConnell MJ, McDermott C, McDonald C, McInerney GM, McKenna SL, McLaughlin B, McLean PJ, McMaster CR, McQuibban GA, Meijer AJ, Meisler MH, Meléndez A, Melia TJ, Melino G, Mena MA, Menendez JA, Menna-Barreto RF, Menon MB, Menzies FM, Mercer CA, Merighi A, Merry DE, Meschini S, Meyer CG, Meyer TF, Miao CY, Miao JY, Michels PA, Michiels C, Mijaljica D, Milojkovic A, Minucci S, Miracco C, Miranti CK, Mitroulis I, Miyazawa K, Mizushima N, Mograbi B, Mohseni S, Molero X, Mollereau B, Mollinedo F, Momoi T, Monastyrska I, Monick MM, Monteiro MJ, Moore MN, Mora R, Moreau K, Moreira PI, Moriyasu Y, Moscat J, Mostowy S, Mottram JC, Motyl T, Moussa CE, Müller S, Muller S, Münger K, Münz C, Murphy LO, Murphy ME, Musarò A, Mysorekar I, Nagata E, Nagata K, Nahimana A, Nair U, Nakagawa T, Nakahira K, Nakano H, Nakatogawa H, Nanjundan M, Naqvi NI, Narendra DP, Narita M, Navarro M, Nawrocki ST, Nazarko TY, Nemchenko A, Netea MG, Neufeld TP, Ney PA, Nezis IP, Nguyen HP, Nie D, Nishino I, Nislow C, Nixon RA, Noda T, Noegel AA, Nogalska A, Noguchi S, Notterpek L, Novak I, Nozaki T, Nukina N, Nürnberger T, Nyfeler B, Obara K, Oberley TD, Oddo S, Ogawa M, Ohashi T, Okamoto K, Oleinick NL, Oliver FJ, Olsen LJ, Olsson S, Opota O, Osborne TF, Ostrander GK, Otsu K, Ou JH, Ouimet M, Overholtzer M, Ozpolat B, Paganetti P, Pagnini U, Pallet N, Palmer GE, Palumbo C, Pan T, Panaretakis T, Pandey UB, Papackova Z, Papassideri I, Paris I, Park J, Park OK, Parys JB, Parzych KR, Patschan S, Patterson C, Pattingre S, Pawelek JM, Peng J, Perlmutter DH, Perrotta I, Perry G, Pervaiz S, Peter M, Peters GJ, Petersen M, Petrovski G, Phang JM, Piacentini M, Pierre P, Pierrefite-Carle V, Pierron G, Pinkas-Kramarski R, Piras A, Piri N, Platanias LC, Pöggeler S, Poirot M, Poletti A, Poüs C, Pozuelo-Rubio M, Prætorius-Ibba M, Prasad A, Prescott M, Priault M, Produit-Zengaffinen N, Progulske-Fox A, Proikas-Cezanne T, Przedborski S, Przyklenk K, Puertollano R, Puyal J, Qian SB, Qin L, Qin ZH, Quaggin SE, Raben N, Rabinowich H, Rabkin SW, Rahman I, Rami A, Ramm G, Randall G, Randow F, Rao VA, Rathmell JC, Ravikumar B, Ray SK, Reed BH, Reed JC, Reggiori F, Régnier-Vigouroux A, Reichert AS, Reiners JJ, Reiter RJ, Ren J, Revuelta JL, Rhodes CJ, Ritis K, Rizzo E, Robbins J, Roberge M, Roca H, Roccheri MC, Rocchi S, Rodemann HP, Rodríguez de Córdoba S, Rohrer B, Roninson IB, Rosen K, Rost-Roszkowska MM, Rouis M, Rouschop KM, Rovetta F, Rubin BP, Rubinsztein DC, Ruckdeschel K, Rucker EB, Rudich A, Rudolf E, Ruiz-Opazo N, Russo R, Rusten TE, Ryan KM, Ryter SW, Sabatini DM, Sadoshima J, Saha T, Saitoh T, Sakagami H, Sakai Y, Salekdeh GH, Salomoni P, Salvaterra PM, Salvesen G, Salvioli R, Sanchez AM, Sánchez-Alcázar JA, Sánchez-Prieto R, Sandri M, Sankar U, Sansanwal P, Santambrogio L, Saran S, Sarkar S, Sarwal M, Sasakawa C, Sasnauskiene A, Sass M, Sato K, Sato M, Schapira AH, Scharl M, Schätzl HM, Scheper W, Schiaffino S, Schneider C, Schneider ME, Schneider-Stock R, Schoenlein PV, Schorderet DF, Schüller C, Schwartz GK, Scorrano L, Sealy L, Seglen PO, Segura-Aguilar J, Seiliez I, Seleverstov O, Sell C, Seo JB, Separovic D, Setaluri V, Setoguchi T, Settembre C, Shacka JJ, Shanmugam M, Shapiro IM, Shaulian E, Shaw RJ, Shelhamer JH, Shen HM, Shen WC, Sheng ZH, Shi Y, Shibuya K, Shidoji Y, Shieh JJ, Shih CM, Shimada Y, Shimizu S, Shintani T, Shirihai OS, Shore GC, Sibirny AA, Sidhu SB, Sikorska B, Silva-Zacarin EC, Simmons A, Simon AK, Simon HU, Simone C, Simonsen A, Sinclair DA, Singh R, Sinha D, Sinicrope FA, Sirko A, Siu PM, Sivridis E, Skop V, Skulachev VP, Slack RS, Smaili SS, Smith DR, Soengas MS, Soldati T, Song X, Sood AK, Soong TW, Sotgia F, Spector SA, Spies CD, Springer W, Srinivasula SM, Stefanis L, Steffan JS, Stendel R, Stenmark H, Stephanou A, Stern ST, Sternberg C, Stork B, Strålfors P, Subauste CS, Sui X, Sulzer D, Sun J, Sun SY, Sun ZJ, Sung JJ, Suzuki K, Suzuki T, Swanson MS, Swanton C, Sweeney ST, Sy LK, Szabadkai G, Tabas I, Taegtmeyer H, Tafani M, Takács-Vellai K, Takano Y, Takegawa K, Takemura G, Takeshita F, Talbot NJ, Tan KS, Tanaka K, Tanaka K, Tang D, Tang D, Tanida I, Tannous BA, Tavernarakis N, Taylor GS, Taylor GA, Taylor JP, Terada LS, Terman A, Tettamanti G, Thevissen K, Thompson CB, Thorburn A, Thumm M, Tian F, Tian Y, Tocchini-Valentini G, Tolkovsky AM, Tomino Y, Tönges L, Tooze SA, Tournier C, Tower J, Towns R, Trajkovic V, Travassos LH, Tsai TF, Tschan MP, Tsubata T, Tsung A, Turk B, Turner LS, Tyagi SC, Uchiyama Y, Ueno T, Umekawa M, Umemiya-Shirafuji R, Unni VK, Vaccaro MI, Valente EM, Van den Berghe G, van der Klei IJ, van Doorn W, van Dyk LF, van Egmond M, van Grunsven LA, Vandenabeele P, Vandenberghe WP, Vanhorebeek I, Vaquero EC, Velasco G, Vellai T, Vicencio JM, Vierstra RD, Vila M, Vindis C, Viola G, Viscomi MT, Voitsekhovskaja OV, von Haefen C, Votruba M, Wada K, Wade-Martins R, Walker CL, Walsh CM, Walter J, Wan XB, Wang A, Wang C, Wang D, Wang F, Wang F, Wang G, Wang H, Wang HG, Wang HD, Wang J, Wang K, Wang M, Wang RC, Wang X, Wang X, Wang YJ, Wang Y, Wang Z, Wang ZC, Wang Z, Wansink DG, Ward DM, Watada H, Waters SL, Webster P, Wei L, Weihl CC, Weiss WA, Welford SM, Wen LP, Whitehouse CA, Whitton JL, Whitworth AJ, Wileman T, Wiley JW, Wilkinson S, Willbold D, Williams RL, Williamson PR, Wouters BG, Wu C, Wu DC, Wu WK, Wyttenbach A, Xavier RJ, Xi Z, Xia P, Xiao G, Xie Z, Xie Z, Xu DZ, Xu J, Xu L, Xu X, Yamamoto A, Yamamoto A, Yamashina S, Yamashita M, Yan X, Yanagida M, Yang DS, Yang E, Yang JM, Yang SY, Yang W, Yang WY, Yang Z, Yao MC, Yao TP, Yeganeh B, Yen WL, Yin JJ, Yin XM, Yoo OJ, Yoon G, Yoon SY, Yorimitsu T, Yoshikawa Y, Yoshimori T, Yoshimoto K, You HJ, Youle RJ, Younes A, Yu L, Yu L, Yu SW, Yu WH, Yuan ZM, Yue Z, Yun CH, Yuzaki M, Zabirnyk O, Silva-Zacarin E, Zacks D, Zacksenhaus E, Zaffaroni N, Zakeri Z, Zeh HJ, Zeitlin SO, Zhang H, Zhang HL, Zhang J, Zhang JP, Zhang L, Zhang L, Zhang MY, Zhang XD, Zhao M, Zhao YF, Zhao Y, Zhao ZJ, Zheng X, Zhivotovsky B, Zhong Q, Zhou CZ, Zhu C, Zhu WG, Zhu XF, Zhu X, Zhu Y, Zoladek T, Zong WX, Zorzano A, Zschocke J, Zuckerbraun B";;"Sep 2012";1347408000;;"In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field." 12858;"Mitochondrial oxidative stress is the Achille's heel of melanoma cells resistant to Braf-mutant inhibitor.";"S. Rocchi";"Equipe 12, Team 12";24161908;Oncotarget;"Corazao-Rozas P, Guerreschi P, Jendoubi M, André F, Jonneaux A, Scalbert C, Garçon G, Malet-Martino M, Balayssac S, Rocchi S, Savina A, Formstecher P, Mortier L, Kluza J, Marchetti P";;"Oct 2013";1383004800;;"Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition." 12856;"Is it time to test biguanide metformin in the treatment of melanoma?";"M. Cerezo, R. Ballotti, S. Rocchi";"Equipe 12, Team 12, Equipe 01, Team 01";24862830;"Pigment cell & melanoma research";"Cerezo M, Tomic T, Ballotti R, Rocchi S";;"06 2014";1401580800;;"Metformin is the most widely used antidiabetic drug that belongs to the biguanide class. It is very well tolerated and has the major clinical advantage of not inducing hypoglycemia. Metformin decreases hepatic glucose production via a mechanism requiring liver kinase B1, which controls the metabolic checkpoint, AMP-activated protein kinase-mammalian target of rapamycin and neoglucogenic genes. The effects of metformin on this pathway results in reduced protein synthesis and cell proliferation. These observations have given the impetus for many investigations on the role of metformin in the regulation of tumor cell proliferation, cell-cycle regulation, apoptosis, and autophagy. Encouraging results from these studies have shown that metformin could potentially be used as an efficient anticancer drug in various neoplasms such as prostate, breast, lung, pancreas cancers, and melanoma. These findings are strengthened by retrospective epidemiological studies that have found a decrease in cancer risk in diabetic patients treated with metformin. In this review, we have focused our discussion on recent molecular mechanisms of metformin that have been described in various solid tumors in general and in melanoma in particular. " 12854;"Regulation of NADPH-dependent Nitric Oxide and reactive oxygen species signalling in endothelial and melanoma cells by a photoactive NADPH analogue.";"S. Rocchi";"Equipe 12, Team 12";25296975;Oncotarget;"Rouaud F, Romero-Perez M, Wang H, Lobysheva I, Ramassamy B, Henry E, Tauc P, Giacchero D, Boucher JL, Deprez E, Rocchi S, Slama-Schwok A";;"Oct 2014";1412899200;;"Nitric Oxide (NO) and Reactive oxygen species (ROS) are endogenous regulators of angiogenesis-related events as endothelial cell proliferation and survival, but NO/ROS defect or unbalance contribute to cancers. We recently designed a novel photoactive inhibitor of NO-Synthases (NOS) called NS1, which binds their NADPH site in vitro. Here, we show that NS1 inhibited NO formed in aortic rings. NS1-induced NO decrease led to an inhibition of angiogenesis in a model of VEGF-induced endothelial tubes formation. Beside this effect, NS1 reduced ROS levels in endothelial and melanoma A375 cells and in aorta. In metastatic melanoma cells, NS1 first induced a strong decrease of VEGF and blocked melanoma cell cycle at G2/M. NS1 decreased NOX(4) and ROS levels that could lead to a specific proliferation arrest and cell death. In contrast, NS1 did not perturb melanocytes growth. Altogether, NS1 revealed a possible cross-talk between eNOS- and NOX(4) -associated pathways in melanoma cells via VEGF, Erk and Akt modulation by NS1 that could be targeted to stop proliferation. NS1 thus constitutes a promising tool that modulates NO and redox stresses by targeting and directly inhibiting eNOS and, at least indirectly, NADPH oxidase(s), with great potential to control angiogenesis." 12852;"Increased CD271 expression by the NF-kB pathway promotes melanoma cell survival and drives acquired resistance to BRAF inhibitor vemurafenib.";"C. Bertolotto, M. Cerezo, P. Abbe, R. Ballotti, S. Rocchi, V. Imbert, Y. Cheli";"Equipe 01, Team 01, Equipe 12, Team 12, Equipe 04, Team 04";27462428;"Cell discovery";"Lehraiki A, Cerezo M, Rouaud F, Abbe P, Allegra M, Kluza J, Marchetti P, Imbert V, Cheli Y, Bertolotto C, Ballotti R, Rocchi S";;"10 2015";1443657600;;"Specific BRAFV600E inhibitors (BRAFi) are highly effective in the treatment of melanoma. However, acquired drug resistances invariably develop after the initial response. Therefore, the identification of new mechanisms of acquired resistance gives important clues towards the development of therapies that could elicit long lasting responses. Here we report that CD271 confers resistance to BRAFi in melanoma cells. The expression of CD271 is increased by BRAFi through a stimulation of tumor necrosis factor-alpha (TNFα) secretion that leads to NF-κB signaling pathway activation. CD271 is upregulated in a subset of BRAFi-resistant melanoma cells. The inhibition of TNFα/NF-κB pathway and CD271 silencing restore the BRAFi sensitivity of resistant melanoma cells. Finally, increase of CD271 expression is validated in BRAFi-resistant xenografts tumors and also in tumors from the patients who relapsed under BRAFi. In summary, these results reveal a novel TNFα/NF-κB/CD271 axis whose activation contributes to the acquisition of resistance to BRAFi and therefore may represent a novel therapeutic target to improve the efficacy of therapy in melanoma. " 12850;"The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML.";"A. Jacquel, G. MICHEL, G. Robert, L. Boyer, M. Cerezo, P. Auberger, S. Marchetti, S. Rocchi, T. Cluzeau";"Equipe 02, Team 02, Equipe 06, Team 06, Equipe 12, Team 12, Team 03, Equipe 03";26029847;Autophagy;"Obba S, Hizir Z, Boyer L, Selimoglu-Buet D, Pfeifer A, Michel G, Hamouda MA, Gonçalvès D, Cerezo M, Marchetti S, Rocchi S, Droin N, Cluzeau T, Robert G, Luciano F, Robaye B, Foretz M, Viollet B, Legros L, Solary E, Auberger P, Jacquel A";;"Jun 2015";1433203200;;"Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1-ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2RY6 to the induction of autophagy, and we decipher the signaling network that links the CSF1 receptor to P2RY6-mediated autophagy and monocyte differentiation. In addition, we show that the physiological P2RY6 ligand UDP and the specific P2RY6 agonist MRS2693 can restore normal monocyte differentiation through reinduction of autophagy in primary myeloid cells from some but not all chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for PRKAA1-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML. " 12847;"Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges.";"S. Rocchi";"Equipe 12, Team 12";27569556;"Medicinal research reviews";"Millet A, Martin AR, Ronco C, Rocchi S, Benhida R";;"08 2016";1470009600;;"Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma. Second, there are the immunotherapies, with anti-CTLA-4 and anti-PD-1 antibodies that are used for patients harboring a B-Raf wild-type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events." 12846;"Discovery and Optimization of N-(4-(3-Aminophenyl)thiazol-2-yl)acetamide as a Novel Scaffold Active against Sensitive and Resistant Cancer Cells.";"M. Cerezo, P. Abbe, S. Rocchi";"Equipe 12, Team 12";27575313;"Journal of medicinal chemistry";"Millet A, Plaisant M, Ronco C, Cerezo M, Abbe P, Jaune E, Cavazza E, Rocchi S, Benhida R";;"09 2016";1472688000;;"Cancer is the second cause of deaths worldwide and is forecasted to affect more that 22 million people in 2020. Despite dramatic improvement in its care over the last two decades, the treatment of resistant forms of cancer is still an unmet challenge. Thus, innovative and efficient treatments are still needed. In this context, we report herein the synthesis and the evaluation of a new class of bioactive molecules belonging to the N-(4-(3-aminophenyl(thiazol-2-yl)acetamide family. Structure-activity relationships could be driven and resulted in the discovery of lead compound 6b. The latter display high in vitro potency against both sensitive and resistant cancer cell lines on three models: melanoma, pancreatic cancer, and chronic myeloid leukemia (CML). 6b leads to cell death by concomitant induction of apoptosis and autophagy, shows good pharmacokinetic properties, and demonstrates a significant reduction of tumor growth in vivo on A375 xenograft model in mice." 12844;"Mechanism of melanoma cells selective apoptosis induced by a photoactive NADPH analogue.";"S. Rocchi";"Equipe 12, Team 12";27756874;Oncotarget;"Rouaud F, Boucher JL, Slama-Schwok A, Rocchi S";;"Oct 2016";1477008000;;"Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment.NS1 established an early Endoplasmic Reticulum stress by the early release of calcium mediated by (a) calcium-dependent redox-sensitive ion channel(s). These events initiated autophagy and apoptosis in all tested melanoma cells independently of their mutational status. The autophagy promoted by NS1 was incomplete. The autophagic flux was blocked at late stage events, consistent with the accumulation of p62, and a close localization of LC3 with NS1 associated with NS1 inhibition of NOX1 in autophagosomes. This hypothesis of a specific incomplete autophagy and apoptosis driven by NS1 was comforted by the use of siRNAs and pharmacological inhibitors blocking different processes. This study highlights the potential therapeutic interest of NS1 inducing cell death by triggering a selective ER stress and incomplete autophagy in melanoma cells harbouring wt and BRAF mutation." 12842;"New anti-cancer molecules targeting HSPA5/BIP to induce endoplasmic reticulum stress, autophagy and apoptosis.";"M. Cerezo, S. Rocchi";"Equipe 12, Team 12";27791469;Autophagy;"Cerezo M, Rocchi S";;"10 2016";1475280000;;"Treatment of melanoma has significantly advanced over the last decade, with the development of targeted therapies against the MAPK pathway and immunotherapies to reactivate antitumor immunity. Unfortunately, currently more than 50% of patients are in treatment failure. Thus, identification of new common cellular vulnerability among melanoma cells is an urgent need and will help in the discovery of more efficient treatments against melanoma. We have focused our study on protein processing and have identified a new compound, HA15, targeting HSPA5/BiP, the master regulator of the unfolded protein response (UPR). By inhibiting HSPA5 specifically, our molecule increases the UPR and leads to the death of cancer cells by concomitant induction of autophagy and apoptosis, an effect seen both in vitro and in vivo. Our study provides compelling evidence to support the idea that endoplasmic reticulum (ER) stress inducers could be useful as a new therapeutic approach in melanoma treatment." 12840;"Targeting BIP to induce Endoplasmic Reticulum stress and cancer cell death.";"M. Cerezo, S. Rocchi";"Equipe 12, Team 12";28105450;Oncoscience;"Cerezo M, Benhida R, Rocchi S";;"12 2016";1480550400;; 12838;"Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and resistant cells.";"N. Tekaya, P. Abbe, S. Rocchi";"Team 12, Equipe 12";28372910;"Bioorganic & medicinal chemistry letters";"Ronco C, Millet A, Plaisant M, Abbe P, Hamouda-Tekaya N, Rocchi S, Benhida R";;"03 2017";1488326400;;"We recently described a new family of bioactive molecules with interesting anti-cancer activities: the N-(4-(3-aminophenyl)thiazol-2-yl)acetamides. The lead compound of the series (1) displays significant anti-proliferative and cytotoxic activities against a panel of cancer cell lines, either sensitive or resistant to standard treatments. This molecule also shows a good pharmacological profile and high in vivo potency towards mice xenografts, without signs of toxicity on the animals. In the present article, we disclose the structure-activity relationships of this lead compound, which have provided clear information about the replacement of the acetamide function and the substitution pattern of the benzenesulfonamide ring. An improved high-yielding synthetic procedure towards these compounds has also been developed. Our drug design resulted in potency enhancement of 1, our new optimized lead compound being 19. These findings are of great interest to further improve this scaffold for the development of future clinical candidates." 12836;"Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression.";"C. Bertolotto, K. Bille, M. Ohanna, R. Ballotti, S. Marchetti, S. Rocchi, T. Strub, Y. Cheli";"Equipe 01, Team 01, Equipe 11, Team 11, Team 03, Equipe 03, Equipe 12, Team 12";28376192;"Journal of the National Cancer Institute";"Bonet C, Luciani F, Ottavi JF, Leclerc J, Jouenne FM, Boncompagni M, Bille K, Hofman V, Bossis G, Marco de Donatis G, Strub T, Cheli Y, Ohanna M, Luciano F, Marchetti S, Rocchi S, Birling MC, Avril MF, Poulalhon N, Luc T, Hofman P, Lacour JP, Davidson I, Bressac-de Paillerets B, Ballotti R, Marine JC, Bertolotto C";;"Apr 2017";1491350400;;"MITF encodes an oncogenic lineage-specific transcription factor in which a germline mutation ( MITFE318K ) was identified in human patients predisposed to both nevus formation and, among other tumor types, melanoma. The molecular mechanisms underlying the oncogenic activity of MITF E318K remained uncharacterized." 12834;"The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells.";"F. BOST, JF. Tanti, J. GILLERON, M. Cormont, N. Mazure, S. Rocchi";"Equipe 05, Team 05, Equipe 07, Team 07, Equipe 12, Team 12";28698627;"Scientific reports";"Loubiere C, Clavel S, Gilleron J, Harisseh R, Fauconnier J, Ben-Sahra I, Kaminski L, Laurent K, Herkenne S, Lacas-Gervais S, Ambrosetti D, Alcor D, Rocchi S, Cormont M, Michiels JF, Mari B, Mazure NM, Scorrano L, Lacampagne A, Gharib A, Tanti JF, Bost F";;"07 2017";1498867200;;"Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake of calcium into the mitochondria, thus leading to mitochondrial swelling. Metformin triggers the disorganization of the cristae and inner mitochondrial membrane in several cancer cells and tumors. Mechanistically, these alterations were found to be due to calcium entry into the mitochondria, because the swelling induced by metformin was reversed by the inhibition of mitochondrial calcium uniporter (MCU). We also demonstrated that metformin inhibits the opening of mPTP and induces mitochondrial biogenesis. Altogether, the inhibition of mPTP and the increase in mitochondrial biogenesis may account for the poor pro-apoptotic effect of metformin in cancer cells." 12832;"The GRP78/BiP inhibitor HA15 synergizes with mitotane action against adrenocortical carcinoma cells through convergent activation of ER stress pathways.";"S. Rocchi";"Equipe 12, Team 12";29474877;"Molecular and cellular endocrinology";"Ruggiero C, Doghman-Bouguerra M, Ronco C, Benhida R, Rocchi S, Lalli E";;"02 2018";1517443200;;"Many types of cancer cells present constitutively activated ER stress pathways because of their significant burden of misfolded proteins coded by mutated and rearranged genes. Further increase of ER stress by pharmacological intervention may shift the balance towards cell death and can be exploited therapeutically. Recent studies have shown that an important component in the mechanism of action of mitotane, the only approved drug for the medical treatment of adrenocortical carcinoma (ACC), is represented by activation of ER stress through inhibition of the SOAT1 enzyme and accumulation of toxic lipids. Here we show that HA15, a novel inhibitor of the essential ER chaperone GRP78/BiP, inhibits ACC H295R cell proliferation and steroidogenesis and is able to synergize with mitotane action. These results suggest that convergent activation of ER stress pathways by drugs acting via different mechanisms represents a valuable therapeutic option for ACC." 12830;"Metformin: Focus on Melanoma.";"S. Rocchi";"Equipe 12, Team 12";30186236;"Frontiers in endocrinology";"Jaune E, Rocchi S";;"08 2018";1533081600;;"Metformin is the most common biguanide used in the treatment of diabetes, with 120 million treated patients worldwide. Metformin decreases hyperglycemia without inducing hypoglycemia in diabetic patients and is very well tolerated. The principal effects of metformin are to decrease hepatic gluconeogenesis and increase glucose absorption by skeletal muscles. These effects are primarily due to metformin's action on mitochondria, which requires the activation of metabolic checkpoint AMP-activated protein kinase (AMPK). AMPK is implicated in several pathways, and following metformin activation, it decreases protein synthesis and cell proliferation. Many studies have examined the role of metformin in the regulation of cancer cells, particularly its effects on cancer cell proliferation and cell death. Encouraging results have been obtained in different types of cancers, including prostate, breast, lung, and skin cancers (melanoma). Furthermore, many retrospective epidemiological studies in diabetes patients have shown that metformin treatment decreased the risk of cancers compared with other antidiabetic treatments. In this review, we will discuss the effects of metformin on melanoma cells. Together, our novel data demonstrate the importance of developing metformin and new biguanide-derived compounds as potential treatments against a number of different cancers, particularly melanoma." 12828;"PGC1α Inhibits Polyamine Synthesis to Suppress Prostate Cancer Aggressiveness.";"F. BOST, JF. Tanti, N. Mazure, S. Rocchi";"Equipe 05, Team 05, Equipe 07, Team 07, Equipe 12, Team 12";31064849;"Cancer research";"Kaminski L, Torrino S, Dufies M, Djabari Z, Haider R, Roustan FR, Jaune E, Laurent K, Nottet N, Michiels JF, Gesson M, Rocchi S, Mazure NM, Durand M, Tanti JF, Ambrosetti D, Clavel S, Ben-Sahra I, Bost F";;"May 2019";1557360000;;"Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer. Here, we show that PGC1α represses the metastatic properties of prostate cancer cells via modulation of the polyamine biosynthesis pathway. Mechanistically, PGC1α inhibits the expression of c-MYC and ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme for polyamine synthesis. Analysis of metastases and clinical data from patients with prostate cancer support the proposition that the PGC1α/c-MYC/ODC1 axis regulates polyamine biosynthesis and prostate cancer aggressiveness. In conclusion, downregulation of PGC1α renders prostate cancer cells dependent on polyamine to promote metastasis. SIGNIFICANCE: These findings show that a major regulator of mitochondrial metabolism controls polyamine synthesis and prostate cancer aggressiveness, with potential applications in therapy and identification of new biomarkers." 12824;"Sulfonylguanidine Derivatives as Potential Antimelanoma Agents.";"N. Tekaya, S. Rocchi";"Team 12, Equipe 12";32347004;ChemMedChem;"Baladi T, Hamouda-Tekaya N, Gonçalves LCP, Rocchi S, Ronco C, Benhida R";;"05 2020";1588291200;;"Sulfonylguanidines are interesting bioactive compounds with a broad range of applications in the treatment of different pathologies. 2-Aminobenzazole-based structures are well employed in the development of new anticancer drugs. Two series of novel N-benzazol-2-yl-N'-sulfonyl guanidine derivatives were synthesized with the sulfonylguanidine in either an extra- or intracyclic frame. They were evaluated for their antiproliferative activity against malignant melanoma tumor cells, thus allowing structure-activity relationships to be defined. Additionally, NCI-60 screening was performed for the best analogue to study its efficiency against a panel of other cancer cell lines. The stability profile of this promising compound was then validated. During the synthetic process, an unexpected new deamidination of the sulfonylguanidine towards sulfonamide function was also identified." 12825;"Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses.";"R. Ballotti, S. Rocchi, T. Botton";"Equipe 01, Team 01, Equipe 12, Team 12";31618628;"Cell reports";"Botton T, Talevich E, Mishra VK, Zhang T, Shain AH, Berquet C, Gagnon A, Judson RL, Ballotti R, Ribas A, Herlyn M, Rocchi S, Brown KM, Hayward NK, Yeh I, Bastian BC";;"Oct 2019";1571270400;;"BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions." 12822;"Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy.";"M. Cerezo, S. Rocchi";"Equipe 12, Team 12";33177494;"Cell death & disease";"Cerezo M, Rocchi S";;"11 2020";1604188800;;"By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response." 12820;"Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).";"JE. Ricci, P. Auberger, S. Marchetti, S. Giuliano, S. Rocchi, C. Lefebvre";"Equipe 03, Team 03, Equipe 02, Team 02, Equipe 01, Team 01, Equipe 12, Team 12";33634751;Autophagy;"Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar PV, Ahmad ST, Ahmed ZM, Ahumada-Castro U, Aits S, Aizawa S, Akkoc Y, Akoumianaki T, Akpinar HA, Al-Abd AM, Al-Akra L, Al-Gharaibeh A, Alaoui-Jamali MA, Alberti S, Alcocer-Gómez E, Alessandri C, Ali M, Alim Al-Bari MA, Aliwaini S, Alizadeh J, Almacellas E, Almasan A, Alonso A, Alonso GD, Altan-Bonnet N, Altieri DC, Álvarez ÉMC, Alves S, Alves da Costa C, Alzaharna MM, Amadio M, Amantini C, Amaral C, Ambrosio S, Amer AO, Ammanathan V, An Z, Andersen SU, Andrabi SA, Andrade-Silva M, Andres AM, Angelini S, Ann D, Anozie UC, Ansari MY, Antas P, Antebi A, Antón Z, Anwar T, Apetoh L, Apostolova N, Araki T, Araki Y, Arasaki K, Araújo WL, Araya J, Arden C, Arévalo MA, Arguelles S, Arias E, Arikkath J, Arimoto H, Ariosa AR, Armstrong-James D, Arnauné-Pelloquin L, Aroca A, Arroyo DS, Arsov I, Artero R, Asaro DML, Aschner M, Ashrafizadeh M, Ashur-Fabian O, Atanasov AG, Au AK, Auberger P, Auner HW, Aurelian L, Autelli R, Avagliano L, Ávalos Y, Aveic S, Aveleira CA, Avin-Wittenberg T, Aydin Y, Ayton S, Ayyadevara S, Azzopardi M, Baba M, Backer JM, Backues SK, Bae DH, Bae ON, Bae SH, Baehrecke EH, Baek A, Baek SH, Baek SH, Bagetta G, Bagniewska-Zadworna A, Bai H, Bai J, Bai X, Bai Y, Bairagi N, Baksi S, Balbi T, Baldari CT, Balduini W, Ballabio A, Ballester M, Balazadeh S, Balzan R, Bandopadhyay R, Banerjee S, Banerjee S, Bánréti Á, Bao Y, Baptista MS, Baracca A, Barbati C, Bargiela A, Barilà D, Barlow PG, Barmada SJ, Barreiro E, Barreto GE, Bartek J, Bartel B, Bartolome A, Barve GR, Basagoudanavar SH, Bassham DC, Bast RC, Basu A, Batoko H, Batten I, Baulieu EE, Baumgarner BL, Bayry J, Beale R, Beau I, Beaumatin F, Bechara LRG, Beck GR, Beers MF, Begun J, Behrends C, Behrens GMN, Bei R, Bejarano E, Bel S, Behl C, Belaid A, Belgareh-Touzé N, Bellarosa C, Belleudi F, Belló Pérez M, Bello-Morales R, Beltran JSO, Beltran S, Benbrook DM, Bendorius M, Benitez BA, Benito-Cuesta I, Bensalem J, Berchtold MW, Berezowska S, Bergamaschi D, Bergami M, Bergmann A, Berliocchi L, Berlioz-Torrent C, Bernard A, Berthoux L, Besirli CG, Besteiro S, Betin VM, Beyaert R, Bezbradica JS, Bhaskar K, Bhatia-Kissova I, Bhattacharya R, Bhattacharya S, Bhattacharyya S, Bhuiyan MS, Bhutia SK, Bi L, Bi X, Biden TJ, Bijian K, Billes VA, Binart N, Bincoletto C, Birgisdottir AB, Bjorkoy G, Blanco G, Blas-Garcia A, Blasiak J, Blomgran R, Blomgren K, Blum JS, Boada-Romero E, Boban M, Boesze-Battaglia K, Boeuf P, Boland B, Bomont P, Bonaldo P, Bonam SR, Bonfili L, Bonifacino JS, Boone BA, Bootman MD, Bordi M, Borner C, Bornhauser BC, Borthakur G, Bosch J, Bose S, Botana LM, Botas J, Boulanger CM, Boulton ME, Bourdenx M, Bourgeois B, Bourke NM, Bousquet G, Boya P, Bozhkov PV, Bozi LHM, Bozkurt TO, Brackney DE, Brandts CH, Braun RJ, Braus GH, Bravo-Sagua R, Bravo-San Pedro JM, Brest P, Bringer MA, Briones-Herrera A, Broaddus VC, Brodersen P, Brodsky JL, Brody SL, Bronson PG, Bronstein JM, Brown CN, Brown RE, Brum PC, Brumell JH, Brunetti-Pierri N, Bruno D, Bryson-Richardson RJ, Bucci C, Buchrieser C, Bueno M, Buitrago-Molina LE, Buraschi S, Buch S, Buchan JR, Buckingham EM, Budak H, Budini M, Bultynck G, Burada F, Burgoyne JR, Burón MI, Bustos V, Büttner S, Butturini E, Byrd A, Cabas I, Cabrera-Benitez S, Cadwell K, Cai J, Cai L, Cai Q, Cairó M, Calbet JA, Caldwell GA, Caldwell KA, Call JA, Calvani R, Calvo AC, Calvo-Rubio Barrera M, Camara NO, Camonis JH, Camougrand N, Campanella M, Campbell EM, Campbell-Valois FX, Campello S, Campesi I, Campos JC, Camuzard O, Cancino J, Candido de Almeida D, Canesi L, Caniggia I, Canonico B, Cantí C, Cao B, Caraglia M, Caramés B, Carchman EH, Cardenal-Muñoz E, Cardenas C, Cardenas L, Cardoso SM, Carew JS, Carle GF, Carleton G, Carloni S, Carmona-Gutierrez D, Carneiro LA, Carnevali O, Carosi JM, Carra S, Carrier A, Carrier L, Carroll B, Carter AB, Carvalho AN, Casanova M, Casas C, Casas J, Cassioli C, Castillo EF, Castillo K, Castillo-Lluva S, Castoldi F, Castori M, Castro AF, Castro-Caldas M, Castro-Hernandez J, Castro-Obregon S, Catz SD, Cavadas C, Cavaliere F, Cavallini G, Cavinato M, Cayuela ML, Cebollada Rica P, Cecarini V, Cecconi F, Cechowska-Pasko M, Cenci S, Ceperuelo-Mallafré V, Cerqueira JJ, Cerutti JM, Cervia D, Cetintas VB, Cetrullo S, Chae HJ, Chagin AS, Chai CY, Chakrabarti G, Chakrabarti O, Chakraborty T, Chakraborty T, Chami M, Chamilos G, Chan DW, Chan EYW, Chan ED, Chan HYE, Chan HH, Chan H, Chan MTV, Chan YS, Chandra PK, Chang CP, Chang C, Chang HC, Chang K, Chao J, Chapman T, Charlet-Berguerand N, Chatterjee S, Chaube SK, Chaudhary A, Chauhan S, Chaum E, Checler F, Cheetham ME, Chen CS, Chen GC, Chen JF, Chen LL, Chen L, Chen L, Chen M, Chen MK, Chen N, Chen Q, Chen RH, Chen S, Chen W, Chen W, Chen XM, Chen XW, Chen X, Chen Y, Chen YG, Chen Y, Chen Y, Chen YJ, Chen YQ, Chen ZS, Chen Z, Chen ZH, Chen ZJ, Chen Z, Cheng H, Cheng J, Cheng SY, Cheng W, Cheng X, Cheng XT, Cheng Y, Cheng Z, Chen Z, Cheong H, Cheong JK, Chernyak BV, Cherry S, Cheung CFR, Cheung CHA, Cheung KH, Chevet E, Chi RJ, Chiang AKS, Chiaradonna F, Chiarelli R, Chiariello M, Chica N, Chiocca S, Chiong M, Chiou SH, Chiramel AI, Chiurchiù V, Cho DH, Choe SK, Choi AMK, Choi ME, Choudhury KR, Chow NS, Chu CT, Chua JP, Chua JJE, Chung H, Chung KP, Chung S, Chung SH, Chung YL, Cianfanelli V, Ciechomska IA, Cifuentes M, Cinque L, Cirak S, Cirone M, Clague MJ, Clarke R, Clementi E, Coccia EM, Codogno P, Cohen E, Cohen MM, Colasanti T, Colasuonno F, Colbert RA, Colell A, Čolić M, Coll NS, Collins MO, Colombo MI, Colón-Ramos DA, Combaret L, Comincini S, Cominetti MR, Consiglio A, Conte A, Conti F, Contu VR, Cookson MR, Coombs KM, 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Reigada D, Reiling JH, Rein T, Reipert S, Rekha RS, Ren H, Ren J, Ren W, Renault T, Renga G, Reue K, Rewitz K, Ribeiro de Andrade Ramos B, Riazuddin SA, Ribeiro-Rodrigues TM, Ricci JE, Ricci R, Riccio V, Richardson DR, Rikihisa Y, Risbud MV, Risueño RM, Ritis K, Rizza S, Rizzuto R, Roberts HC, Roberts LD, Robinson KJ, Roccheri MC, Rocchi S, Rodney GG, Rodrigues T, Rodrigues Silva VR, Rodriguez A, Rodriguez-Barrueco R, Rodriguez-Henche N, Rodriguez-Rocha H, Roelofs J, Rogers RS, Rogov VV, Rojo AI, Rolka K, Romanello V, Romani L, Romano A, Romano PS, Romeo-Guitart D, Romero LC, Romero M, Roney JC, Rongo C, Roperto S, Rosenfeldt MT, Rosenstiel P, Rosenwald AG, Roth KA, Roth L, Roth S, Rouschop KMA, Roussel BD, Roux S, Rovere-Querini P, Roy A, Rozieres A, Ruano D, Rubinsztein DC, Rubtsova MP, Ruckdeschel K, Ruckenstuhl C, Rudolf E, Rudolf R, Ruggieri A, Ruparelia AA, Rusmini P, Russell RR, Russo GL, Russo M, Russo R, Ryabaya OO, Ryan KM, Ryu KY, Sabater-Arcis M, Sachdev U, Sacher M, Sachse C, Sadhu A, Sadoshima J, Safren N, Saftig P, Sagona AP, Sahay G, Sahebkar A, Sahin M, Sahin O, Sahni S, Saito N, Saito S, Saito T, Sakai R, Sakai Y, Sakamaki JI, Saksela K, Salazar G, Salazar-Degracia A, Salekdeh GH, Saluja AK, Sampaio-Marques B, Sanchez MC, Sanchez-Alcazar JA, Sanchez-Vera V, Sancho-Shimizu V, Sanderson JT, Sandri M, Santaguida S, Santambrogio L, Santana MM, Santoni G, Sanz A, Sanz P, Saran S, Sardiello M, Sargeant TJ, Sarin A, Sarkar C, Sarkar S, Sarrias MR, Sarkar S, Sarmah DT, Sarparanta J, Sathyanarayan A, Sathyanarayanan R, Scaglione KM, Scatozza F, Schaefer L, Schafer ZT, Schaible UE, Schapira AHV, Scharl M, Schatzl HM, Schein CH, Scheper W, Scheuring D, Schiaffino MV, Schiappacassi M, Schindl R, Schlattner U, Schmidt O, Schmitt R, Schmidt SD, Schmitz I, Schmukler E, Schneider A, Schneider BE, Schober R, Schoijet AC, Schott MB, Schramm M, Schröder B, Schuh K, Schüller C, Schulze RJ, Schürmanns L, Schwamborn JC, Schwarten M, Scialo F, Sciarretta S, Scott MJ, Scotto KW, Scovassi AI, Scrima A, Scrivo A, Sebastian D, Sebti S, Sedej S, Segatori L, Segev N, Seglen PO, Seiliez I, Seki E, Selleck SB, Sellke FW, Selsby JT, Sendtner M, Senturk S, Seranova E, Sergi C, Serra-Moreno R, Sesaki H, Settembre C, Setty SRG, Sgarbi G, Sha O, Shacka JJ, Shah JA, Shang D, Shao C, Shao F, Sharbati S, Sharkey LM, Sharma D, Sharma G, Sharma K, Sharma P, Sharma S, Shen HM, Shen H, Shen J, Shen M, Shen W, Shen Z, Sheng R, Sheng Z, Sheng ZH, Shi J, Shi X, Shi YH, Shiba-Fukushima K, Shieh JJ, Shimada Y, Shimizu S, Shimozawa M, Shintani T, Shoemaker CJ, Shojaei S, Shoji I, Shravage BV, Shridhar V, Shu CW, Shu HB, Shui K, Shukla AK, Shutt TE, Sica V, Siddiqui A, Sierra A, Sierra-Torre V, Signorelli S, Sil P, Silva BJA, Silva JD, Silva-Pavez E, Silvente-Poirot S, Simmonds RE, Simon AK, Simon HU, Simons M, Singh A, Singh LP, Singh R, Singh SV, Singh SK, Singh SB, Singh S, Singh SP, Sinha D, Sinha RA, Sinha S, Sirko A, Sirohi K, Sivridis EL, Skendros P, Skirycz A, Slaninová I, Smaili SS, Smertenko A, Smith MD, Soenen SJ, Sohn EJ, Sok SPM, Solaini G, Soldati T, Soleimanpour SA, Soler RM, Solovchenko A, Somarelli JA, Sonawane A, Song F, Song HK, Song JX, Song K, Song Z, Soria LR, Sorice M, Soukas AA, Soukup SF, Sousa D, Sousa N, Spagnuolo PA, Spector SA, Srinivas Bharath MM, St Clair D, Stagni V, Staiano L, Stalnecker CA, Stankov MV, Stathopulos PB, Stefan K, Stefan SM, Stefanis L, Steffan JS, Steinkasserer A, Stenmark H, Sterneckert J, Stevens C, Stoka V, Storch S, Stork B, Strappazzon F, Strohecker AM, Stupack DG, Su H, Su LY, Su L, Suarez-Fontes AM, Subauste CS, Subbian S, Subirada PV, Sudhandiran G, Sue CM, Sui X, Summers C, Sun G, Sun J, Sun K, Sun MX, Sun Q, Sun Y, Sun Z, Sunahara KKS, Sundberg E, Susztak K, Sutovsky P, Suzuki H, Sweeney G, Symons JD, Sze SCW, Szewczyk NJ, Tabęcka-Łonczynska A, Tabolacci C, Tacke F, Taegtmeyer H, Tafani M, Tagaya M, Tai H, Tait SWG, Takahashi Y, Takats S, Talwar P, Tam C, Tam SY, Tampellini D, Tamura A, Tan CT, Tan EK, Tan YQ, Tanaka M, Tanaka M, Tang D, Tang J, Tang TS, Tanida I, Tao Z, Taouis M, Tatenhorst L, Tavernarakis N, Taylor A, Taylor GA, Taylor JM, Tchetina E, Tee AR, Tegeder I, Teis D, Teixeira N, Teixeira-Clerc F, Tekirdag KA, Tencomnao T, Tenreiro S, Tepikin AV, Testillano PS, Tettamanti G, Tharaux PL, Thedieck K, Thekkinghat AA, Thellung S, Thinwa JW, Thirumalaikumar VP, Thomas SM, Thomes PG, Thorburn A, Thukral L, Thum T, Thumm M, Tian L, Tichy A, Till A, Timmerman V, Titorenko VI, Todi SV, Todorova K, Toivonen JM, Tomaipitinca L, Tomar D, Tomas-Zapico C, Tomić S, Tong BC, Tong C, Tong X, Tooze SA, Torgersen ML, Torii S, Torres-López L, Torriglia A, Towers CG, Towns R, Toyokuni S, Trajkovic V, Tramontano D, Tran QG, Travassos LH, Trelford CB, Tremel S, Trougakos IP, Tsao BP, Tschan MP, Tse HF, Tse TF, Tsugawa H, Tsvetkov AS, Tumbarello DA, Tumtas Y, Tuñón MJ, Turcotte S, Turk B, Turk V, Turner BJ, Tuxworth RI, Tyler JK, Tyutereva EV, Uchiyama Y, Ugun-Klusek A, Uhlig HH, Ułamek-Kozioł M, Ulasov IV, Umekawa M, Ungermann C, Unno R, Urbe S, Uribe-Carretero E, Üstün S, Uversky VN, Vaccari T, Vaccaro MI, Vahsen BF, Vakifahmetoglu-Norberg H, Valdor R, Valente MJ, Valko A, Vallee RB, Valverde AM, Van den Berghe G, van der Veen S, Van Kaer L, van Loosdregt J, van Wijk SJL, Vandenberghe W, Vanhorebeek I, Vannier-Santos MA, Vannini N, Vanrell MC, Vantaggiato C, Varano G, Varela-Nieto I, Varga M, Vasconcelos MH, Vats S, Vavvas DG, Vega-Naredo I, Vega-Rubin-de-Celis S, Velasco G, Velázquez AP, Vellai T, Vellenga E, Velotti F, Verdier M, Verginis P, Vergne I, Verkade P, Verma M, Verstreken P, Vervliet T, Vervoorts J, Vessoni AT, Victor VM, Vidal M, Vidoni C, Vieira OV, Vierstra RD, Viganó S, Vihinen H, Vijayan V, Vila M, Vilar M, Villalba JM, Villalobo A, Villarejo-Zori B, Villarroya F, Villarroya J, Vincent O, Vindis C, Viret C, Viscomi MT, Visnjic D, Vitale I, Vocadlo DJ, Voitsekhovskaja OV, Volonté C, Volta M, Vomero M, Von Haefen C, Vooijs MA, Voos W, Vucicevic L, Wade-Martins R, Waguri S, Waite KA, Wakatsuki S, Walker DW, Walker MJ, Walker SA, Walter J, Wandosell FG, Wang B, Wang CY, Wang C, Wang C, Wang C, Wang CY, Wang D, Wang F, Wang F, Wang F, Wang G, Wang H, Wang H, Wang H, Wang HG, Wang J, Wang J, Wang J, Wang J, Wang K, Wang L, Wang L, Wang MH, Wang M, Wang N, Wang P, Wang P, Wang P, Wang P, Wang QJ, Wang Q, Wang QK, Wang QA, Wang WT, Wang W, Wang X, Wang X, Wang Y, Wang Y, Wang Y, Wang YY, Wang Y, Wang Y, Wang Y, Wang Y, Wang Z, Wang Z, Wang Z, Warnes G, Warnsmann V, Watada H, Watanabe E, Watchon M, Wawrzyńska A, Weaver TE, Wegrzyn G, Wehman AM, Wei H, Wei L, Wei T, Wei Y, Weiergräber OH, Weihl CC, Weindl G, Weiskirchen R, Wells A, Wen RH, Wen X, Werner A, Weykopf B, Wheatley SP, Whitton JL, Whitworth AJ, Wiktorska K, Wildenberg ME, Wileman T, Wilkinson S, Willbold D, Williams B, Williams RSB, Williams RL, Williamson PR, Wilson RA, Winner B, Winsor NJ, Witkin SS, Wodrich H, Woehlbier U, Wollert T, Wong E, Wong JH, Wong RW, Wong VKW, Wong WW, Wu AG, Wu C, Wu J, Wu J, Wu KK, Wu M, Wu SY, Wu S, Wu SY, Wu S, Wu WKK, Wu X, Wu X, Wu YW, Wu Y, Xavier RJ, Xia H, Xia L, Xia Z, Xiang G, Xiang J, Xiang M, Xiang W, Xiao B, Xiao G, Xiao H, Xiao HT, Xiao J, Xiao L, Xiao S, Xiao Y, Xie B, Xie CM, Xie M, Xie Y, Xie Z, Xie Z, Xilouri M, Xu C, Xu E, Xu H, Xu J, Xu J, Xu L, Xu WW, Xu X, Xue Y, Yakhine-Diop SMS, Yamaguchi M, Yamaguchi O, Yamamoto A, Yamashina S, Yan S, Yan SJ, Yan Z, Yanagi Y, Yang C, Yang DS, Yang H, Yang HT, Yang H, Yang JM, Yang J, Yang J, Yang L, Yang L, Yang M, Yang PM, Yang Q, Yang S, Yang S, Yang SF, Yang W, Yang WY, Yang X, Yang X, Yang Y, Yang Y, Yao H, Yao S, Yao X, Yao YG, Yao YM, Yasui T, Yazdankhah M, Yen PM, Yi C, Yin XM, Yin Y, Yin Z, Yin Z, Ying M, Ying Z, Yip CK, Yiu SPT, Yoo YH, Yoshida K, Yoshii SR, Yoshimori T, Yousefi B, Yu B, Yu H, Yu J, Yu J, Yu L, Yu ML, Yu SW, Yu VC, Yu WH, Yu Z, Yu Z, Yuan J, Yuan LQ, Yuan S, Yuan SF, Yuan Y, Yuan Z, Yue J, Yue Z, Yun J, Yung RL, Zacks DN, Zaffagnini G, Zambelli VO, Zanella I, Zang QS, Zanivan S, Zappavigna S, Zaragoza P, Zarbalis KS, Zarebkohan A, Zarrouk A, Zeitlin SO, Zeng J, Zeng JD, Žerovnik E, Zhan L, Zhang B, Zhang DD, Zhang H, Zhang H, Zhang H, Zhang H, Zhang H, Zhang H, Zhang H, Zhang HL, Zhang J, Zhang J, Zhang JP, Zhang KYB, Zhang LW, Zhang L, Zhang L, Zhang L, Zhang L, Zhang M, Zhang P, Zhang S, Zhang W, Zhang X, Zhang XW, Zhang X, Zhang X, Zhang X, Zhang X, Zhang XD, Zhang Y, Zhang Y, Zhang Y, Zhang YD, Zhang Y, Zhang YY, Zhang Y, Zhang Z, Zhang Z, Zhang Z, Zhang Z, Zhang Z, Zhang Z, Zhao H, Zhao L, Zhao S, Zhao T, Zhao XF, Zhao Y, Zhao Y, Zhao Y, Zhao Y, Zheng G, Zheng K, Zheng L, Zheng S, Zheng XL, Zheng Y, Zheng ZG, Zhivotovsky B, Zhong Q, Zhou A, Zhou B, Zhou C, Zhou G, Zhou H, Zhou H, Zhou H, Zhou J, Zhou J, Zhou J, Zhou J, Zhou K, Zhou R, Zhou XJ, Zhou Y, Zhou Y, Zhou Y, Zhou ZY, Zhou Z, Zhu B, Zhu C, Zhu GQ, Zhu H, Zhu H, Zhu H, Zhu WG, Zhu Y, Zhu Y, Zhuang H, Zhuang X, Zientara-Rytter K, Zimmermann CM, Ziviani E, Zoladek T, Zong WX, Zorov DB, Zorzano A, Zou W, Zou Z, Zou Z, Zuryn S, Zwerschke W, Brand-Saberi B, Dong XC, Kenchappa CS, Li Z, Lin Y, Oshima S, Rong Y, Sluimer JC, Stallings CL, Tong CK";;"02 2021";1612137600;;"In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field." 12818;"Distinction between 2'- and 3'-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration.";"P. Abbe, S. Rocchi";"Equipe 12, Team 12";34064498;"Antioxidants (Basel, Switzerland)";"Manuel R, Lima MS, Dilly S, Daunay S, Abbe P, Pramil E, Solier S, Guillaumond F, Tubiana SS, Escargueil A, Pêgas Henriques JA, Ferrand N, Erdelmeier I, Boucher JL, Bertho G, Agranat I, Rocchi S, Sabbah M, Slama Schwok A";;"05 2021";1619827200;;"Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2'- and 3'-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2'- and 3'-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging. The 2'-phosphate isomer of NS1 exerted more pronounced effects on NOS and NOX-dependent physiological responses than the 3'-phosphate isomer did. Docking and molecular dynamics simulations explain this specificity at the level of the NADPH site of NOX and NOS, where conserved arginine residues distinguished between the 2'-phosphate over the 3'-phosphate group, in favor of the 2'-phosphate." 12816;"Development and evaluation of fused benzazole analogs of anti-melanoma agent HA15.";"P. Abbe, S. Rocchi";"Equipe 12, Team 12";34096325;"Future medicinal chemistry";"Millet A, Filho MS, Hamouda-Tekaya N, Cavazza E, Abbe P, Rüdiger J, Plaisant M, Mayen J, Rocchi S, Ronco C, Benhida R";;"06 2021";1622505600;;" In line with our recent discovery of an efficient anticancer thiazolebenzenesulfonamide framework HA15 () based on a remarkable endoplasmic reticulum stress inducement mode of action, we report herein a series of innovative constrained HA15 analogs, featuring four types of bicylic derivatives. The structure-activity relationship analysis, using a cell line assay, led us to identify a novel version of HA15: a new benzothiazole derivative () exhibiting important anti-melanoma effect against sensitive and resistant melanoma cells. Meanwhile, compound induced a significant tumor growth inhibition with no apparent signs of toxicity. These results consistently open new directions to improve and develop more powerful anticancer therapeutics harboring this type of fused framework." 12814;"Biguanides drugs: Past success stories and promising future for drug discovery.";"S. Rocchi";"Equipe 12, Team 12";34364161;"European journal of medicinal chemistry";"Grytsai O, Myrgorodska I, Rocchi S, Ronco C, Benhida R";;"07 2021";1625097600;;"Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment." 12812;"Meeting report of the 4th biennial Metabolism and Cancer symposium.";"F. BOST, JE. Ricci, N. Mazure, S. Rocchi";"Equipe 05, Team 05, Equipe 03, Team 03, Equipe 12, Team 12";34817127;"The FEBS journal";"Abdel Hadi N, Boet E, Lahalle A, Lauture L, Refeyton A, Reyes-Castellanos G, Caplet N, Carrier A, Le Cam L, Mazure NM, Ricci JE, Rocchi S, Sarry JE, Vasseur S, Vlaski-Lafarge M, Rossignol R, Bost F";;"11 2021";1635724800;;"The 4th International meeting Metabolism and Cancer initially programed to take place in Bordeaux (France) was held virtually on May 27-29, 2021. The three-day event was followed by around 600 participants daily from 47 countries around the world. The meeting hosted 21 speakers including selected talks and a keynote lecture from the Nobel Prize winner Sir Peter J. Ratcliffe (Oxford, UK). Presentations and discussions were divided in four scientific sessions: (a) Redox and energy metabolism (b) Redox and hypoxia (c) Metabolic profiling and epigenetic control and (d) Signalling, fuelling and metabolism in cancer and a general public session on cancer and nutrition. This report summarises the presentations and outcomes of the 4th annual Metabolism and Cancer symposium. We provide here a summary of the scientific highlights of this exciting meeting." 12808;"Modulation of allergic response in nasal mucosa by antisense oligodeoxynucleotides for IL-4.";"M. Tulic";"Equipe 12, Team 12";12642840;"The Journal of allergy and clinical immunology";"Fiset PO, Soussi-Gounni A, Christodoulopoulos P, Tulic M, Sobol SE, Frenkiel S, Lavigne F, Lamkhioued B, Hamid Q";;"Mar 2003";1048032000;;"The cytokine IL-4 is highly involved in T(H)2 inflammation, such as that seen in allergic rhinitis. IL-4 can induce IgE synthesis and eotaxin. Recent studies have shown that stimulation of allergic nasal tissue with ragweed allergen can induce local IL-4 mRNA production." 12809;"Modulation of allergic response in nasal mucosa by antisense oligodeoxynucleotides for IL-4.";"M. Tulic";"Equipe 12, Team 12";12642840;"The Journal of allergy and clinical immunology";"Fiset PO, Soussi-Gounni A, Christodoulopoulos P, Tulic M, Sobol SE, Frenkiel S, Lavigne F, Lamkhioued B, Hamid Q";;"Mar 2003";1048032000;;"The cytokine IL-4 is highly involved in T(H)2 inflammation, such as that seen in allergic rhinitis. IL-4 can induce IgE synthesis and eotaxin. Recent studies have shown that stimulation of allergic nasal tissue with ragweed allergen can induce local IL-4 mRNA production." 12806;"Inflammatory cells in asthma: mechanisms and implications for therapy.";"M. Tulic";"Equipe 12, Team 12";12532083;"The Journal of allergy and clinical immunology";"Hamid Q, Tulic' MK, Liu MC, Moqbel R";;"Jan 2003";1042848000;;"Recent clinical studies have brought asthma's complex inflammatory processes into clearer focus, and understanding them can help to delineate therapeutic implications. Asthma is a chronic airway inflammatory disease characterized by the infiltration of airway T cells, CD(+) (T helper) cells, mast cells, basophils, macrophages, and eosinophils. The cysteinyl leukotrienes also are important mediators in asthma and modulators of cytokine function, and they have been implicated in the pathophysiology of asthma through multiple mechanisms. Although the role of eosinophils in asthma and their contribution to bronchial hyperresponsiveness are still debated, it is widely accepted that their numbers and activation status are increased. Eosinophils may be targets for various pharmacologic activities of leukotriene receptor antagonists through their ability to downregulate a number of events that may be key to the effector function of these cells." 12801;"Role of microbial toxins in the induction of glucocorticoid receptor beta expression in an explant model of rhinosinusitis.";"M. Tulic";"Equipe 12, Team 12";14967085;"The Journal of otolaryngology";"Fakhri S, Christodoulopoulos P, Tulic M, Fukakusa M, Frenkiel S, Leung DY, Hamid QA";;"Feb 2004";1077062400;;"Glucocorticoids (GCs) are the most potent agents currently available for relieving the symptoms of chronic rhinosinusitis. The pathogenesis and molecular basis of GC insensitivity in allergic rhinosinusitis are unknown. Studies done on patients with GC-insensitive asthma demonstrated an overexpression of GC receptor beta (GRbeta), an abnormal splice variant and an endogenous inhibitor of the classic GC receptor alpha. The mechanisms that induce the overexpression of GRbeta remain poorly understood." 12803;"Marked up-regulation of T lymphocytes and expression of interleukin-9 in bronchial biopsies from patients With chronic bronchitis with obstruction.";"M. Tulic";"Equipe 12, Team 12";14605067;Chest;"Panzner P, Lafitte JJ, Tsicopoulos A, Hamid Q, Tulic MK";;"Nov 2003";1068249600;;"To examine the differences in the inflammatory cell and cytokine profile between patients with chronic bronchitis (CB) with and without airway obstruction compared to control subjects." 12799;"Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response.";"M. Tulic";"Equipe 12, Team 12";14767435;"The Journal of allergy and clinical immunology";"Tulic MK, Fiset PO, Christodoulopoulos P, Vaillancourt P, Desrosiers M, Lavigne F, Eiden J, Hamid Q";;"Feb 2004";1076371200;;"Amb a 1-immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) is a novel immunotherapeutic compound consisting of purified Amb a 1 from short ragweed proteins covalently linked to an immunostimulatory phosphorothioate oligodeoxyribonucleotide. In sensitized animals AIC can stimulate an Amb a 1-specific T(H)1 response and decrease pulmonary reactivity to ragweed challenge. Clinical trials have documented reduced allergic response to AIC in comparison with licensed ragweed extract." 12798;"Oral corticosteroids decrease eosinophil and CC chemokine expression but increase neutrophil, IL-8, and IFN-gamma-inducible protein 10 expression in asthmatic airway mucosa.";"M. Tulic";"Equipe 12, Team 12";15696082;"The Journal of allergy and clinical immunology";"Fukakusa M, Bergeron C, Tulic MK, Fiset PO, Al Dewachi O, Laviolette M, Hamid Q, Chakir J";;"Feb 2005";1107820800;;"Cytokines and chemokines have been implicated in the pathogenesis of asthma. Inhaled corticosteroids have been shown to decrease the number of eosinophils and to downregulate T H 2 cytokines but to increase neutrophils. The effect of corticosteroids on chemokine expression in asthma has not yet been investigated." 12792;"Microbial superantigens induce glucocorticoid receptor beta and steroid resistance in a nasal explant model.";"M. Tulic";"Equipe 12, Team 12";15126750;"The Laryngoscope";"Fakhri S, Tulic M, Christodoulopoulos P, Fukakusa M, Frenkiel S, Leung DY, Hamid QA";;"May 2004";1083801600;;"To study the role of superantigen (SAg) in inducing glucocorticoid (GC) receptor beta and steroid resistance in an explant model of nasal tissue." 12793;"The role of the distal lung in asthma.";"M. Tulic";"Equipe 12, Team 12";16088628;"Seminars in respiratory and critical care medicine";"Tulic MK, Hamid Q";;"Aug 2005";1123632000;;"Accumulating patholological and physiological evidence in the last few years suggests that the airway inflammation and remodeling that characterize asthma occur not only in the central airways but extend to the distal lung and the lung parenchyma. The distal airways are capable of producing T-helper (Th)2 cytokines as well as chemokines, and more recently, they have been recognized as a predominant site of airflow obstruction in asthmatics. A similar TH2-type cytokine profile and infiltration of inflammatory cells has also been reported in the lung parenchyma. The inflammation at this distal site has been described as more severe when compared with the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance highlighting the need also to consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease." 12794;"Selective irrigation of the sinuses in the management of chronic rhinosinusitis refractory to medical therapy: a promising start.";"M. Tulic";"Equipe 12, Team 12";15291270;"The Journal of otolaryngology";"Lavigne F, Tulic MK, Gagnon J, Hamid Q";;"Aug 2004";1091664000;;"Although endoscopic sinus surgery has been widely used for the treatment of chronic rhinosinusitis, some patients fail to derive clinical benefit from this procedure. We evaluated the efficacy of a treatment regimen consisting of selective irrigation of diseased sinus mucosa with topical antibiotics and steroids in conjunction with oral antibiotics and steroids." 12790;"New insights into the pathophysiology of the small airways in asthma.";"M. Tulic";"Equipe 12, Team 12";16543051;"Clinics in chest medicine";"Tulic MK, Hamid Q";;"Mar 2006";1142640000;;"Airway inflammation and remodeling in asthma occur in the central airways and also in the small airways and in the lung parenchyma. The small airways and the lung parenchyma can produce many Th2 cytokines, chemokines, and mediators involved in initiation and perpetuation of the inflammatory process. The distal lung has been recognized as a predominant site of airflow obstruction in asthmatics. Distal inflammation has been described as more severe than large airway inflammation, and strong evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has clinical significance, highlighting the need to target the distal lung in any strategy for effective treatment of this disease." 12788;"New insights into the pathophysiology of the small airways in asthma.";"M. Tulic";"Equipe 12, Team 12";19724673;"Annals of thoracic medicine";"Hamid Q, Tulic MK";;"Sep 2009";1251936000;;"Asthma is a lung disease characterized by inflammation and remodeling of the airways, which leads to airflow obstruction and symptoms of wheeze, chest tightness, cough and dyspnea. It is now widely accepted that airway inflammation and remodeling occur not only in the central airways but also in the small airways and even in the lung parenchyma. Inflammation of the distal lung can be observed even in mild asthmatics with normal or noncompromised lung function. Moreover, the small airways and the lung parenchyma can produce many Th2 cytokines and chemokines involved in initiation and perpetuation of the inflammatory process. In addition, the distal parts of the lung have been recognized as a predominant site of airflow obstruction in asthmatics. In fact, the inflammation at this distal site has been described as more severe when compared to the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance, highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease." 12786;"TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide.";"M. Tulic";"Equipe 12, Team 12";17579031;"Journal of immunology (Baltimore, Md. : 1950)";"Tulic MK, Hurrelbrink RJ, Prêle CM, Laing IA, Upham JW, Le Souef P, Sly PD, Holt PG";;"Jun 2007";1182384000;;"Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the (299)Gly and (399)Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence ((299)Asp/(399)Thr), or the (299)Gly or (399)Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing (299)Gly or (399)Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-kappaB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-alpha. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus." 12784;"A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma.";"M. Tulic";"Equipe 12, Team 12";11842292;"The Journal of allergy and clinical immunology";"Toda M, Tulic MK, Levitt RC, Hamid Q";;"Feb 2002";1013644800;;"One of the cardinal features of airway remodeling in asthma is mucus gland hyperplasia and mucus overproduction and hypersecretion. Recently, a calcium-activated chloride channel, HCLCA1, was described that is upregulated by IL-9 and thought to regulate the expression of soluble gel-forming mucins, such as MUC5A/C, a critical component of mucus in the airways." 12781;"Allergen-induced increases in bone marrow T lymphocytes and interleukin-5 expression in subjects with asthma.";"M. Tulic";"Equipe 12, Team 12";12231502;"American journal of respiratory and critical care medicine";"Wood LJ, Sehmi R, Dorman S, Hamid Q, Tulic MK, Watson RM, Foley R, Wasi P, Denburg JA, Gauvreau G, O'Byrne PM";;"Sep 2002";1032220800;;"Inhaled allergen challenge of subjects with atopic asthmatic increases bone marrow eosinophil progenitor cells. Interleukin-5 (IL-5) specifically induces growth and maturation of eosinophils. This study examined the effect of allergen challenge on the number of bone marrow total and CD3+ cells expressing IL-5 protein and IL-5 mRNA in subjects with asthma who developed either allergen-induced isolated early responses, or early and late asthmatic responses (dual responders). At 24 hours after allergen challenge, dual responders had significantly greater blood and airway eosinophilia compared with early responders. There were significant increases in the percentage of bone marrow CD3+ cells (p < 0.005) in both groups. However, there were significant differences in the increases in bone marrow IL-5 mRNA+ (p < 0.005), CD3+ (p < 0.005), and IL-5 mRNA+ CD3+ (p < 0.005) cells between the dual and early responder groups. These results suggest that, in subjects with atopic asthma, inhaled allergen causes trafficking of T lymphocytes to the bone marrow, and that in subjects who develop late responses and greater blood and airway eosinophilia after inhalation of allergen, there is a significant increase in the ability of bone marrow cells, particularly T lymphocytes, to produce IL-5." 12780;"T-cell proliferation induced by local application of LPS in the nasal mucosa of nonatopic children.";"M. Tulic";"Equipe 12, Team 12";12417887;"The Journal of allergy and clinical immunology";"Tulic MK, Manoukian JJ, Eidelman DH, Hamid Q";;"Nov 2002";1036540800;;"Recently, there has been a great deal of interest in the role of bacterial products in altering the allergic immune response in early life." 12778;"Synthesis of IL-13 by human B lymphocytes: regulation and role in IgE production.";"M. Tulic";"Equipe 12, Team 12";15356573;"The Journal of allergy and clinical immunology";"Hajoui O, Janani R, Tulic M, Joubert P, Ronis T, Hamid Q, Zheng H, Mazer BD";;"Sep 2004";1094774400;;"Our laboratory has demonstrated previously that human tonsillar B lymphocytes express IL-13 mRNA OBJECTIVE: We sought to investigate IL-13 production by human B cells and the association between B cell-derived IL-13 and IgE secretion." 12776;"Modulation of allergic response in nasal mucosa by antisense oligodeoxynucleotides for IL-4.";"M. Tulic";"Equipe 12, Team 12";12642840;"The Journal of allergy and clinical immunology";"Fiset PO, Soussi-Gounni A, Christodoulopoulos P, Tulic M, Sobol SE, Frenkiel S, Lavigne F, Lamkhioued B, Hamid Q";;"Mar 2003";1048032000;;"The cytokine IL-4 is highly involved in T(H)2 inflammation, such as that seen in allergic rhinitis. IL-4 can induce IgE synthesis and eotaxin. Recent studies have shown that stimulation of allergic nasal tissue with ragweed allergen can induce local IL-4 mRNA production." 12773;"Inflammatory cells in asthma: mechanisms and implications for therapy.";"M. Tulic";"Equipe 12, Team 12";12532083;"The Journal of allergy and clinical immunology";"Hamid Q, Tulic' MK, Liu MC, Moqbel R";;"Jan 2003";1042848000;;"Recent clinical studies have brought asthma's complex inflammatory processes into clearer focus, and understanding them can help to delineate therapeutic implications. Asthma is a chronic airway inflammatory disease characterized by the infiltration of airway T cells, CD(+) (T helper) cells, mast cells, basophils, macrophages, and eosinophils. The cysteinyl leukotrienes also are important mediators in asthma and modulators of cytokine function, and they have been implicated in the pathophysiology of asthma through multiple mechanisms. Although the role of eosinophils in asthma and their contribution to bronchial hyperresponsiveness are still debated, it is widely accepted that their numbers and activation status are increased. Eosinophils may be targets for various pharmacologic activities of leukotriene receptor antagonists through their ability to downregulate a number of events that may be key to the effector function of these cells." 12772;"Contribution of the distal lung to the pathologic and physiologic changes in asthma: potential therapeutic target Roger S. Mitchell lecture.";"M. Tulic";"Equipe 12, Team 12";12628971;Chest;"Tulić MK, Hamid Q";;"Mar 2003";1047427200;;"Pathologic and physiologic evidence has emerged in the last few years suggesting that the airway inflammation and remodeling that characterize asthma occur not only in the central airways but extend to the distal lung and the lung parenchyma. The distal airways are capable of producing T helper (Th) type 2 cytokines and chemokines, and, more recently, they have been recognized as a predominant site of airflow obstruction in asthmatic patients. In the lung parenchyma, a similar Th2 cytokine profile and infiltration of inflammatory cells also has been reported. The inflammation at this distal site has been described as being more severe when compared to the large amount of airway inflammation, and evidence of remodeling in the lung periphery is emerging. The recognition of asthma as a disease of the entire respiratory tract has an important clinical significance highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease." 12770;"Marked up-regulation of T lymphocytes and expression of interleukin-9 in bronchial biopsies from patients With chronic bronchitis with obstruction.";"M. Tulic";"Equipe 12, Team 12";14605067;Chest;"Panzner P, Lafitte JJ, Tsicopoulos A, Hamid Q, Tulic MK";;"Nov 2003";1068249600;;"To examine the differences in the inflammatory cell and cytokine profile between patients with chronic bronchitis (CB) with and without airway obstruction compared to control subjects." 12768;"Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response.";"M. Tulic";"Equipe 12, Team 12";14767435;"The Journal of allergy and clinical immunology";"Tulic MK, Fiset PO, Christodoulopoulos P, Vaillancourt P, Desrosiers M, Lavigne F, Eiden J, Hamid Q";;"Feb 2004";1076371200;;"Amb a 1-immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) is a novel immunotherapeutic compound consisting of purified Amb a 1 from short ragweed proteins covalently linked to an immunostimulatory phosphorothioate oligodeoxyribonucleotide. In sensitized animals AIC can stimulate an Amb a 1-specific T(H)1 response and decrease pulmonary reactivity to ragweed challenge. Clinical trials have documented reduced allergic response to AIC in comparison with licensed ragweed extract." 12764;"Microbial superantigens induce glucocorticoid receptor beta and steroid resistance in a nasal explant model.";"M. Tulic";"Equipe 12, Team 12";15126750;"The Laryngoscope";"Fakhri S, Tulic M, Christodoulopoulos P, Fukakusa M, Frenkiel S, Leung DY, Hamid QA";;"May 2004";1083801600;;"To study the role of superantigen (SAg) in inducing glucocorticoid (GC) receptor beta and steroid resistance in an explant model of nasal tissue." 12762;"Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults.";"M. Tulic";"Equipe 12, Team 12";15158630;"Lancet (London, England)";"Tulic MK, Fiset PO, Manoukian JJ, Frenkiel S, Lavigne F, Eidelman DH, Hamid Q";;"May 2004";1085529600;;"Exposure to bacterial products in early life could protect against development of atopy. We examined the effect of bacterial lipopolysaccharide on allergic inflammation and expression of cytokines and lipopolysaccharide receptor (toll-like receptor 4 TLR4) in nasal mucosa of 15 atopic children and ten atopic adults." 12758;"Toll-like receptors and atopy.";"M. Tulic";"Equipe 12, Team 12";16083812;"The Journal of allergy and clinical immunology";"Fiset PO, Tulic MK, Hamid Q";;"Aug 2005";1123545600;; 12756;"Oral corticosteroids decrease eosinophil and CC chemokine expression but increase neutrophil, IL-8, and IFN-gamma-inducible protein 10 expression in asthmatic airway mucosa.";"M. Tulic";"Equipe 12, Team 12";15696082;"The Journal of allergy and clinical immunology";"Fukakusa M, Bergeron C, Tulic MK, Fiset PO, Al Dewachi O, Laviolette M, Hamid Q, Chakir J";;"Feb 2005";1107820800;;"Cytokines and chemokines have been implicated in the pathogenesis of asthma. Inhaled corticosteroids have been shown to decrease the number of eosinophils and to downregulate T H 2 cytokines but to increase neutrophils. The effect of corticosteroids on chemokine expression in asthma has not yet been investigated." 12754;"Toll-like receptors 4 and 2 expression in the bronchial mucosa of patients with cystic fibrosis.";"M. Tulic";"Equipe 12, Team 12";15776129;"Canadian respiratory journal";"Hauber HP, Tulic MK, Tsicopoulos A, Wallaert B, Olivenstein R, Daigneault P, Hamid Q";;"Feb Jan 2005";1104624000;;"Cystic fibrosis (CF) is a lung disease characterized by chronic infection with Gram-negative bacteria Pseudomonas aeruginosa and Gram-positive bacteria Staphylococcus aureus. Recently, toll-like receptor (TLR) 4 has been shown to be responsible for the lipopolysaccharide (LPS)-mediated immune response. While TLR2 mediates responses driven by bacterial lipoproteins and peptidoglycans from Gram-positive bacteria, LPS derived from P aeruginosa may stimulate the immune response in the airways of patients with CF via activation of TLR4." 12750;"NOS 1 is required for allergen-induced expression of NOS 2 in mice.";"M. Tulic";"Equipe 12, Team 12";16103686;"International archives of allergy and immunology";"Iijima H, Tulic MK, Duguet A, Shan J, Carbonara P, Hamid Q, Eidelman DH";;"Aug 2005";1124236800;;"Although increased nitric oxide (NO) production in asthma is mediated largely by upregulation of the inducible form of nitric oxide synthase (iNOS, or NOS 2), some studies have suggested an important role for the usually constitutive neural NOS isoform (nNOS, or NOS 1)." 12748;"New insights into the pathophysiology of the small airways in asthma.";"M. Tulic";"Equipe 12, Team 12";19724673;"Annals of thoracic medicine";"Hamid Q, Tulic MK";;"Sep 2009";1251936000;;"Asthma is a lung disease characterized by inflammation and remodeling of the airways, which leads to airflow obstruction and symptoms of wheeze, chest tightness, cough and dyspnea. It is now widely accepted that airway inflammation and remodeling occur not only in the central airways but also in the small airways and even in the lung parenchyma. Inflammation of the distal lung can be observed even in mild asthmatics with normal or noncompromised lung function. Moreover, the small airways and the lung parenchyma can produce many Th2 cytokines and chemokines involved in initiation and perpetuation of the inflammatory process. In addition, the distal parts of the lung have been recognized as a predominant site of airflow obstruction in asthmatics. In fact, the inflammation at this distal site has been described as more severe when compared to the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance, highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease." 12746;"New insights into the pathophysiology of the small airways in asthma.";"M. Tulic";"Equipe 12, Team 12";16543051;"Clinics in chest medicine";"Tulic MK, Hamid Q";;"Mar 2006";1142640000;;"Airway inflammation and remodeling in asthma occur in the central airways and also in the small airways and in the lung parenchyma. The small airways and the lung parenchyma can produce many Th2 cytokines, chemokines, and mediators involved in initiation and perpetuation of the inflammatory process. The distal lung has been recognized as a predominant site of airflow obstruction in asthmatics. Distal inflammation has been described as more severe than large airway inflammation, and strong evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has clinical significance, highlighting the need to target the distal lung in any strategy for effective treatment of this disease." 12744;"TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide.";"M. Tulic";"Equipe 12, Team 12";17579031;"Journal of immunology (Baltimore, Md. : 1950)";"Tulic MK, Hurrelbrink RJ, Prêle CM, Laing IA, Upham JW, Le Souef P, Sly PD, Holt PG";;"Jun 2007";1182384000;;"Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the (299)Gly and (399)Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence ((299)Asp/(399)Thr), or the (299)Gly or (399)Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing (299)Gly or (399)Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-kappaB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-alpha. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus." 12742;"Children with egg allergy have evidence of reduced neonatal CD4(+)CD25(+)CD127(lo/-) regulatory T cell function.";"M. Tulic";"Equipe 12, Team 12";18455222;"The Journal of allergy and clinical immunology";"Smith M, Tourigny MR, Noakes P, Thornton CA, Tulic MK, Prescott SL";;"05 2008";1209600000;;"The role of regulatory T (Treg) cells in allergic predisposition is not known." 12740;"Presymptomatic differences in Toll-like receptor function in infants who have allergy.";"M. Tulic";"Equipe 12, Team 12";18571707;"The Journal of allergy and clinical immunology";"Prescott SL, Noakes P, Chow BW, Breckler L, Thornton CA, Hollams EM, Ali M, van den Biggelaar AH, Tulic MK";;"06 2008";1212278400;;"Microbial exposure might play a key role in allergy development, but little is known about the role of Toll-like receptors (TLRs)." 12738;"Differences in innate immune function between allergic and nonallergic children: new insights into immune ontogeny.";"M. Tulic";"Equipe 12, Team 12";21093030;"The Journal of allergy and clinical immunology";"Tulic MK, Hodder M, Forsberg A, McCarthy S, Richman T, D'Vaz N, van den Biggelaar AH, Thornton CA, Prescott SL";;"11 2010";1288569600;;"Microbial products are of central interest in the modulation of allergic propensity." 12736;"Thymic indoleamine 2,3-dioxygenase-positive eosinophils in young children: potential role in maturation of the naive immune system.";"M. Tulic";"Equipe 12, Team 12";19815714;"The American journal of pathology";"Tulic MK, Sly PD, Andrews D, Crook M, Davoine F, Odemuyiwa SO, Charles A, Hodder ML, Prescott SL, Holt PG, Moqbel R";;"Oct 2009";1255132800;;"Eosinophils expressing indoleamine 2, 3-dioxygenase (IDO) may contribute to T-helper cell (Th)2 predominance. To characterize human thymus IDO+ eosinophil ontogeny relative to Th2 regulatory gene expression, we processed surgically obtained thymi from 22 children (age: 7 days to 12 years) for immunohistochemistry and molecular analysis, and measured cytokine and kynurenine levels in tissue homogenates. Luna+ eosinophils ( approximately 2% of total thymic cells) decreased in number with age (P = 0.02) and were IDO+. Thymic IDO immunoreactivity (P = 0.01) and kynurenine concentration (P = 0.01) decreased with age as well. In addition, constitutively-expressed interleukin (IL)-5 and IL-13 in thymus supernatants was highest in youngest children. Eosinophil numbers correlated positively with expression of the Th2 cytokines IL-5, IL-13 (r = 0.44, P = 0.002), and IL-4 (r = 0.46, P = 0.005), transcription factor signal transducer and activator of transcription-6 (r = 0.68, P = 0.001), and the chemokine receptor, CCR3 (r = 0.17, P = 0.04), but negatively with IL-17 mRNA (r = -0.57, P = 0.02) and toll-like receptor 4 expression (r = -0.74, P = 0.002). Taken together, these results suggest that functional thymic IDO+ eosinophils during human infant life may have an immunomodulatory role in Th2 immune responses." 12734;"Algorithmic models to predict allergic disease using multiple neonatal markers.";"M. Tulic";"Equipe 12, Team 12";19383988;"Indian pediatrics";"Hodder M, Tulic MK, Prescott SL";;"Apr 2009";1240444800;;"Childhood blindness and visual impairment are as important and perhaps more devastating and disabling than adult onset blindness, because of the long span of life still remaining to be lived. Refractive errors and more particularly myopia, place a substantial burden on the individual and society. School-age children constitute a particularly vulnerable group where uncorrected refractive errors may have a dramatic impact on learning capability and educational potential. This article provides an overview of school eye screening from the perspective of National Program for Control of Blindness (NPCB), Government of India; and challenges, future directions and thrust area envisaged under the program for amelioration of childhood blindness." 12732;"Neonatal innate cytokine responses to BCG controlling T-cell development vary between populations.";"M. Tulic";"Equipe 12, Team 12";19500827;"The Journal of allergy and clinical immunology";"van den Biggelaar AH, Prescott SL, Roponen M, Nadal-Sims MA, Devitt CJ, Phuanukoonnon S, Pomat W, Tulic MK, Lehmann D, Siba PM, Richmond PC, Holt PG";;"06 2009";1243814400;;"The protective effect of Mycobacterium bovis BCG vaccination against infection and atopy varies between populations." 12730;"Immunobiology of asthma.";"M. Tulic";"Equipe 12, Team 12";19575684;"Annual review of physiology";"Hamid Q, Tulic M";;"Jul 2009";1246924800;;"Asthma is characterized by chronic inflammation of the airways in which there is an overabundance of eosinophils, mast cells, and activated T helper lymphocytes. These inflammatory cells release mediators that then trigger bronchoconstriction, mucus secretion, and remodeling. The inflammatory mediators that drive this process include cytokines, chemokines, growth factors, lipid mediators, immunoglobulins, and histamine. The inflammation in allergic asthma can be difficult to control. This is mainly due to the development of an adaptive immunity to an allergen, leading to immunological memory. This leads to recall reactions to the allergen, causing persistent inflammation and damage to the airways. Generally, in asthma inflammation is directed by Th2 cytokines, which can act by positive feedback mechanisms to promote the production of more inflammatory mediators including other cytokines and chemokines. This review discusses the role of cytokines and chemokines in the immunobiology of asthma and attempts to relate their expression to morphological and functional abnormalities in the lungs of asthmatic subjects. We also discuss new concepts in asthma immunology, in particular the role of cytokines in airway remodeling and the interaction between cytokines and infection." 12728;"Local induction of a specific Th1 immune response by allergen linked immunostimulatory DNA in the nasal explants of ragweed-allergic subjects.";"M. Tulic";"Equipe 12, Team 12";19776676;"Allergology international : official journal of the Japanese Society of Allergology";"Tulic MK, Christodoulopoulos P, Fiset PO, Vaillancourt P, Lavigne F, Marshall JD, Van Nest G, Eiden JJ, Hamid Q";;"09 2009";1251763200;;"Allergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS." 12726;"Progress in understanding postnatal immune dysregulation in allergic disease.";"M. Tulic";"Equipe 12, Team 12";23268427;"The World Allergy Organization journal";"Prescott SL, Martino D, Hodder M, Richman T, Tulic MK";;"Dec 2012";1356566400;;"It is increasingly unlikely that allergic disease is the result of isolated immune defects, but rather the result of altered gene activation patterns in intricate immune networks. This appears to be driven by complex environmental changes, including microbial exposure, diet, and pollutants, which are known to modify immune development in early life, beginning in pregnancy. The first models showing possible epigenetic mechanisms for these effects are beginning to emerge. This review focuses on recent advances in our knowledge of the consequent effects on postnatal immune development, highlighting recognized differences in children with and without allergies. Although we characterized essential differences in longitudinal T-cell development more than 10 years ago, new technologies using whole genome microarrays are now being used to examine for differential gene expression in T cells from individuals with allergies. We have also recently performed the first comprehensive study of the longitudinal development of innate toll-like receptor responses in children with and without allergies during the first 5 years of life, identifying significant differences in these pathways as well. Finally, although there are preliminary differences in regulatory T-cell function at birth, longitudinal studies are limited by difficulties isolating these cells in sufficient numbers from young children for functional studies. Thymic tissue isolated during cardiac surgery is a rich source of regulatory T-cell function in children and may provide further avenues for assessing differences in maturation of these cells in individuals with allergies. To further understand the pathogenesis of these altered patterns of immune response, future research needs to encompass the complexity of gene-environmental interactions, which confer individual susceptibility to environmental exposures." 12724;"Airway remodelling in asthma: from benchside to clinical practice.";"M. Tulic";"Equipe 12, Team 12";20808979;"Canadian respiratory journal";"Bergeron C, Tulic MK, Hamid Q";;"Aug Jul 2010";1278547200;;"Airway remodelling refers to the structural changes that occur in both large and small airways relevant to miscellaneous diseases including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, gland enlargement, neovascularization and epithelial alterations. Although controversial, airway remodelling is commonly attributed to an underlying chronic inflammatory process. These remodelling changes contribute to thickening of airway walls and, consequently, lead to airway narrowing, bronchial hyper-responsiveness, airway edema and mucous hypersecretion. Airway remodelling is associated with poor clinical outcomes among asthmatic patients. Early diagnosis and prevention of airway remodelling has the potential to decrease disease severity, improve control and prevent disease expression. The relationship between structural changes and clinical and functional abnormalities clearly deserves further investigation. The present review briefly describes the characteristic features of airway remodelling observed in asthma, its clinical consequences and relevance for physicians, and its modulation by therapeutic approaches used in the treatment of asthmatic patients." 12722;"Maternal allergy modulates cord blood hematopoietic progenitor Toll-like receptor expression and function.";"M. Tulic";"Equipe 12, Team 12";21167570;"The Journal of allergy and clinical immunology";"Reece P, Thanendran A, Crawford L, Tulic MK, Thabane L, Prescott SL, Sehmi R, Denburg JA";;"Dec 2010";1292889600;;"Little is known regarding the prenatal determinants of innate immune responses in relation to infant allergic risk. Environmental exposures, including microbial stimuli, might predispose susceptible subjects to atopy and asthma in early infancy or even in utero." 12720;"Reduced placental FOXP3 associated with subsequent infant allergic disease.";"M. Tulic";"Equipe 12, Team 12";21719077;"The Journal of allergy and clinical immunology";"Prescott SL, Tulic M, Kumah AO, Richman T, Crook M, Martino D, Dunstan JA, Novakovic B, Saffery R, Clifton VL";;"06 2011";1306886400;; 12718;"Vitamin D and allergic disease: sunlight at the end of the tunnel?";"M. Tulic";"Equipe 12, Team 12";22347615;Nutrients;"Jones AP, Tulic MK, Rueter K, Prescott SL";;"Feb 2012";1329782400;;"A role for vitamin D in the regulation of immune function was first proposed after the identification of Vitamin D receptors in lymphocytes. It has since been recognized that the active form of vitamin D, 1α,25(OH)₂D₃, has direct affects on naïve and activated helper T cells, regulatory T cells, activated B cells and dendritic cells. There is a growing body of literature linking vitamin D (serum 25(OH)D, oral intake and surrogate indicators such as latitude) to various immune-related conditions, including allergy, although the nature of this relationship is still unclear. This review explores the findings of epidemiological, clinical and laboratory research, and the potential role of vitamin D in promoting the inappropriate immune responses which underpin the rise in a broad range of immune diseases." 12716;"Evidence for age-related and individual-specific changes in DNA methylation profile of mononuclear cells during early immune development in humans.";"M. Tulic";"Equipe 12, Team 12";21814035;Epigenetics;"Martino DJ, Tulic MK, Gordon L, Hodder M, Richman TR, Metcalfe J, Prescott SL, Saffery R";;"09 2011";1314835200;;"Environment induced epigenetic effects on gene expression in early life are likely to play important roles in mediating the risk of several immune-related diseases. In order to investigate this fully, it is essential to first document temporal changes in epigenetic profile in disease-free individuals as a prelude to defining environmentally mediated changes. Mononuclear cells (MC) were collected longitudinally from a small number of females at birth, 1 year, 2.5 years and 5 years of age and examined for changes in genome-scale DNA methylation profiles using the Illumina Infinium HumanMethylation27 BeadChip array platform. MC from two males were included for comparative purposes. Flow cytometry was used to define MC cell populations in each sample in order to exclude this as the major driver of epigenetic change. The data underwent quality control and normalization within the R programming environment. Unsupervised hierarchical clustering of samples clearly delineated neonatal MC from all other ages. A further clear distinction was observed between 1 year and 5 year samples, with 2.5 year samples showing a mixed distribution between the 1 and 5 year groups. Gene ontology of probes significantly variable over the neonatal period revealed methylation changes in genes associated with cell surface receptor and signal transduction events. In the postnatal period, methylation changes were mostly associated with the development of effector immune responses and homeostasis. Unlike all other chromosomes tested, a predominantly genetic effect was identified as controlling maintenance of X-chromosome methylation profile in females, largely refractory to change over time. This data suggests that the primary driver of neonatal epigenome is determined in utero, whilst postnatally, multiple genetic and environmental factors are implicated in the development of MC epigenetic profile, particularly between the ages of 1-5 years, when the highest level of inter individual variation is apparent. This supports a model for differential sensitivity of specific individuals to disruption in the developing epigenome during the first years of life. Further studies are now needed to examine evolving epigenetic variations in specific cell populations in relation to environmental exposures, immune phenotype and subsequent disease susceptibility." 12714;"Vitamin D deficiency as a strong predictor of asthma in children.";"M. Tulic";"Equipe 12, Team 12";21986034;"International archives of allergy and immunology";"Bener A, Ehlayel MS, Tulic MK, Hamid Q";;"10 2011";1317427200;;"Epidemiological studies suggest a link between vitamin D deficiency in early life and development of asthma in later life." 12712;"Changes in thymic regulatory T-cell maturation from birth to puberty: differences in atopic children.";"M. Tulic";"Equipe 12, Team 12";22104606;"The Journal of allergy and clinical immunology";"Tulic MK, Andrews D, Crook ML, Charles A, Tourigny MR, Moqbel R, Prescott SL";;"Nov 2011";1322006400;;"Characterization of regulatory immune pathways is a research priority for both the pathogenesis of allergic disease and potential therapeutic strategies." 12710;"Genetic variations in IL28B and allergic disease in children.";"M. Tulic";"Equipe 12, Team 12";22295096;"PloS one";"Gaudieri S, Lucas M, Lucas A, McKinnon E, Albloushi H, Rauch A, di Iulio J, Martino D, Prescott SL, Tulic MK";;"01 2012";1325376000;;"Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences." 12707;"IFN-λ and IgE-mediated allergic disease: a potential future role?";"M. Tulic";"Equipe 12, Team 12";22448789;"Biomarkers in medicine";"Gaudieri S, Tulic MK, Lucas A, Lucas M";;"Mar 2012";1332892800;;"Reduced early microbial exposure has become a leading candidate to explain the rise in allergic disease, and research has focused on studying the interaction between the developing immune system and the microbial environment. However, despite intense interest, the pathways that lead to dysregulation of the immune system in allergic disease are still poorly understood. The newly described type III IFN-λ molecules were initially shown to exhibit antiviral activity, but these molecules are also likely to have an important role to play in the immune-epithelial interface, given their immunomodulatory functions and restricted receptor expression to immune and epithelial cells. Previous studies on the role of IFN-λ in allergic disease have been limited to allergic asthma. More recently, a genetic variation flanking IL28B encoding IFN-λ3 has been associated with allergic disease. Here, we examine this family and suggest how IFN-λ may be an important player in allergic disease." 12704;"Associations between maternal antioxidant intakes in pregnancy and infant allergic outcomes.";"M. Tulic";"Equipe 12, Team 12";23201845;Nutrients;"West CE, Dunstan J, McCarthy S, Metcalfe J, D'Vaz N, Meldrum S, Oddy WH, Tulic MK, Prescott SL";;"11 2012";1351728000;;"Antioxidant intakes in pregnancy may influence fetal immune programming and the risk of allergic disease. We investigated associations between maternal intakes of β-carotene, vitamin C, vitamin E, copper and zinc, and infant allergic outcomes. Antioxidant intakes of pregnant women (n = 420) assessed prospectively by a food frequency questionnaire, were examined in relation to allergic outcomes at 1 year of age (n = 300). The main relationships with allergic outcomes were seen with dietary vitamin C and copper. Specifically, higher maternal dietary vitamin C intake was associated with a reduced risk of any diagnosed infant allergic disease and wheeze. After adjustment for potential confounders the relationship with wheeze remained statistically significant. There was also an inverse linear relationship between vitamin C and food allergy. Higher dietary copper intake was associated with reduced risk of eczema, wheeze and any allergic disease. The relationship with wheeze and any allergic disease remained statistically significant in multivariate analysis, and there was also an inverse linear relationship between copper and food allergy. However, these relationships were only seen for nutrients present in food. There were no relationships between β-carotene, vitamin E or zinc and any allergic outcomes. In summary, this study suggests that maternal diet of fresh foods rich in vitamin C is associated with reduced risk of infant wheeze, and that copper intake is associated with reduced risk of several allergic outcomes." 12702;"Vitamin D in pregnancy and early life: the right target for prevention of allergic disease?";"M. Tulic";"Equipe 12, Team 12";24070045;"Expert review of clinical immunology";"Tulic MK";;"Sep 2013";1380326400;;"EVALUATION OF: Weisse et al. Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study. Allergy 68, 220-228 (2013). Allergic diseases are the most common chronic disorders of childhood. The alarming trend is that these diseases are expressed early in life and are no longer outgrown in childhood. Over the last 10 years, the rates of food allergy and eczema have continued to increase dramatically in children as part of what appears to be a 'second wave' of the allergy epidemic. Although the risk factors for allergic disease are multifactorial, the early onset has implicated lifestyle and environmental factors as significant contributors to this escalating trend. Weisse et al. present supporting evidence for vitamin D being positively associated with children's risk for food allergy or sensitization against food allergens during their first 2 years of life and argue against the use of vitamin D supplements to protect against allergy. Here, the authors provide a mechanistic insight into how high cord blood vitamin D levels can result in increased food allergy risk in children." 12698;"Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction.";"M. Tulic";"Equipe 12, Team 12";26646935;Gut;"Tulic MK, Vivinus-Nébot M, Rekima A, Rabelo Medeiros S, Bonnart C, Shi H, Walker A, Dainese R, Boyer J, Vergnolle N, Piche T, Verhasselt V";;"12 2015";1448928000;;"Abnormal gut barrier function is the basis of gut inflammatory disease. It is known that house dust mite (HDM) aero-allergens induce inflammation in respiratory mucosa. We have recently reported allergen from Dermatophagoides pteronyssinus (Der p1) to be present in rodent gut." 12694;"Early oral exposure to house dust mite allergen through breast milk: A potential risk factor for allergic sensitization and respiratory allergies in children.";"M. Tulic";"Equipe 12, Team 12";27566456;"The Journal of allergy and clinical immunology";"Baïz N, Macchiaverni P, Tulic MK, Rekima A, Annesi-Maesano I, Verhasselt V, ";;"08 2016";1470009600;; 12695;"Epigenetic Regulation in Early Childhood: A Miniaturized and Validated Method to Assess Histone Acetylation.";"M. Tulic";"Equipe 12, Team 12";26789836;"International archives of allergy and immunology";"Harb H, Amarasekera M, Ashley S, Tulic MK, Pfefferle PI, Potaczek DP, Martino D, Kesper DA, Prescott SL, Renz H";;"01 2016";1451606400;;"Chronic inflammatory diseases including allergies and asthma are the result of complex interactions between genes and environmental factors. Epigenetic mechanisms comprise a set of biochemical reactions that regulate gene expression. In order to understand the cause-effect relationship between environmental exposures and disease development, methods capable of assessing epigenetic regulation (also) in large cohorts are needed." 12692;"Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy.";"M. Tulic";"Equipe 12, Team 12";27895398;"World journal of gastroenterology";"Baird AC, Mallon D, Radford-Smith G, Boyer J, Piche T, Prescott SL, Lawrance IC, Tulic MK";;"Nov 2016";1480464000;;"To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy." 12690;"Ovalbumin in breastmilk is associated with a decreased risk of IgE-mediated egg allergy in children.";"M. Tulic";"Equipe 12, Team 12";31808162;Allergy;"Verhasselt V, Genuneit J, Metcalfe JR, Tulic MK, Rekima A, Palmer DJ, Prescott SL";;"01 2020";1577836800;; 12688;"A role for early oral exposure to house dust mite allergens through breast milk in IgE-mediated food allergy susceptibility.";"M. Tulic";"Equipe 12, Team 12";31954775;"The Journal of allergy and clinical immunology";"Rekima A, Bonnart C, Macchiaverni P, Metcalfe J, Tulic MK, Halloin N, Rekima S, Genuneit J, Zanelli S, Medeiros S, Palmer DJ, Prescott S, Verhasselt V";;"01 2020";1577836800;;"Successful prevention of food allergy requires the identification of the factors adversely affecting the capacity to develop oral tolerance to food antigen in early life." 12686;"Differential and Overlapping Effects of Melatonin and Its Metabolites on Keratinocyte Function: Bioinformatics and Metabolic Analyses.";"M. Tulic";"Equipe 12, Team 12";33920561;"Antioxidants (Basel, Switzerland)";"Stefan J, Kim TK, Schedel F, Janjetovic Z, Crossman DK, Steinbrink K, Slominski RM, Zmijewski J, Tulic MK, Reiter RJ, Kleszczyński K, Slominski AT";;"04 2021";1617235200;;"We investigated the effects of melatonin and its selected metabolites, i.e., -Acetyl--formyl-5-methoxykynurenamine (AFMK) and 6-hydroxymelatonin (6(OH)Mel), on cultured human epidermal keratinocytes (HEKs) to assess their homeostatic activities with potential therapeutic implications. RNA analysis revealed a significant number of genes with distinct and overlapping patterns, resulting in common regulation of top diseases and disorders. Gene Set Enrichment Analysis (GSEA), Reactome FIViZ, and Ingenuity Pathway Analysis (IPA) showed overrepresentation of the p53-dependent G1 DNA damage response gene set, activation of p53 signaling, and NRF2-mediated antioxidative pathways. Additionally, GSEA exhibited an overrepresentation of circadian clock and antiaging signaling gene sets by melatonin derivatives and upregulation of extension of telomere signaling in HEKs, which was subsequently confirmed by increased telomerase activity in keratinocytes, indicating possible antiaging properties of metabolites of melatonin. Furthermore, Gene Ontology (GO) showed the activation of a keratinocyte differentiation program by melatonin, and GSEA indicated antitumor and antilipidemic potential of melatonin and its metabolites. IPA also indicated the role of Protein Kinase R (PKR) in interferon induction and antiviral response. In addition, the test compounds decreased lactate dehydrogenase A () and lactate dehydrogenase C () gene expression. These results were validated by qPCR and by Seahorse metabolic assay with significantly decreased glycolysis and lactate production under influence of AFMK or 6(OH)Mel in cells with a low oxygen consumption rate. In summary, melatonin and its metabolites affect keratinocytes' functions via signaling pathways that overlap for each tested molecule with some distinctions." 12674;"Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny.";"C. Bertolotto, P. Bahadoran, R. Ballotti, S. Giuliano, S. Rocchi, T. Botton, Y. Cheli";"Equipe 01, Team 01, Equipe 12, Team 12";21278797;Oncogene;"Cheli Y, Giuliano S, Guiliano S, Botton T, Rocchi S, Hofman V, Hofman P, Bahadoran P, Bertolotto C, Ballotti R";;"01 2011";1293840000;;"In melanoma, as well as in other solid tumors, the cells within a given tumor exhibit strong morphological, functional and molecular heterogeneity that might reflect the existence of different cancer cell populations, among which are melanoma-initiating cells (MICs) with 'stemness' properties and their differentiated, fast-growing progeny. The existence of a slow-growing population might explain the resistance of melanoma to classical chemotherapies that target fast growing cells. Therefore, elucidating the biologic properties of MICs and, more importantly, the molecular mechanisms that drive the transition between MICs and their proliferating progeny needs to be addressed to develop an efficient melanoma therapy. Using B16 mouse melanoma cells and syngeneic mice, we show that the inhibition of microphthalmia-associated transcription factor (Mitf), the master regulator of melanocyte differentiation, increases the tumorigenic potential of melanoma cells and upregulates the stem cell markers Oct4 and Nanog. Notably, p27, the CDK inhibitor, is increased in Mitf-depleted cells and is required for exacerbation of the tumorigenic properties of melanoma cells. Further, a slow-growing population with low-Mitf level and high tumorigenic potential exists spontaneously in melanoma. Ablation of this population dramatically decreases tumor formation. Importantly, these data were confirmed using human melanoma cell lines and freshly isolated human melanoma cell from lymph node and skin melanoma metastasis. Taken together our data, identified Mitf and p27 as the key molecular switches that control the transition between MICs and their differentiated progeny. Eradication of low-Mitf cells might be an appealing strategy to cure melanoma." 12672;"Rac1 dynamics in the human opportunistic fungal pathogen Candida albicans.";"T. Botton";"Equipe 12, Team 12";21060846;"PloS one";"Vauchelles R, Stalder D, Botton T, Arkowitz RA, Bassilana M";;"10 2010";1285891200;;"The small Rho G-protein Rac1 is highly conserved from fungi to humans, with approximately 65% overall sequence identity in Candida albicans. As observed with human Rac1, we show that C. albicans Rac1 can accumulate in the nucleus, and fluorescence recovery after photobleaching (FRAP) together with fluorescence loss in photobleaching (FLIP) studies indicate that this Rho G-protein undergoes nucleo-cytoplasmic shuttling. Analyses of different chimeras revealed that nuclear accumulation of C. albicans Rac1 requires the NLS-motifs at its carboxyl-terminus, which are blocked by prenylation of the adjacent cysteine residue. Furthermore, we show that C. albicans Rac1 dynamics, both at the plasma membrane and in the nucleus, are dependent on its activation state and in particular that the inactive form accumulates faster in the nucleus. Heterologous expression of human Rac1 in C. albicans also results in nuclear accumulation, yet accumulation is more rapid than that of C. albicans Rac1. Taken together our results indicate that Rac1 nuclear accumulation is an inherent property of this G-protein and suggest that the requirements for its nucleo-cytoplasmic shuttling are conserved from fungi to humans." 12670;"Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy.";"P. Bahadoran, R. Ballotti, S. Rocchi, T. Botton";"Equipe 01, Team 01, Equipe 12, Team 12";23890088;"Pigment cell & melanoma research";"Botton T, Yeh I, Nelson T, Vemula SS, Sparatta A, Garrido MC, Allegra M, Rocchi S, Bahadoran P, McCalmont TH, LeBoit PE, Burton EA, Bollag G, Ballotti R, Bastian BC";;"08 2013";1375315200;;"BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib. " 12668;"Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.";"T. Botton";"Equipe 12, Team 12";24445538;"Nature communications";"Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, Lipson D, Otto G, Brennan K, Murali R, Garrido M, Miller VA, Ross JS, Berger MF, Sparatta A, Palmedo G, Cerroni L, Busam KJ, Kutzner H, Cronin MT, Stephens PJ, Bastian BC";;"Jan 2014";1390348800;;"Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas. " 12665;"Melanoma BRAF fusions--letter.";"T. Botton";"Equipe 12, Team 12";25512635;"Clinical cancer research : an official journal of the American Association for Cancer Research";"Botton T, Yeh I, Bastian BC";;"Dec 2014";1418774400;; 12664;"Activating MET kinase rearrangements in melanoma and Spitz tumours.";"T. Botton";"Equipe 12, Team 12";26013381;"Nature communications";"Yeh I, Botton T, Talevich E, Shain AH, Sparatta AJ, de la Fouchardiere A, Mully TW, North JP, Garrido MC, Gagnon A, Vemula SS, McCalmont TH, LeBoit PE, Bastian BC";;"May 2015";1432771200;;"Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist. " 12662;"Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion.";"T. Botton";"Equipe 12, Team 12";26072686;"Pigment cell & melanoma research";"Menzies AM, Yeh I, Botton T, Bastian BC, Scolyer RA, Long GV";;"07 2015";1435708800;; 12659;"Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.";"T. Botton";"Equipe 12, Team 12";26343386;"Nature genetics";"Shain AH, Garrido M, Botton T, Talevich E, Yeh I, Sanborn JZ, Chung J, Wang NJ, Kakavand H, Mann GJ, Thompson JF, Wiesner T, Roy R, Olshen AB, Gagnon A, Gray JW, Huh N, Hur JS, Busam KJ, Scolyer RA, Cho RJ, Murali R, Bastian BC";;"09 2015";1441065600;;"Desmoplastic melanoma is an uncommon variant of melanoma with sarcomatous histology, distinct clinical behavior and unknown pathogenesis. We performed low-coverage genome and high-coverage exome sequencing of 20 desmoplastic melanomas, followed by targeted sequencing of 293 genes in a validation cohort of 42 cases. A high mutation burden (median of 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers. Mutation patterns strongly implicate ultraviolet radiation as the dominant mutagen, indicating a superficially located cell of origin. Newly identified alterations included recurrent promoter mutations of NFKBIE, encoding NF-κB inhibitor ɛ (IκBɛ), in 14.5% of samples. Common oncogenic mutations in melanomas, in particular in BRAF (encoding p.Val600Glu) and NRAS (encoding p.Gln61Lys or p.Gln61Arg), were absent. Instead, other genetic alterations known to activate the MAPK and PI3K signaling cascades were identified in 73% of samples, affecting NF1, CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS and PIK3CA, some of which are candidates for targeted therapies." 12658;"CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing.";"T. Botton";"Equipe 12, Team 12";27100738;"PLoS computational biology";"Talevich E, Shain AH, Botton T, Bastian BC";;"04 2016";1459468800;;"Germline copy number variants (CNVs) and somatic copy number alterations (SCNAs) are of significant importance in syndromic conditions and cancer. Massively parallel sequencing is increasingly used to infer copy number information from variations in the read depth in sequencing data. However, this approach has limitations in the case of targeted re-sequencing, which leaves gaps in coverage between the regions chosen for enrichment and introduces biases related to the efficiency of target capture and library preparation. We present a method for copy number detection, implemented in the software package CNVkit, that uses both the targeted reads and the nonspecifically captured off-target reads to infer copy number evenly across the genome. This combination achieves both exon-level resolution in targeted regions and sufficient resolution in the larger intronic and intergenic regions to identify copy number changes. In particular, we successfully inferred copy number at equivalent to 100-kilobase resolution genome-wide from a platform targeting as few as 293 genes. After normalizing read counts to a pooled reference, we evaluated and corrected for three sources of bias that explain most of the extraneous variability in the sequencing read depth: GC content, target footprint size and spacing, and repetitive sequences. We compared the performance of CNVkit to copy number changes identified by array comparative genomic hybridization. We packaged the components of CNVkit so that it is straightforward to use and provides visualizations, detailed reporting of significant features, and export options for integration into existing analysis pipelines. CNVkit is freely available from https://github.com/etal/cnvkit. " 12656;"Hybrid Capture-Based Tumor Sequencing and Copy Number Analysis to Confirm Origin of Metachronous Metastases in Mutant Cholangiocarcinoma Harboring a Novel Fusion.";"T. Botton";"Equipe 12, Team 12";29622700;"The oncologist";"Lim HC, Montesion M, Botton T, Collisson EA, Umetsu SE, Behr SC, Gordan JD, Stephens PJ, Kelley RK";;"04 2018";1522540800;;"Biliary tract cancers such as cholangiocarcinoma represent a heterogeneous group of cancers that can be difficult to diagnose. Recent comprehensive genomic analyses in large cholangiocarcinoma cohorts have defined important molecular subgroups within cholangiocarcinoma that may relate to anatomic location and etiology [1], [2], [3], [4] and may predict responsiveness to targeted therapies in development [5], [6], [7]. These emerging data highlight the potential for tumor genomics to inform diagnosis and treatment options in this challenging tumor type. We report the case of a patient with a germline mutation who presented with a cholangiocarcinoma driven by the novel fusion. Hybrid capture-based DNA sequencing and copy number analysis performed as part of clinical care demonstrated that two later-occurring tumors were clonally derived from the primary cholangiocarcinoma rather than distinct new primaries, revealing an unusual pattern of late metachronous metastasis. We discuss the clinical significance of these genetic alterations and their relevance to therapeutic strategies." 12654;"NTRK3 kinase fusions in Spitz tumours.";"T. Botton";"Equipe 12, Team 12";27477320;"The Journal of pathology";"Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon A, Vemula SS, Garrido MC, Nakamaru K, Isoyama T, McCalmont TH, LeBoit PE, Bastian BC";;"Aug 2016";1470096000;;"Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd." 12652;"Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation.";"T. Botton";"Equipe 12, Team 12";29990501;"Cancer cell";"Zeng H, Jorapur A, Shain AH, Lang UE, Torres R, Zhang Y, McNeal AS, Botton T, Lin J, Donne M, Bastian IN, Yu R, North JP, Pincus L, Ruben BS, Joseph NM, Yeh I, Bastian BC, Judson RL";;"Jul 2018";1531267200;;"Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16 permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2." 12650;"Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses.";"R. Ballotti, S. Rocchi, T. Botton";"Equipe 01, Team 01, Equipe 12, Team 12";31618628;"Cell reports";"Botton T, Talevich E, Mishra VK, Zhang T, Shain AH, Berquet C, Gagnon A, Judson RL, Ballotti R, Ribas A, Herlyn M, Rocchi S, Brown KM, Hayward NK, Yeh I, Bastian BC";;"Oct 2019";1571270400;;"BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions." 12648;"Identification by mutation of the tyrosine residues in the insulin receptor substrate-1 affecting association with the tyrosine phosphatase 2C and phosphatidylinositol 3-kinase.";"S. Tartare-Deckert, S. Rocchi";"Equipe 11, Team 11, Equipe 12, Team 12";7588273;Endocrinology;"Rocchi S, Tartare-Deckert S, Mothe I, Van Obberghen E";;"Dec 1995";817776000;;"The insulin receptor substrate-1 (IRS-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Phosphorylated IRS-1 acts as a docking protein for Src homology-2 (SH2) domain-containing proteins involved in insulin signaling. These include in vivo the regulatory subunit p85 of the phosphatidylinositol 3-kinase (PI3-K) and the phosphotyrosine phosphatase-2C (PTP2C). In this report, we examined which tyrosine residues of IRS-1 are required for the interactions of IRS-1 with PI3-K and PTP2C. To address this issue, we constructed different rat IRS-1 mutants containing mutations in the tyrosine residues that interact with the SH2 domains of PI3-K and PTP2C in vitro. Each of the IRS-1 mutants obtained have been transiently expressed in 293 EBNA cells to study their ability to interact with PI3-K and PTP2C in vivo. Our results demonstrate that mutation of tyrosine 608 affects the PI3-K activity associated with IRS-1, suggesting that this tyrosine is likely to be a principal site of interaction with the SH2 domains of p85 in response to insulin. Furthermore, we found that mutation of tyrosines 1172 and 1222 totally prevents the insulin-induced association of IRS-1 with the SH2 domains of PTP2C, demonstrating that both tyrosines 1172 and 1222 are key elements in the binding sites for the SH2 domains of PTP2C. Finally, we found that the ability of purified PTP2C to dephosphorylate IRS-1 is dependent on the association of PTP2C with phosphorylated IRS-1." 12646;"Interaction of SH2-containing protein tyrosine phosphatase 2 with the insulin receptor and the insulin-like growth factor-I receptor: studies of the domains involved using the yeast two-hybrid system.";"S. Tartare-Deckert, S. Rocchi";"Equipe 11, Team 11, Equipe 12, Team 12";8895367;Endocrinology;"Rocchi S, Tartare-Deckert S, Sawka-Verhelle D, Gamha A, van Obberghen E";;"Nov 1996";846806400;;"Activated insulin and insulin-like growth factor-I receptors transmit downstream signals via the insulin receptor substrate (IRS-1 and IRS-2) and a series of proteins containing Src homology-2 (SH2) domains, including SH2-containing protein tyrosine phosphatase 2 (SHP-2). In the present study, we analyzed in the yeast two-hybrid system the interaction between both receptors and SHP-2. We found that a catalytically inactive SHP-2 is able to bind to tyrosine-phosphorylated IR beta-subunit and IGF-I R beta-subunit. However, with wild-type SHP-2, we were unable to detect an interaction with these receptors, which is likely to be due to dephosphorylation of the receptors by the phosphatase. Further, our results demonstrate that tyrosine 1322 of the IR, and the corresponding tyrosine 1316 of the IGF-I R are implicated in the interaction with the SHP-2 SH2 domain. At the level of SHP-2, it would appear that both SH2 domains of SHP-2 are necessary for optimal association with either receptor. Finally, using several insulin and IGF-I receptor mutants, we found that the kinase regulatory autophosphorylation sites play an important role in the interaction of these receptors with the SHP-2 SH2 domain. These sites are also necessary for the interaction with full-length IRS-1. We conclude that 1) the IR and IGF-I R directly interact with SHP-2; 2) the C-terminus autophosphorylation of these receptors sites are involved in this process; and 3) the receptors' kinase autophosphorylation sites are necessary for the interaction with SHP-2 and also with IRS-1." 12642;"Surfing the insulin signaling web.";"S. Giorgetti-Peraldi, S. Tartare-Deckert, S. Rocchi";"Equipe 07, Team 07, Equipe 11, Team 11, Equipe 12, Team 12";11737239;"European journal of clinical investigation";"Van Obberghen E, Baron V, Delahaye L, Emanuelli B, Filippa N, Giorgetti-Peraldi S, Lebrun P, Mothe-Satney I, Peraldi P, Rocchi S, Sawka-Verhelle D, Tartare-Deckert S, Giudicelli J";;"Dec 2001";1008115200;;"The diverse biological actions of insulin and insulin-like growth factor I (IGF-I) are initiated by binding of the polypeptides to their respective cell surface tyrosine kinase receptors. These activated receptors phosphorylate a series of endogenous substrates on tyrosine, amongst which the insulin receptor substrate (IRS) proteins are the best characterized. Their phosphotyrosine-containing motifs become binding sites for Src homology 2 (SH2) domains on proteins such as SH2 domain-containing protein-tyrosine-phosphatase (SHP)-2/Syp, growth factor receptor bound-2 protein, (Grb-2), and phosphatidyl inositol 3 kinase (PI3 kinase), which participate in activation of specific signaling cascades. However, the IRS molecules are not only platforms for signaling molecules, they also orchestrate the generation of signal specificity, integration of signals induced by several extracellular stimuli, and signal termination and modulation. An extensive review is beyond the scope of the present article, which will be centered on our own contribution and reflect our biases." 12640;"HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1.";"G. Robert, M. Deckert, P. Abbe, R. Ballotti, S. Tartare-Deckert";"Equipe 02, Team 02, Equipe 11, Team 11, Equipe 12, Team 12, Equipe 01, Team 01";15608673;Oncogene;"Gaggioli C, Deckert M, Robert G, Abbe P, Batoz M, Ehrengruber MU, Ortonne JP, Ballotti R, Tartare-Deckert S";;"Dec 2004";1103587200;;"The matrix fibronectin protein is a multifunctional adhesive molecule that promotes migration and invasiveness of many tumors including melanomas. Increased fibronectin synthesis has been associated with the metastatic potential of melanoma cells; however, the molecular mechanisms underlying fibronectin overexpression during melanoma development are poorly understood. We report that hepatocyte growth factor/scatter factor (HGF) induces fibronectin expression and its extracellular assembly on the surface of melanoma cells through activation of mitogen-activated protein (MAP) kinase pathway, and induction and transcriptional activation of Early growth response-1 (Egr-1). Inhibition of B-RAF/MAP kinase pathway by dominant-negative mutants and by U0126-abrogated HGF-induced Egr-1, and chromatin immunoprecipitation showed that Egr-1 is bound to the fibronectin promoter in response to HGF. Exogenously expressed Egr-1 increased fibronectin levels, while blockage of Egr-1 activation by expression of the Egr-1 corepressor NAB2 interfered with the upregulation of fibronectin synthesis induced by HGF, indicating that Egr-1 exerts a significant role in fibronectin expression in response to HGF. Finally, analysis of the expression pattern of fibronectin in melanoma cells demonstrated that fibronectin levels are correlated with constitutive MAP kinase signaling. Our data define a novel mechanism that might have important implications in regulation of melanoma progression by autocrine HGF signaling or by constitutive activation of MAP kinase pathway." 12630;"[SH3BP2 heterozygous mutation amplifies macrophage inflammatory responses to infection in a mouse model of cherubism].";"M. Deckert, V. PROD'HOMME";"Equipe 11, Team 11";26152156;"Medecine sciences : M/S";"Deckert M, Prod'Homme V";;"07 2015";1435708800;; 12607;"Specific expression of BMP2/4 ortholog in biomineralizing tissues of corals and action on mouse BMP receptor.";"G. Beranger";"Equipe 12, Team 12";18795368;"Marine biotechnology (New York, N.Y.)";"Zoccola D, Moya A, Béranger GE, Tambutté E, Allemand D, Carle GF, Tambutté S";;"09 2008";1220227200;;"Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta superfamily, and have been identified by their ability to induce bone formation in vertebrates. The biomineral-forming process, called biomineralization, is a widespread process, present in all kingdoms of living organisms and among which stony corals are one of the major groups of calcifying animals. Here, we report the presence of a BMP2/4 ortholog in eight species of adult corals. The synthesis of such a protein by the calcifying epithelium of corals suggests that coral BMP2/4 plays a role in skeletogenesis, making BMP the first common protein involved in biomineralization among Eumetazoans. In addition we show that recombinant coral BMP2/4 is able to inhibit human BMP2-induced osteoblastic differentiation in mesenchymal C2C12 cells. We suggest that this inhibition results from a competition between coral BMP2/4 and human BMP2, indicating conservation of binding affinity of BMP and its receptor during evolution from corals to vertebrates. Further studies are needed to understand interactions between coral BMP2/4 and its receptors, and, thus, the action of BMP2/4 in adult corals." 12605;"Differentiation of Human Adipose-Derived Stem Cells into ""Brite"" (Brown-in-White) Adipocytes.";"G. Beranger";"Equipe 12, Team 12";22654831;"Frontiers in endocrinology";"Pisani DF, Djedaini M, Beranger GE, Elabd C, Scheideler M, Ailhaud G, Amri EZ";;"Jun 2012";1338595200;;"It is well established now that adult humans possess active brown adipose tissue (BAT) which represents a potential pharmacological target to combat obesity and associated diseases. Moreover thermogenic brown-like adipocytes (""brite adipocytes"") appear also in mouse white adipose tissue (WAT) upon β3-adrenergic stimulation. We had previously shown that human multipotent adipose-derived stem cells (hMADS) are able to differentiate into cells which exhibit the key properties of human white adipocytes, and then to convert into functional brown adipocytes upon PPARγ activation. In light of a wealth of data indicating that thermogenic adipocytes from BAT and WAT have a distinct cellular origin, we have characterized at the molecular level UCP1 positive hMADS adipocytes from both sexes as brite adipocytes. Conversion of white to brown hMADS adipocytes is dependent on PPARγ activation with rosiglitazone as the most potent agonist and is inhibited by a PPARγ antagonist. In contrast to mouse cellular models, hMADS cells conversion into brown adipocytes is weakly induced by BMP7 treatment and not modulated by activation of the Hedgehog pathway. So far no primary or clonal precursor cells of human brown adipocytes have been obtained that can be used as a tool to develop therapeutic drugs and to gain further insights into the molecular mechanisms of brown adipogenesis in humans. Thus hMADS cells represent a suitable human cell model to delineate the formation and/or the uncoupling capacity of brown/brite adipocytes that could help to dissipate caloric excess intake among individuals." 12601;"In vitro brown and ""brite""/""beige"" adipogenesis: human cellular models and molecular aspects.";"G. Beranger";"Equipe 12, Team 12";23146742;"Biochimica et biophysica acta";"Beranger GE, Karbiener M, Barquissau V, Pisani DF, Scheideler M, Langin D, Amri EZ";;"11 2012";1351728000;;"Brown adipose tissue (BAT) has long been thought to be absent or very scarce in human adults so that its contribution to energy expenditure was not considered as relevant. The recent discovery of thermogenic BAT in human adults opened the field for innovative strategies to combat overweight/obesity and associated diseases. This energy-dissipating function of BAT is responsible for adaptive thermogenesis in response to cold stimulation. In this context, adipocytes can be converted, within white adipose tissue (WAT), into multilocular adipocytes expressing UCP1, a mitochondrial protein that plays a key role in heat production by uncoupling the activity of the respiratory chain from ATP synthesis. These adipocytes have been named ""brite"" or ""beige"" adipocytes. Whereas BAT has been studied for a long time in murine models both in vivo and in vitro, there is now a strong demand for human cellular models to validate and/or identify critical factors involved in the induction of a thermogenic program within adipocytes. In this review we will discuss the different human cellular models described in the literature and what is known regarding the regulation of their differentiation and/or activation process. In addition, the role of microRNAs as novel regulators of brown/""brite"" adipocyte differentiation and conversion will be depicted. Finally, investigation of both the conversion and the metabolism of white-to-brown converted adipocytes is required for the development of therapeutic strategies targeting overweight/obesity and associated diseases. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease." 12597;"Oxytocin reverses ovariectomy-induced osteopenia and body fat gain.";"G. Beranger";"Equipe 12, Team 12";24506069;Endocrinology;"Beranger GE, Pisani DF, Castel J, Djedaini M, Battaglia S, Amiaud J, Boukhechba F, Ailhaud G, Michiels JF, Heymann D, Luquet S, Amri EZ";;"02 2014";1391212800;;"Osteoporosis and overweight/obesity constitute major worldwide public health burdens that are associated with aging. A high proportion of women develop osteoporosis and increased intraabdominal adiposity after menopause. which leads to bone fractures and metabolic disorders. There is no efficient treatment without major side effects for these 2 diseases. We previously showed that the administration of oxytocin (OT) normalizes ovariectomy-induced osteopenia and bone marrow adiposity in mice. Ovariectomized mice, used as an animal model mimicking menopause, were treated with OT or vehicle. Trabecular bone parameters and fat mass were analyzed using micro-computed tomography. Herein, we show that this effect on trabecular bone parameters was mediated through the restoration of osteoblast/osteoclast cross talk via the receptor activator of nuclear factor-κB ligand /osteoprotegerin axis. Moreover, the daily administration of OT normalized body weight and intraabdominal fat depots in ovariectomized mice. Intraabdominal fat mass is more sensitive to OT that sc fat depots, and this inhibitory effect is mediated through inhibition of adipocyte precursor's differentiation with a tendency to lower adipocyte size. OT treatment did not affect food intake, locomotors activity, or energy expenditure, but it did promote a shift in fuel utilization favoring lipid oxidation. In addition, the decrease in fat mass resulted from the inhibition of the adipose precursor's differentiation. Thus, OT constitutes an effective strategy for targeting osteopenia, overweight, and fat mass redistribution without any detrimental effects in a mouse model mimicking the menopause. " 12598;"Chondrogenic potential of stem cells derived from adipose tissue: a powerful pharmacological tool.";"G. Beranger";"Equipe 12, Team 12";24134848;"Biochemical and biophysical research communications";"Roux C, Pisani DF, Yahia HB, Djedaini M, Beranger GE, Chambard JC, Ambrosetti D, Michiels JF, Breuil V, Ailhaud G, Euller-Ziegler L, Amri EZ";;"10 2013";1380585600;;"Chondrogenesis has been widely investigated in vitro using bone marrow-derived mesenchymal stromal cells (BM-MSCs) or primary chondrocytes. However, their use raises some issues partially circumvented by the availability of Adipose tissue-derived MSCs. Herein; we characterized the chondrogenic potential of human Multipotent Adipose-Derived Stem (hMADS) cells, and their potential use as pharmacological tool. hMADS cells are able to synthesize matrix proteins including COMP, Aggrecan and type II Collagen. Furthermore, hMADS cells express BMP receptors in a similar manner to BM-MSC, and BMP6 treatment of differentiated cells prevents expression of the hypertrophic marker type X Collagen. We tested whether IL-1β and nicotine could impact chondrocyte differentiation. As expected, IL-1β induced ADAMTS-4 gene expression and modulated negatively chondrogenesis while these effects were reverted in the presence of the IL-1 receptor antagonist. Nicotine, at concentrations similar to those observed in blood of smokers, exhibited a dose dependent increase of Aggrecan expression, suggesting an unexpected protective effect of the drug under these conditions. Therefore, hMADS cells represent a valuable tool for the analysis of in vitro chondrocyte differentiation and to screen for potentially interesting pharmacological drugs. " 12595;"The ω6-fatty acid, arachidonic acid, regulates the conversion of white to brite adipocyte through a prostaglandin/calcium mediated pathway.";"G. Beranger";"Equipe 12, Team 12";25506549;"Molecular metabolism";"Pisani DF, Ghandour RA, Beranger GE, Le Faouder P, Chambard JC, Giroud M, Vegiopoulos A, Djedaini M, Bertrand-Michel J, Tauc M, Herzig S, Langin D, Ailhaud G, Duranton C, Amri EZ";;"Dec 2014";1418688000;;"Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases." 12593;"Oxytocin reverses osteoporosis in a sex-dependent manner.";"G. Beranger";"Equipe 12, Team 12";26042090;"Frontiers in endocrinology";"Beranger GE, Djedaini M, Battaglia S, Roux CH, Scheideler M, Heymann D, Amri EZ, Pisani DF";;"05 2015";1430438400;;"The increase of life expectancy has led to the increase of age-related diseases such as osteoporosis. Osteoporosis is characterized by bone weakening promoting the occurrence of fractures with defective bone regeneration. Men aged over 50 have a prevalence for osteoporosis of 20%, which is related to a decline in sex hormones occurring during andropause or surgical orchidectomy. As we previously demonstrated in a mouse model for menopause in women that treatment with the neurohypophyseal peptide hormone oxytocin (OT) normalizes body weight and prevents the development of osteoporosis, herein we addressed the effects of OT in male osteoporosis. Thus, we treated orchidectomized mice, an animal model suitable for the study of male osteoporosis, for 8 weeks with OT and then analyzed trabecular and cortical bone parameters as well as fat mass using micro-computed tomography. Orchidectomized mice displayed severe bone loss, muscle atrophy accompanied by fat mass gain as expected in andropause. Interestingly, OT treatment in male mice normalized fat mass as it did in female mice. However, although OT treatment led to a normalization of bone parameters in ovariectomized mice, this did not happen in orchidectomized mice. Moreover, loss of muscle mass was not reversed in orchidectomized mice upon OT treatment. All of these observations indicate that OT acts on fat physiology in both sexes, but in a sex specific manner with regard to bone physiology. " 12591;"Let-7i-5p represses brite adipocyte function in mice and humans.";"G. Beranger";"Equipe 12, Team 12";27345691;"Scientific reports";"Giroud M, Karbiener M, Pisani DF, Ghandour RA, Beranger GE, Niemi T, Taittonen M, Nuutila P, Virtanen KA, Langin D, Scheideler M, Amri EZ";;"Jun 2016";1467072000;;"In response to cold or β3-adrenoreceptor stimulation brown adipose tissue (BAT) promotes non-shivering thermogenesis, leading to energy dissipation. BAT has long been thought to be absent or scarce in adult humans. The recent discovery of thermogenic brite/beige adipocytes has opened the way to development of novel innovative strategies to combat overweight/obesity and associated diseases. Thus it is of great interest to identify regulatory factors that govern the brite adipogenic program. Here, we carried out global microRNA (miRNA) expression profiling on human adipocytes to identify miRNAs that are regulated upon the conversion from white to brite adipocytes. Among the miRNAs that were differentially expressed, we found that Let-7i-5p was down regulated in brite adipocytes. A detailed analysis of the Let-7i-5p levels showed an inverse expression of UCP1 in murine and human brite adipocytes both in vivo and in vitro. Functional studies with Let-7i-5p mimic in human brite adipocytes in vitro revealed a decrease in the expression of UCP1 and in the oxygen consumption rate. Moreover, the Let-7i-5p mimic when injected into murine sub-cutaneous white adipose tissue inhibited partially β3-adrenergic activation of the browning process. These results suggest that the miRNAs Let-7i-5p participates in the recruitment and the function of brite adipocytes." 12579;"Focus on cutaneous and uveal melanoma specificities.";"C. Bertolotto, G. Beranger, R. Ballotti";"Equipe 01, Team 01, Equipe 12, Team 12";28512236;"Genes & development";"Pandiani C, Béranger GE, Leclerc J, Ballotti R, Bertolotto C";;"May 2017";1495065600;;"Cutaneous melanoma (CM) and uveal melanoma (UM) derive from cutaneous and uveal melanocytes that share the same embryonic origin and display the same cellular function. However, the etiopathogenesis and biological behaviors of these melanomas are very different. CM and UM display distinct landscapes of genetic alterations and show different metastatic routes and tropisms. Hence, therapeutic improvements achieved in the last few years for the treatment of CM have failed to ameliorate the clinical outcomes of patients with UM. The scope of this review is to discuss the differences in tumorigenic processes (etiologic factors and genetic alterations) and tumor biology (gene expression and signaling pathways) between CM and UM. We develop hypotheses to explain these differences, which might provide important clues for research avenues and the identification of actionable vulnerabilities suitable for the development of new therapeutic strategies for metastatic UM." 12571;"Focus on cutaneous and uveal melanoma specificities.";"C. Bertolotto, R. Ballotti";"Equipe 01, Team 01";28512236;"Genes & development";"Pandiani C, Béranger GE, Leclerc J, Ballotti R, Bertolotto C";;"May 2017";1495065600;;"Cutaneous melanoma (CM) and uveal melanoma (UM) derive from cutaneous and uveal melanocytes that share the same embryonic origin and display the same cellular function. However, the etiopathogenesis and biological behaviors of these melanomas are very different. CM and UM display distinct landscapes of genetic alterations and show different metastatic routes and tropisms. Hence, therapeutic improvements achieved in the last few years for the treatment of CM have failed to ameliorate the clinical outcomes of patients with UM. The scope of this review is to discuss the differences in tumorigenic processes (etiologic factors and genetic alterations) and tumor biology (gene expression and signaling pathways) between CM and UM. We develop hypotheses to explain these differences, which might provide important clues for research avenues and the identification of actionable vulnerabilities suitable for the development of new therapeutic strategies for metastatic UM." 12561;"Focus on cutaneous and uveal melanoma specificities.";"C. Bertolotto, R. Ballotti";"Equipe 01, Team 01";28512236;"Genes & development";"Pandiani C, Béranger GE, Leclerc J, Ballotti R, Bertolotto C";;"May 2017";1495065600;;"Cutaneous melanoma (CM) and uveal melanoma (UM) derive from cutaneous and uveal melanocytes that share the same embryonic origin and display the same cellular function. However, the etiopathogenesis and biological behaviors of these melanomas are very different. CM and UM display distinct landscapes of genetic alterations and show different metastatic routes and tropisms. Hence, therapeutic improvements achieved in the last few years for the treatment of CM have failed to ameliorate the clinical outcomes of patients with UM. The scope of this review is to discuss the differences in tumorigenic processes (etiologic factors and genetic alterations) and tumor biology (gene expression and signaling pathways) between CM and UM. We develop hypotheses to explain these differences, which might provide important clues for research avenues and the identification of actionable vulnerabilities suitable for the development of new therapeutic strategies for metastatic UM." 12552;"Poly(adp-ribose) polymerase-1 regulates Tracp gene promoter activity during RANKL-induced osteoclastogenesis.";;;18021007;"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research";"Beranger GE, Momier D, Rochet N, Carle GF, Scimeca JC";;"Nov 2007";1195603200;;"The Tracp gene encodes an acid phosphatase strongly upregulated during osteoclastogenesis on RANKL treatment. Using the mouse osteoclastic model RAW264.7, we studied Tracp gene expression, and we identified PARP-1 as a transcriptional repressor negatively regulated by RANKL during osteoclastogenesis." 12551;"Cloning and use of a coral 36B4 gene to study the differential expression of coral genes between light and dark conditions.";"G. Beranger";"Equipe 12, Team 12";18425549;"Marine biotechnology (New York, N.Y.)";"Moya A, Tambutté S, Béranger G, Gaume B, Scimeca JC, Allemand D, Zoccola D";;"04 2008";1207008000;;"This paper aims to validate reference genes for gene expression studies between light and dark conditions in the scleractinian coral Stylophora pistillata for future gene expression studies of the ""light-enhanced calcification"" phenomenon. For this purpose, we cloned, sequenced, and characterized a candidate reference gene, the 36B4 gene from the coral S. pistillata, and validated 36B4 and beta-actin as reference genes. To illustrate the future applications of these reference genes, we tested the dark and light expression of two photosynthetic genes (Rubisco and D1 protein of the photosystem II) and two genes encoding proteins involved in calcium transport for coral calcification (a calcium ATPase and a calcium channel). Results show that both photosynthetic genes are enhanced during the light when standardized against 36B4 and beta-actin, whereas the two genes encoding proteins involved in calcium transport are not differentially expressed between light and dark conditions. The characterization of a coral 36B4 and the establishment of such valid reference genes will be useful for future gene expression studies between diverse conditions (aposymbiotic/symbiotic, stress/control, light/dark conditions) in scleractinian corals." 12547;"Monocytes differentiation upon treatment with a peptide corresponding to the C-terminus of activated T cell-expressed Tirc7 protein.";;;22015593;"Journal of cellular physiology";"Mouline CC, Beranger GE, Schmid-Antomarchi H, Quincey D, Momier D, Boukhechba F, Carle GF, Rochet N, Scimeca JC";;"Oct 2011";1319241600;;"Atp6v0a3 gene encodes for two alternative products, Tirc7 and a3 proteins, which are differentially expressed in activated T cells and resorbing osteoclasts, respectively. Tirc7 plays a central role in T cell activation, while a3 protein is critical for osteoclast-mediated bone matrix resorption. Based on the large body of evidences documenting the relationships between T cells and osteoclasts, we hypothesized that the extracellular C-terminus of Tirc7 protein could directly interact with osteoclast precursor cells. To address this issue, we performed the molecular cloning of a mouse Atp6v0a3 cDNA segment encoding the last 40 amino acids of Tirc7 protein, and we used this peptide as a ligand added to mouse osteoclast precursor cells. We evidenced that Tirc7-Cter peptide induced the differentiation of RAW264.7 cells into osteoclast-like cells, stimulated an autocrine/paracrine regulatory loop potentially involved in osteoclastic differentiation control, and strongly up-regulated F4/80 protein expression within multinucleated osteoclast-like cells. Using a mouse bone marrow-derived CD11b(+) cell line, or total bone marrow primary cells, we observed that similarly to Rankl, Tirc7-Cter peptide induced the formation of TRACP-positive large multinucleated cells. At last, using mouse primary monocytes purified from total bone marrow, we determined that Tirc7-Cter peptide induced the appearance of small multinucleated cells (3-4 nuclei), devoid of resorbing activity, and which displayed modulations of dendritic cell marker genes expression. In conclusion, we report for the first time on biological effects mediated by a peptide corresponding to the C-terminus of Tirc7 protein, which interfere with monocytic differentiation pathways." 12539;"Antagonistic functions of LMNA isoforms in energy expenditure and lifespan.";"G. Beranger";"Equipe 12, Team 12";24639560;"EMBO reports";"Lopez-Mejia IC, de Toledo M, Chavey C, Lapasset L, Cavelier P, Lopez-Herrera C, Chebli K, Fort P, Beranger G, Fajas L, Amri EZ, Casas F, Tazi J";;"03 2014";1393632000;;"Alternative RNA processing of LMNA pre-mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson-Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging. Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. In contrast, progerin-expressing mice show increased energy metabolism and are lipodystrophic. Increased mitochondrial biogenesis is found in adipose tissue from HGPS-like mice, whereas lamin C-only mice have fewer mitochondria. Consistently, transcriptome analyses of adipose tissues from HGPS and lamin C-only mice reveal inversely correlated expression of key regulators of energy expenditure, including Pgc1a and Sfrp5. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals." 12533;"The K+ channel TASK1 modulates β-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway.";"N. Mazure";"Equipe 05, Team 05";26527067;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Pisani DF, Beranger GE, Corinus A, Giroud M, Ghandour RA, Altirriba J, Chambard JC, Mazure NM, Bendahhou S, Duranton C, Michiels JF, Frontini A, Rohner-Jeanrenaud F, Cinti S, Christian M, Barhanin J, Amri EZ";;"11 2015";1446336000;;"Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired β3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of β-adrenergic receptor signaling." 12529;"Focus on cutaneous and uveal melanoma specificities.";"C. Bertolotto, R. Ballotti";"Equipe 01, Team 01";28512236;"Genes & development";"Pandiani C, Béranger GE, Leclerc J, Ballotti R, Bertolotto C";;"May 2017";1495065600;;"Cutaneous melanoma (CM) and uveal melanoma (UM) derive from cutaneous and uveal melanocytes that share the same embryonic origin and display the same cellular function. However, the etiopathogenesis and biological behaviors of these melanomas are very different. CM and UM display distinct landscapes of genetic alterations and show different metastatic routes and tropisms. Hence, therapeutic improvements achieved in the last few years for the treatment of CM have failed to ameliorate the clinical outcomes of patients with UM. The scope of this review is to discuss the differences in tumorigenic processes (etiologic factors and genetic alterations) and tumor biology (gene expression and signaling pathways) between CM and UM. We develop hypotheses to explain these differences, which might provide important clues for research avenues and the identification of actionable vulnerabilities suitable for the development of new therapeutic strategies for metastatic UM." 12527;"Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells.";"C. Bertolotto, H. Bzioueche, R. Ballotti, Y. Cheli, G. Beranger";"Equipe 01, Team 01, Equipe 12, Team 12";29515254;"Cell death and differentiation";"El-Hachem N, Habel N, Naiken T, Bzioueche H, Cheli Y, Beranger GE, Jaune E, Rouaud F, Nottet N, Reinier F, Gaudel C, Colosetti P, Bertolotto C, Ballotti R";;"Mar 2018";1520553600;;"HACE1 is an E3 ubiquitin ligase described as a tumour suppressor because HACE1-knockout mice develop multi-organ, late-onset cancers and because HACE1 expression is lost in several neoplasms, such as Wilms' tumours and colorectal cancer. However, a search of public databases indicated that HACE1 expression is maintained in melanomas. We demonstrated that HACE1 promoted melanoma cell migration and adhesion in vitro and was required for mouse lung colonisation by melanoma cells in vivo. Transcriptomic analysis of HACE1-depleted melanoma cells revealed an inhibition of ITGAV and ITGB1 as well changes in other genes involved in cell migration. We revealed that HACE1 promoted the K27 ubiquitination of fibronectin and regulated its secretion. Secreted fibronectin regulated ITGAV and ITGB1 expression, as well as melanoma cell adhesion and migration. Our findings disclose a novel molecular cascade involved in the regulation of fibronectin secretion, integrin expression and melanoma cell adhesion. By controlling this cascade, HACE1 displays pro-tumoural properties and is an important regulator of melanoma cell invasive properties." 12525;"Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype.";"C. Bertolotto, G. Beranger, K. Bille, L. Yvan-Charvet, M. Cerezo, M. Ohanna, R. Ballotti, S. Rocchi";"Equipe 01, Team 01, Equipe 12, Team 12, Equipe 13, Team 13, Equipe 11, Team 11";29567766;"Genes & development";"Ohanna M, Cerezo M, Nottet N, Bille K, Didier R, Beranger G, Mograbi B, Rocchi S, Yvan-Charvet L, Ballotti R, Bertolotto C";;"03 2018";1519862400;;"In BRAF melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies. Therefore, NAMPT, the key enzyme in the NAD salvage pathway, appears as a rational target in targeted therapy-resistant melanoma cells and a key player in phenotypic plasticity of melanoma cells." 12523;"FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells.";"C. Bertolotto, F. SOYSOUVANH, G. Beranger, R. Ballotti, S. Giuliano";"Equipe 01, Team 01, Team 08, Equipe 08, Equipe 12, Team 12";33462405;"Cell death and differentiation";"Habel N, El-Hachem N, Soysouvanh F, Hadhiri-Bzioueche H, Giuliano S, Nguyen S, Horák P, Gay AS, Debayle D, Nottet N, Béranger G, Paillerets BB, Bertolotto C, Ballotti R";;"01 2021";1609459200;;"Ubiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells." 12521;"Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease.";"A. Martel, C. Husser, C. Bertolotto, G. Beranger, K. Bille, M. IRONDELLE, M. Dalmasso, R. Ballotti, S. Nahon-Esteve, S. Baillif, T. Strub, Y. Cheli";"Equipe 01, Team 01, Equipe 12, Team 12";33462406;"Cell death and differentiation";"Pandiani C, Strub T, Nottet N, Cheli Y, Gambi G, Bille K, Husser C, Dalmasso M, Béranger G, Lassalle S, Magnone V, Pédeutour F, Irondelle M, Maschi C, Nahon-Estève S, Martel A, Caujolle JP, Hofman P, LeBrigand K, Davidson I, Baillif S, Barbry P, Ballotti R, Bertolotto C";;"01 2021";1609459200;;"Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression." 12517;"Vitiligo: 30 years to put together the puzzle pieces and to give rise to a new era of therapeutic options.";"T. Passeron";"Equipe 12, Team 12";34647661;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Oct 2021";1634169600;; 12513;"Vitiligo: 30 years to put together the puzzle pieces and to give rise to a new era of therapeutic options.";"T. Passeron";"Equipe 12, Team 12";34647661;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Oct 2021";1634169600;; 12509;"Activation of the unfolded protein response in vitiligo: the missing link?";"T. Passeron";"Equipe 12, Team 12";23069909;"The Journal of investigative dermatology";"Passeron T, Ortonne JP";;"Oct 2012";1350432000;;"Vitiligo is characterized by a substantial loss of functional melanocytes in the epidermis and sometimes in hair follicles. Genetic and pathophysiological studies have provided strong evidence that vitiligo is a polygenetic, multifactorial disorder. The key roles of oxidative stress within melanocytes and anti-melanocyte immune responses have been addressed in many studies, but the relationship between these mechanisms remains unclear. In this issue, Toosi et al. report the upregulation of IL-6 and IL-8 after the activation of the unfolded protein response (UPR) following exposure of melanocytes to phenols. Their results shed light on the missing link between oxidative stress and immune responses in vitiligo." 12505;[Lasers].;"T. Passeron";"Equipe 12, Team 12";23260518;"Annales de dermatologie et de venereologie";"Passeron T";;"Dec 2012";1356393600;;"Lasers are a very effective approach for treating many hyperpigmented lesions. They are the gold standard treatment for actinic lentigos and dermal hypermelanocytosis, such as Ota nevus. Becker nevus, hyperpigmented mosaicisms, and lentigines can also be successfully treated with lasers, but they could be less effective and relapses can be observed. However, lasers cannot be proposed for all types of hyperpigmentation. Thus, freckles and café-au-lait macules should not be treated as the relapses are nearly constant. Due to its complex pathophysiology, melasma has a special place in hyperpigmented dermatoses. Q-switched lasers (using standard parameters or low fluency) should not be used because of consistent relapses and the high risk of post-inflammatory hyperpigmentation. Paradoxically, targeting the vascular component of the melasma lesion with lasers could have a beneficial effect. However, these results have yet to be confirmed. In all cases, a precise diagnosis of the type of hyperpigmentation is mandatory before any laser treatment, and the limits and the potential side effects of the treatment must be clearly explained to patients." 12506;"Melasma pathogenesis and influencing factors - an overview of the latest research.";"T. Passeron";"Equipe 12, Team 12";23205539;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Dec 2012";1354665600;;"Melasma is an acquired, symmetrical hypermelanosis of the face. The pathogenesis of melasma is complex and the treatment is often challenging with frequent relapses. Genetic background, exposure to ultraviolet radiation, and female sex hormones are classical influencing factors. To the light of the recent literature, other factors could promote melasma lesions. Moreover, there are increasing evidences showing that melanocytes are not the only cells involved, and that other players probably have a key role in the development and the relapses of melasma. Identifying those associated factors should provide new targets for a more efficient treatment of melasma and a better prevention of the relapses." 12502;Lasers.;"T. Passeron";"Equipe 12, Team 12";23522632;"Annales de dermatologie et de venereologie";"Passeron T";;"Mar 2013";1364256000;;"Lasers are a very effective approach for treating many hyperpigmented lesions. They are the gold standard treatment for actinic lentigos and dermal hypermelanocytosis, such as Ota nevus. Becker nevus, hyperpigmented mosaicisms, and lentigines can also be successfully treated with lasers, but they could be less effective and relapses can be observed. However, lasers cannot be proposed for all types of hyperpigmentation. Thus, freckles and café-au-lait macules should not be treated as the relapses are nearly constant. Due to its complex pathophysiology, melasma has a special place in hyperpigmented dermatoses. Q-switched lasers (using standard parameters or low fluency) should not be used because of consistent relapses and the high risk of post-inflammatory hyperpigmentation. Paradoxically, targeting the vascular component of the melasma lesion with lasers could have a beneficial effect. However, these results have yet to be confirmed. In all cases, a precise diagnosis of the type of hyperpigmentation is mandatory before any laser treatment, and the limits and the potential side effects of the treatment must be clearly explained to patients." 12500;"Secondary hyperpigmentation during interferon alfa treatment for chronic hepatitis C virus infection.";"A. TRAN, R. ANTY, T. Passeron";"Equipe 08, Team 08, Equipe 12, Team 12";23553009;"JAMA dermatology";"Tsilika K, Tran A, Trucchi R, Pop S, Anty R, Cardot-Leccia N, Lacour JP, Ortonne JP, Passeron T";;"Apr 2013";1365120000;;"Interferon alfa remains the central treatment for chronic hepatitis C virus (HCV) infection. Cases of cutaneous and mucous hyperpigmentations during interferon alfa treatment have been reported, but they are considered rare adverse effects." 12499;"Interest of confocal laser scanning microscopy for the diagnosis and treatment monitoring of demodicosis.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23659565;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Harmelin Y, Delaunay P, Erfan N, Tsilika K, Zorzi K, Passeron T, Lacour JP, Bahadoran P";;"May 2013";1368230400;; 12494;"Use of high-definition optical coherent tomography (HD-OCT) for imaging of melanoma.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23663029;"The British journal of dermatology";"Picard A, Tsilika K, Long-Mira E, Hofman P, Passeron T, Lacour JP, Bahadoran P";;"May 2013";1368489600;; 12497;"Iatrogenic kwashiorkor developing after bypass surgery.";"T. Passeron";"Equipe 12, Team 12";23659833;"Clinical and experimental dermatology";"Ghorbel HH, Broussard JF, Lacour JP, Passeron T";;"May 2013";1368230400;; 12493;"Flexural agminated eruptive nevi in Langerhans cell histiocytosis.";"C. Chiaverini, H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";23677112;"JAMA dermatology";"Surinach C, Bahadoran P, Vabres P, Chiaverini C, Montaudie H, Erfan N, Deville A, Ben Signor C, Benchetrit M, Passeron T, Lacour JP";;"May 2013";1368748800;; 12491;"Reflectance confocal microscopy features of Degos disease.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23864231;"JAMA dermatology";"Cavalié M, Tsilika K, Sillard L, Cardot-Leccia N, Passeron T, Lacour JP, Bahadoran P";;"Jul 2013";1374192000;; 12489;"Long-lasting effect of vascular targeted therapy of melasma.";"T. Passeron";"Equipe 12, Team 12";23957991;"Journal of the American Academy of Dermatology";"Passeron T";;"Aug 2013";1377043200;; 12487;"Macular eruption revealing hypomelanotic cutaneous melanoma metastases: diagnostic role of dermoscopy.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";24355285;"Journal of the American Academy of Dermatology";"Hammami-Ghorbel H, Giacchero D, Hofman V, Poissonnet G, Passeron T, Lacour JP, Bahadoran P";;"Dec 2013";1387584000;; 12485;"Treatment of port wine stains with pulsed dye laser and topical timolol: a multicenter randomized controlled trial.";"T. Passeron";"Equipe 12, Team 12";24641096;"The British journal of dermatology";"Passeron T, Maza A, Fontas E, Toubel G, Vabres P, Livideanu C, Mazer JM, Rossi B, Boukari F, Harmelin Y, Dreyfus I, Mazereeuw-Hautier J, Lacour JP";;"Mar 2014";1395273600;;"Neoangiogenesis occurs within days following laser treatment of port wine stains (PWS), and plays a central role in treatment failures. Topical use of timolol can significantly reduce the production of vascular endothelial growth factor in vitro, and in animal models." 12483;"Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";24872229;"JAMA dermatology";"Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, Lacour JP, Passeron T";;"May 2014";1401408000;;"An impaired inhibitory function of circulating CD4+CD25+ regulatory T (Treg) cells was reported to play a key role in alopecia areata (AA). We report the first use to our knowledge of low-dose interleukin 2 for treating severe AA by promoting the recruitment of Treg cells." 12479;"Treatment of linear and whorled hypermelanosis with Q-switched laser.";"T. Passeron";"Equipe 12, Team 12";25099293;"Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]";"Catherine S, Lacour JP, Passeron T";;"Aug 2014";1407456000;; 12477;"Trichoblastoma with dermoscopic features of a malignant tumor: three cases.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";25128125;"Journal of the American Academy of Dermatology";"Picard A, Tsilika K, Cardot-Leccia N, Passeron T, Lacour JP, Bahadoran P";;"Aug 2014";1408233600;; 12475;"Solar urticaria to visible light triggered by light-emitting diode therapy.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";25128130;"Journal of the American Academy of Dermatology";"Montaudié H, Lacour JP, Rostain G, Duteil L, Passeron T";;"Aug 2014";1408233600;; 12473;"Indications and limitations of afamelanotide for treating vitiligo.";"T. Passeron";"Equipe 12, Team 12";25607635;"JAMA dermatology";"Passeron T";;"Jan 2015";1421884800;; 12471;"Copper Bromide Laser vs Triple-Combination Cream for the Treatment of Melasma: A Randomized Clinical Trial.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";25715311;"JAMA dermatology";"Hammami Ghorbel H, Boukari F, Fontas E, Montaudié H, Bahadoran P, Lacour JP, Passeron T";;"Feb 2015";1424908800;; 12469;"Successful treatment of refractory neuropathic pruritus with capsaicin 8% patch: a bicentric retrospective study with long-term follow-up.";"T. Passeron";"Equipe 12, Team 12";25740045;"Acta dermato-venereologica";"Misery L, Erfan N, Castela E, Brenaut E, Lantéri-Minet M, Lacour JP, Passeron T";;"Mar 2015";1425600000;; 12463;"Comparative Methods for Improving Transepidermal Methylaminolevulinate Delivery: A Randomized Clinical Trial.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";26351818;"JAMA dermatology";"Bahadoran P, Le Duff F, Pascual T, Petit L, Martel P, Lacour JP, Passeron T";;"Sep 2015";1441843200;; 12461;"Pigmented macules of bony prominences (PMBP): A distinct presentation in patients with red hair.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";26775783;"Journal of the American Academy of Dermatology";"Marmottant E, Chiaverini C, Bessis D, Hubiche T, Mallet S, Maruani A, Abasq C, Miquel J, Cardot-Leccia N, Lacour JP, Passeron T";;"Jan 2016";1453161600;; 12457;"NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2.";"C. Bertolotto, P. Bahadoran, R. Ballotti, S. Rocchi, T. Passeron, Y. Cheli";"Equipe 01, Team 01, Equipe 12, Team 12";27225420;Oncogene;"De Donatis GM, Le Pape E, Pierron A, Cheli Y, Hofman V, Hofman P, Allegra M, Zahaf K, Bahadoran P, Rocchi S, Bertolotto C, Ballotti R, Passeron T";;"May 2016";1464307200;; 12458;"Micro holes for delivering melanocytes into the skin: an ex vivo approach.";"C. Regazzetti, T. Passeron";"Equipe 12, Team 12";27172992;"Pigment cell & melanoma research";"Regazzetti C, Alcor D, Chignon-Sicard B, Passeron T";;"May 2016";1463184000;; 12455;"Centrifugal hypomelanosis: a new clinical phenotype of Malassezia infection.";"T. Passeron";"Equipe 12, Team 12";27655069;"European journal of dermatology : EJD";"Alkhalifah A, Gari-Toussaint M, Cardot-Leccia N, Lacour JP, Passeron T";;"Sep 2016";1474588800;; 12453;"Appearance of lentigines in psoriasis patients treated with apremilast.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27846946;"Journal of the American Academy of Dermatology";"Sfecci A, Khemis A, Lacour JP, Montaudié H, Passeron T";;"Nov 2016";1479340800;; 12451;"Topical timolol for chronic wounds in patients with junctional epidermolysis bullosa.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";27846969;"Journal of the American Academy of Dermatology";"Chiaverini C, Passeron T, Lacour JP";;"Nov 2016";1479340800;; 12449;"Repigmentation in vitiligo: position paper of the Vitiligo Global Issues Consensus Conference.";"T. Passeron";"Equipe 12, Team 12";27864868;"Pigment cell & melanoma research";"Gan EY, Eleftheriadou V, Esmat S, Hamzavi I, Passeron T, Böhm M, Anbar T, Goh BK, Lan CE, Lui H, Ramam M, Raboobee N, Katayama I, Suzuki T, Parsad D, Seth V, Lim HW, van Geel N, Mulekar S, Harris J, Wittal R, Benzekri L, Gauthier Y, Kumarasinghe P, Thng ST, Silva de Castro CC, Abdallah M, Vrijman C, Bekkenk M, Seneschal J, Pandya AG, Ezzedine K, Picardo M, Taïeb A, ";;"Nov 2016";1479600000;;"The Vitiligo Global Issues Consensus Conference (VGICC), through an international e-Delphi consensus, concluded that 'repigmentation' and 'maintenance of gained repigmentation' are essential core outcome measures in future vitiligo trials. This VGICC position paper addresses these core topics in two sections and includes an atlas depicting vitiligo repigmentation patterns and color match. The first section delineates mechanisms and characteristics of vitiligo repigmentation, and the second section summarizes the outcomes of international meeting discussions and two e-surveys on vitiligo repigmentation, which had been carried out over 3 yr. Treatment is defined as successful if repigmentation exceeds 80% and at least 80% of the gained repigmentation is maintained for over 6 months. No agreement was found on the best outcome measure for assessing target or global repigmentation, therefore highlighting the limitations of e-surveys in addressing clinical measurements. Until there is a clear consensus, existing tools should be selected according to the specific needs of each study. A workshop will be conducted to address the remaining issues so as to achieve a consensus." 12447;"[Post-inflammatory hyperpigmentation].";"T. Passeron";"Equipe 12, Team 12";29452653;"Annales de dermatologie et de venereologie";"Passeron T";;"Feb 2018";1518912000;;"Post-inflammatory hyperpigmentation (PIH) is a hyperpigmentation of the skin occurring after and sometimes during an inflammatory process. Although more frequent in dark skinned individuals, PIH can be observed in any type of skin and at all ages. In most case a strong impact on the quality of life of affected individuals is observed. The pathophysiology of PIH remains largely unknown. The activation of the melanocytes occurs in the first week following the inflammation emphasizing the crucial role of early preventive measures. Photoprotection with balanced UVA and UVB protection is required. Visible light could also play a role in PIH but this remains to be demonstrated. Healing topics with anti-inflammatory properties are of interest after a skin procedure. When the risk of PIH is high or when PIH occurs, topical steroids remains the gold standard approach." 12445;"[What's new in instrumental dermatology (laser)?]";"T. Passeron";"Equipe 12, Team 12";29429504;"Annales de dermatologie et de venereologie";"Passeron T";;"Feb 2018";1518480000;;"This year, What's new in Interventional Dermatology will be dedicated to lasers and other interventional devices. Many articles have been published these past two years emphasizing how dynamic this field of dermatology is. However, most of published papers were case reports or open series. Thus, innovative approaches, prospective randomized trials and large retrospective studies were the main criteria of selection of the articles." 12443;"Interleukin 6 and high-sensitivity C-reactive protein are potential predictive markers of response to infliximab in hidradenitis suppurativa.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27986139;"Journal of the American Academy of Dermatology";"Montaudié H, Seitz-Polski B, Cornille A, Benzaken S, Lacour JP, Passeron T";;"Dec 2016";1482019200;; 12439;"Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With Cetuximab.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";28259104;"JAMA dermatology";"Picard A, Pedeutour F, Peyrade F, Saudes L, Duranton-Tanneur V, Chamorey E, Cardot-Leccia N, Sudaka A, Ettaiche M, Benchetrit M, Poissonnet G, Weinbreck N, Dadone B, Lacour JP, Passeron T, Montaudié H";;"Mar 2017";1488672000;;"Cetuximab was recently proposed for advanced cutaneous squamous cell carcinomas (cSCC); however, its efficacy is inconsistent and identification of predictive biomarkers for response is necessary." 12437;"Medical and Maintenance Treatments for Vitiligo.";"T. Passeron";"Equipe 12, Team 12";28317526;"Dermatologic clinics";"Passeron T";;"Mar 2017";1490054400;;"Medical treatments alone, or in combination with phototherapy, are key approaches for treating nonsegmental vitiligo and, to a lesser extent, segmental vitiligo. The treatments are useful for halting disease progression and have been proven effective for inducing repigmentation and decreasing risk of relapses. Although the treatments have side effects and limitations, vitiligo often induces a marked decrease in quality of life and in most cases the risk:benefit ratio is in favor of an active approach. Systemic and topical agents targeting the pathways involved in loss of melanocytes and in differentiation of melanocyte stem cells should provide more effective approaches in the near future." 12435;"Efficacy and Tolerance of Anti-Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases.";"T. Passeron";"Equipe 12, Team 12";28564695;"JAMA dermatology";"Heidelberger V, Ingen-Housz-Oro S, Marquet A, Mahevas M, Bessis D, Bouillet L, Caux F, Chapelon-Abric C, Debarbieux S, Delaporte E, Duval-Modeste AB, Fain O, Joly P, Marchand-Adam S, Monfort JB, Noël N, Passeron T, Ruivard M, Sarrot-Reynauld F, Verrot D, Bouvry D, Fardet L, Chosidow O, Sève P, Valeyre D";;"Jun 2017";1496275200;;"Evidence for the long-term efficacy and safety of anti-tumor necrosis factor α agents (anti-TNF) in treating cutaneous sarcoidosis is lacking." 12432;"Treatment of Elastosis Perforans Serpiginosa Using a Fractional Carbon Dioxide Laser.";"T. Passeron";"Equipe 12, Team 12";28746703;"JAMA dermatology";"Kelati A, Lagrange S, Le Duff F, Lacour JP, Passeron T";;"Jul 2017";1501113600;; 12431;"Clinical Outcomes of Metastatic Melanoma Treated With Checkpoint Inhibitors and Multisite Radiotherapy.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";28746710;"JAMA dermatology";"Doyen J, Picard A, Naghavi AO, Thyss A, Passeron T, Lacour JP, Montaudié H";;"Jul 2017";1501113600;; 12429;"Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance.";"B. Bailly-Maitre, E. Verhoeyen, JE. Ricci, J. Chiche, S. Marchetti, T. Passeron";"Equipe 13, Team 13, Team 03, Equipe 03, Equipe 12, Team 12";29551590;"Cell metabolism";"Rubio-Patiño C, Bossowski JP, De Donatis GM, Mondragón L, Villa E, Aira LE, Chiche J, Mhaidly R, Lebeaupin C, Marchetti S, Voutetakis K, Chatziioannou A, Castelli FA, Lamourette P, Chu-Van E, Fenaille F, Avril T, Passeron T, Patterson JB, Verhoeyen E, Bailly-Maitre B, Chevet E, Ricci JE";;"Mar 2018";1521504000;;"Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8 T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors." 12427;"Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo: A Randomized Clinical Trial.";"T. Passeron";"Equipe 12, Team 12";29617528;"JAMA dermatology";"Nguyen S, Chuah SY, Fontas E, Khemis A, Jhingan A, Thng STG, Passeron T";;"Apr 2018";1522886400;; 12425;"Painful acute thyroiditis following a first cure of Ipilimumab plus Nivolumab for metastatic melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";29916989;"Melanoma research";"Montaudié H, Picard A, Panaia-Ferrari P, Boukari F, Passeron T, Sadoul JL, Brucker-Davis F";;"Jun 2018";1529452800;; 12423;"Treatment of Severe Hailey-Hailey Disease With Apremilast.";"C. Chiaverini, H. Montaudie, T. Passeron";"Equipe 12, Team 12";30304341;"JAMA dermatology";"Kieffer J, Le Duff F, Montaudié H, Chiaverini C, Lacour JP, Passeron T";;"Oct 2018";1539216000;;"Hailey-Hailey disease (HHD) is a rare, autosomal-dominant acantholytic dermatosis characterized clinically by development of recurrent blisters and erosions in friction areas. Despite progression in our understanding of the molecular genetics of HHD, therapy remains suboptimal and there is no known cure." 12421;"Antiphospholipid Syndrome Following Pembrolizumab Treatment of Stage IIIB Unresectable Melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";30326507;"JAMA dermatology";"Sanchez A, Montaudie H, Bory P, Belgodere X, Passeron T, Lacour JP, Picard A";;"Oct 2018";1539734400;; 12419;"Filling the gap in the scoring of pigmentary disorders.";"T. Passeron";"Equipe 12, Team 12";31259449;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Jul 2019";1562025600;; 12417;"Plasma cell-directed therapies in monoclonal gammopathy-associated scleromyxedema.";"T. Passeron";"Equipe 12, Team 12";32027747;Blood;"Mahévas T, Arnulf B, Bouaziz JD, Livideanu CB, Osio A, Servy A, Cribier B, Sassolas B, Jachiet M, Michel L, Aucouturier P, Lipsker D, Frances C, Sbidian E, Rybojad M, Descamps V, D'Incan M, Humbert P, Beylot-Barry M, Passeron T, de Moreuil C, Taha RY, Hermine O, Dupuy A, Barbarot S, Debarbieux S, Carpentier O, Brault F, Schmutz JL, Thomas-Beaulieu D, Modiano P, Zarnitsky C, Lifermann F, Baubion E, Limal N, Le Bras F, Le Moigne M, Tauber M, Talbot A, Prud'homme R, Peltier S, De Masson A, Battistella M, Bagot M, Mékinian A, Fain O";;"Feb 2020";1581033600;;"Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French multicenter retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an immunoglobulin G isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4 of 33 patients (12%) (smoldering myeloma, n = 2; chronic lymphoid leukemia, n = 1; and refractory cytopenia with multilineage dysplasia, n = 1). Carpal tunnel syndrome (33%), arthralgia (25%), and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. High-dose IV immunoglobulin (HDIVig), alone or in combination with steroids, appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4 of 5 patients. Quantitative reverse-transcriptase polymerase chain reaction analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor β and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management." 12415;"First step in a new era for treatment of patients with vitiligo.";"T. Passeron";"Equipe 12, Team 12";32653058;"Lancet (London, England)";"Passeron T";;"Jul 2020";1594598400;; 12413;"The skin exposome. An exciting growing field of research.";"T. Passeron";"Equipe 12, Team 12";32677067;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Jul 2020";1595030400;; 12411;"Clinical and biological impact of the exposome on the skin.";"T. Passeron";"Equipe 12, Team 12";32677068;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Krutmann J, Andersen ML, Katta R, Zouboulis CC";;"Jul 2020";1595030400;;"The skin exposome is defined as the totality of environmental exposures over the life course that can induce or modify various skin conditions. Here, we review the impact on the skin of solar exposure, air pollution, hormones, nutrition and psychological factors. Photoageing, photocarcinogenesis and pigmentary changes are well-established consequences of chronic exposure of the skin to solar radiation. Exposure to traffic-related air pollution contributes to skin ageing. Particulate matter and nitrogen dioxide cause skin pigmentation/lentigines, while ozone causes wrinkles and has an impact on atopic eczema. Human skin is a major target of hormones, and they exhibit a wide range of biological activities on the skin. Hormones decline with advancing age influencing skin ageing. Nutrition has an impact on numerous biochemical processes, including oxidation, inflammation and glycation, which may result in clinical effects, including modification of the course of skin ageing and photoageing. Stress and lack of sleep are known to contribute to a pro-inflammatory state, which, in turn, affects the integrity of extracellular matrix proteins, in particular collagen. Hormone dysregulation, malnutrition and stress may contribute to inflammatory skin disorders, such as atopic dermatitis, psoriasis, acne and rosacea." 12409;"Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic.";"C. Chiaverini, J. Courjon, J. Contenti, T. Passeron, V. Giordanengo";"Equipe 12, Team 12, Equipe 06, Team 06, Equipe 05, Team 05";33237291;"JAMA dermatology";"Hubiche T, Cardot-Leccia N, Le Duff F, Seitz-Polski B, Giordana P, Chiaverini C, Giordanengo V, Gonfrier G, Raimondi V, Bausset O, Adjtoutah Z, Garnier M, Burel-Vandenbos F, Dadone-Montaudié B, Fassbender V, Palladini A, Courjon J, Mondain V, Contenti J, Dellamonica J, Leftheriotis G, Passeron T";;"Nov 2020";1606262400;;"Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown." 12407;"Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";34088741;"Journal for immunotherapy of cancer";"Gérard A, Doyen J, Cremoni M, Bailly L, Zorzi K, Ruetsch-Chelli C, Brglez V, Picard-Gauci A, Troin L, Esnault VLM, Passeron T, Montaudié H, Seitz-Polski B";;"Jun 2021";1622851200;;"Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma." 12405;"Vitiligo: 30 years to put together the puzzle pieces and to give rise to a new era of therapeutic options.";"T. Passeron";"Equipe 12, Team 12";34647661;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Oct 2021";1634169600;; 12401;"Paraneoplastic pemphigus presenting as erosive lichen planus.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";10233293;"The British journal of dermatology";"Passeron T, Bahadoran P, Lacour JP, Perrin C, Gilbert D, Benzaken S, Fuzibet JG, Ortonne JP";;"May 1999";926121600;; 12399;"[Psoriasis. Clinical cutaneous aspects].";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";10420895;"Presse medicale (Paris, France : 1983)";"Passeron T, Bahadoran P, Lacour JP, Ortonne JP";;"Jul 1999";933033600;;"PREDOMINANT FEATURES: Psoriasis is a frequent inflammatory dermatosis. All age groups are involved. The typical lesion is a well-limited erythemato-squamaous non-pruriginous lesion. All skin areas may be involved but each individual has preferential zones." 12396;"Lack of hypocomplementemia in chronic urticaria.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";10768665;"Archives of dermatology";"Passeron T, Bahadoran P, Pugliese P, Lacour JP, Ortonne JP";;"Apr 2000";956016000;; 12395;"Disseminated papulopustular eruption due to Mycobacterium fortuitum in an immunocompetent patient.";"T. Passeron";"Equipe 12, Team 12";10825072;"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America";"Passeron T, Desruelles F, Fosse T, Weiller M, Perrin C, Lacour JP, Ortonne JP";;"May 2000";959558400;; 12393;"Radiation myo-fasciitis.";"T. Passeron";"Equipe 12, Team 12";11028874;"Acta dermato-venereologica";"Desruelles F, Lacour JP, Chevallier P, Courdi A, Passeron T, Ortonne JP";;"Oct 2000";971308800;; 12391;"[Bordetella bronchiseptica infection in a Senegalese HIV positive patient: carrier state or illness?].";"T. Passeron";"Equipe 12, Team 12";11413848;"Presse medicale (Paris, France : 1983)";"Hovette P, Colbacchini P, Camara P, Aubron C, N'Dir MC, Passeron T";;"Jun 2001";993081600;; 12389;"Thalidomide-induced amenorrhoea: two cases.";"T. Passeron";"Equipe 12, Team 12";11422077;"The British journal of dermatology";"Passeron T, Lacour JP, Murr D, Ortonne JP";;"Jun 2001";993513600;; 12387;"[Typhoid cerebellitis].";"T. Passeron";"Equipe 12, Team 12";11819924;"Presse medicale (Paris, France : 1983)";"Aubron C, Camara P, Passeron T, Tuan JF, Wade B, Hovette P";;"Dec 2001";1007164800;; 12383;"[Salmonella enteritidis splenic abscess complicating a Plasmodium falciparum malaria attack].";"T. Passeron";"Equipe 12, Team 12";11826578;"Presse medicale (Paris, France : 1983)";"Hovette P, Camara P, Passeron T, Tuan JF, Ba K, Barberet G, Moncade F";;"Feb 2002";1012953600;;"Salmonella splenic abscesses are rare and usually occur on pre-existing lesions." 12384;"Kawasaki disease with exceptional cutaneous manifestations.";"T. Passeron";"Equipe 12, Team 12";12014395;"European journal of pediatrics";"Passeron T, Olivier V, Sirvent N, Khalfi A, Boutté P, Lacour JP";;"May 2002";1021593600;; 12381;"[Urticarial vasculitis].";"T. Passeron";"Equipe 12, Team 12";12218927;"Annales de dermatologie et de venereologie";"Angeli K, Passeron T, Lacour JP";;"Jul Jun 2002";1023408000;; 12379;"Treatment of vitiligo by topical calcipotriol.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";12046816;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Chiavérini C, Passeron T, Ortonne JP";;"Jun 2002";1023321600;;"Evaluation of the efficiency of topical calcipotriol monotherapy in vitiligo." 12377;"The new 940-nanometer diode laser: an effective treatment for leg venulectasia.";"T. Passeron";"Equipe 12, Team 12";12734507;"Journal of the American Academy of Dermatology";"Passeron T, Olivier V, Duteil L, Desruelles F, Fontas E, Ortonne JP";;"May 2003";1052352000;;"The 940-nm diode laser has been shown to be an effective treatment for leg veins." 12373;"Extensive cutaneous herpes following meningococcal meningitis: two cases.";"T. Passeron";"Equipe 12, Team 12";14632822;"The British journal of dermatology";"Passeron T, Imbert P, Colbacchini P, Dosseh A, Pasquier L, Kâ AS, Lacour JP";;"Nov 2003";1069718400;; 12374;"[Skin ageing and its prevention].";"T. Passeron";"Equipe 12, Team 12";14534483;"Presse medicale (Paris, France : 1983)";"Passeron T, Ortonne JP";;"Oct 2003";1065744000;;"INTRINSIC AND EXTRINSIC FACTORS: Skin ageing is due to the conjunction of intrinsic (chronological ageing) and extrinsic factors (fundamentally photo-ageing). The physiopathological mechanisms of intrinsic ageing rejoin those of the ageing of all the other organs. Among the intrinsic causes, tobacco and above all ultra-violet radiation, UVB and also UVA, play a preponderant role. Photo-ageing is secondary to complex mechanisms that are increasingly known. The UVB directly interact with the DNA of the cutaneous cells. The deleterious effects of UVA are principally due to the formation of free radical oxygen, which result in an alteration in the nuclear and also mitochondrial DNA, but also an activation of the enzymes, metalloproteinase, capable of damaging the extra-cellular matrix. DELETERIOUS CONSEQUENCES: The phenomena of ageing provoke the decline in defence, healing and perception mechanisms and in the thermoregulation of the skin tissue. There are numerous and often unsightly clinical manifestations. Photo-ageing can be considered as a marker of risk of photo-carcinogenesis requiring increased clinical surveillance. PREVENTIVE AND CURATIVE MEASURES: The prevention of skin ageing must be based on the use of sunscreens protecting against both UVB and UVA, but, in order for them to be effective, they require a change in general life style. There are many efficient therapeutic means, but the possible side effects must be known and explained to the patient. Retinoids, in view of their innocuousness and efficacy not only in prevention but also treatment of skin ageing, should be considered as a therapeutic option of choice." 12371;"Infectious and toxic cellulitis due to suicide attempt by subcutaneous injection of ricin.";"A. IANNELLI, T. Passeron";"Team 08, Equipe 08, Equipe 12, Team 12";14746634;"The British journal of dermatology";"Passeron T, Mantoux F, Lacour JP, Roger PM, Fosse T, Iannelli A, Ortonne JP";;"Jan 2004";1075420800;; 12369;"[First case of cutaneous plasmocytoma in Africa].";"T. Passeron";"Equipe 12, Team 12";15773188;"Dakar medical";"Passeron T, Thiam M, Colbachini P, Fall F";;"Mar 2005";1111190400;;"Cutaneous plasmacytoma are dermo-hypodermic plasmacytic infiltrations. Occurrence is quite rare. Primary plasmacytoma and metastatic plasmacytoma in myeloma are distinguished. Firm, asymptomatic unique or multiple nodules are the common clinical form. We report the first african case of cutaneous plasmacytoma occurring in an IgG myeloma. It was a 73 year-old man with history of IgG myeloma, stade III of Durie and Salmon classification. At his third chemotherapy, he presented a pre-stemal nodule growing since 15 days. Histologic examination confirmed the diagnosis of cutaneous plasmacytoma. One months later news nodules and cranial lacunas were observed. It is important for the clinician to well known this complication of myeloma because of its bad prognosis. Moreover it should make modify the therapeutic protocol, if it's possible." 12367;"Chronic anal ulceration due to nicorandil.";"T. Passeron";"Equipe 12, Team 12";14996132;"The British journal of dermatology";"Passeron T, Lacour JP, Mantoux F, Fabiani P, Dubois D, Ortonne JP";;"Mar 2004";1078444800;; 12363;"Treatment of erosive oral lichen planus by the 308 nm excimer laser.";"T. Passeron";"Equipe 12, Team 12";15022246;"Lasers in surgery and medicine";"Passeron T, Zakaria W, Ostovari N, Mantoux F, Lacour JP, Ortonne JP";;"Mar 2004";1079481600;; 12365;"Topical tacrolimus and the 308-nm excimer laser: a synergistic combination for the treatment of vitiligo.";"T. Passeron";"Equipe 12, Team 12";15381545;"Archives of dermatology";"Passeron T, Ostovari N, Zakaria W, Fontas E, Larrouy JC, Lacour JP, Ortonne JP";;"Sep 2004";1095984000;;"To compare the efficacy of combined tacrolimus and 308-nm excimer laser therapy vs 308-nm excimer laser monotherapy in treating vitiligo." 12361;"Drug rash with eosinophilia and systemic symptoms (DRESS) due to streptomycin.";"T. Passeron";"Equipe 12, Team 12";15040497;"Acta dermato-venereologica";"Passeron T, Ndir MC, Aubron C, Hovette P";;"Mar 2004";1080259200;; 12359;"[Concurrent mycetoma and chromomycosis: case report from Senegal].";"T. Passeron";"Equipe 12, Team 12";15077427;"Medecine tropicale : revue du Corps de sante colonial";"Passeron T, Barberet P, Colbachini P, Hovette P, Lacour JP";;"Apr 2004";1081900800;;"A 68-year-old cattle farmer from northern Senegal sought medical attention for tumefaction that had been progressing on the right foot and leg for 20 years. Physical examination of the right extremity revealed very firm tumefaction involving the foot and whole leg associated with numerous nodules. Bone radiographs and CT-scan of the foot and leg disclosed extensive osteolytic involvement. A specimen of squamous tissue from the top of nodules showed the presence of fumagoid cells characteristic of chromomycosis. Histologic examination after skin biopsy demonstrated fungal myocetoma. Due to the extent of involvement surgical and antifungal treatment was proposed but the patient refused to undergo surgery. Only one previous case of concurrent chromomycosis and mycetoma has been described. However the previous case involved actinomycetoma. The rarity of this combination of diseases despite their common contamination mode is due to different geographical distribution with mycetoma being found in the Sahelian region and chromomycosis in the humid equatorial region." 12357;"Treatment of vitiligo by 308-nm excimer laser: an evaluation of variables affecting treatment response.";"T. Passeron";"Equipe 12, Team 12";15334620;"Lasers in surgery and medicine";"Ostovari N, Passeron T, Zakaria W, Fontas E, Larouy JC, Blot JF, Lacour JP, Ortonne JP";;"Aug 2004";1093910400;;"To determine the true efficacy of the 308-nm excimer laser for the treatment of vitiligo, while taking into account confounding factors such as anatomic site of treatment, age, sex, skin type, MED, and duration of evolution of the vitiligo." 12353;"308-nm excimer laser therapy in alopecia areata.";"T. Passeron";"Equipe 12, Team 12";15523373;"Journal of the American Academy of Dermatology";"Zakaria W, Passeron T, Ostovari N, Lacour JP, Ortonne JP";;"Nov 2004";1099526400;; 12354;"Efficacy of the 308-nm excimer laser in the treatment of mycosis fungoides.";"T. Passeron";"Equipe 12, Team 12";15492207;"Archives of dermatology";"Passeron T, Zakaria W, Ostovari N, Perrin C, Larrouy JC, Lacour JP, Ortonne JP";;"Oct 2004";1098230400;; 12349;"Melanin pigmentary disorders: treatment update.";"T. Passeron";"Equipe 12, Team 12";15837152;"Dermatologic clinics";"Ortonne JP, Passeron T";;"Apr 2005";1113955200;;"Most of the melanin pigmentary disorders are cosmetically important and have a strong impact on the quality of life of affected individuals. This article examines recent advances in the treatment of melanin pigmentary disorder including hypermelanosis and hypomelanosis. The development of laser technologies has completed the use of the increasing number of bleaching agents in treating hyperpigmented lesions. The treatment of hypomelanotic disorders is still often disappointing, but new therapeutic options provide encouraging results." 12350;"[The 308 nm excimer laser in dermatology].";"T. Passeron";"Equipe 12, Team 12";15798552;"Presse medicale (Paris, France : 1983)";"Passeron T, Ortonne JP";;"Mar 2005";1112227200;;"THE EFFICACY OF THE 308 NM EXCIMER LASER in the treatment of common psoriasis has been demonstrated. THE DOSES USED have progressively decreased, hence, limiting the adverse events that appear redhibitory with high doses. THE ADAPTATION OF THE DOSES not to the patients themselves but to each of the plaques treated should reduce the number of sessions and the cumulated close necessary to obtain clinical remission. THE 308 NM EXCIMER LASER is effective and tolerance is good in the treatment of vitiligo. It should be proposed for limited vitiligo and essentially of the ""UV sensitive"" areas, which have shown aesthetically correct percentage of repigmentation. THE PLACE AND INTEREST of its association with other treatments, notably with topical tacrolimus, remains to be defined. Although the results obtained in the treatment of vitiligo are promising, they have to be confirmed in larger cohorts and ensure the absence of median and long term side effects. This therefore limits its use in combined treatments in the context of controlled clinical traits. THE 30 NM EXCIMER LASER IS AN EFFECTIVE AND WELL TOLERATED TREATMENT in localised and non-nodular forms of mycosis fungoid (MF). Although the number of patients treated is limited, the clinical and histological cure observed demonstrates the interest of this new technique in the treatment of MF. These results must be confirmed in a greater number of patients. THE 308 NM EXCIMER LASER is an interesting therapeutic alternative in the treatment of plaques of alopecia areata, erosive oral lichen planus, post-surgical hypopigmentation, vergetures and localised forms of atopic dermatitis. Because of the sparcity of data and in the absence of long term follow-up, it must not be proposed in first intention." 12347;"Neurogenic pulmonary oedema mimicking an anaphylactic reaction to interferon alpha-2b.";"T. Passeron";"Equipe 12, Team 12";16372499;"Clinical oncology (Royal College of Radiologists (Great Britain))";"Hyvernat H, Badia E, Passeron T, Pereira C, Roques A, Bernardin G";;"Dec 2005";1135382400;; 12345;"Lack of efficacy of tacrolimus in the treatment of vitiligo in the absence of UV-B exposure.";"T. Passeron";"Equipe 12, Team 12";16490866;"Archives of dermatology";"Ostovari N, Passeron T, Lacour JP, Ortonne JP";;"Feb 2006";1140739200;; 12343;"Prebiotics and synbiotics: two promising approaches for the treatment of atopic dermatitis in children above 2 years.";"T. Passeron";"Equipe 12, Team 12";16512804;Allergy;"Passeron T, Lacour JP, Fontas E, Ortonne JP";;"Mar 2006";1141430400;;"Appropriate use of prebiotics and optimal combinations of probiotics and prebiotics (synbiotics) could allow significantly better results to be obtained in the treatment of atopic dermatitis (AD)." 12341;"What's new in hypochromy.";"T. Passeron";"Equipe 12, Team 12";16766328;"The Journal of dermatological treatment";"Passeron T, Ortonne JP";;"Jun 2006";1150156800;;"Hypochromy is a common dermatological disorder. However, its treatment still gives unsatisfactory results. Interesting clues into the understanding of the pathophysiology of hypochromy have been recently brought about thanks to the pigmentary side effects reported with the new tyrosine kinase inhibition treatments. New therapeutic approaches to hypochromy are further discussed." 12339;"Regulation of human skin pigmentation and responses to ultraviolet radiation.";"T. Passeron";"Equipe 12, Team 12";17250543;"Pigment cell research";"Miyamura Y, Coelho SG, Wolber R, Miller SA, Wakamatsu K, Zmudzka BZ, Ito S, Smuda C, Passeron T, Choi W, Batzer J, Yamaguchi Y, Beer JZ, Hearing VJ";;"Jan 2007";1169769600;;"Pigmentation of human skin is closely involved in protection against environmental stresses, in particular exposure to ultraviolet (UV) radiation. It is well known that darker skin is significantly more resistant to the damaging effects of UV, such as photocarcinogenesis and photoaging, than is lighter skin. Constitutive skin pigmentation depends on the amount of melanin and its distribution in that tissue. Melanin is significantly photoprotective and epidermal cells in darker skin incur less DNA damage than do those in lighter skin. This review summarizes current understanding of the regulation of constitutive human skin pigmentation and responses to UV radiation, with emphasis on physiological factors that influence those processes. Further research is needed to characterize the role of skin pigmentation to reduce photocarcinogenesis and to develop effective strategies to minimize such risks." 12337;"Immunohistochemistry and in situ hybridization in the study of human skin melanocytes.";"T. Passeron";"Equipe 12, Team 12";17286807;"Experimental dermatology";"Passeron T, Coelho SG, Miyamura Y, Takahashi K, Hearing VJ";;"Feb 2007";1170979200;;"Although keratinocytes are the most numerous type of cell in the skin, melanocytes are also key players as they produce and distribute melanin that protects the skin from ultraviolet (UV) radiation. In vitro experiments on melanocytic cell lines are useful to study melanogenesis and their progression towards melanoma. However, interactions of melanocytes with keratinocytes and with other types of cells in the skin, such as fibroblasts and Langerhans cells, are also crucial. We describe two techniques, immunohistochemistry (IHC) and tissue in situ hybridization (TISH), that can be used to identify and study melanocytes in the skin and their responses to UV or other stimuli in situ. We describe a practical method to localize melanocytic antigens on formalin-fixed, paraffin-embedded tissue sections and in frozen sections using indirect immunofluorescence with conjugated secondary antibodies. In addition, we detail the use of TISH and its combination with IHC to study mRNA levels of genes expressed in the skin at cellular resolution. This methodology, along with relevant tips and troubleshooting items, are important tools to identify and study melanocytes in the skin." 12334;"[595 nm pulse dye laser therapy for viral warts: a single-blind randomized comparative study versus placebo].";"T. Passeron";"Equipe 12, Team 12";17375008;"Annales de dermatologie et de venereologie";"Passeron T, Sebban K, Mantoux F, Fontas E, Lacour JP, Ortonne JP";;"Mar 2007";1174521600;;"Pulse dye laser (PDL) appears an attractive method to treat warts. However, data concerning the efficacy of this approach are based chiefly upon open clinical studies or case reports and results vary widely from one study to another. The purpose of this study was to compare the efficacy and safety of PDL with a placebo in the treatment of a homogeneous group of patients presenting palmoplantar warts." 12333;"[Treatment of mycosis fungoides by 308 nm excimer laser: a clinical and histological study in 10 patients].";"T. Passeron";"Equipe 12, Team 12";17389845;"Annales de dermatologie et de venereologie";"Passeron T, Angeli K, Cardot-Leccia N, Perrin C, Lacour JP, Ortonne JP";;"Mar 2007";1175126400;;"Mycosis fungoides is a cutaneous T-cell lymphoma. The early stages have a good prognosis but pose therapeutic problems due to chronic disease status and the frequent recurrence of lesions. We performed a retrospective clinical and histological study in 10 patients presenting mycosis fungoides in order to evaluate the efficacy of 308 nm excimer laser in this indication." 12331;"Treatment of oral erosive lichen planus with 1% pimecrolimus cream: a double-blind, randomized, prospective trial with measurement of pimecrolimus levels in the blood.";"T. Passeron";"Equipe 12, Team 12";17438179;"Archives of dermatology";"Passeron T, Lacour JP, Fontas E, Ortonne JP";;"Apr 2007";1176854400;;"To evaluate the efficacy of 1% pimecrolimus cream in treating oral erosive lichen planus and to assess its tolerance." 12329;"Pulsed dye laser-mediated photodynamic therapy for acne inversa is not successful: a pilot study on four cases.";"T. Passeron";"Equipe 12, Team 12";19370441;"The Journal of dermatological treatment";"Passeron T, Khemis A, Ortonne JP";;"Apr 2009";1239926400;;"The relapses and the chronicity of acne inversa cause a significant impact on the quality of life of the affected patients and urge for a search of more effective treatments. We report the treatment of four consecutive acne inversa patients with pulse dye laser-mediated photodynamic therapy (PDL-PDT). Three months after the end of the treatment there was no improvement in comparison with opposite control sites. Intense pain during treatment was reported by all the patients. These cases do not support the use of PDL-PDT for treating acne inversa." 12325;"Blue pseudochromhidrosis secondary to topiramate treatment.";"T. Passeron";"Equipe 12, Team 12";19734991;"Acta dermato-venereologica";"Castela E, Thomas P, Bronsard V, Lacour JP, Ortonne JP, Passeron T";;"Sep 2009";1252368000;; 12327;"What are melanocytes really doing all day long...?";"T. Passeron";"Equipe 12, Team 12";19659579;"Experimental dermatology";"Plonka PM, Passeron T, Brenner M, Tobin DJ, Shibahara S, Thomas A, Slominski A, Kadekaro AL, Hershkovitz D, Peters E, Nordlund JJ, Abdel-Malek Z, Takeda K, Paus R, Ortonne JP, Hearing VJ, Schallreuter KU";;"07 2009";1246406400;;"Everyone knows and seems to agree that melanocytes are there to generate melanin - an intriguing, but underestimated multipurpose molecule that is capable of doing far more than providing pigment and UV protection to skin (1). What about the cell that generates melanin, then? Is this dendritic, neural crest-derived cell still serving useful (or even important) functions when no-one looks at the pigmentation of our skin and its appendages and when there is essentially no UV exposure? In other words, what do epidermal and hair follicle melanocytes do in their spare time - at night, under your bedcover? How much of the full portfolio of physiological melanocyte functions in mammalian skin has really been elucidated already? Does the presence or absence of melanocytes matter for normal epidermal and/or hair follicle functions (beyond pigmentation and UV protection), and for skin immune responses? Do melanocytes even deserve as much credit for UV protection as conventional wisdom attributes to them? In which interactions do these promiscuous cells engage with their immediate epithelial environment and who is controlling whom? What lessons might be distilled from looking at lower vertebrate melanophores and at extracutaneous melanocytes in the endeavour to reveal the 'secret identity' of melanocytes? The current Controversies feature explores these far too infrequently posed, biologically and clinically important questions. Complementing a companion viewpoint essay on malignant melanocytes (2), this critical re-examination of melanocyte biology provides a cornucopia of old, but under-appreciated concepts and novel ideas on the slowly emerging complexity of physiological melanocyte functions, and delineates important, thought-provoking questions that remain to be definitively answered by future research." 12323;"Erythema gyratum repens, not always a bad omen for patients.";"T. Passeron";"Equipe 12, Team 12";19807824;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Demonchy E, Lacour JP, Ortonne JP, Passeron T";;"10 2009";1254355200;; 12319;"[Efficacy of intravenous immunoglobulin in the treatment of scleromyxoedema].";"T. Passeron";"Equipe 12, Team 12";20110069;"Annales de dermatologie et de venereologie";"Sillard L, Passeron T, Cardot-Leccia N, Perrin C, Lacour JP, Ortonne JP";;"12 2009";1259625600;;"Scleromyxoedema is a rare disorder of unknown pathogenesis that is very difficult to treat. We report a case resistant to corticosteroid treatment but controlled by intravenous gammaglobulin (IVIG)." 12321;"[Pigmentary lasers].";"T. Passeron";"Equipe 12, Team 12";19931693;"Annales de dermatologie et de venereologie";"Passeron T, Toubel G";;"Nov 2009";1259193600;;"The pigmentary disorders are a very heterogeneous group with a high therapeutic demand from the patients. The lasers have provided a major advance in the treatment of some pigmentary lesions. The indication and the optimal parameters are actually quite well defined. However, pigmentary lasers have limits and some dermatosis can even be worsened after laser treatment. Those limitations as well as the potential side effects have to clearly be explained to the patients that often seek for a miracle cure." 12317;"308-nm excimer lamp vs. 308-nm excimer laser for treating vitiligo: a randomized study.";"T. Passeron";"Equipe 12, Team 12";20346025;"The British journal of dermatology";"Le Duff F, Fontas E, Giacchero D, Sillard L, Lacour JP, Ortonne JP, Passeron T";;"03 2010";1267401600;;"The 308-nm excimer laser and 308-nm excimer lamp have both been shown to be effective in treating vitiligo but a direct comparison has never been performed." 12314;"In vivo reflectance confocal microscopy detects pigmentary changes in melasma at a cellular level resolution.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";20497220;"Experimental dermatology";"Kang HY, Bahadoran P, Suzuki I, Zugaj D, Khemis A, Passeron T, Andres P, Ortonne JP";;"May 2010";1274832000;;"Melasma is a frequent pigmentary disorder caused by abnormal melanin deposits in the skin. In vivo reflectance confocal microscopy (RCM) is a repetitive imaging tool that provides real-time images of the skin at nearly histological resolution. As melanin is the strongest endogenous contrast in human skin, pigmentary disorders are the most suitable candidates for RCM examination but RCM features of melasma have never been reported. This study investigates the pilot use of RCM in melasma to provide a set of well-described morphological criteria with histological correlations. RCM images were acquired from melasma skin and compared to adjacent control skin in 26 patients. Skin biopsies were obtained from eight patients. In the epidermis, RCM showed in all patients a significant increase in hyperrefractile cobblestoning cells. These cells corresponded to hyperpigmented basal keratinocytes in histology. In six patients, dendritic cells corresponding to activated melanocytes were also found in the epidermis. In the dermis, RCM identified in nine patients plump bright cells corresponding to melanophages. Interestingly, for a given patient, the topographic distribution of melanophages in melasma lesions was very heterogeneous. RCM also showed a significant increase in solar elastosis and blood vessels in the dermis. RCM is a non-invasive technique that detects pigmentary changes in melasma at a cellular level resolution. Therefore, RCM provides an innovative way to classify melasma by pigment changes." 12312;"[What is the impact of the new clinical trial data? What are the lessons for patient management?].";"T. Passeron";"Equipe 12, Team 12";20510174;"Annales de dermatologie et de venereologie";"Passeron T, Boulinguez S";;"Jun 2010";1275350400;; 12311;"Drug rash with eosinophilia and systemic symptoms due to telaprevir.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";20798484;"Dermatology (Basel, Switzerland)";"Montaudié H, Passeron T, Cardot-Leccia N, Sebbag N, Lacour JP";;"08 2010";1280620800;;"We report a case of drug rash with eosinophilia and systemic symptoms (DRESS) due to telaprevir (VX-950), a specific inhibitor of the hepatitis C virus (HCV) serine protease. A 57-year-old woman with chronic hepatitis C was included in a phase 2 rollover study of VX-950. She received VX-950 in combination with pegylated interferon alfa-2a and ribavirin. Six weeks later, she developed a generalized pruritic maculopapular exanthema with malaise, fever, dyspnoea and lymph node swelling. She had an eosinophilia (up to 2.7 × 109 cells/l), large activated lymphocytes and increased concentrations of aminotransferases. Histological examination of a cutaneous biopsy was consistent with a drug rash reaction. The HCV treatment was stopped, and she was treated with topical and oral steroids. Cutaneous and systemic symptoms disappeared within 1 month. Telaprevir was considered the culprit drug. We report to our knowledge the first case of DRESS syndrome due to telaprevir. The safety data of telaprevir is derived mainly from the PROVE1, PROVE2 and PROVE3 studies. They showed a high frequency of cutaneous side effects reported under the imprecise terms of pruritus and rash, leading to an increased rate of treatment discontinuation. Telaprevir, due to its efficacy, is probably on the way to obtaining regulatory approval in the near future. It is therefore important to be aware of the high incidence of cutaneous side effects and better describe them. Our observation suggests that potentially severe hypersensitivity reactions may belong to the spectrum of rashes induced by this drug." 12309;"A noninvasive technique, reflectance confocal microscopy, for the characterization of melanocyte loss in untreated and treated vitiligo lesions.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";20950736;"Journal of the American Academy of Dermatology";"Kang HY, le Duff F, Passeron T, Lacour JP, Ortonne JP, Bahadoran P";;"Oct 2010";1287446400;; 12307;"The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin.";"T. Passeron";"Equipe 12, Team 12";20979596;"Pigment cell & melanoma research";"Miyamura Y, Coelho SG, Schlenz K, Batzer J, Smuda C, Choi W, Brenner M, Passeron T, Zhang G, Kolbe L, Wolber R, Hearing VJ";;"Oct 2010";1288310400;;"The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV-induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV-protective effects against DNA damage in UVB-tanned skin (but not in UVA-tanned skin) were significantly higher. UVA-induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up-regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB-exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV-induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis." 12305;"Urticarial vasculitis secondary to H1N1 vaccination.";"T. Passeron";"Equipe 12, Team 12";21057759;"Acta dermato-venereologica";"Hughes R, Lacour JP, Baldin B, Reverte M, Ortonne JP, Passeron T";;"Nov 2010";1289260800;; 12303;"[What's new in dermatological research?].";"T. Passeron";"Equipe 12, Team 12";21193117;"Annales de dermatologie et de venereologie";"Passeron T";;"Jan 2011";1294099200;;"Dermatology research has been very rich this year, once again. The physiopathological mechanisms of paradoxical reactions to anti-TNF are better understood and new therapeutic targets for psoriasis have been evidenced. Targeted therapy in oncodermatology have shown their potential usefulness clinically but fundamental data have also clarified their mechanisms of action as well as their limits. The key role played by the immune system in nonsegmental vitiligo has also been clearly demonstrated. Fibroblasts as well as visible light seem to play a key role that has been poorly understood to date within the complex mechanisms of cutaneous pigmentation. Specific receptors of pruritus have been reported and foster hope for the development of more effective antipruriginous treatments in the near future. Other studies report new potential targets for diseases such as fungoid mycosis, atopic dermatitis, or scleroderma. Finally, physiopathological explanations have contributed to a variety of domains such as greying hair, axillary odors, HIV and herpes virus interrelations, and the teratogenicity of thalidomide." 12299;"Nd:YAG laser treatment for multiple cutaneous glomangiomas: report of 3 cases.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";21339466;"Archives of dermatology";"Hughes R, Lacour JP, Chiaverini C, Rogopoulos A, Passeron T";;"Feb 2011";1298419200;; 12297;"[Recommendations on the management of psoriatic arthritis].";"T. Passeron";"Equipe 12, Team 12";21703468;"Annales de dermatologie et de venereologie";"Passeron T, Goupille P, Boulinguez S";;"Jun 2011";1309219200;; 12295;"Pigmentary sequelae of AIDS-related cutaneous Kaposi sarcoma: successful treatment by Q-switched 755-nm alexandrite and 532-nm Nd:YAG lasers.";"T. Passeron";"Equipe 12, Team 12";21768476;"Archives of dermatology";"Hughes R, Lacour JP, Passeron T";;"Jul 2011";1311120000;; 12293;"A pilot study using reflectance confocal microscopy (RCM) in the assessment of a novel formulation for the treatment of melasma.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";22052305;"Journal of drugs in dermatology : JDD";"Tsilika K, Levy JL, Kang HY, Duteil L, Khemis A, Hughes R, Passeron T, Ortonne JP, Bahadoran P";;"Nov 2011";1320451200;;"Melasma is a common pigmentary disorder caused by abnormal melanin deposits within the skin. Hydroquinone (HQ) is presently the most popular depigmenting agent, however the treatment of melasma remains unsatisfactory, resulting in a need to evaluate new depigmenting agents." 12289;"Melasma treatment with pulsed-dye laser and triple combination cream: a prospective, randomized, single-blind, split-face study.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";21931054;"Archives of dermatology";"Passeron T, Fontas E, Kang HY, Bahadoran P, Lacour JP, Ortonne JP";;"Sep 2011";1316563200;; 12291;"Effect of a preceding laser dermabrasion on the outcome of combined therapy with narrowband ultraviolet B and potent topical steroids for treating nonsegmental vitiligo in resistant localizations.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";21824124;"The British journal of dermatology";"Bayoumi W, Fontas E, Sillard L, Le Duff F, Ortonne JP, Bahadoran P, Lacour JP, Passeron T";;"Aug 2011";1312934400;;"The treatment of vitiligo remains unsatisfactory." 12287;"Signalling and chemosensitivity assays in melanoma: is mutated status a prerequisite for targeted therapy?";"C. Bertolotto, P. Bahadoran, R. Ballotti, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";22092579;"Experimental dermatology";"Passeron T, Lacour JP, Allegra M, Ségalen C, Deville A, Thyss A, Giacchero D, Ortonne JP, Bertolotto C, Ballotti R, Bahadoran P";;"Nov 2011";1321660800;;"Selection for targeted therapies in melanoma is currently based on the search for mutations in selected genes. We aimed at evaluating the interest of signalling and chemosensitivity studies in addition to genotyping for assessing the best suitable treatment in an individual patient. We extracted genomic DNA and melanoma cells from tumor tissue of a skin metastasis of a 17-year-old woman with stage IV melanoma progressing despite three successive lines of treatment. Despite the absence of mutation in BRAF, NRAS cKIT, the MAPK pathway was activated and a significant response to sorafenib, a mitogen-activated protein kinase (MAPK)/RAF inhibitor, was found in signalling and chemosensitivity assays. A treatment combining sorafenib and dacarbazine produced a partial response for 9 months, with marked necrosis in some lesions. Chemosensitivity assays and signalling pathway studies could be of great value in addition to genotyping for assessing the most appropriate treatment in melanoma." 12285;"Treatment of granuloma annulare with the 595-nm pulsed dye laser, a multicentre retrospective study with long-term follow-up.";"T. Passeron";"Equipe 12, Team 12";22188443;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Fusade T, Vabres P, Bousquet-Rouaud R, Collet-Vilette AM, Dahan S, Toubel G";;"12 2011";1322697600;;"Granuloma annulare (GA) is limited in most cases to isolated lesions, but more widespread generalized forms can be observed. In both cases, the treatment remains highly challenging. Isolated case reports suggested the interest of treating GA with a pulsed dye laser (PDL)." 12281;"Laser-assisted depigmentation for resistant vitiligo: a retrospective case series with long-term follow-up.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23167541;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Boukari F, Lacour JP, Ortonne JP, Bahadoran P, Passeron T";;"Nov 2012";1353542400;;"Blanching creams are used to depigment and to achieve uniform skin tone in widespread vitiligo. Length of the treatment and side-effects strongly limit their use in common practice." 12282;"Localized depigmentation on genital melanosis: a clue for the understanding of vitiligo.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";22897568;"The British journal of dermatology";"Harmelin Y, Cardot-Leccia N, Ortonne JP, Bahadoran P, Lacour JP, Passeron T";;"Aug 2012";1345248000;; 12279;"Kaposi's varicelliform eruption in a patient with pityriasis rubra pilaris (pityriasis rubra pilaris herpeticum).";"T. Passeron";"Equipe 12, Team 12";23432393;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Cavalié M, Giacchero D, Cardot-Leccia N, Passeron T, Lacour JP";;"Feb 2013";1361836800;; 12273;"Use of high-definition optical coherent tomography (HD-OCT) for imaging of melanoma.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23663029;"The British journal of dermatology";"Picard A, Tsilika K, Long-Mira E, Hofman P, Passeron T, Lacour JP, Bahadoran P";;"May 2013";1368489600;; 12274;"Flexural agminated eruptive nevi in Langerhans cell histiocytosis.";"C. Chiaverini, H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";23677112;"JAMA dermatology";"Surinach C, Bahadoran P, Vabres P, Chiaverini C, Montaudie H, Erfan N, Deville A, Ben Signor C, Benchetrit M, Passeron T, Lacour JP";;"May 2013";1368748800;; 12275;"Iatrogenic kwashiorkor developing after bypass surgery.";"T. Passeron";"Equipe 12, Team 12";23659833;"Clinical and experimental dermatology";"Ghorbel HH, Broussard JF, Lacour JP, Passeron T";;"May 2013";1368230400;; 12270;"Labial melanotic macule: a potential pitfall on reflectance confocal microscopy.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";22414589;"Dermatology (Basel, Switzerland)";"Erfan N, Hofman V, Desruelles F, Passeron T, Ortonne JP, Lacour JP, Bahadoran P";;"03 2012";1330560000;; 12267;"Activation of the unfolded protein response in vitiligo: the missing link?";"T. Passeron";"Equipe 12, Team 12";23069909;"The Journal of investigative dermatology";"Passeron T, Ortonne JP";;"Oct 2012";1350432000;;"Vitiligo is characterized by a substantial loss of functional melanocytes in the epidermis and sometimes in hair follicles. Genetic and pathophysiological studies have provided strong evidence that vitiligo is a polygenetic, multifactorial disorder. The key roles of oxidative stress within melanocytes and anti-melanocyte immune responses have been addressed in many studies, but the relationship between these mechanisms remains unclear. In this issue, Toosi et al. report the upregulation of IL-6 and IL-8 after the activation of the unfolded protein response (UPR) following exposure of melanocytes to phenols. Their results shed light on the missing link between oxidative stress and immune responses in vitiligo." 12268;"Guidelines for the management of vitiligo: the European Dermatology Forum consensus.";"T. Passeron";"Equipe 12, Team 12";22860621;"The British journal of dermatology";"Taieb A, Alomar A, Böhm M, Dell'anna ML, De Pase A, Eleftheriadou V, Ezzedine K, Gauthier Y, Gawkrodger DJ, Jouary T, Leone G, Moretti S, Nieuweboer-Krobotova L, Olsson MJ, Parsad D, Passeron T, Tanew A, van der Veen W, van Geel N, Whitton M, Wolkerstorfer A, Picardo M, , , ";;"11 2012";1351728000;;"The aetiopathogenic mechanisms of vitiligo are still poorly understood, and this has held back progress in diagnosis and treatment. Up until now, treatment guidelines have existed at national levels, but no common European viewpoint has emerged. This guideline for the treatment of segmental and nonsegmental vitiligo has been developed by the members of the Vitiligo European Task Force and other colleagues. It summarizes evidence-based and expert-based recommendations (S1 level)." 12264;[Lasers].;"T. Passeron";"Equipe 12, Team 12";23260518;"Annales de dermatologie et de venereologie";"Passeron T";;"Dec 2012";1356393600;;"Lasers are a very effective approach for treating many hyperpigmented lesions. They are the gold standard treatment for actinic lentigos and dermal hypermelanocytosis, such as Ota nevus. Becker nevus, hyperpigmented mosaicisms, and lentigines can also be successfully treated with lasers, but they could be less effective and relapses can be observed. However, lasers cannot be proposed for all types of hyperpigmentation. Thus, freckles and café-au-lait macules should not be treated as the relapses are nearly constant. Due to its complex pathophysiology, melasma has a special place in hyperpigmented dermatoses. Q-switched lasers (using standard parameters or low fluency) should not be used because of consistent relapses and the high risk of post-inflammatory hyperpigmentation. Paradoxically, targeting the vascular component of the melasma lesion with lasers could have a beneficial effect. However, these results have yet to be confirmed. In all cases, a precise diagnosis of the type of hyperpigmentation is mandatory before any laser treatment, and the limits and the potential side effects of the treatment must be clearly explained to patients." 12263;Lasers.;"T. Passeron";"Equipe 12, Team 12";23522632;"Annales de dermatologie et de venereologie";"Passeron T";;"Mar 2013";1364256000;;"Lasers are a very effective approach for treating many hyperpigmented lesions. They are the gold standard treatment for actinic lentigos and dermal hypermelanocytosis, such as Ota nevus. Becker nevus, hyperpigmented mosaicisms, and lentigines can also be successfully treated with lasers, but they could be less effective and relapses can be observed. However, lasers cannot be proposed for all types of hyperpigmentation. Thus, freckles and café-au-lait macules should not be treated as the relapses are nearly constant. Due to its complex pathophysiology, melasma has a special place in hyperpigmented dermatoses. Q-switched lasers (using standard parameters or low fluency) should not be used because of consistent relapses and the high risk of post-inflammatory hyperpigmentation. Paradoxically, targeting the vascular component of the melasma lesion with lasers could have a beneficial effect. However, these results have yet to be confirmed. In all cases, a precise diagnosis of the type of hyperpigmentation is mandatory before any laser treatment, and the limits and the potential side effects of the treatment must be clearly explained to patients." 12261;"Secondary hyperpigmentation during interferon alfa treatment for chronic hepatitis C virus infection.";"A. TRAN, R. ANTY, T. Passeron";"Equipe 08, Team 08, Equipe 12, Team 12";23553009;"JAMA dermatology";"Tsilika K, Tran A, Trucchi R, Pop S, Anty R, Cardot-Leccia N, Lacour JP, Ortonne JP, Passeron T";;"Apr 2013";1365120000;;"Interferon alfa remains the central treatment for chronic hepatitis C virus (HCV) infection. Cases of cutaneous and mucous hyperpigmentations during interferon alfa treatment have been reported, but they are considered rare adverse effects." 12255;"Use of high-definition optical coherent tomography (HD-OCT) for imaging of melanoma.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23663029;"The British journal of dermatology";"Picard A, Tsilika K, Long-Mira E, Hofman P, Passeron T, Lacour JP, Bahadoran P";;"May 2013";1368489600;; 12256;"Long-lasting effect of vascular targeted therapy of melasma.";"T. Passeron";"Equipe 12, Team 12";23957991;"Journal of the American Academy of Dermatology";"Passeron T";;"Aug 2013";1377043200;; 12258;"Reflectance confocal microscopy features of Degos disease.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23864231;"JAMA dermatology";"Cavalié M, Tsilika K, Sillard L, Cardot-Leccia N, Passeron T, Lacour JP, Bahadoran P";;"Jul 2013";1374192000;; 12253;"[Sneddon-Wilkinson disease: efficacy of intermittent adalimumab therapy after lost response to infliximab and etanercept].";"T. Passeron";"Equipe 12, Team 12";24315227;"Annales de dermatologie et de venereologie";"Versini M, Mantoux F, Angeli K, Passeron T, Lacour JP";;"08 2013";1375315200;;"Sneddon-Wilkinson disease (SWD) is a rare chronic neutrophilic dermatosis. The first-line treatment is dapsone but resistance to treatment may sometimes pose a challenge." 12251;"Impact of systemic treatment of psoriasis on inflammatory parameters and markers of comorbidities and cardiovascular risk: results of a prospective longitudinal observational study.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";23981008;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Montaudié H, Albert-Sabonnadière C, Acquacalda E, Fontas E, Danré A, Roux C, Ortonne JP, Lacour JP, Euller-Ziegler L, Passeron T";;"08 2013";1375315200;;"Several markers of comorbidities and cardiovascular (CV) risk are disturbed in moderate to severe psoriasis (PsO). The effect of systemic treatments of psoriasis on these markers remains poorly understood." 12249;"Treatment of inflammatory linear verrucous epidermal nevus with 2940 nm erbium fractional laser.";"T. Passeron";"Equipe 12, Team 12";24112692;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Hammami Ghorbel H, Lacour JP, Passeron T";;"09 2013";1377993600;; 12247;"Macular eruption revealing hypomelanotic cutaneous melanoma metastases: diagnostic role of dermoscopy.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";24355285;"Journal of the American Academy of Dermatology";"Hammami-Ghorbel H, Giacchero D, Hofman V, Poissonnet G, Passeron T, Lacour JP, Bahadoran P";;"Dec 2013";1387584000;; 12245;"Successful treatment with 532-nm Q-switched Nd:YAG laser of cutaneous siderosis following intravenous iron extravasation.";"T. Passeron";"Equipe 12, Team 12";24588937;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Hammami Ghorbel H, Lacour JP, Passeron T";;"03 2014";1393632000;; 12242;"Acquired dermal melanocytosis of the nose.";"T. Passeron";"Equipe 12, Team 12";24611970;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Chuah SY, Hammami Ghorbel H, Lacour JP, Passeron T";;"Mar 2014";1394582400;; 12240;"Treatment of port wine stains with pulsed dye laser and topical timolol: a multicenter randomized controlled trial.";"T. Passeron";"Equipe 12, Team 12";24641096;"The British journal of dermatology";"Passeron T, Maza A, Fontas E, Toubel G, Vabres P, Livideanu C, Mazer JM, Rossi B, Boukari F, Harmelin Y, Dreyfus I, Mazereeuw-Hautier J, Lacour JP";;"Mar 2014";1395273600;;"Neoangiogenesis occurs within days following laser treatment of port wine stains (PWS), and plays a central role in treatment failures. Topical use of timolol can significantly reduce the production of vascular endothelial growth factor in vitro, and in animal models." 12237;"Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";24872229;"JAMA dermatology";"Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, Lacour JP, Passeron T";;"May 2014";1401408000;;"An impaired inhibitory function of circulating CD4+CD25+ regulatory T (Treg) cells was reported to play a key role in alopecia areata (AA). We report the first use to our knowledge of low-dose interleukin 2 for treating severe AA by promoting the recruitment of Treg cells." 12235;"Trichoblastoma with dermoscopic features of a malignant tumor: three cases.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";25128125;"Journal of the American Academy of Dermatology";"Picard A, Tsilika K, Cardot-Leccia N, Passeron T, Lacour JP, Bahadoran P";;"Aug 2014";1408233600;; 12233;"Treatment of linear and whorled hypermelanosis with Q-switched laser.";"T. Passeron";"Equipe 12, Team 12";25099293;"Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]";"Catherine S, Lacour JP, Passeron T";;"Aug 2014";1407456000;; 12231;"Solar urticaria to visible light triggered by light-emitting diode therapy.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";25128130;"Journal of the American Academy of Dermatology";"Montaudié H, Lacour JP, Rostain G, Duteil L, Passeron T";;"Aug 2014";1408233600;; 12229;"Hypochromic vitiligo: delineation of a new entity.";"T. Passeron";"Equipe 12, Team 12";25255745;"The British journal of dermatology";"Ezzedine K, Mahé A, van Geel N, Cardot-Leccia N, Gauthier Y, Descamps V, Al Issa A, Ly F, Chosidow O, Taïeb A, Passeron T";;"12 2014";1417392000;;"Hypochromic vitiligo is a rare entity that has been reported only twice under the term 'vitiligo minor', with an absence of clear delineation." 12223;"Indications and limitations of afamelanotide for treating vitiligo.";"T. Passeron";"Equipe 12, Team 12";25607635;"JAMA dermatology";"Passeron T";;"Jan 2015";1421884800;; 12224;"Interest of high-definition optical coherent tomography (HD-OCT) for non-invasive imaging of dermatofibroma: a pilot study.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";25588890;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Picard A, Long-Mira E, Chuah SY, Passeron T, Lacour JP, Bahadoran P";;"01 2015";1420070400;; 12221;"Copper Bromide Laser vs Triple-Combination Cream for the Treatment of Melasma: A Randomized Clinical Trial.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";25715311;"JAMA dermatology";"Hammami Ghorbel H, Boukari F, Fontas E, Montaudié H, Bahadoran P, Lacour JP, Passeron T";;"Feb 2015";1424908800;; 12219;"Successful treatment of refractory neuropathic pruritus with capsaicin 8% patch: a bicentric retrospective study with long-term follow-up.";"T. Passeron";"Equipe 12, Team 12";25740045;"Acta dermato-venereologica";"Misery L, Erfan N, Castela E, Brenaut E, Lantéri-Minet M, Lacour JP, Passeron T";;"Mar 2015";1425600000;; 12179;"[Item 237 - UE 8 Acrosyndromes (Raynaud's phenomenon, erythermalgia, acrocyanosis, frostbite, digital ischemia)].";;;25982864;"Annales de dermatologie et de venereologie";" ";;"05 2015";1430438400;; 12173;"[Item 211 - UE 7 Purpura in children and adults].";;;25979757;"Annales de dermatologie et de venereologie";" ";;"May 2015";1431820800;; 12174;"[Item 345 - UE 11 Acute enlarged red leg].";;;25979756;"Annales de dermatologie et de venereologie";" ";;"05 2015";1430438400;; 12175;"[Item 322 - UE 10 Iatrogenicity. Diagnosis and Prevention: Drug toxidermia].";;;25960383;"Annales de dermatologie et de venereologie";" ";;"May 2015";1431388800;; 12170;"[Item 299 - UE 9 Epithelial skin tumors and melanoma].";;;25982865;"Annales de dermatologie et de venereologie";" ";;"05 2015";1430438400;; 12167;"Long pulse Alexandrite laser for recalcitrant viral warts on the hands.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";26289532;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Pharaon M, Le Duff F, Montaudié H, Lacour JP, Passeron T";;"08 2015";1438387200;; 12165;"Treatment of resistant port-wine stains with bosentan and pulsed dye laser: a pilot prospective study.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";26304141;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Taquin H, Lacour JP, Le Duff F, Chiaverini C, Passeron T";;"08 2015";1438387200;; 12163;"Comparative Methods for Improving Transepidermal Methylaminolevulinate Delivery: A Randomized Clinical Trial.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";26351818;"JAMA dermatology";"Bahadoran P, Le Duff F, Pascual T, Petit L, Martel P, Lacour JP, Passeron T";;"Sep 2015";1441843200;; 12161;"NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2.";"C. Bertolotto, P. Bahadoran, R. Ballotti, S. Rocchi, T. Passeron, Y. Cheli";"Equipe 01, Team 01, Equipe 12, Team 12";26364600;Oncogene;"De Donatis GM, Le Pape E, Pierron A, Cheli Y, Hofman V, Hofman P, Allegra M, Zahaf K, Bahadoran P, Rocchi S, Bertolotto C, Ballotti R, Passeron T";;"09 2015";1441065600;;"Enhancer of Zeste homologue 2 (EZH2) belongs to the polycomb repressive complex 2 and catalyzes the methylation of histone H3 lysine 27. These pivotal epigenetic marks are altered in many cancers, including melanoma, as a result of EZH2 overexpression. Here, we show that the non-canonical-NF-kB pathway accounts for most of the NF-kB activity in melanoma cells, in contrast to non-cancer cells. We identify the non-canonical-NF-kB pathway as a key regulator of EZH2 expression in melanoma. We show a striking correlation between NF-kB2 and EZH2 expression in human melanoma metastases. We demonstrate that inhibition of the non-canonical NF-kB pathway by targeting NF-kB2/p52 or the upstream kinase NIK restores the senescence program in melanoma cells through the decrease of EZH2. On the contrary, the overexpression of NF-kB2/p52 in normal human melanocytes prevents stress- and oncogene-induced senescence. Finally, we show in mouse models that the inhibition of the non-canonical NF-kB pathway restores senescence and induces a dramatic reduction in tumor growth compared with controls, thus providing potential drug targets for the re-induction of senescence in melanoma and other cancers where EZH2 is overexpressed." 12159;"Maintenance of remission following successful treatment of papulopustular rosacea with ivermectin 1% cream vs. metronidazole 0.75% cream: 36-week extension of the ATTRACT randomized study.";"T. Passeron";"Equipe 12, Team 12";26691278;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Taieb A, Khemis A, Ruzicka T, Barańska-Rybak W, Berth-Jones J, Schauber J, Briantais P, Jacovella J, Passeron T, ";;"12 2015";1448928000;;"There are a limited number of approved treatments for papulopustular rosacea (PPR) and remission is difficult to maintain after successful treatment." 12157;"Centrifugal hypomelanosis: a new clinical phenotype of Malassezia infection.";"T. Passeron";"Equipe 12, Team 12";27655069;"European journal of dermatology : EJD";"Alkhalifah A, Gari-Toussaint M, Cardot-Leccia N, Lacour JP, Passeron T";;"Sep 2016";1474588800;; 12155;"Pigmented macules of bony prominences (PMBP): A distinct presentation in patients with red hair.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";26775783;"Journal of the American Academy of Dermatology";"Marmottant E, Chiaverini C, Bessis D, Hubiche T, Mallet S, Maruani A, Abasq C, Miquel J, Cardot-Leccia N, Lacour JP, Passeron T";;"Jan 2016";1453161600;; 12153;"Evaluation of learning disabilities in segmental neurofibromatosis.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";26833272;"The British journal of dermatology";"Marmottant-Debled E, Chiaverini C, Fossoud C, Passeron T, Barbarot S, Lacour JP";;"03 2016";1456790400;; 12151;"Ivermectin cream improves health-related quality of life in patients with rosacea: data from a randomized trial.";"T. Passeron";"Equipe 12, Team 12";27061926;"The British journal of dermatology";"Taieb A, Passeron T, Ruzicka T, Berth-Jones J, Jacovella J, Huang MY, Wertheimer A";;"09 2016";1472688000;; 12149;"Micro holes for delivering melanocytes into the skin: an ex vivo approach.";"C. Regazzetti, T. Passeron";"Equipe 12, Team 12";27172992;"Pigment cell & melanoma research";"Regazzetti C, Alcor D, Chignon-Sicard B, Passeron T";;"May 2016";1463184000;; 12147;"NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2.";"C. Bertolotto, P. Bahadoran, R. Ballotti, S. Rocchi, T. Passeron, Y. Cheli";"Equipe 01, Team 01, Equipe 12, Team 12";27225420;Oncogene;"De Donatis GM, Le Pape E, Pierron A, Cheli Y, Hofman V, Hofman P, Allegra M, Zahaf K, Bahadoran P, Rocchi S, Bertolotto C, Ballotti R, Passeron T";;"May 2016";1464307200;; 12144;"Pulmonary sarcoid-like granulomatosis induced by nivolumab.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27291635;"The British journal of dermatology";"Montaudié H, Pradelli J, Passeron T, Lacour JP, Leroy S";;"12 2016";1480550400;;"The use of antibodies against programmed death (PD)1, such as nivolumab and pembrolizumab, has dramatically improved the prognosis of patients with advanced melanoma. Nivolumab is also approved in advanced squamous cell nonsmall-cell lung cancer. These immunotherapies are associated with a unique set of toxicities termed immune-related adverse events, which are different from toxicities observed with conventional cytotoxic chemotherapy. We report the case of a 56-year-old man who was diagnosed with metastatic melanoma and who received nivolumab. One week after the second infusion, he developed pulmonary symptoms, dry eye syndrome and a bilateral swelling of the parotid glands. Investigations were negative for infection. The bronchoalveolar lavage differential cell count showed 32% lymphocytes with an increased CD4 : CD8 ratio, and bronchial biopsies revealed noncaseating epithelioid granulomas, without malignant cells. The clinical and radiological courses were rapidly favourable with oral corticosteroid. This case illustrates that sarcoidosis can be induced by nivolumab treatment. With the increasing use of anti-PD1 inhibitors in patients with advanced melanoma and squamous cell nonsmall-cell lung cancer, clinicians should be aware of this potential associated immune-related adverse event." 12143;"Exacerbation of Hailey-Hailey disease by topiramate.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27510943;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Alkhalifah A, Montaudié H, Lacour JP, Lantéri-Minet M, Passeron T";;"08 2016";1470009600;; 12140;"Rebound pustular psoriasis after brodalumab discontinuation.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27037661;"The British journal of dermatology";"Khemis A, Cavalié M, Montaudié H, Lacour JP, Passeron T";;"08 2016";1470009600;; 12139;"Successful treatment of angiokeratoma circumscriptum naeviforme with long pulse alexandrite laser.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";27511129;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Lorgeou A, Chiaverini C, Le Duff F, Lacour JP, Passeron T";;"08 2016";1470009600;; 12137;"Appearance of lentigines in psoriasis patients treated with apremilast.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27846946;"Journal of the American Academy of Dermatology";"Sfecci A, Khemis A, Lacour JP, Montaudié H, Passeron T";;"Nov 2016";1479340800;; 12135;"Topical corticosteroids application in the evening is more effective than in the morning in psoriasis: results of a prospective comparative study.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27790782;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Nguyen S, Bahakeem H, Alkhalifah A, Cavalié M, Boukari F, Montaudié H, Lacour JP, Passeron T";;"11 2016";1477958400;; 12133;"Topical timolol for chronic wounds in patients with junctional epidermolysis bullosa.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";27846969;"Journal of the American Academy of Dermatology";"Chiaverini C, Passeron T, Lacour JP";;"Nov 2016";1479340800;; 12131;"Repigmentation in vitiligo: position paper of the Vitiligo Global Issues Consensus Conference.";"T. Passeron";"Equipe 12, Team 12";27864868;"Pigment cell & melanoma research";"Gan EY, Eleftheriadou V, Esmat S, Hamzavi I, Passeron T, Böhm M, Anbar T, Goh BK, Lan CE, Lui H, Ramam M, Raboobee N, Katayama I, Suzuki T, Parsad D, Seth V, Lim HW, van Geel N, Mulekar S, Harris J, Wittal R, Benzekri L, Gauthier Y, Kumarasinghe P, Thng ST, Silva de Castro CC, Abdallah M, Vrijman C, Bekkenk M, Seneschal J, Pandya AG, Ezzedine K, Picardo M, Taïeb A, ";;"Nov 2016";1479600000;;"The Vitiligo Global Issues Consensus Conference (VGICC), through an international e-Delphi consensus, concluded that 'repigmentation' and 'maintenance of gained repigmentation' are essential core outcome measures in future vitiligo trials. This VGICC position paper addresses these core topics in two sections and includes an atlas depicting vitiligo repigmentation patterns and color match. The first section delineates mechanisms and characteristics of vitiligo repigmentation, and the second section summarizes the outcomes of international meeting discussions and two e-surveys on vitiligo repigmentation, which had been carried out over 3 yr. Treatment is defined as successful if repigmentation exceeds 80% and at least 80% of the gained repigmentation is maintained for over 6 months. No agreement was found on the best outcome measure for assessing target or global repigmentation, therefore highlighting the limitations of e-surveys in addressing clinical measurements. Until there is a clear consensus, existing tools should be selected according to the specific needs of each study. A workshop will be conducted to address the remaining issues so as to achieve a consensus." 12126;"[Post-inflammatory hyperpigmentation].";"T. Passeron";"Equipe 12, Team 12";29452653;"Annales de dermatologie et de venereologie";"Passeron T";;"Feb 2018";1518912000;;"Post-inflammatory hyperpigmentation (PIH) is a hyperpigmentation of the skin occurring after and sometimes during an inflammatory process. Although more frequent in dark skinned individuals, PIH can be observed in any type of skin and at all ages. In most case a strong impact on the quality of life of affected individuals is observed. The pathophysiology of PIH remains largely unknown. The activation of the melanocytes occurs in the first week following the inflammation emphasizing the crucial role of early preventive measures. Photoprotection with balanced UVA and UVB protection is required. Visible light could also play a role in PIH but this remains to be demonstrated. Healing topics with anti-inflammatory properties are of interest after a skin procedure. When the risk of PIH is high or when PIH occurs, topical steroids remains the gold standard approach." 12129;"[What's new in instrumental dermatology (laser)?]";"T. Passeron";"Equipe 12, Team 12";29429504;"Annales de dermatologie et de venereologie";"Passeron T";;"Feb 2018";1518480000;;"This year, What's new in Interventional Dermatology will be dedicated to lasers and other interventional devices. Many articles have been published these past two years emphasizing how dynamic this field of dermatology is. However, most of published papers were case reports or open series. Thus, innovative approaches, prospective randomized trials and large retrospective studies were the main criteria of selection of the articles." 12125;"Interleukin 6 and high-sensitivity C-reactive protein are potential predictive markers of response to infliximab in hidradenitis suppurativa.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27986139;"Journal of the American Academy of Dermatology";"Montaudié H, Seitz-Polski B, Cornille A, Benzaken S, Lacour JP, Passeron T";;"Dec 2016";1482019200;; 12119;"Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With Cetuximab.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";28259104;"JAMA dermatology";"Picard A, Pedeutour F, Peyrade F, Saudes L, Duranton-Tanneur V, Chamorey E, Cardot-Leccia N, Sudaka A, Ettaiche M, Benchetrit M, Poissonnet G, Weinbreck N, Dadone B, Lacour JP, Passeron T, Montaudié H";;"Mar 2017";1488672000;;"Cetuximab was recently proposed for advanced cutaneous squamous cell carcinomas (cSCC); however, its efficacy is inconsistent and identification of predictive biomarkers for response is necessary." 12120;"Topical corticosteroids application in the evening is more effective than in the morning in psoriasis: in reply.";"T. Passeron";"Equipe 12, Team 12";28295619;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Nguyen S, Lacour JP, Passeron T";;"03 2017";1488326400;; 12117;"Medical and Maintenance Treatments for Vitiligo.";"T. Passeron";"Equipe 12, Team 12";28317526;"Dermatologic clinics";"Passeron T";;"Mar 2017";1490054400;;"Medical treatments alone, or in combination with phototherapy, are key approaches for treating nonsegmental vitiligo and, to a lesser extent, segmental vitiligo. The treatments are useful for halting disease progression and have been proven effective for inducing repigmentation and decreasing risk of relapses. Although the treatments have side effects and limitations, vitiligo often induces a marked decrease in quality of life and in most cases the risk:benefit ratio is in favor of an active approach. Systemic and topical agents targeting the pathways involved in loss of melanocytes and in differentiation of melanocyte stem cells should provide more effective approaches in the near future." 12115;"Treatment of Elastosis Perforans Serpiginosa Using a Fractional Carbon Dioxide Laser.";"T. Passeron";"Equipe 12, Team 12";28746703;"JAMA dermatology";"Kelati A, Lagrange S, Le Duff F, Lacour JP, Passeron T";;"Jul 2017";1501113600;; 12113;"[The value of reflectance confocal microscopy in detection of Demodex mites].";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";28347561;"Annales de dermatologie et de venereologie";"Harmelin Y, Le Duff F, Passeron T, Lacour JP, Bahadoran P";;"Mar 2017";1490745600;; 12111;"Prepubertal vulvar fibroma, a rare entity little known to dermatologists: report of two cases.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";28419575;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Nguyen S, Fraitag S, Cardot-Leccia N, Lagrange S, Trastour C, Passeron T, Croce S, Coindre JM, Lacour JP, Montaudié H";;"Apr 2017";1492560000;; 12109;"Efficacy and Tolerance of Anti-Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases.";"T. Passeron";"Equipe 12, Team 12";28564695;"JAMA dermatology";"Heidelberger V, Ingen-Housz-Oro S, Marquet A, Mahevas M, Bessis D, Bouillet L, Caux F, Chapelon-Abric C, Debarbieux S, Delaporte E, Duval-Modeste AB, Fain O, Joly P, Marchand-Adam S, Monfort JB, Noël N, Passeron T, Ruivard M, Sarrot-Reynauld F, Verrot D, Bouvry D, Fardet L, Chosidow O, Sève P, Valeyre D";;"Jun 2017";1496275200;;"Evidence for the long-term efficacy and safety of anti-tumor necrosis factor α agents (anti-TNF) in treating cutaneous sarcoidosis is lacking." 12107;"[Lymphedema of the lower limbs: Initial manifestation of gastric linitis plastica].";"H. Montaudie, S. PATOURAUX, T. Passeron";"Equipe 12, Team 12, Equipe 08, Team 08";28647380;"Annales de dermatologie et de venereologie";"Nguyen S, Ouvrier D, Massalou D, Viau P, Chevallier A, Patouraux S, Passeron T, Lacour JP, Montaudié H";;"06 2017";1496275200;;"Primary lymphedemas are constitutional abnormalities of the lymphatic system. Secondary lymphedemas occur after damage to the lymphatic system, mainly after cancer treatments or tumour mass compression. There are many other causes, including filariasis, which is nonetheless very rare in France." 12103;"Comparison of two picosecond lasers to a nanosecond laser for treating tattoos: a prospective randomized study on 49 patients.";"T. Passeron";"Equipe 12, Team 12";28758261;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Lorgeou A, Perrillat Y, Gral N, Lagrange S, Lacour JP, Passeron T";;"08 2017";1501545600;;"Q-switched nanosecond lasers demonstrated their efficacy in treating most types of tattoos, but complete disappearance is not always achieved even after performing numerous laser sessions. Picosecond lasers are supposed to be more efficient in clearing tattoos than nanosecond lasers, but prospective comparative data remain limited." 12104;"Clinical Outcomes of Metastatic Melanoma Treated With Checkpoint Inhibitors and Multisite Radiotherapy.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";28746710;"JAMA dermatology";"Doyen J, Picard A, Naghavi AO, Thyss A, Passeron T, Lacour JP, Montaudié H";;"Jul 2017";1501113600;; 12101;"Psoriatic arthritis screening by the dermatologist: development and first validation of the 'PURE-4 scale'.";"T. Passeron";"Equipe 12, Team 12";29430720;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Audureau E, Roux F, Lons Danic D, Bagot M, Cantagrel A, Dernis E, Gouyette N, Hilliquin P, Jullien D, Lioté F, Passeron T, A Richard M, Claudepierre P";;"03 2018";1519862400;;"Dermatologists are recommended to ask psoriasis patients about musculoskeletal complaints to allow early detection and treatment of psoriatic arthritis (PsA). Screening tools have been developed to help identify patients warranting further rheumatologic assessment, but evidence suggests room for improvement in their diagnostic value and ease of use for outpatient practice." 12099;"Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance.";"B. Bailly-Maitre, E. Verhoeyen, JE. Ricci, J. Chiche, S. Marchetti, T. Passeron";"Equipe 13, Team 13, Team 03, Equipe 03, Equipe 12, Team 12";29551590;"Cell metabolism";"Rubio-Patiño C, Bossowski JP, De Donatis GM, Mondragón L, Villa E, Aira LE, Chiche J, Mhaidly R, Lebeaupin C, Marchetti S, Voutetakis K, Chatziioannou A, Castelli FA, Lamourette P, Chu-Van E, Fenaille F, Avril T, Passeron T, Patterson JB, Verhoeyen E, Bailly-Maitre B, Chevet E, Ricci JE";;"Mar 2018";1521504000;;"Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8 T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors." 12097;"Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo: A Randomized Clinical Trial.";"T. Passeron";"Equipe 12, Team 12";29617528;"JAMA dermatology";"Nguyen S, Chuah SY, Fontas E, Khemis A, Jhingan A, Thng STG, Passeron T";;"Apr 2018";1522886400;; 12095;"Laser hair removal after surgery vs. surgery alone for the treatment of pilonidal cysts: a retrospective case-control study.";"T. Passeron";"Equipe 12, Team 12";29633368;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Kelati A, Lagrange S, Le Duff F, Lacour JP, Benasaid R, Breaud J, Passeron T";;"07 2018";1530403200;;"Based on the presumed role of hair in pilonidal cyst (PNC) pathogenesis, laser epilation has been used to decrease recurrences. However, most of the data rely on case reports and uncontrolled series, and the rare controlled studies reported conflicting results. The objective of this study was to investigate the efficacy of laser hair removal (LHR) to decrease the recurrence rate after surgery of PNC vs. surgery alone." 12093;"Painful acute thyroiditis following a first cure of Ipilimumab plus Nivolumab for metastatic melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";29916989;"Melanoma research";"Montaudié H, Picard A, Panaia-Ferrari P, Boukari F, Passeron T, Sadoul JL, Brucker-Davis F";;"Jun 2018";1529452800;; 12091;"Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment.";"C. Chiaverini, M. Tulic, T. Passeron";"Equipe 12, Team 12";29932457;"The British journal of dermatology";"Castela E, Tulic MK, Rozières A, Bourrat E, Nicolas JF, Kanitakis J, Vabres P, Bessis D, Mazereeuw J, Morice-Picard F, Baty D, Berard F, Lacour JP, Passeron T, Chiaverini C";;"Jun 2018";1529712000;;"Epidermolysis bullosa simplex generalized severe (EBS-gen sev) is a genetic disorder caused by mutation in the KRT5 or KRT14 genes. Although it is usually considered a mechanical disease, recent data argue for additional inflammatory mechanisms." 12087;"[Prurigo pigmentosa during pregnancy].";"T. Passeron";"Equipe 12, Team 12";30104019;"Annales de dermatologie et de venereologie";"Devred I, Sfecci A, Cardot-Leccia N, Lacour JP, Passeron T";;"08 2018";1533081600;;"Prurigo pigmentosa is a rare inflammatory dermatosis characterized by pruritic and reticulate papules on the trunk leaving hyperpigmentation. This dermatosis has been rarely described outside Asia. The pathophysiology remains obscure." 12088;"Efficacy and safety data for checkpoint inhibitors in advanced melanoma under real-life conditions: A monocentric study conducted in Nice from 2010 to 2016.";"G. Beranger, H. Montaudie, T. Passeron";"Equipe 12, Team 12";30098818;"Annales de dermatologie et de venereologie";"Taquin H, Fontas E, Massol O, Chevallier P, Balloti R, Beranger G, Lacour JP, Passeron T, Montaudié H";;"08 2018";1533081600;;"Immunotherapies using anti-CTLA4 and anti-PD1 antibodies have revolutionised the management of patients with advanced melanoma. The aim of our study was to analyse the efficacy and safety of immunotherapies in patients with advanced melanoma under real-life conditions." 12083;"Treatment of Severe Hailey-Hailey Disease With Apremilast.";"C. Chiaverini, H. Montaudie, T. Passeron";"Equipe 12, Team 12";30304341;"JAMA dermatology";"Kieffer J, Le Duff F, Montaudié H, Chiaverini C, Lacour JP, Passeron T";;"Oct 2018";1539216000;;"Hailey-Hailey disease (HHD) is a rare, autosomal-dominant acantholytic dermatosis characterized clinically by development of recurrent blisters and erosions in friction areas. Despite progression in our understanding of the molecular genetics of HHD, therapy remains suboptimal and there is no known cure." 12084;"Successful treatment of resistant condylomas with nitrizinc complex solution: a retrospective study in 11 patients.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";30198596;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Kelati A, Khemis A, Montaudié H, Lacour JP, Passeron T";;"09 2018";1535760000;; 12080;"Antiphospholipid Syndrome Following Pembrolizumab Treatment of Stage IIIB Unresectable Melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";30326507;"JAMA dermatology";"Sanchez A, Montaudie H, Bory P, Belgodere X, Passeron T, Lacour JP, Picard A";;"Oct 2018";1539734400;; 12079;"Comparison of microneedling and full surface erbium laser dermabrasion for autologous cell suspension grafting in nonsegmental vitiligo: a randomized controlled trial.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";30488531;"The British journal of dermatology";"Lagrange S, Montaudié H, Fontas E, Bahadoran P, Lacour JP, Passeron T";;"02 2019";1548979200;; 12077;"Acquired linear hyperpigmentation of the lips - a new entity?";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";30719768;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Almutairi A, Claeys A, Bahadoran P, Brun P, Guardoli D, Freychet F, Hakimi S, Sebbag N, Lacour JP, Passeron T";;"03 2019";1551398400;; 12075;"A case of lymphoplasmacytic plaque in children.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";30811664;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Tsilika K, Montaudié H, Castela E, Cardot-Leccia N, Passeron T, Lacour JP";;"02 2019";1548979200;; 12073;"Laser treatment of hyperpigmented lesions: position statement of the European Society of Laser in Dermatology.";"T. Passeron";"Equipe 12, Team 12";30873649;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Genedy R, Salah L, Fusade T, Kositratna G, Laubach HJ, Marini L, Badawi A";;"03 2019";1551398400;;"Lasers and intense pulsed light sources (IPLS) are proposed for the treatment of many pigmentary disorders. They are sometimes considered as magic tools able to remove any type of lesions. Although being the best option for several hyperpigmented lesions, they can also worsen some conditions and have potential side-effects." 12071;"Sunscreen photoprotection and vitamin D status.";"T. Passeron";"Equipe 12, Team 12";31069788;"The British journal of dermatology";"Passeron T, Bouillon R, Callender V, Cestari T, Diepgen TL, Green AC, van der Pols JC, Bernard BA, Ly F, Bernerd F, Marrot L, Nielsen M, Verschoore M, Jablonski NG, Young AR";;"07 2019";1561939200;;"Global concern about vitamin D deficiency has fuelled debates on photoprotection and the importance of solar exposure to meet vitamin D requirements." 12069;"Filling the gap in the scoring of pigmentary disorders.";"T. Passeron";"Equipe 12, Team 12";31259449;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Jul 2019";1562025600;; 12067;"A systematic review of outcome reporting in laser treatments for dermatological diseases.";"T. Passeron";"Equipe 12, Team 12";31469447;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Fransen F, Tio DCKS, Prinsen CAC, Haedersdal M, Hedelund L, Laubach HJ, Marini L, Paasch U, Passeron T, Wolkerstorfer A";;"10 2019";1569888000;;"The standardization of outcome reporting is crucial for interpretation and comparison of studies related to laser treatment of skin disorders. In collaboration with the Cochrane Skin-Core Outcome Set Initiative (CS-COUSIN), a procedure has been proposed to find consensus on the most important generic outcome domains (what to measure) for implementation in the international Laser TrEAtment in Dermatology (LEAD) registry. As the first step in the development of a generic outcome set for the LEAD registry, we undertook a systematic review to identify outcomes, outcome measurement instruments, methods and definitions reported in recently published literature of laser treatments for skin disorders. A systematic search was conducted and generated a total of 707 papers. We assessed 150 studies including all types of studies involving laser treatments for the skin. Two researchers independently extracted the type, definition and frequency of all outcomes and used outcome measurement instruments. We identified 105 verbatim outcomes that were categorized into eight domains recommended by the COMET framework: appearance, long-term effects, physician and patient-reported physical signs, satisfaction, health-related quality of life, psychological functioning and adverse events. Heterogeneity in outcome reporting (e.g. categories and outcome measurement instruments) was high, and definitions were insufficiently reported. There was a clear under representation of life impact domains, including satisfaction (23%) quality of life (3%) and psychological functioning (1%). Outcome reporting concerning laser treatments for the skin is heterogeneous. Standardized outcomes are needed for improving evidence synthesis. Results of this review will be used in the next step to reach consensus between stakeholders on the outcome domains to be implemented in the LEAD registry." 12065;"Association of combined PD-L1 expression and tumour-infiltrating lymphocyte features with survival and treatment outcomes in patients with metastatic melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";31625630;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Bence C, Hofman V, Chamorey E, Long-Mira E, Lassalle S, Albertini AF, Liolios I, Zahaf K, Picard A, Montaudié H, Lacour JP, Passeron T, Andea AA, Ilie M, Hofman P";;"11 2019";1572566400;;"Recent advances obtained with immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) protein have significantly improved the outcome of patients with metastatic melanoma. The PD-L1 expression in tumour cells as detected by immunohistochemistry is a predictive biomarker in some solid tumours, but appears insufficient as prognostic or predictive factor of response to ICIs in metastatic melanomas." 12063;"Everyday sunscreen use may compromise vitamin D in temperate climes: reply from authors.";"T. Passeron";"Equipe 12, Team 12";31858587;"The British journal of dermatology";"Young AR, Passeron T";;"02 2020";1580515200;; 12061;"Efficacy and tolerability on melasma of a topical cosmetic product acting on melanocytes, fibroblasts and endothelial cells: a randomized comparative trial against 4% hydroquinone.";"T. Passeron";"Equipe 12, Team 12";31858658;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Bronzina E, Clement A, Marie B, Fook Chong KT, Faure P, Passeron T";;"01 2020";1577836800;;"Recent data demonstrated that an altered basal membrane, activated melanocytes and secreted factors from keratinocytes but also fibroblasts and endothelial cells are involved in the pathophysiology of melasma." 12059;"Short-term exposure to blue light emitted by electronic devices does not worsen melasma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";31887321;"Journal of the American Academy of Dermatology";"Duteil L, Queille-Roussel C, Lacour JP, Montaudié H, Passeron T";;"12 2019";1575158400;; 12057;"Photoprotection of the future: challenges and opportunities.";"T. Passeron";"Equipe 12, Team 12";31898355;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Krutmann J, Passeron T, Gilaberte Y, Granger C, Leone G, Narda M, Schalka S, Trullas C, Masson P, Lim HW";;"01 2020";1577836800;;"The use of sunscreens is an important and essential component of photoprotection. Since their introduction during the first half of the last century, sunscreens have benefited enormously from major technological advances such as the development of novel UV filters; as a result, their efficacy in preventing UV-induced erythema is unequivocal. More recently, however, new challenges have appeared, which have prompted a robust discussion about the safety of sunscreens. These include topics directly related to photoprotection of human skin such as improved/alternative methods for standardization of assessment of the efficacy of sunscreens, but also many others such as photoprotection beyond UV, concerns about human toxicity and ecological safety, the potential of oral photoprotective measures, consequences of innovative galenic formulations. On a first glance, some of these might raise questions and doubts among dermatologists, physicians and the general public about the use sunscreens as a means of photoprotection. This situation has prompted us to critically review such challenges, but also opportunities, based on existing scientific evidence. We conclude by providing our vision about how such challenges can be met best in the future in an attempt to create the ideal sunscreen, which should provide adequate and balanced protection and be easy and safe to use." 12055;"Probiotics for recurrent idiopathic aphthous stomatitis in adults: a placebo-controlled randomized trial.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";31954066;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Dugourd PM, Martin H, Fontas E, Velin M, Montaudié H, Lacour JP, Passeron T";;"02 2020";1580515200;; 12053;"Proceeding Report of the Second Vitiligo International Symposium-November 9-10, 2018, Detroit, Michigan, USA.";"T. Passeron";"Equipe 12, Team 12";31984599;"Pigment cell & melanoma research";"Lyons AB, Ghia D, Abdallah M, Abdel-Malek Z, Esmat S, Ezzedine K, Grimes P, Harris JE, Lui H, Manga P, Mi QS, Pandya A, Parsad D, Passeron T, Picardo M, Seneschal J, Silpa-Archa N, Taieb A, Xiang F, Lim HW, Hamzavi IH";;"03 2020";1583020800;; 12051;"Plasma cell-directed therapies in monoclonal gammopathy-associated scleromyxedema.";"T. Passeron";"Equipe 12, Team 12";32027747;Blood;"Mahévas T, Arnulf B, Bouaziz JD, Livideanu CB, Osio A, Servy A, Cribier B, Sassolas B, Jachiet M, Michel L, Aucouturier P, Lipsker D, Frances C, Sbidian E, Rybojad M, Descamps V, D'Incan M, Humbert P, Beylot-Barry M, Passeron T, de Moreuil C, Taha RY, Hermine O, Dupuy A, Barbarot S, Debarbieux S, Carpentier O, Brault F, Schmutz JL, Thomas-Beaulieu D, Modiano P, Zarnitsky C, Lifermann F, Baubion E, Limal N, Le Bras F, Le Moigne M, Tauber M, Talbot A, Prud'homme R, Peltier S, De Masson A, Battistella M, Bagot M, Mékinian A, Fain O";;"Feb 2020";1581033600;;"Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French multicenter retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an immunoglobulin G isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4 of 33 patients (12%) (smoldering myeloma, n = 2; chronic lymphoid leukemia, n = 1; and refractory cytopenia with multilineage dysplasia, n = 1). Carpal tunnel syndrome (33%), arthralgia (25%), and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. High-dose IV immunoglobulin (HDIVig), alone or in combination with steroids, appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4 of 5 patients. Quantitative reverse-transcriptase polymerase chain reaction analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor β and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management." 12048;"Reliability and validity of the Vitiligo Signs of Activity Score (VSAS).";"T. Passeron";"Equipe 12, Team 12";32064583;"The British journal of dermatology";"van Geel N, Passeron T, Wolkerstorfer A, Speeckaert R, Ezzedine K";;"03 2020";1583020800;;"The associations between disease activity and several clinical signs in vitiligo have been described, but a widely accepted and validated scoring system is lacking." 12047;"Topical rapamycin versus betamethasone dipropionate ointment for treating oral erosive lichen planus: a randomized, double-blind, controlled study.";"T. Passeron";"Equipe 12, Team 12";32128907;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Samimi M, Le Gouge A, Boralevi F, Passeron T, Pascal F, Bernard P, Agbo-Godeau S, Leducq S, Fricain JC, Vaillant L, Francès C";;"04 2020";1585699200;;"Although superpotent topical corticosteroids are the first-line treatment for oral erosive lichen planus (OELP), topical rapamycin was found efficient in a previous case series." 12045;"First step in a new era for treatment of patients with vitiligo.";"T. Passeron";"Equipe 12, Team 12";32653058;"Lancet (London, England)";"Passeron T";;"Jul 2020";1594598400;; 12043;"Skin manifestations associated with irritable bowel syndrome.";"T. Passeron";"Equipe 12, Team 12";32314430;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Piche T";;"05 2020";1588291200;; 12039;"Clinical and biological impact of the exposome on the skin.";"T. Passeron";"Equipe 12, Team 12";32677068;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Krutmann J, Andersen ML, Katta R, Zouboulis CC";;"Jul 2020";1595030400;;"The skin exposome is defined as the totality of environmental exposures over the life course that can induce or modify various skin conditions. Here, we review the impact on the skin of solar exposure, air pollution, hormones, nutrition and psychological factors. Photoageing, photocarcinogenesis and pigmentary changes are well-established consequences of chronic exposure of the skin to solar radiation. Exposure to traffic-related air pollution contributes to skin ageing. Particulate matter and nitrogen dioxide cause skin pigmentation/lentigines, while ozone causes wrinkles and has an impact on atopic eczema. Human skin is a major target of hormones, and they exhibit a wide range of biological activities on the skin. Hormones decline with advancing age influencing skin ageing. Nutrition has an impact on numerous biochemical processes, including oxidation, inflammation and glycation, which may result in clinical effects, including modification of the course of skin ageing and photoageing. Stress and lack of sleep are known to contribute to a pro-inflammatory state, which, in turn, affects the integrity of extracellular matrix proteins, in particular collagen. Hormone dysregulation, malnutrition and stress may contribute to inflammatory skin disorders, such as atopic dermatitis, psoriasis, acne and rosacea." 12040;"The skin exposome. An exciting growing field of research.";"T. Passeron";"Equipe 12, Team 12";32677067;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Jul 2020";1595030400;; 12037;"Reactive angioendotheliomatosis revealing a glomerulopathy secondary to a monoclonal gammopathy successfully treated with lenalidomide.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";32735354;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Di Filippo Y, Cardot-Leccia N, Long-Mira E, Andreani M, Richez V, Lacour JP, Passeron T, Montaudié H";;"08 2020";1596240000;; 12035;"Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic.";"C. Chiaverini, J. Courjon, J. Contenti, T. Passeron, V. Giordanengo";"Equipe 12, Team 12, Equipe 06, Team 06, Equipe 05, Team 05";33237291;"JAMA dermatology";"Hubiche T, Cardot-Leccia N, Le Duff F, Seitz-Polski B, Giordana P, Chiaverini C, Giordanengo V, Gonfrier G, Raimondi V, Bausset O, Adjtoutah Z, Garnier M, Burel-Vandenbos F, Dadone-Montaudié B, Fassbender V, Palladini A, Courjon J, Mondain V, Contenti J, Dellamonica J, Leftheriotis G, Passeron T";;"Nov 2020";1606262400;;"Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown." 12033;"Successful treatment of recalcitrant genital lichen planus with secukinumab.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";33617056;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Rezzag-Mahcene C, Cardot-Leccia N, Lacour JP, Montaudié H, Passeron T";;"12 2020";1606780800;; 12031;"Successful treatment of pyoderma gangrenosum associated with IgA gammopathy with the IL-1 receptor antagonist anakinra.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";33657262;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Rousset P, Dugourd PM, Lanteri A, Montaudié H, Passeron T";;"Mar 2021";1614729600;; 12029;"Photoprotection according to skin phototype and dermatoses: practical recommendations from an expert panel.";"T. Passeron";"Equipe 12, Team 12";33764577;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Lim HW, Goh CL, Kang HY, Ly F, Morita A, Ocampo Candiani J, Puig S, Schalka S, Wei L, Dréno B, Krutmann J";;"05 2021";1619827200;;"Increasing evidence on the impact of the different wavelengths of sunlight on the skin demonstrates the need for tailored recommendations of sunscreen according to skin phototype and dermatoses, which is now possible due to advances in the filters and formulations of sunscreens. A selective literature search was performed by an international expert panel, focusing on the type of sunscreen to recommend for photoaging, skin cancers, photodermatoses, pigmentary disorders and skin inflammatory disorders. Protection against ultraviolet (UV)B is especially important for light skin as there is a high risk of sunburn, DNA damage and skin cancers. Darker skin may be naturally better protected against UVB but is more prone to hyperpigmentation induced by visible light (VL) and UVA. Protection against UVA, VL and infrared A can be helpful for all skin phototypes as they penetrate deeply and cause photoaging. Long-wave UVA1 plays a critical role in pigmentation, photoaging, skin cancer, DNA damage and photodermatoses. Adapting the formulation and texture of the sunscreen to the type of skin and dermatoses is also essential. Practical recommendations on the type of sunscreen to prescribe are provided to support the clinician in daily practice." 12027;"Development of a shared decision-making tool in vitiligo: an international study.";"T. Passeron";"Equipe 12, Team 12";33830502;"The British journal of dermatology";"Shourick J, Ahmed M, Seneschal J, Passeron T, Andreux N, Qureshi A, Chow EY, Natella PA, Harris J, Tran VT, Ezzedine K";;"06 2021";1622505600;;"Shared decision-making tools (SDMt) are visual tools developed to promote joint medical decisions between physicians and patients. There is a paucity of such tools in dermatology." 12025;"Oral gliadin-protected superoxide dismutase in addition to phototherapy for treating non-segmental vitiligo: A 24-week prospective randomized placebo-controlled study.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";33931900;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Fontas E, Montaudié H, Passeron T";;"05 2021";1619827200;;"Despite a solid rationale, the usefulness of antioxidants in treating vitiligo has not been clearly demonstrated. Combining superoxide dismutase (SOD) with a wheat gliadin biopolymer protects it during the passage through the gastrointestinal tract." 12023;"Adult skin acute stress responses to short-term environmental and internal aggression from exposome factors.";"T. Passeron";"Equipe 12, Team 12";34077579;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T, Zouboulis CC, Tan J, Andersen ML, Katta R, Lyu X, Aguilar L, Kerob D, Morita A, Krutmann J, Peters EMJ";;"06 2021";1622505600;;"Exposome factors that lead to stressed skin can be defined as any disturbance to homeostasis from environmental (meteorological factors, solar radiation, pollution or tobacco smoke) and/or internal exposure (unhealthy diet, hormonal variations, lack of sleep, psychosocial stress). The clinical and biological impact of chronic exposome effects on skin functions has been extensively reviewed, whereas there is a paucity of information on the impact of short-term acute exposure. Acute stress, which would typically last minutes to hours (and generally no more than a week), provokes a transient but robust neuroendocrine-immune and tissue remodelling response in the skin and can alter the skin barrier. Firstly, we provide an overview of the biological effects of various acute stressors on six key skin functions, namely the skin physical barrier, pigmentation, defences (antioxidant, immune cell-mediated, microbial and microbiome maintenance), structure (extracellular matrix and appendages), neuroendocrine and thermoregulation functions. Secondly, we describe the biological and clinical effects on adult skin from individual exposome factors that elicit an acute stress response and their consequences in skin health maintenance. Clinical manifestations of acutely stressed skin may include dry skin that might accentuate fine lines, oily skin, sensitive skin, pruritus, erythema, pale skin, sweating, oedema and flares of inflammatory skin conditions such as acne, rosacea, atopic dermatitis, pigmentation disorders and skin superinfection such as viral reactivation. Acute stresses can also induce scalp sensitivity, telogen effluvium and worsen alopecia." 12021;"Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";34088741;"Journal for immunotherapy of cancer";"Gérard A, Doyen J, Cremoni M, Bailly L, Zorzi K, Ruetsch-Chelli C, Brglez V, Picard-Gauci A, Troin L, Esnault VLM, Passeron T, Montaudié H, Seitz-Polski B";;"Jun 2021";1622851200;;"Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma." 12019;"Relapse of chilblain-like lesions during the second wave of the COVID-19 pandemic: a cohort follow-up.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";34128539;"The British journal of dermatology";"Hubiche T, Le Duff F, Fontas E, Rapp J, Chiaverini C, Passeron T";;"07 2021";1625097600;; 12017;"Male genital vitiligo.";"T. Passeron";"Equipe 12, Team 12";34226034;"Annales de dermatologie et de venereologie";"Dauendorffer JN, Skayem C, Passeron T";;"07 2021";1625097600;;"Vitiligo is a polygenetic multifactorial disease leading to melanocytic loss in skin and sometimes in hair. Genital areas may be involved and represent a specific therapeutic challenge. Surprisingly, data on male genital vitiligo remain scarce. This review aims to collate current knowledge on male genital vitiligo and to discuss the risks and benefits of the various therapeutic approaches. Male genital vitiligo is relatively frequent and often induces marked impairment of quality of life, with a specific impact on sex life. Prompt recognition of activity remains mandatory to halt disease progression, as repigmentation remains difficult to achieve in most cases. Thanks to progress in understanding of the pathophysiology of vitiligo, new therapeutic approaches are under development. Topical ruxolitinib, a JAK pathway inhibitor, is currently the product in the most advanced stage of development, with a very encouraging repigmentation rate on the face, although specific efficacy in genital area remains to be assessed. The next generation of treatments, such as topical WNT agonists, could be of great interest in genital vitiligo as they will not require combination with UV therapy and they may be able to enhance the differentiation and proliferation of melanocyte stem cells in this difficult-to-treat area." 12015;"Vitiligo: 30 years to put together the puzzle pieces and to give rise to a new era of therapeutic options.";"T. Passeron";"Equipe 12, Team 12";34647661;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Passeron T";;"Oct 2021";1634169600;; 12013;"Severe necrotizing myopathy after COVID-19 vaccine with BNT162b2 and regimen with ipilimumab plus nivolumab in a patient with advanced melanoma.";"A. Martel, H. Montaudie, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";34661938;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Blaise M, Rocher F, Spittler H, Sanchez A, Lanteri E, Coco L, Puma A, Martel A, Gonfrier G, Passeron T, Montaudié H";;"11 2021";1635724800;; 12011;"Efficacy and safety of methotrexate, omalizumab and dupilumab for bullous pemphigoid in patients resistant or contraindicated to oral steroids. A monocentric real-life study.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";35143077;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Velin M, Dugourd PM, Sanchez A, Bahadoran P, Montaudié H, Passeron T";;"02 2022";1643673600;; 12009;"The use of lasers in vitiligo, an overview.";"T. Passeron";"Equipe 12, Team 12, Equipe 07";35176186;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Post NF, Ezekwe N, Narayan VS, Bekkenk MW, Van Geel N, Hamzavi I, Passeron T, Wolkerstorfer A";;"Feb 2022";1645056000;;"Various types of lasers have been demonstrated to be effective in the treatment of vitiligo. The mode of action of these lasers is just as varied as the purpose of intervention. Many clinicians are not aware of the unique opportunity these lasers offer to improve the outcomes of vitiligo treatment. To date, no clear overview exists of the use of lasers in vitiligo treatment. Thus, the aim of this review is to discuss the various types of lasers and provide an overview of the evidence for their efficacy. We found good evidence from a systematic review that the excimer laser is effective, induces repigmentation rates comparable to NB-UVB and has improved outcomes when combined with calcineurin inhibitors. Ablative lasers are commonly used for tissue graft or melanocyte-keratinocyte cell graft transplantation. They provide safe, fast and uniform denudation of the epidermis with propitious repigmentation outcomes. We found conflicting evidence from two systematic reviews regarding the efficacy of fractional ablative lasers for improving outcomes of NB-UVB therapy, a systematic review including only fractional ablative lasers provided evidence for efficacy. Q-switched nanosecond lasers have shown to be safe and effective for inducing depigmentation, although recurrence is common, and most studies were small and retrospective. Despite proven efficacy and safety, laser treatments are relatively expensive and suited for limited body surface areas and selected cases. Each type of laser has benefits and risks associated and should, therefore, be individually chosen based on location, extent, activity and type of vitiligo." 12007;"A new in vitro method to predict in vivo photoprotection of skin hyperpigmentation induced by visible light.";"T. Passeron";"Equipe 12, Team 12, Equipe 07";35224781;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Duteil L, Cadars B, Queille-Roussel C, Giraud I, Drulhon F, Graizeau C, Guyoux A, Passeron T";;"02 2022";1643673600;;"Ultraviolet radiation is the main cause of skin pigmentation, but more recently visible light has been shown to be an important contributor especially in melano-competent subjects. Photoprotection from visible light can improve several hyperpigmentation disorders. Recently, a visible light photoprotection assessment method has been proposed based on in vivo pigmentation; the visible light photoprotection factor (VL-PF) is determined by assessment of the change in colorimetry parameter ITA over several days measured using a chromameter. Although in vivo methods remain the most representative of real life, in vitro methods are more suited to screening sunscreen formulations." 12005;"Artificial Intelligence analysis of over half a million European and Chinese women reveals striking differences in the facial skin ageing process.";"T. Passeron";"Equipe 12, Team 12, Equipe 07";35279898;"Journal of the European Academy of Dermatology and Venereology : JEADV";"Flament F, Jacquet L, Ye C, Amar D, Kerob D, Jiang R, Zhang Y, Kroely C, Delaunay C, Passeron T";;"Mar 2022";1647129600;;"Artificial Intelligence (A.I) and deep learning-based algorithms are increasingly being used in dermatology following the emergence of powerful smartphones with high-resolution cameras." 12001;"Dual Covalent Inhibition of PKM and IMPDH Targets Metabolism in Cutaneous Metastatic Melanoma.";"A. Jacquel, C. Regazzetti, G. Robert, M. Tulic, N. Tekaya, P. Abbe, P. Auberger, S. Rocchi, T. Passeron, T. Cluzeau, G. Beranger, N. Tekaya";"Equipe 02, Team 02, Equipe 12, Team 12";34099492;"Cancer research";"Zerhouni M, Martin AR, Furstoss N, Gutierrez VS, Jaune E, Tekaya N, Beranger GE, Abbe P, Regazzetti C, Amdouni H, Driowya M, Dubreuil P, Luciano F, Jacquel A, Tulic MK, Cluzeau T, O'Hara BP, Ben-Sahra I, Passeron T, Benhida R, Robert G, Auberger P, Rocchi S";;"06 2021";1622505600;;"Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAF cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines . Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. SIGNIFICANCE: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer." 11999;"Photoprotection of the Skin from Visible Light‒Induced Pigmentation: Current Testing Methods and Proposed Harmonization.";"T. Passeron";"Equipe 12, Team 12";34112516;"The Journal of investigative dermatology";"Lim HW, Kohli I, Granger C, Trullàs C, Piquero-Casals J, Narda M, Masson P, Krutmann J, Passeron T";;"06 2021";1622505600;;"Visible light (VL) can induce pigmentary alterations, especially in dark-skinned individuals, and exacerbate photodermatoses and pigmentary disorders. Currently, there is no standardized method for assessing sunscreen protection against VL. On the basis of a critical review of published in vitro and in vivo methods, a VL photoprotection assessment method based on pigmentation is proposed." 11997;"Daily photoprotection: What does it really mean?";"T. Passeron";"Equipe 12, Team 12";34133801;"Photodermatology, photoimmunology & photomedicine";"Krutmann J, Granger C, Trullàs C, Passeron T";;"06 2021";1622505600;; 11995;"Increased Activation of Innate Immunity and Pro-Apoptotic CXCR3B in Normal-Appearing Skin on the Lesional Site of Patients with Segmental Vitiligo.";"H. Bzioueche, M. Tulic, S. Marchetti, S. Rocchi, T. Passeron";"Equipe 12, Team 12, Team 03, Equipe 03";34343558;"The Journal of investigative dermatology";"Passeron T, Malmqvst VEA, Bzioueche H, Marchetti S, Rocchi S, Tulic MK";;"07 2021";1625097600;; 11993;"Male sex, discoid lupus erythematosus, and lower limb involvement are associated with systemic lupus in lupus panniculitis patients: A multicenter case series of 74 patients.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";34352346;"Journal of the American Academy of Dermatology";"Lemasson J, Frumholtz L, Jachiet M, Lenormand C, Lipsker D, Moulin S, Chiaverini C, Le Duff F, Passeron T, Cordoliani F, Bagot M, Monfort JB, Senet P, De Masson A, Cassius C, Petit A, Misery L, Moguelet P, Cordel N, Fardet L, Begon E, Frances C, Bessis D, Bouaziz JD, Chasset F";;"08 2021";1627776000;; 11991;"Thiamidol in moderate-to-severe melasma: 24-week, randomized, double-blind, vehicle-controlled clinical study with subsequent regression phase.";"T. Passeron";"Equipe 12, Team 12";34676600;"The Journal of dermatology";"Roggenkamp D, Sammain A, Fürstenau M, Kausch M, Passeron T, Kolbe L";;"10 2021";1633046400;;"Thiamidol was the most potent inhibitor of human tyrosinase out of 50 000 screened substances. In vivo, it was well tolerated and improved melasma significantly. This was the first 24-week, randomized, double-blind, vehicle-controlled, cosmetic clinical study to assess the efficacy and tolerability of thiamidol in moderate-to-severe melasma of phototype III-V subjects with subsequent regression phase. Females allocated to verum (n = 23), applied daily Dual Serum followed either by Day Care SPF30 in the morning or by Night Care in the evening, all containing Thiamidol. The vehicle group (25 females) followed the same skin care routine using the corresponding vehicle formulations. Subjects came back for a follow-up visit 13-20 weeks after treatment (regression phase). Assessments included clinical photography, Melasma Area and Severity Index (MASI), skin lightness, quality of life, and tolerability. Baseline demographics and hyperpigmentation were well balanced across the treatment groups. Clinical photography and MASI improved with Thiamidol significantly versus baseline (p < 0.001) and vehicle (p < 0.001-0.043) at all time points up to treatment end. At follow-up, the MASI was still significantly lower than at baseline but similar for verum and vehicle. Skin lightness and quality of life improved significantly versus baseline without significant differences between verum and vehicle. This study demonstrated that Thiamidol is well tolerated and superior in improving melasma compared to baseline and vehicle over a treatment period of 24 weeks." 11989;"Allogeneic stem cell transplantation as a curative therapeutic approach for VEXAS syndrome: a case report.";"M. Loschi, T. Passeron, T. Cluzeau";"Equipe 02, Team 02, Equipe 12, Team 12";34999727;"Bone marrow transplantation";"Loschi M, Roux C, Sudaka I, Ferrero-Vacher C, Marceau-Renaut A, Duployez N, Passeron T, Cluzeau T";;"01 2022";1640995200;;"VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly described entity linked to somatic mutation of UBA1, encompassing inflammatory disorders and hematological malignancies. Patients experiments symptoms related to inflammatory manifestations on the skin, joints, lungs. Most patients are refractory to usual anti-inflammatory or immunosuppressive treatments. Half of them will develop hematological diseases, mostly myelodysplastic syndromes. VEXAS patients with hematological malignancies have a poor outcome and no curative option has been described so far. Because in the first reported cohort of VEXAS patients the UBA1 mutation was only found in hematopoietic stem cells but not in fibroblasts, we hypothesized that bone marrow transplantation would provide a cure for the disease. Here we report the case of a VEXAS patient who successfully received an allogeneic hematopoietic stem cell transplantation as a curative option." 11987;"Efficacy of 308-nm excimer therapy in alopecia areata: A retrospective study with long-term follow-up.";"T. Passeron, H. Montaudie";"Equipe 12, Team 12";35064603;"Photodermatology, photoimmunology & photomedicine";"Y DF, H M, Passeron T";;"01 2022";1640995200;; 11981;"Comparison of Two Rapid Assays for the Detection of V600 Mutations in Metastatic Melanoma including Positive Sentinel Lymph Nodes.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12, Equipe 07";35328303;"Diagnostics (Basel, Switzerland)";"Long-Mira E, Picard-Gauci A, Lassalle S, Hofman V, Lalvée S, Tanga V, Zahaf K, Bonnetaud C, Lespinet V, Camuzard O, Montaudié H, Poissonnet G, Passeron T, Ilié M, Hofman P";;"03 2022";1646092800;;"Testing for the mutation is mandatory for the management of patients with locally advanced or metastatic melanoma. Molecular analysis based on DNA sequencing remains the gold-standard method for the screening of the different mutations. These methods must be rapid, sensitive, and specific enough to allow optimal therapeutic management in daily practice and also to include patients in clinical trials. Here, we compared the Idylla Mutation Test and the anti- (clone VE1) immunohistochemistry (IHC) in 90 melanoma samples, with a focus on a challenging cohort of 32 positive sentinel lymph nodes. The status was assessed with both methods independently of the percentage of tumor cells. The concordance rate was calculated excluding both non-contributory analyses and mutants due to the specific V600E-IHC test design. The incidence of the mutation was 33% with both Idylla and IHC. The agreement rate was 91% (72/79). Although the agreement rate was high, we suggest that the use of IHC is more suitable for rapid testing on sentinel lymph node biopsies when associated with a low percentage and scattered tumor cells, which gave a high risk of non-contributory analysis and/or false negative results with the Idylla Mutation Test." 11982;"Melasma: The need for tailored photoprotection to improve clinical outcomes.";"T. Passeron";"Equipe 12, Team 12";35229368;"Photodermatology, photoimmunology & photomedicine";"Morgado-Carrasco D, Piquero-Casals J, Granger C, Trullàs C, Passeron T";;"03 2022";1646092800;;"Melasma is a frequent photoexacerbated hyperpigmentary disorder, which can significantly impact on the quality of life. We sought to review the pathogenesis of melasma, and the role of photoprotection in the prevention and treatment of this disorder." 11977;"Association of TRF2 expression and myeloid-derived suppressor cells infiltration with clinical outcome of patients with cutaneous melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";33796413;Oncoimmunology;"Ilié M, Lantéri E, Chamorey E, Thamphya B, Hamila M, Montaudié H, Picard-Gauci A, Gardrat S, Passeron T, Lassalle S, Long-Mira E, Cherfils-Vicini J, Gilson E, Hofman V, Hofman P";;"03 2021";1614556800;;"The outcome of patients with cutaneous melanoma has been strongly modified by recent advances obtained with Immune Checkpoint Inhibitors (ICIs). However, despite this breakthrough, durable response to ICIs is limited to a subset of patients. We investigated whether the expression of TRF2, which preserves telomere integrity, and have an effect on tumor immunosurveillance notably by directly recruiting and activating myeloid-derived suppressor cells (MDSCs), could be a prognostic biomarker in patients with relapsed or metastatic melanoma based on different treatment regimens. We evaluated retrospectively the association of TRF2 expressed in melanoma cells in combination with intratumoral CD33+ CD15+ CD14- MDSCs, as detected by immunohistochemistry and quantified by digital analysis, to clinicopathological features and overall survival (OS) among 48 patients treated with ICIs and 77 patients treated with other treatment options. The densities/mm of TRF2+ cells (=.003) and CD33+ cells (=.004) were individually significantly related to poor OS. In addition, only the combined expression of CD33+/CD15+/CD14- cells/mm was significantly correlated to poor OS (=.017) in the whole study population as well as in patients treated by ICIs (=.023). There was no significant difference in OS when analyzing the other markers individually or in combination according to the treatment regimen. The pre-treatment assessment of TRF2 expression and CD33+ cells/mm along with the density of CD33+/CD15+/CD14- cells/mm could assess OS and better predict clinical response of patients with melanoma treated by ICIs." 11975;"Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";34088741;"Journal for immunotherapy of cancer";"Gérard A, Doyen J, Cremoni M, Bailly L, Zorzi K, Ruetsch-Chelli C, Brglez V, Picard-Gauci A, Troin L, Esnault VLM, Passeron T, Montaudié H, Seitz-Polski B";;"Jun 2021";1622851200;;"Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma." 11973;"Efficacy and Safety of Tacrolimus 0.1% for the Treatment of Facial Vitiligo: A Multicenter Randomized, Double-Blinded, Vehicle-Controlled Study.";"T. Passeron";"Equipe 12, Team 12";33549606;"The Journal of investigative dermatology";"Seneschal J, Duplaine A, Maillard H, Passeron T, Andreu N, Lassalle R, Favary C, Droitcourt C, Taïeb A, Ezzedine K";;"Feb 2021";1612656000;;"Topical calcineurin inhibitors are used off label in the treatment of vitiligo, and there is a lack of placebo-controlled, blinded studies to support their use." 11971;"Targeting Innate Immunity to Combat Cutaneous Stress: The Vitiligo Perspective.";"M. Tulic, T. Passeron";"Equipe 12, Team 12";33936032;"Frontiers in immunology";"Boniface K, Passeron T, Seneschal J, Tulic MK";;"04 2021";1617235200;;"Multiple factors are involved in the process leading to melanocyte loss in vitiligo including environmental triggers, genetic polymorphisms, metabolic alterations, and autoimmunity. This review aims to highlight current knowledge on how danger signals released by stressed epidermal cells in a predisposed patient can trigger the innate immune system and initiate a cascade of events leading to an autoreactive immune response, ultimately contributing to melanocyte disappearance in vitiligo. We will explore the genetic data available, the specific role of damage-associated-molecular patterns, and pattern-recognition receptors, as well as the cellular players involved in the innate immune response. Finally, the relevance of therapeutic strategies targeting this pathway to improve this inflammatory and autoimmune condition is also discussed." 11968;"Analysis of Matched Skin and Gut Microbiome of Patients with Vitiligo Reveals Deep Skin Dysbiosis: Link with Mitochondrial and Immune Changes.";"H. Bzioueche, M. Tulic, S. Rocchi, T. Passeron";"Equipe 12, Team 12";33771527;"The Journal of investigative dermatology";"Bzioueche H, Simonyté Sjödin K, West CE, Khemis A, Rocchi S, Passeron T, Tulic MK";;"03 2021";1614556800;;"Vitiligo is an autoimmune disease characterized by patchy, white skin owing to melanocyte loss. Commensal cutaneous or gut dysbiosis has been linked to various dermatological disorders. In this study, we studied the skin and gut microbiota of patients with vitiligo compared with those of healthy controls. We obtained swabs and biopsies from both lesional and nonlesional skin as well as stool and blood samples from each individual. We detected reduced richness and diversity of microbiota in the stools of subjects with vitiligo compared with the stools of the controls (P < 0.01). Skin swabs had greater α-diversity than biopsies (P < 0.001); swabs from lesional sites were primarily depleted of Staphylococcus compared with those from nonlesional sites (P < 0.02). Sampling deeper layers from the same patients showed differences in both α- and β-diversity between samples with decreased richness and distribution of species (P < 0.01) in the lesional site. Biopsy microbiota from the lesional skin had distinct microbiota composition, which was depleted of protective Bifidobacterium and Bacteroides but was enriched in Proteobacteria, Streptococcus, Mycoplasma, and mtDNA (P < 0.001); the latter increased in the same patients with heightened innate immunity and stress markers in their blood (P < 0.05). These data describe vitiligo-specific cutaneous and gut microbiota and a link between skin dysbiosis, mitochondrial damage, and immunity in patients with vitiligo." 11964;"Correction to: ITGBL1 is a new immunomodulator that favors development of melanoma tumors by inhibiting natural killer cells cytotoxicity.";"A. Jacquel, C. Bertolotto, H. Montaudie, K. Bille, M. Tulic, R. Ballotti, T. Passeron, T. Strub, Y. Cheli";"Equipe 02, Team 02, Equipe 01, Team 01, Equipe 12, Team 12";33504341;"Molecular cancer";"Cheli Y, Tulic MK, El Hachem N, Nottet N, Jacquel A, Gesson M, Strub T, Bille K, Picard-Gauci A, Montaudié H, Beranger GE, Passeron T, Close P, Bertolotto C, Ballotti R";;"01 2021";1609459200;; 11963;"Germline variants in exonic regions have limited impact on immune checkpoint blockade clinical outcomes in advanced melanoma.";"H. Montaudie, R. Ballotti, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";33449414;"Pigment cell & melanoma research";"Montaudié H, Beranger GE, Reinier F, Nottet N, Martin H, Picard-Gauci A, Troin L, Ballotti R, Passeron T";;"01 2021";1609459200;;"Immune checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, up to 60% of treated patients do not respond to ICI and/or develop immune-related adverse events (irAEs). Currently, robust and reliable biomarker to predict response and/or occurrence of irAEs to ICI are missing. Herein, we wanted to explore whether germline variants (SNPs) could predict the clinical outcomes of melanoma patients treated with ICIs. We performed a whole exome sequencing using gDNA isolated from blood, from a discovery cohort of 57 patients with metastatic melanoma. The top associations were then tested in a validation cohort of 57 patients. Our work suggests that individual germline genetic variants have no or weak impact on the response to ICIs. Only, variants in IL1RL1 have a significant impact in treatment response. The role of IL1RL1 in the immune response against melanoma and as a theranostic marker warrants further investigations." 11959;"Discovery of a new molecule inducing melanoma cell death: dual AMPK/MELK targeting for novel melanoma therapies.";"F. BOST, G. Beranger, M. Tulic, N. Tekaya, P. Abbe, R. Ballotti, S. Rocchi, T. Passeron, T. Botton";"Equipe 05, Team 05, Equipe 12, Team 12, Equipe 01, Team 01";33431809;"Cell death & disease";"Jaune E, Cavazza E, Ronco C, Grytsai O, Abbe P, Tekaya N, Zerhouni M, Beranger G, Kaminski L, Bost F, Gesson M, Tulic M, Hofman P, Ballotti R, Passeron T, Botton T, Benhida R, Rocchi S";;"01 2021";1609459200;;"In the search of biguanide-derived molecules against melanoma, we have discovered and developed a series of bioactive products and identified the promising new compound CRO15. This molecule exerted anti-melanoma effects on cells lines and cells isolated from patients including the ones derived from tumors resistant to BRAF inhibitors. Moreover, CRO15 was able to decrease viability of cells lines from a broad range of cancer types. This compound acts by two distinct mechanisms. First by activating the AMPK pathway induced by a mitochondrial disorder. Second by inhibition of MELK kinase activity, which induces cell cycle arrest and activation of DNA damage repair pathways by p53 and REDD1 activation. All of these mechanisms activate autophagic and apoptotic processes resulting in melanoma cell death. The strong efficacy of CRO15 to reduce the growth of melanoma xenograft sensitive or resistant to BRAF inhibitors opens interesting perspective." 11961;"[Histopathological features due to the SARS-CoV-2].";"T. Passeron";"Equipe 12, Team 12";33446414;"Annales de pathologie";"Hofman P, Copin MC, Tauziede-Espariat A, Adle-Biassette H, Fortarezza F, Passeron T, Salmon I, Calabrese F";;"Jan 2021";1610668800;;"The infection due to the SARS-CoV-2 leads lesions mainly observed at the respiratory tract level, but not exclusively. The analyses of these lesions benefited from different autopsy studies. Thus, these lesions were observed in different organs, tissues and cells. These observations allowed us to rapidly improve the knowledge of the pathophysiological mechanisms associated with this emergent infectious disease. The virus can be detected in formalin fixed paraffin embedded tissues using immunohistochemistry, in situ hybridization, molecular biology and/or electron microscopy approaches. However, many uncertainties are still present concerning the direct role of the SARS-CoV-2 on the different lesions observed in different organs, outside the lung, such as the heart, the brain, the liver, the gastrointestinal tract, the kidney and the skin. In this context, it is pivotal to keep going to increase the different tissue and cellular studies in the COVID-19 positive patients aiming to better understanding the consequences of this new infectious disease, notably considering different epidemiological and co-morbidities associated factors. This could participate to the development of new therapeutic strategies too. The purpose of this review is to describe the main histological and cellular lesions associated with the infection due to the SARS-CoV-2." 11957;"Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic.";"C. Chiaverini, J. Courjon, J. Contenti, T. Passeron, V. Giordanengo";"Equipe 12, Team 12, Equipe 06, Team 06, Equipe 05, Team 05";33237291;"JAMA dermatology";"Hubiche T, Cardot-Leccia N, Le Duff F, Seitz-Polski B, Giordana P, Chiaverini C, Giordanengo V, Gonfrier G, Raimondi V, Bausset O, Adjtoutah Z, Garnier M, Burel-Vandenbos F, Dadone-Montaudié B, Fassbender V, Palladini A, Courjon J, Mondain V, Contenti J, Dellamonica J, Leftheriotis G, Passeron T";;"Nov 2020";1606262400;;"Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown." 11955;"Assessing the minimal important change in the vitiligo extent score and the self-assessment vitiligo extent score.";"T. Passeron";"Equipe 12, Team 12";33122021;"Journal of the American Academy of Dermatology";"Uitentuis SE, Wolkerstorfer A, Bae JM, Esmat S, Mogawer RM, Ragab N, Chuah SY, Passeron T, van Geel N, Thng STG, Terwee CB, Bekkenk MW";;"10 2020";1601510400;; 11951;"Low-Dose IL-2 for Treating Moderate to Severe Alopecia Areata: A 52-Week Multicenter Prospective Placebo-Controlled Study Assessing its Impact on T Regulatory Cell and NK Cell Populations.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";32941917;"The Journal of investigative dermatology";"Le Duff F, Bouaziz JD, Fontas E, Ticchioni M, Viguier M, Dereure O, Reygagne P, Montaudié H, Lacour JP, Monestier S, Richard MA, Passeron T";;"09 2020";1598918400;; 11949;"The continuous development of a complete and objective automatic grading system of facial signs from selfie pictures: Asian validation study and application to women of three ethnic origins, differently aged.";"T. Passeron";"Equipe 12, Team 12";32686236;"Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)";"Flament F, Lee YW, Lee DH, Passeron T, Zhang Y, Jiang R, Prunel A, Dwivedi S, Kroely C, Park YJ, Chuberre B, Aarabi P";;"07 2020";1593561600;;"To evaluate the capacity of the automatic detection system to accurately grade, from smartphones' selfie pictures, the severity of seven new facial signs added to the nine previously integrated." 11947;"Apoptosis and pericyte loss in alveolar capillaries in COVID-19 infection: choice of markers matters. Author's reply.";"T. Passeron";"Equipe 12, Team 12";32844260;"Intensive care medicine";"Burel-Vandenbos F, Cardot-Leccia N, Passeron T";;"08 2020";1596240000;; 11945;"Pulmonary Vascular Pathology in Covid-19.";"T. Passeron";"Equipe 12, Team 12";32678531;"The New England journal of medicine";"Burel-Vandenbos F, Cardot-Leccia N, Passeron T";;"07 2020";1593561600;; 11943;"First step in a new era for treatment of patients with vitiligo.";"T. Passeron";"Equipe 12, Team 12";32653058;"Lancet (London, England)";"Passeron T";;"Jul 2020";1594598400;; 11941;"Generic outcome set for the international registry on Laser trEAtments in Dermatology (LEAD): a protocol for a Delphi study to achieve consensus on to measure.";"T. Passeron";"Equipe 12, Team 12";32595165;"BMJ open";"Fransen F, Spuls P, Alam M, Badawi A, Boixeda P, Haedersdal M, Hamzavi I, Hedelund L, Kelly KM, Kono T, Laubach HJ, Manuskiatti W, Marini L, Nouri K, Paasch U, Passeron T, Prinsen CACS, Verner I, Wolkerstorfer A";;"06 2020";1590969600;;"While laser technology has expanded the armamentarium of treatment for various skin diseases during the past years, heterogeneity in study outcomes hampers comparability and appropriate evidence synthesis. Part of these issues can be addressed by developing a generic outcome set. Using the Delphi method, this study aims to seek consensus between key stakeholders on relevant generic outcomes ( to measure) for implementation in the international registry on Laser trEAtments in Dermatology (LEAD). The registry is focused on collecting research data on various laser treatments for skin disorders." 11939;"Ingenol mebutate to treat lentigo maligna of the head (face and scalp): A prospective, multicenter, single-arm phase 2 trial indicates no benefit.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";31325551;"Journal of the American Academy of Dermatology";"Montaudié H, Le Duff F, Butori C, Hofman V, Fontas E, Roger-Cruzel C, Bahadoran P, Perrot JL, Desmedt E, Legoupil D, Passeron T, Lacour JP";;"07 2019";1561939200;; 11937;"Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo: A Randomized Clinical Trial.";"T. Passeron";"Equipe 12, Team 12";29617528;"JAMA dermatology";"Nguyen S, Chuah SY, Fontas E, Khemis A, Jhingan A, Thng STG, Passeron T";;"Apr 2018";1522886400;; 11935;"E2F1 inhibition mediates cell death of metastatic melanoma.";"C. Bertolotto, M. Tulic, M. Cerezo, M. Ohanna, P. Abbe, R. Ballotti, S. Rocchi, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12, Equipe 11, Team 11";29743521;"Cell death & disease";"Rouaud F, Hamouda-Tekaya N, Cerezo M, Abbe P, Zangari J, Hofman V, Ohanna M, Mograbi B, El-Hachem N, Benfodda Z, Lebeau A, Tulic MK, Hofman P, Bertolotto C, Passeron T, Annicotte JS, Ballotti R, Rocchi S";;"05 2018";1525132800;;"Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite advancements in targeted therapies (BRAF inhibitors) or immunotherapies (anti-CTLA-4 or anti-PD1), most patients with melanoma will need additional treatment. Thus, there is an urgent need to develop new therapeutical approaches to bypass resistance and achieve more prolonged responses. In this context, we were interested in E2F1, a transcription factor that plays a major role in the control of cell cycle under physiological and pathological conditions. Here we confirmed that E2F1 is highly expressed in melanoma cells. Inhibition of E2F1 activity further increased melanoma cell death and senescence, both in vitro and in vivo. Moreover, blocking E2F1 also induced death of melanoma cells resistant to BRAF inhibitors. In conclusion, our studies suggest that targeting the E2F1 signaling pathway may be therapeutically relevant for melanoma." 11933;"Painful acute thyroiditis following a first cure of Ipilimumab plus Nivolumab for metastatic melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";29916989;"Melanoma research";"Montaudié H, Picard A, Panaia-Ferrari P, Boukari F, Passeron T, Sadoul JL, Brucker-Davis F";;"Jun 2018";1529452800;; 11931;"Treatment of Severe Hailey-Hailey Disease With Apremilast.";"C. Chiaverini, H. Montaudie, T. Passeron";"Equipe 12, Team 12";30304341;"JAMA dermatology";"Kieffer J, Le Duff F, Montaudié H, Chiaverini C, Lacour JP, Passeron T";;"Oct 2018";1539216000;;"Hailey-Hailey disease (HHD) is a rare, autosomal-dominant acantholytic dermatosis characterized clinically by development of recurrent blisters and erosions in friction areas. Despite progression in our understanding of the molecular genetics of HHD, therapy remains suboptimal and there is no known cure." 11929;"The key question of irradiance when it comes to the effects of visible light in the skin.";"T. Passeron";"Equipe 12, Team 12";30655105;"Journal of dermatological science";"Passeron T";;"12 2018";1543622400;; 11927;"Antiphospholipid Syndrome Following Pembrolizumab Treatment of Stage IIIB Unresectable Melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";30326507;"JAMA dermatology";"Sanchez A, Montaudie H, Bory P, Belgodere X, Passeron T, Lacour JP, Picard A";;"Oct 2018";1539734400;; 11925;"Caspase 1/11 Deficiency or Pharmacological Inhibition Mitigates Psoriasis-Like Phenotype in Mice.";"A. Jacquel, B. Bailly-Maitre, G. Robert, JE. Ricci, J. Chiche, L. Boyer, P. Auberger, R. Paul-Bellon, S. Marchetti, T. Passeron";"Equipe 02, Team 02, Equipe 13, Team 13, Equipe 03, Team 03, Equipe 06, Team 06, Equipe 12, Team 12";30571969;"The Journal of investigative dermatology";"Aira LE, Gonçalves D, Bossowski JP, Rubio-Patiño C, Chiche J, Paul-Bellon R, Mondragón L, Gesson M, Lecucq-Ottavi P, Obba S, Colosetti P, Luciano F, Bailly-Maitre B, Boyer L, Jacquel A, Robert G, Ricci JE, Ortonne JP, Passeron T, Lacour JP, Auberger P, Marchetti S";;"Dec 2018";1545350400;;"Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1β/IL-18. Although their expression in psoriasis was shown several years ago, little is known about the role of inflammatory caspases in the context of psoriasis. Here, we confirmed that caspases 1, 4, and 5 are activated in lesional skin from psoriasis patients. We showed in three psoriasis-like models that inflammatory caspases are activated, and accordingly, caspase 1/11 invalidation or pharmacological inhibition by Ac-YVAD-CMK (i.e., Ac-Tyr-Val-Ala-Asp-chloromethylketone) injection induced a decrease in ear thickness, erythema, scaling, inflammatory cytokine expression, and immune cell infiltration in mice. We observed that keratinocytes were primed to secrete IL-1β when cultured in conditions mimicking psoriasis. Generation of chimeric mice by bone marrow transplantation was carried out to decipher the respective contribution of keratinocytes and/or immune cells in the activation of inflammatory caspases during psoriasis-like inflammatory response. Our data showed that the presence of caspase 1/11 in the immune system is sufficient for a fully inflammatory response, whereas the absence of caspase 1/11 in keratinocytes/fibroblasts had no impact. In summary, our study indicates that inflammatory caspases activated in immune cells are implicated in psoriasis pathogenesis." 11923;"Innate lymphocyte-induced CXCR3B-mediated melanocyte apoptosis is a potential initiator of T-cell autoreactivity in vitiligo.";"A. Jacquel, C. LUCI, C. Regazzetti, C. Bertolotto, M. Tulic, P. Abbe, R. Ballotti, S. Rocchi, T. Passeron, Y. Cheli";"Equipe 02, Team 02, Equipe 08, Team 08, Equipe 12, Team 12, Equipe 01, Team 01";31097717;"Nature communications";"Tulic MK, Cavazza E, Cheli Y, Jacquel A, Luci C, Cardot-Leccia N, Hadhiri-Bzioueche H, Abbe P, Gesson M, Sormani L, Regazzetti C, Beranger GE, Lereverend C, Pons C, Khemis A, Ballotti R, Bertolotto C, Rocchi S, Passeron T";;"05 2019";1556668800;;"T-cells play a crucial role in progression of autoimmunity, including vitiligo, yet the initial steps triggering their activation and tissue damage remain unknown. Here we demonstrate increased presence of type-1 innate lymphoid cells (NK and ILC1)-producing interferon gamma (IFNγ) in the blood and in non-lesional skin of vitiligo patients. Melanocytes of vitiligo patients have strong basal expression of chemokine-receptor-3 (CXCR3) isoform B which is directly regulated by IFNγ. CXCR3B activation by CXCL10 at the surface of cultured human melanocytes induces their apoptosis. The remaining melanocytes, activated by the IFNγ production, express co-stimulatory markers which trigger T-cell proliferation and subsequent anti-melanocytic immunity. Inhibiting the CXCR3B activation prevents this apoptosis and the further activation of T cells. Our results emphasize the key role of CXCR3B in apoptosis of melanocytes and identify CXCR3B as a potential target to prevent and to treat vitiligo by acting at the early stages of melanocyte destruction." 11921;"Laser treatment of epidermal nevi: A multicenter retrospective study with long-term follow-up.";"T. Passeron";"Equipe 12, Team 12";31202870;"Journal of the American Academy of Dermatology";"Alkhalifah A, Fransen F, Le Duff F, Lacour JP, Wolkerstorfer A, Passeron T";;"06 2019";1559347200;;"Patients with epidermal nevi strongly demand cosmetic improvement. Laser treatment appears appealing and is frequently used in clinical practice. Nevertheless, large series with long-term follow-up are missing, preventing definitive conclusions about its real benefit." 11918;"Comment on 'Testing for BRAF fusions in patients with advanced BRAF/NRAS/KIT wild-type melanomas permits to identify patients who could benefit of anti-MEK targeted therapy'.";"S. Rocchi, T. Passeron, T. Botton";"Equipe 12, Team 12";31852719;"Journal of clinical pathology";"Botton T, Passeron T, Rocchi S";;"12 2019";1575158400;; 11917;"New Methodology to Evaluate Sunscreens Under Outdoor Conditions: A Double-Blind, Randomized Intra-Individual Clinical Study of a Water-Based Broad-Spectrum SPF50+ Versus SPF15 (P3) and SPF50.";"T. Passeron";"Equipe 12, Team 12";31352672;"Dermatology and therapy";"Granger C, Krutmann J, Bustos J, Sola Y, Hosenally M, Trullàs C, Andres P, Passeron T";;"07 2019";1561939200;;"This study explored a new method to test sunscreens in outdoor conditions (very high to extreme ultraviolet [UV] radiation) approximating real-life solar exposure while maintaining scientific standards and acceptable conditions, and assessed the efficacy of a water-based sun-protection factor (SPF) 50+ versus a reference SPF15 and two comparator SPF50+ products." 11915;"In-house Implementation of Tumor Mutational Burden Testing to Predict Durable Clinical Benefit in Non-small Cell Lung Cancer and Melanoma Patients.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";31470674;Cancers;"Heeke S, Benzaquen J, Long-Mira E, Audelan B, Lespinet V, Bordone O, Lalvée S, Zahaf K, Poudenx M, Humbert O, Montaudié H, Dugourd PM, Chassang M, Passeron T, Delingette H, Marquette CH, Hofman V, Stenzinger A, Ilié M, Hofman P";;"08 2019";1564617600;;"Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC ( = 0.73) and melanoma ( = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC." 11913;"Short-term exposure to blue light emitted by electronic devices does not worsen melasma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";31887321;"Journal of the American Academy of Dermatology";"Duteil L, Queille-Roussel C, Lacour JP, Montaudié H, Passeron T";;"Dec 2019";1577750400;; 11911;"Apremilast in Combination with Narrowband UVB in the Treatment of Vitiligo: A 52-Week Monocentric Prospective Randomized Placebo-Controlled Study.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";32004567;"The Journal of investigative dermatology";"Khemis A, Fontas E, Moulin S, Montaudié H, Lacour JP, Passeron T";;"01 2020";1577836800;;"Scientific rationale and encouraging first clinical results suggest the interest of using apremilast for treating vitiligo." 11909;"Plasma cell-directed therapies in monoclonal gammopathy-associated scleromyxedema.";"T. Passeron";"Equipe 12, Team 12";32027747;Blood;"Mahévas T, Arnulf B, Bouaziz JD, Livideanu CB, Osio A, Servy A, Cribier B, Sassolas B, Jachiet M, Michel L, Aucouturier P, Lipsker D, Frances C, Sbidian E, Rybojad M, Descamps V, D'Incan M, Humbert P, Beylot-Barry M, Passeron T, de Moreuil C, Taha RY, Hermine O, Dupuy A, Barbarot S, Debarbieux S, Carpentier O, Brault F, Schmutz JL, Thomas-Beaulieu D, Modiano P, Zarnitsky C, Lifermann F, Baubion E, Limal N, Le Bras F, Le Moigne M, Tauber M, Talbot A, Prud'homme R, Peltier S, De Masson A, Battistella M, Bagot M, Mékinian A, Fain O";;"Feb 2020";1581033600;;"Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French multicenter retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an immunoglobulin G isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4 of 33 patients (12%) (smoldering myeloma, n = 2; chronic lymphoid leukemia, n = 1; and refractory cytopenia with multilineage dysplasia, n = 1). Carpal tunnel syndrome (33%), arthralgia (25%), and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. High-dose IV immunoglobulin (HDIVig), alone or in combination with steroids, appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4 of 5 patients. Quantitative reverse-transcriptase polymerase chain reaction analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor β and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management." 11907;"Treatment of hidradenitis suppurativa using a long-pulsed hair removal neodymium:yttrium-aluminium-garnet laser: A multicenter, prospective, randomized, intraindividual, comparative trial.";"T. Passeron";"Equipe 12, Team 12";32348825;"Journal of the American Academy of Dermatology";"Naouri M, Maruani A, Lagrange S, Cogrel O, Servy A, Collet Vilette AM, Fourcade S, Gral N, Perrillat Y, Rouaud RB, Cartier H, Maire C, Boineau D, Toubel G, Ollivier I, Le Pillouer-Prost A, Passeron T";;"04 2020";1585699200;; 11905;"Pericyte alteration sheds light on micro-vasculopathy in COVID-19 infection.";"T. Passeron";"Equipe 12, Team 12";32533198;"Intensive care medicine";"Cardot-Leccia N, Hubiche T, Dellamonica J, Burel-Vandenbos F, Passeron T";;"06 2020";1590969600;; 11903;"Negative SARS-CoV-2 PCR in patients with chilblain-like lesions.";"C. Chiaverini, T. Passeron, V. Giordanengo";"Equipe 12, Team 12, Equipe 06, Team 06";32563281;"The Lancet. Infectious diseases";"Hubiche T, Le Duff F, Chiaverini C, Giordanengo V, Passeron T";;"06 2020";1590969600;; 11901;"Successful treatment of severe psoriasis relapse with secukinumab (interleukin 17 A inhibitor) after abrupt brodalumab (interleukin 17 receptor inhibitor) discontinuation: A retrospective study evaluating long-term efficacy and safety.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";29596876;"Journal of the American Academy of Dermatology";"Khemis A, Kelati A, Montaudié H, Lacour JP, Passeron T";;"03 2018";1519862400;; 11897;"Development and validation of a reproducible model for studying post-inflammatory hyperpigmentation.";"T. Passeron";"Equipe 12, Team 12";29436173;"Pigment cell & melanoma research";"Passeron T, Nouveau S, Duval C, Cardot-Leccia N, Piffaut V, Bourreau E, Queille-Roussel C, Bernerd F";;"03 2018";1519862400;; 11899;"Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance.";"B. Bailly-Maitre, E. Verhoeyen, JE. Ricci, J. Chiche, S. Marchetti, T. Passeron";"Equipe 13, Team 13, Team 03, Equipe 03, Equipe 12, Team 12";29551590;"Cell metabolism";"Rubio-Patiño C, Bossowski JP, De Donatis GM, Mondragón L, Villa E, Aira LE, Chiche J, Mhaidly R, Lebeaupin C, Marchetti S, Voutetakis K, Chatziioannou A, Castelli FA, Lamourette P, Chu-Van E, Fenaille F, Avril T, Passeron T, Patterson JB, Verhoeyen E, Bailly-Maitre B, Chevet E, Ricci JE";;"Mar 2018";1521504000;;"Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8 T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors." 11895;"Melasma, a photoaging disorder.";"T. Passeron";"Equipe 12, Team 12";29285880;"Pigment cell & melanoma research";"Passeron T, Picardo M";;"01 2018";1514764800;;"Melasma is a common hyperpigmentary disorder. The impact on the quality of life of affected individuals is well demonstrated, demanding new therapeutic strategies. However, the treatment of melasma remains highly challenging. Melasma is often considered as the main consequence of female hormone stimulation on a predisposed genetic background. Although these two factors do contribute to this acquired pigmentary disorder, the last decade has revealed several other key players and brought new pieces to the complex puzzle of the pathophysiology of melasma. Here, we summarize the latest evidence on the pathophysiology of melasma, and we suggest that melasma might be a photoaging skin disorder affecting genetically predisposed individuals. Such data must be taken into consideration by clinicians as they could have a profound impact on the treatment and the prevention of melasma." 11893;"Melanocytes Sense Blue Light and Regulate Pigmentation through Opsin-3.";"C. Regazzetti, M. Tulic, S. Rocchi, T. Passeron";"Equipe 12, Team 12";28842328;"The Journal of investigative dermatology";"Regazzetti C, Sormani L, Debayle D, Bernerd F, Tulic MK, De Donatis GM, Chignon-Sicard B, Rocchi S, Passeron T";;"08 2017";1501545600;;"The shorter wavelengths of the visible light spectrum have been recently reported to induce a long-lasting hyperpigmentation but only in melano-competent individuals. Here, we provide evidence showing that OPN3 is the key sensor in melanocytes responsible for hyperpigmentation induced by the shorter wavelengths of visible light. The melanogenesis induced through OPN3 is calcium dependent and further activates CAMKII followed by CREB, extracellular signal-regulated kinase, and p38, leading to the phosphorylation of MITF and ultimately to the increase of the melanogenesis enzymes: tyrosinase and dopachrome tautomerase. Furthermore, blue light induces the formation of a protein complex that we showed to be formed by tyrosinase and dopachrome tautomerase. This multimeric tyrosinase/tyrosinase-related protein complex is mainly formed in dark-skinned melanocytes and induces a sustained tyrosinase activity, thus explaining the long-lasting hyperpigmentation that is observed only in skin type III and higher after blue light irradiation. OPN3 thus functions as the sensor for visible light pigmentation. OPN3 and the multimeric tyrosinase/tyrosinase-related protein complex induced after its activation appear as new potential targets for regulating melanogenesis but also to protect dark skins against blue light in physiological conditions and in pigmentary disorders." 11890;"Clinical Outcomes of Metastatic Melanoma Treated With Checkpoint Inhibitors and Multisite Radiotherapy.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";28746710;"JAMA dermatology";"Doyen J, Picard A, Naghavi AO, Thyss A, Passeron T, Lacour JP, Montaudié H";;"Jul 2017";1501113600;; 11886;"A method to assess the protective efficacy of sunscreens against visible light-induced pigmentation.";"T. Passeron";"Equipe 12, Team 12";28602025;"Photodermatology, photoimmunology & photomedicine";"Duteil L, Esdaile J, Maubert Y, Cathelineau AC, Bouloc A, Queille-Roussel C, Passeron T";;"Jun 2017";1497225600;;"Until now, photoprotection of human skin has involved the development of sunscreens effective in the ultraviolet (UV) domain. During the last ten years, several studies have shown that besides the well-known damaging effects of UV, visible (400-700 nm) and even infrared light (> 700 nm) can induce damage which contributes to photoaging. Furthermore, many photodermatoses are also known to be triggered by visible light (VL)." 11889;"Treatment of Elastosis Perforans Serpiginosa Using a Fractional Carbon Dioxide Laser.";"T. Passeron";"Equipe 12, Team 12";28746703;"JAMA dermatology";"Kelati A, Lagrange S, Le Duff F, Lacour JP, Passeron T";;"Jul 2017";1501113600;; 11885;"Efficacy and Tolerance of Anti-Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases.";"T. Passeron";"Equipe 12, Team 12";28564695;"JAMA dermatology";"Heidelberger V, Ingen-Housz-Oro S, Marquet A, Mahevas M, Bessis D, Bouillet L, Caux F, Chapelon-Abric C, Debarbieux S, Delaporte E, Duval-Modeste AB, Fain O, Joly P, Marchand-Adam S, Monfort JB, Noël N, Passeron T, Ruivard M, Sarrot-Reynauld F, Verrot D, Bouvry D, Fardet L, Chosidow O, Sève P, Valeyre D";;"Jun 2017";1496275200;;"Evidence for the long-term efficacy and safety of anti-tumor necrosis factor α agents (anti-TNF) in treating cutaneous sarcoidosis is lacking." 11883;"Medical and Maintenance Treatments for Vitiligo.";"T. Passeron";"Equipe 12, Team 12";28317526;"Dermatologic clinics";"Passeron T";;"Mar 2017";1490054400;;"Medical treatments alone, or in combination with phototherapy, are key approaches for treating nonsegmental vitiligo and, to a lesser extent, segmental vitiligo. The treatments are useful for halting disease progression and have been proven effective for inducing repigmentation and decreasing risk of relapses. Although the treatments have side effects and limitations, vitiligo often induces a marked decrease in quality of life and in most cases the risk:benefit ratio is in favor of an active approach. Systemic and topical agents targeting the pathways involved in loss of melanocytes and in differentiation of melanocyte stem cells should provide more effective approaches in the near future." 11881;"Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With Cetuximab.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";28259104;"JAMA dermatology";"Picard A, Pedeutour F, Peyrade F, Saudes L, Duranton-Tanneur V, Chamorey E, Cardot-Leccia N, Sudaka A, Ettaiche M, Benchetrit M, Poissonnet G, Weinbreck N, Dadone B, Lacour JP, Passeron T, Montaudié H";;"Mar 2017";1488672000;;"Cetuximab was recently proposed for advanced cutaneous squamous cell carcinomas (cSCC); however, its efficacy is inconsistent and identification of predictive biomarkers for response is necessary." 11877;"Differential expression of CXCL9, CXCL10, and IFN-γ in vitiligo and alopecia areata patients.";"T. Passeron";"Equipe 12, Team 12";27863059;"Pigment cell & melanoma research";"Maouia A, Sormani L, Youssef M, Helal AN, Kassab A, Passeron T";;"03 2017";1488326400;; 11875;"Metformin monotherapy in melanoma: a pilot, open-label, prospective, and multicentric study indicates no benefit.";"H. Montaudie, M. Cerezo, P. Bahadoran, R. Ballotti, S. Rocchi, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";28122176;"Pigment cell & melanoma research";"Montaudié H, Cerezo M, Bahadoran P, Roger C, Passeron T, Machet L, Arnault JP, Verneuil L, Maubec E, Aubin F, Granel F, Giacchero D, Hofman V, Lacour JP, Maryline A, Ballotti R, Rocchi S";;"04 2017";1491004800;; 11873;"Interleukin 6 and high-sensitivity C-reactive protein are potential predictive markers of response to infliximab in hidradenitis suppurativa.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27986139;"Journal of the American Academy of Dermatology";"Montaudié H, Seitz-Polski B, Cornille A, Benzaken S, Lacour JP, Passeron T";;"Dec 2016";1482019200;; 11869;"Repigmentation in vitiligo: position paper of the Vitiligo Global Issues Consensus Conference.";"T. Passeron";"Equipe 12, Team 12";27864868;"Pigment cell & melanoma research";"Gan EY, Eleftheriadou V, Esmat S, Hamzavi I, Passeron T, Böhm M, Anbar T, Goh BK, Lan CE, Lui H, Ramam M, Raboobee N, Katayama I, Suzuki T, Parsad D, Seth V, Lim HW, van Geel N, Mulekar S, Harris J, Wittal R, Benzekri L, Gauthier Y, Kumarasinghe P, Thng ST, Silva de Castro CC, Abdallah M, Vrijman C, Bekkenk M, Seneschal J, Pandya AG, Ezzedine K, Picardo M, Taïeb A, ";;"Nov 2016";1479600000;;"The Vitiligo Global Issues Consensus Conference (VGICC), through an international e-Delphi consensus, concluded that 'repigmentation' and 'maintenance of gained repigmentation' are essential core outcome measures in future vitiligo trials. This VGICC position paper addresses these core topics in two sections and includes an atlas depicting vitiligo repigmentation patterns and color match. The first section delineates mechanisms and characteristics of vitiligo repigmentation, and the second section summarizes the outcomes of international meeting discussions and two e-surveys on vitiligo repigmentation, which had been carried out over 3 yr. Treatment is defined as successful if repigmentation exceeds 80% and at least 80% of the gained repigmentation is maintained for over 6 months. No agreement was found on the best outcome measure for assessing target or global repigmentation, therefore highlighting the limitations of e-surveys in addressing clinical measurements. Until there is a clear consensus, existing tools should be selected according to the specific needs of each study. A workshop will be conducted to address the remaining issues so as to achieve a consensus." 11870;"Posterior reversible encephalopathy syndrome due to combination of vemurafenib and cobimetinib for metastatic melanoma.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27885826;"Pigment cell & melanoma research";"Boukari F, Dugourd PM, Chassang M, Mondot L, Passeron T, Lacour JP, Montaudie H";;"Nov 2016";1480118400;; 11867;"Topical timolol for chronic wounds in patients with junctional epidermolysis bullosa.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";27846969;"Journal of the American Academy of Dermatology";"Chiaverini C, Passeron T, Lacour JP";;"Nov 2016";1479340800;; 11865;"Appearance of lentigines in psoriasis patients treated with apremilast.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";27846946;"Journal of the American Academy of Dermatology";"Sfecci A, Khemis A, Lacour JP, Montaudié H, Passeron T";;"Nov 2016";1479340800;; 11863;"The skin aging exposome.";"T. Passeron";"Equipe 12, Team 12";27720464;"Journal of dermatological science";"Krutmann J, Bouloc A, Sore G, Bernard BA, Passeron T";;"09 2016";1472688000;;"The term ""exposome"" describes the totality of exposures to which an individual is subjected from conception to death. It includes both external and internal factors as well as the human body's response to these factors. Current exposome research aims to understand the effects all factors have on specific organs, yet today, the exposome of human skin has not received major attention and a corresponding definition is lacking. This review was compiled with the collaboration of European scientists, specialized in either environmental medicine or skin biology. A comprehensive review of the existing literature was performed using PubMed. The search was restricted to exposome factors and skin aging. Key review papers and all relevant, epidemiological, in vitro, ex vivo and clinical studies were analyzed to determine the key elements of the exposome influencing skin aging. Here we propose a definition of the skin aging exposome. It is based on a summary of the existing scientific evidence for the role of exposome factors in skin aging. We also identify future research needs which concern knowledge about the interaction of distinct exposomal factors with each other and the resulting net effects on skin aging and suggest some protective measures." 11861;"Centrifugal hypomelanosis: a new clinical phenotype of Malassezia infection.";"T. Passeron";"Equipe 12, Team 12";27655069;"European journal of dermatology : EJD";"Alkhalifah A, Gari-Toussaint M, Cardot-Leccia N, Lacour JP, Passeron T";;"Sep 2016";1474588800;; 11857;"Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance.";"C. Bertolotto, M. Cerezo, P. Abbe, P. GUAL, R. Ballotti, S. Rocchi, T. Passeron, T. Botton";"Equipe 01, Team 01, Equipe 12, Team 12, Equipe 08, Team 08";27238082;"Cancer cell";"Cerezo M, Lehraiki A, Millet A, Rouaud F, Plaisant M, Jaune E, Botton T, Ronco C, Abbe P, Amdouni H, Passeron T, Hofman V, Mograbi B, Dabert-Gay AS, Debayle D, Alcor D, Rabhi N, Annicotte JS, Héliot L, Gonzalez-Pisfil M, Robert C, Moréra S, Vigouroux A, Gual P, Ali MMU, Bertolotto C, Hofman P, Ballotti R, Benhida R, Rocchi S";;"05 2016";1462060800;;"We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms." 11858;"Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance.";"C. Bertolotto, M. Cerezo, P. Abbe, P. GUAL, R. Ballotti, S. Rocchi, T. Passeron, T. Botton";"Equipe 01, Team 01, Equipe 12, Team 12, Equipe 08, Team 08";27479035;"Cancer cell";"Cerezo M, Lehraiki A, Millet A, Rouaud F, Plaisant M, Jaune E, Botton T, Ronco C, Abbe P, Amdouni H, Passeron T, Hofman V, Mograbi B, Dabert-Gay AS, Debayle D, Alcor D, Rabhi N, Annicotte JS, Héliot L, Gonzalez-Pisfil M, Robert C, Moréra S, Vigouroux A, Gual P, Ali MMU, Bertolotto C, Hofman P, Ballotti R, Benhida R, Rocchi S";;"07 2016";1467331200;; 11855;"Micro holes for delivering melanocytes into the skin: an ex vivo approach.";"C. Regazzetti, T. Passeron";"Equipe 12, Team 12";27172992;"Pigment cell & melanoma research";"Regazzetti C, Alcor D, Chignon-Sicard B, Passeron T";;"May 2016";1463184000;; 11853;"Fractionated bipolar radiofrequency and bipolar radiofrequency potentiated by infrared light for treating striae: A prospective randomized, comparative trial with objective evaluation.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";27020000;"Lasers in surgery and medicine";"Harmelin Y, Boineau D, Cardot-Leccia N, Fontas E, Bahadoran P, Becker AL, Montaudié H, Castela E, Perrin C, Lacour JP, Passeron T";;"01 2016";1451606400;;"Very few treatments for striae are based on prospective randomized trials. The objective of this study was to assess the efficacy of bipolar fractional radiofrequency and bipolar radiofrequency potentiated with infrared light, alone or combined, for treating abdominal stretch marks." 11851;"Prognosis and response to laser treatment of early-onset hypertrophic port-wine stains (PWS).";"T. Passeron";"Equipe 12, Team 12";27004804;"Journal of the American Academy of Dermatology";"Passeron T, Salhi A, Mazer JM, Lavogiez C, Mazereeuw-Hautier J, Galliot C, Collet-Villette AM, Labreze C, Boon L, Hardy JP, Fayard V, Livideanu CB, Toubel G, Georgescou G, Gral N, Maza A, Lacour JP";;"03 2016";1456790400;;"There is limited information regarding early development of soft-tissue and/or bone hypertrophy with facial port-wine stains (PWS)." 11849;"Comparative Methods for Improving Transepidermal Methylaminolevulinate Delivery: A Randomized Clinical Trial.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";26351818;"JAMA dermatology";"Bahadoran P, Le Duff F, Pascual T, Petit L, Martel P, Lacour JP, Passeron T";;"Sep 2015";1441843200;; 11847;"Pigmented macules of bony prominences (PMBP): A distinct presentation in patients with red hair.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";26775783;"Journal of the American Academy of Dermatology";"Marmottant E, Chiaverini C, Bessis D, Hubiche T, Mallet S, Maruani A, Abasq C, Miquel J, Cardot-Leccia N, Lacour JP, Passeron T";;"Jan 2016";1453161600;; 11845;"Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients.";"C. Regazzetti, R. Ballotti, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";26322948;"The Journal of investigative dermatology";"Regazzetti C, Joly F, Marty C, Rivier M, Mehul B, Reiniche P, Mounier C, Rival Y, Piwnica D, Cavalié M, Chignon-Sicard B, Ballotti R, Voegel J, Passeron T";;"08 2015";1438387200;;"Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions. " 11843;"Endothelial Cells Promote Pigmentation through Endothelin Receptor B Activation.";"C. Regazzetti, P. Bahadoran, R. Ballotti, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";26308584;"The Journal of investigative dermatology";"Regazzetti C, De Donatis GM, Ghorbel HH, Cardot-Leccia N, Ambrosetti D, Bahadoran P, Chignon-Sicard B, Lacour JP, Ballotti R, Mahns A, Passeron T";;"Aug 2015";1440633600;;"Findings of increased vascularization in melasma lesions and hyperpigmentation in acquired bilateral telangiectatic macules suggested a link between pigmentation and vascularization. Using high-magnification digital epiluminescence dermatoscopy, laser confocal microscopy, and histological examination, we showed that benign vascular lesions of the skin have restricted but significant hyperpigmentation compared with the surrounding skin. We then studied the role of microvascular endothelial cells in regulating skin pigmentation using an in vitro co-culture model using endothelial cells and melanocytes. These experiments showed that endothelin 1 released by microvascular endothelial cells induces increased melanogenesis signaling, characterized by microphthalmia-associated transcription factor phosphorylation, and increased tyrosinase and dopachrome tautomerase levels. Immunostaining for endothelin 1 in vascular lesions confirmed the increased expression on the basal layer of the epidermis above small vessels compared with perilesional skin. Endothelin acts through the activation of endothelin receptor B and the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK)1/2, and p38, to induce melanogenesis. Finally, culturing of reconstructed skin with microvascular endothelial cells led to increased skin pigmentation that could be prevented by inhibiting EDNRB. Taken together these results demonstrated the role of underlying microvascularization in skin pigmentation, a finding that could open new fields of research for regulating physiological pigmentation and for treating pigmentation disorders such as melasma. " 11841;"Ultrasound study of entheses in psoriasis patients with or without musculoskeletal symptoms: A prospective study.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";25881759;"Joint bone spine";"Acquacalda E, Albert C, Montaudie H, Fontas E, Danre A, Roux CH, Breuil V, Lacour JP, Passeron T, Ziegler LE";;"04 2015";1427846400;;"To estimate the prevalence of ultrasonographic enthesitis in psoriasis patients with or without musculoskeletal symptoms and to investigate their evolution under systemic treatments given for the cutaneous symptoms." 11839;"New onset of articular inflammatory manifestations in patients with hidradenitis suppurativa under treatment with infliximab.";"T. Passeron";"Equipe 12, Team 12";25776450;"Joint bone spine";"Acquacalda E, Roux CH, Albert C, Breuil V, Passeron T, Euller-Ziegler L";;"03 2015";1425168000;;"Severe hidradenitis suppurativa (HS), under infliximab, can be associated with different forms of arthritis whose mechanism is unclear. Our objective is to establish the frequency and clinical presentation of new-onset arthritis in HS under infliximab." 11837;"Successful treatment of refractory neuropathic pruritus with capsaicin 8% patch: a bicentric retrospective study with long-term follow-up.";"T. Passeron";"Equipe 12, Team 12";25740045;"Acta dermato-venereologica";"Misery L, Erfan N, Castela E, Brenaut E, Lantéri-Minet M, Lacour JP, Passeron T";;"Mar 2015";1425600000;; 11835;"Copper Bromide Laser vs Triple-Combination Cream for the Treatment of Melasma: A Randomized Clinical Trial.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";25715311;"JAMA dermatology";"Hammami Ghorbel H, Boukari F, Fontas E, Montaudié H, Bahadoran P, Lacour JP, Passeron T";;"Feb 2015";1424908800;; 11833;"Indications and limitations of afamelanotide for treating vitiligo.";"T. Passeron";"Equipe 12, Team 12";25607635;"JAMA dermatology";"Passeron T";;"Jan 2015";1421884800;; 11831;"Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment: a randomized, double blind, placebo-controlled study.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";25521460;"The Journal of investigative dermatology";"Cavalié M, Ezzedine K, Fontas E, Montaudié H, Castela E, Bahadoran P, Taïeb A, Lacour JP, Passeron T";;"12 2014";1417392000;;"The risk of relapse after successful repigmentation in vitiligo is estimated to 40% within the first year. It has been shown in atopic dermatitis that continuous low-level use of topical corticosteroids and calcineurin inhibitors in previously affected skin can prevent new flares. We hypothesized that a twice-weekly application of 0.1% tacrolimus ointment might be effective for maintaining repigmentation in therapeutically repigmented lesions of vitiligo patients. After randomization, sixteen patients with 31 patches were assigned to the placebo group and 19 patients with 41 patches were assigned to the tacrolimus group. In the intention-to-treat analysis, 48.4% of lesions showed depigmentation in the placebo group, whereas 26.8% did in the tacrolimus group (P=0.059). The intention-to-treat results did not remain significant after adjustment for within-patient clustering, odds ratio (OR) 2.55; 95% confidence interval (CI; 0.65-9.97); P=0.1765. The per-protocol analysis (n=56) showed that 40% of lesions had some depigmentation in the placebo group, whereas only 9.7% did in the tacrolimus group (P=0.0075). The per-protocol results remained significant after adjustment for within-patient clustering: OR 6.22; 95% CI (1.48-26.12); P=0.0299. Our study shows that twice-weekly application of 0.1% tacrolimus ointment is effective in preventing the depigmentation of vitiligo patches that have been previously successfully repigmented." 11829;"Treatment of keloids with laser-assisted topical steroid delivery: a retrospective study of 23 cases.";"H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";25471297;"Dermatologic therapy";"Cavalié M, Sillard L, Montaudié H, Bahadoran P, Lacour JP, Passeron T";;"12 2014";1417392000;;"Topical or intralesional corticosteroids are referred to as gold standard treatments for keloids. Recent studies showed that ablative fractional laser (AFL) treatment facilitates delivery of topical drug deeply into the skin by creating vertical channels. The objective of the present study was to assess the ablative erbium laser in fractionated mode, combined with topical high potent corticosteroid cream for treating resistant keloid scars. We conducted a retrospective study in the laser center of the Department of Dermatology (University Hospital of Nice, France), from January 2010 to June 2012, on patients with keloids who were resistant to a first-line of treatment. A 2940-nm ablative fractional erbium laser was used. Topical betamethasone cream was applied twice a day under occlusion with transparent film dressings. A total of 23 patients with 70 keloids were treated from January 2010 to June 2012. The median percentage of improvement was 50% (range -43 to 84). The mean follow-up was 8 months (range 3-18), and a recurrence was observed for eight lesions (22%). Although this observation warrants a prospective comparative evaluation, it supports the interest of the laser-assisted delivery of steroids for treating keloids scars. " 11827;"Prevention of melasma relapses with sunscreen combining protection against UV and short wavelengths of visible light: a prospective randomized comparative trial.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";25443629;"Journal of the American Academy of Dermatology";"Boukari F, Jourdan E, Fontas E, Montaudié H, Castela E, Lacour JP, Passeron T";;"10 2014";1412121600;; 11825;"Solar urticaria to visible light triggered by light-emitting diode therapy.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";25128130;"Journal of the American Academy of Dermatology";"Montaudié H, Lacour JP, Rostain G, Duteil L, Passeron T";;"Aug 2014";1408233600;; 11823;"Trichoblastoma with dermoscopic features of a malignant tumor: three cases.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";25128125;"Journal of the American Academy of Dermatology";"Picard A, Tsilika K, Cardot-Leccia N, Passeron T, Lacour JP, Bahadoran P";;"Aug 2014";1408233600;; 11821;"Differences in visible light-induced pigmentation according to wavelengths: a clinical and histological study in comparison with UVB exposure.";"T. Passeron";"Equipe 12, Team 12";24888214;"Pigment cell & melanoma research";"Duteil L, Cardot-Leccia N, Queille-Roussel C, Maubert Y, Harmelin Y, Boukari F, Ambrosetti D, Lacour JP, Passeron T";;"07 2014";1404172800;;"The visible light spectrum is wide, and it can be hypothesized that all the wavelengths between 400-700 nm do not induce the same photobiological effects on pigmentation. We assessed the potential pro-pigmenting effects of two single wavelengths located at both extremities of the visible spectrum: the blue/violet line (λ = 415 nm) and the red line (λ = 630 nm). We made colorimetric, clinical, and histological assessments with increasing doses of those lights on healthy volunteers. Then, we compared these irradiations to non-exposed and UVB-exposed skin. Colorimetric and clinical assessments showed a clear dose effect with the 415-nm irradiation, in both skin type III and IV subjects, whereas the 630 nm did not induce hyperpigmentation. When compared to UVB irradiation, the blue-violet light induced a significantly more pronounced hyperpigmentation that lasted up to 3 months. Histological examination showed a significant increase of keratinocyte necrosis and p53 with UVB, as compared to 415- and 630-nm exposures. " 11817;"Treatment of linear and whorled hypermelanosis with Q-switched laser.";"T. Passeron";"Equipe 12, Team 12";25099293;"Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]";"Catherine S, Lacour JP, Passeron T";;"Aug 2014";1407456000;; 11814;"Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";24872229;"JAMA dermatology";"Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, Lacour JP, Passeron T";;"May 2014";1401408000;;"An impaired inhibitory function of circulating CD4+CD25+ regulatory T (Treg) cells was reported to play a key role in alopecia areata (AA). We report the first use to our knowledge of low-dose interleukin 2 for treating severe AA by promoting the recruitment of Treg cells." 11813;"Diagnosis and treatment monitoring of toenail onychomycosis by reflectance confocal microscopy: prospective cohort study in 58 patients.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";24786418;"Journal of the American Academy of Dermatology";"Pharaon M, Gari-Toussaint M, Khemis A, Zorzi K, Petit L, Martel P, Baran R, Ortonne JP, Passeron T, Lacour JP, Bahadoran P";;"04 2014";1396310400;;"The clinical presentation of onychomycosis is often nonspecific and can lead to inappropriate antifungal therapy. Available mycologic tests share many drawbacks." 11811;"Inhibition of melanogenesis by the antidiabetic metformin.";"C. Regazzetti, C. Bertolotto, M. Cerezo, P. Abbe, R. Ballotti, S. Rocchi, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";24756109;"The Journal of investigative dermatology";"Lehraiki A, Abbe P, Cerezo M, Rouaud F, Regazzetti C, Chignon-Sicard B, Passeron T, Bertolotto C, Ballotti R, Rocchi S";;"Apr 2014";1398297600;;"Several reports have demonstrated the inhibitory effect of metformin, a widely used drug in the treatment of type 2 diabetes, on the proliferation of many cancers including melanoma. Recently, it has been shown that metformin is able to modulate the cAMP level in the liver. As cAMP has a crucial role in melanin synthesis and skin pigmentation, we investigated the effect of metformin on melanogenesis both in vitro and in vivo. We showed that metformin led to reduced melanin content in melanoma cells and in normal human melanocytes by decreasing cAMP accumulation and cAMP-responsive element-binding protein phosphorylation. This inhibitory effect is correlated with decreased expression of master genes of melanogenesis, microphthalmia-associated transcription factor, tyrosinase, dopachrome tautomerase, and tyrosinase-related protein 1. Furthermore, we demonstrated that the antimelanogenic effect of metformin is independent of the AMPK pathway. Interestingly, topical application of metformin induced tail whitening in mice. Finally, we confirmed the antimelanogenic effect of metformin on reconstituted human epidermis and on human skin biopsies. These data emphasize the depigmenting effect of metformin and suggest a clinical strategy for using metformin in the topical treatment of hyperpigmentation disorders. " 11809;"Use of 2940-nm Erbium-Yag fractional laser for treating the skin texture changes in stabilized Parry Romberg syndrome.";"T. Passeron";"Equipe 12, Team 12";24446016;"European journal of dermatology : EJD";"Ghorbel HH, Lacour JP, Passeron T";;"Dec Nov 2013";1384214400;; 11806;"Macular eruption revealing hypomelanotic cutaneous melanoma metastases: diagnostic role of dermoscopy.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";24355285;"Journal of the American Academy of Dermatology";"Hammami-Ghorbel H, Giacchero D, Hofman V, Poissonnet G, Passeron T, Lacour JP, Bahadoran P";;"Dec 2013";1387584000;; 11805;"PGJ2 restores RA sensitivity in melanoma cells by decreasing PRAME and EZH2.";"C. Bertolotto, H. Montaudie, R. Ballotti, S. Rocchi, T. Passeron, Y. Cheli";"Equipe 01, Team 01, Equipe 12, Team 12";24289988;"Journal of dermatological science";"Pierron A, Le Pape E, Montaudié H, Castela E, De Donatis GM, Allegra M, Bertolotto C, Rocchi S, Cheli Y, Ballotti R, Passeron T";;"11 2013";1383264000;; 11803;"Long-lasting effect of vascular targeted therapy of melasma.";"T. Passeron";"Equipe 12, Team 12";23957991;"Journal of the American Academy of Dermatology";"Passeron T";;"Aug 2013";1377043200;; 11801;"Reflectance confocal microscopy features of Degos disease.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23864231;"JAMA dermatology";"Cavalié M, Tsilika K, Sillard L, Cardot-Leccia N, Passeron T, Lacour JP, Bahadoran P";;"Jul 2013";1374192000;; 11799;"Major clinical response to a BRAF inhibitor in a patient with a BRAF L597R-mutated melanoma.";"P. Bahadoran, R. Ballotti, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23715574;"Journal of clinical oncology : official journal of the American Society of Clinical Oncology";"Bahadoran P, Allegra M, Le Duff F, Long-Mira E, Hofman P, Giacchero D, Passeron T, Lacour JP, Ballotti R";;"May 2013";1369872000;; 11797;"Flexural agminated eruptive nevi in Langerhans cell histiocytosis.";"C. Chiaverini, H. Montaudie, P. Bahadoran, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";23677112;"JAMA dermatology";"Surinach C, Bahadoran P, Vabres P, Chiaverini C, Montaudie H, Erfan N, Deville A, Ben Signor C, Benchetrit M, Passeron T, Lacour JP";;"May 2013";1368748800;; 11795;"Activation of the unfolded protein response in vitiligo: the missing link?";"T. Passeron";"Equipe 12, Team 12";23069909;"The Journal of investigative dermatology";"Passeron T, Ortonne JP";;"Oct 2012";1350432000;;"Vitiligo is characterized by a substantial loss of functional melanocytes in the epidermis and sometimes in hair follicles. Genetic and pathophysiological studies have provided strong evidence that vitiligo is a polygenetic, multifactorial disorder. The key roles of oxidative stress within melanocytes and anti-melanocyte immune responses have been addressed in many studies, but the relationship between these mechanisms remains unclear. In this issue, Toosi et al. report the upregulation of IL-6 and IL-8 after the activation of the unfolded protein response (UPR) following exposure of melanocytes to phenols. Their results shed light on the missing link between oxidative stress and immune responses in vitiligo." 11793;"Secondary hyperpigmentation during interferon alfa treatment for chronic hepatitis C virus infection.";"A. TRAN, R. ANTY, T. Passeron";"Equipe 08, Team 08, Equipe 12, Team 12";23553009;"JAMA dermatology";"Tsilika K, Tran A, Trucchi R, Pop S, Anty R, Cardot-Leccia N, Lacour JP, Ortonne JP, Passeron T";;"Apr 2013";1365120000;;"Interferon alfa remains the central treatment for chronic hepatitis C virus (HCV) infection. Cases of cutaneous and mucous hyperpigmentations during interferon alfa treatment have been reported, but they are considered rare adverse effects." 11789;"Usefulness of immunocytochemistry for the detection of the BRAF(V600E) mutation in circulating tumor cells from metastatic melanoma patients.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23303445;"The Journal of investigative dermatology";"Hofman V, Ilie M, Long-Mira E, Giacchero D, Butori C, Dadone B, Selva E, Tanga V, Passeron T, Poissonnet G, Emile JF, Lacour JP, Bahadoran P, Hofman P";;"Jan 2013";1357862400;; 11790;"Dermoscopic changes of melanocytic nevi after laser hair removal.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";23400371;"European journal of dermatology : EJD";"Sillard L, Mantoux F, Larrouy JC, Hofman V, Passeron T, Lacour JP, Bahadoran P";;"Feb Jan 2013";1357084800;; 11785;"Signalling and chemosensitivity assays in melanoma: is mutated status a prerequisite for targeted therapy?";"C. Bertolotto, P. Bahadoran, R. Ballotti, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";22092579;"Experimental dermatology";"Passeron T, Lacour JP, Allegra M, Ségalen C, Deville A, Thyss A, Giacchero D, Ortonne JP, Bertolotto C, Ballotti R, Bahadoran P";;"Nov 2011";1321660800;;"Selection for targeted therapies in melanoma is currently based on the search for mutations in selected genes. We aimed at evaluating the interest of signalling and chemosensitivity studies in addition to genotyping for assessing the best suitable treatment in an individual patient. We extracted genomic DNA and melanoma cells from tumor tissue of a skin metastasis of a 17-year-old woman with stage IV melanoma progressing despite three successive lines of treatment. Despite the absence of mutation in BRAF, NRAS cKIT, the MAPK pathway was activated and a significant response to sorafenib, a mitogen-activated protein kinase (MAPK)/RAF inhibitor, was found in signalling and chemosensitivity assays. A treatment combining sorafenib and dacarbazine produced a partial response for 9 months, with marked necrosis in some lesions. Chemosensitivity assays and signalling pathway studies could be of great value in addition to genotyping for assessing the most appropriate treatment in melanoma." 11786;"Superficial lymphangioma treated with fractional ablative laser: a case report with clinical and reflectance confocal microscopy evaluation.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";22913553;"Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]";"Tsilika K, Bahadoran P, Passeron T";;"08 2012";1343779200;; 11783;"A pilot study using reflectance confocal microscopy (RCM) in the assessment of a novel formulation for the treatment of melasma.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";22052305;"Journal of drugs in dermatology : JDD";"Tsilika K, Levy JL, Kang HY, Duteil L, Khemis A, Hughes R, Passeron T, Ortonne JP, Bahadoran P";;"Nov 2011";1320451200;;"Melasma is a common pigmentary disorder caused by abnormal melanin deposits within the skin. Hydroquinone (HQ) is presently the most popular depigmenting agent, however the treatment of melasma remains unsatisfactory, resulting in a need to evaluate new depigmenting agents." 11781;"Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid.";"T. Passeron";"Equipe 12, Team 12";19273910;"The Journal of clinical investigation";"Passeron T, Valencia JC, Namiki T, Vieira WD, Passeron H, Miyamura Y, Hearing VJ";;"03 2009";1235865600;;"Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to RA. Thus, combined treatment with PGD2 and RA substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma." 11779;"Reflectance confocal microscopy for recurrent lentigo maligna.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";21790847;"Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]";"Erfan N, Kang HY, Cardot-Leccia N, Chignon-Sicard B, Passeron T, Ortonne JP, Lacour JP, Bahadoran P";;"07 2011";1309478400;; 11777;"Melasma treatment with pulsed-dye laser and triple combination cream: a prospective, randomized, single-blind, split-face study.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";21931054;"Archives of dermatology";"Passeron T, Fontas E, Kang HY, Bahadoran P, Lacour JP, Ortonne JP";;"Sep 2011";1316563200;; 11773;"AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma.";"T. Passeron";"Equipe 12, Team 12";21460252;"Proceedings of the National Academy of Sciences of the United States of America";"Namiki T, Tanemura A, Valencia JC, Coelho SG, Passeron T, Kawaguchi M, Vieira WD, Ishikawa M, Nishijima W, Izumo T, Kaneko Y, Katayama I, Yamaguchi Y, Yin L, Polley EC, Liu H, Kawakami Y, Eishi Y, Takahashi E, Yokozeki H, Hearing VJ";;"Apr 2011";1301961600;;"The identification of genes that participate in melanomagenesis should suggest strategies for developing therapeutic modalities. We used a public array comparative genomic hybridization (CGH) database and real-time quantitative PCR (qPCR) analyses to identify the AMP kinase (AMPK)-related kinase NUAK2 as a candidate gene for melanomagenesis, and we analyzed its functions in melanoma cells. Our analyses had identified a locus at 1q32 where genomic gain is strongly associated with tumor thickness, and we used real-time qPCR analyses and regression analyses to identify NUAK2 as a candidate gene at that locus. Associations of relapse-free survival and overall survival of 92 primary melanoma patients with NUAK2 expression measured using immunohistochemistry were investigated using Kaplan-Meier curves, log rank tests, and Cox regression models. Knockdown of NUAK2 induces senescence and reduces S-phase, decreases migration, and down-regulates expression of mammalian target of rapamycin (mTOR). In vivo analysis demonstrated that knockdown of NUAK2 suppresses melanoma tumor growth in mice. Survival analysis showed that the risk of relapse is greater in acral melanoma patients with high levels of NUAK2 expression than in acral melanoma patients with low levels of NUAK2 expression (hazard ratio = 3.88; 95% confidence interval = 1.44-10.50; P = 0.0075). These data demonstrate that NUAK2 expression is significantly associated with the oncogenic features of melanoma cells and with the survival of acral melanoma patients. NUAK2 may provide a drug target to suppress melanoma progression. This study further supports the importance of NUAK2 in cancer development and tumor progression, while AMPK has antioncogenic properties." 11774;"Pigmentary sequelae of AIDS-related cutaneous Kaposi sarcoma: successful treatment by Q-switched 755-nm alexandrite and 532-nm Nd:YAG lasers.";"T. Passeron";"Equipe 12, Team 12";21768476;"Archives of dermatology";"Hughes R, Lacour JP, Passeron T";;"Jul 2011";1311120000;; 11771;"Nd:YAG laser treatment for multiple cutaneous glomangiomas: report of 3 cases.";"C. Chiaverini, T. Passeron";"Equipe 12, Team 12";21339466;"Archives of dermatology";"Hughes R, Lacour JP, Chiaverini C, Rogopoulos A, Passeron T";;"Feb 2011";1298419200;; 11768;"A noninvasive technique, reflectance confocal microscopy, for the characterization of melanocyte loss in untreated and treated vitiligo lesions.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";20950736;"Journal of the American Academy of Dermatology";"Kang HY, le Duff F, Passeron T, Lacour JP, Ortonne JP, Bahadoran P";;"Oct 2010";1287446400;; 11765;"Urticarial vasculitis secondary to H1N1 vaccination.";"T. Passeron";"Equipe 12, Team 12";21057759;"Acta dermato-venereologica";"Hughes R, Lacour JP, Baldin B, Reverte M, Ortonne JP, Passeron T";;"Nov 2010";1289260800;; 11766;"The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin.";"T. Passeron";"Equipe 12, Team 12";20979596;"Pigment cell & melanoma research";"Miyamura Y, Coelho SG, Schlenz K, Batzer J, Smuda C, Choi W, Brenner M, Passeron T, Zhang G, Kolbe L, Wolber R, Hearing VJ";;"Oct 2010";1288310400;;"The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV-induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV-protective effects against DNA damage in UVB-tanned skin (but not in UVA-tanned skin) were significantly higher. UVA-induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up-regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB-exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV-induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis." 11763;"Evolution of nevi during treatment with natalizumab: A prospective follow-up of patients treated with natalizumab for multiple sclerosis.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";20855675;"Archives of dermatology";"Castela E, Lebrun-Frenay C, Laffon M, Rocher F, Cohen M, Leccia NC, Bahadoran P, Lacour JP, Ortonne JP, Passeron T";;"09 2010";1283299200;;"Natalizumab is a monoclonal antibody directed against α₄ integrin used in the treatment of multiple sclerosis (MS). Four cases of melanomas occurring in patients prescribed natalizumab to treat MS were recently reported. Although some fundamental data suggested that α₄β1 integrin could be linked to the invasiveness of melanoma, none showed any relation with the transformation of melanocytes." 11761;"[What is the impact of the new clinical trial data? What are the lessons for patient management?].";"T. Passeron";"Equipe 12, Team 12";20510174;"Annales de dermatologie et de venereologie";"Passeron T, Boulinguez S";;"Jun 2010";1275350400;; 11759;"In vivo reflectance confocal microscopy detects pigmentary changes in melasma at a cellular level resolution.";"P. Bahadoran, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";20497220;"Experimental dermatology";"Kang HY, Bahadoran P, Suzuki I, Zugaj D, Khemis A, Passeron T, Andres P, Ortonne JP";;"May 2010";1274832000;;"Melasma is a frequent pigmentary disorder caused by abnormal melanin deposits in the skin. In vivo reflectance confocal microscopy (RCM) is a repetitive imaging tool that provides real-time images of the skin at nearly histological resolution. As melanin is the strongest endogenous contrast in human skin, pigmentary disorders are the most suitable candidates for RCM examination but RCM features of melasma have never been reported. This study investigates the pilot use of RCM in melasma to provide a set of well-described morphological criteria with histological correlations. RCM images were acquired from melasma skin and compared to adjacent control skin in 26 patients. Skin biopsies were obtained from eight patients. In the epidermis, RCM showed in all patients a significant increase in hyperrefractile cobblestoning cells. These cells corresponded to hyperpigmented basal keratinocytes in histology. In six patients, dendritic cells corresponding to activated melanocytes were also found in the epidermis. In the dermis, RCM identified in nine patients plump bright cells corresponding to melanophages. Interestingly, for a given patient, the topographic distribution of melanophages in melasma lesions was very heterogeneous. RCM also showed a significant increase in solar elastosis and blood vessels in the dermis. RCM is a non-invasive technique that detects pigmentary changes in melasma at a cellular level resolution. Therefore, RCM provides an innovative way to classify melasma by pigment changes." 11757;"[Pigmentary lasers].";"T. Passeron";"Equipe 12, Team 12";19931693;"Annales de dermatologie et de venereologie";"Passeron T, Toubel G";;"Nov 2009";1259193600;;"The pigmentary disorders are a very heterogeneous group with a high therapeutic demand from the patients. The lasers have provided a major advance in the treatment of some pigmentary lesions. The indication and the optimal parameters are actually quite well defined. However, pigmentary lasers have limits and some dermatosis can even be worsened after laser treatment. Those limitations as well as the potential side effects have to clearly be explained to the patients that often seek for a miracle cure." 11755;"Glycoprotein nonmetastatic melanoma protein b, a melanocytic cell marker, is a melanosome-specific and proteolytically released protein.";"T. Passeron";"Equipe 12, Team 12";20056711;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Hoashi T, Sato S, Yamaguchi Y, Passeron T, Tamaki K, Hearing VJ";;"Jan 2010";1262995200;;"Melanosomes are organelles specialized for the production of melanin pigment and are specifically produced by melanocytic cells. More than 150 pigmentation-related genes have been identified, including glycoprotein nonmetastatic melanoma protein b (GPNMB). A recent proteomics analysis revealed that GPNMB is localized in melanosomes, and GPNMB is a membrane-bound glycoprotein that shows high homology with a well-known melanosomal structural protein, Pmel17/gp100. In this study, we show that GPNMB is expressed in melanocytes of normal human skin, as well as in human melanoma cells. GPNMB is heavily glycosylated and is enriched in mature (stage III and IV) melanosomes in contrast to MART-1 and Pmel17, which are abundant in early (stage I and II) melanosomes. MART-1 and Pmel17 play critical roles in the maturation of early melanosomes; thus, we speculate that GPNMB might be important in the functions of late melanosomes, possibly their transport and/or transfer to keratinocytes. We also demonstrate that a secreted form of GPNMB is released by ectodomain shedding from the largely Golgi-modified form of GPNMB and that the PKC and Ca(2+) intracellular signaling pathways regulate that shedding. We conclude that GPNMB is a melanosomal protein that is released by proteolytic ectodomain shedding and might be a useful and specific histological marker of melanocytic cells." 11753;"Blue pseudochromhidrosis secondary to topiramate treatment.";"T. Passeron";"Equipe 12, Team 12";19734991;"Acta dermato-venereologica";"Castela E, Thomas P, Bronsard V, Lacour JP, Ortonne JP, Passeron T";;"Sep 2009";1252368000;; 11751;"Comparative treatment of extragenital lichen sclerosus with methylaminolevulinic Acid pulsed dye laser-mediated photodynamic therapy or pulsed dye laser alone.";"T. Passeron";"Equipe 12, Team 12";19389089;"Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]";"Passeron T, Lacour JP, Ortonne JP";;"03 2009";1235865600;; 11749;"Pulsed dye laser-mediated photodynamic therapy for acne inversa is not successful: a pilot study on four cases.";"T. Passeron";"Equipe 12, Team 12";19370441;"The Journal of dermatological treatment";"Passeron T, Khemis A, Ortonne JP";;"Apr 2009";1239926400;;"The relapses and the chronicity of acne inversa cause a significant impact on the quality of life of the affected patients and urge for a search of more effective treatments. We report the treatment of four consecutive acne inversa patients with pulse dye laser-mediated photodynamic therapy (PDL-PDT). Three months after the end of the treatment there was no improvement in comparison with opposite control sites. Intense pain during treatment was reported by all the patients. These cases do not support the use of PDL-PDT for treating acne inversa." 11747;"Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r.";"T. Passeron";"Equipe 12, Team 12";19174519;"Proceedings of the National Academy of Sciences of the United States of America";"Le Pape E, Passeron T, Giubellino A, Valencia JC, Wolber R, Hearing VJ";;"01 2009";1230768000;;"The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by alpha-melanocyte stimulating hormone (alphaMSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or alphaMSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by alphaMSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk." 11745;"Forskolin protects keratinocytes from UVB-induced apoptosis and increases DNA repair independent of its effects on melanogenesis.";"T. Passeron";"Equipe 12, Team 12";18580960;"The Journal of investigative dermatology";"Passeron T, Namiki T, Passeron HJ, Le Pape E, Hearing VJ";;"06 2008";1212278400;;"Melanin pigments provide efficient protection against ultraviolet B (UVB) radiation but DNA repair also plays a key role in eliminating UV-induced damage and preventing the development of skin cancers. In this study, we demonstrate that forskolin (FSK), an agent that increases intracellular levels of cAMP, protects keratinocytes from UVB-induced apoptosis independently from the amount of melanin in the skin. FSK enhances the removal of the two major types of UVB-induced DNA damage, cyclobutane pyrimidine dimers and 6,4-photoproducts, by facilitating DNA repair. These findings suggest new preventive approaches with topical formulations of FSK or other bioactive agents that could be applied to the skin before sun exposure to increase its ability to repair DNA damage." 11743;"Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/beta-catenin signaling in keratinocytes.";"T. Passeron";"Equipe 12, Team 12";17984176;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Yamaguchi Y, Passeron T, Hoashi T, Watabe H, Rouzaud F, Yasumoto K, Hara T, Tohyama C, Katayama I, Miki T, Hearing VJ";;"11 2007";1193875200;;"The epidermis (containing primarily keratinocytes and melanocytes) overlies the dermis (containing primarily fibroblasts) of human skin. We previously reported that dickkopf 1 (DKK1) secreted by fibroblasts in the dermis elicits the hypopigmented phenotype of palmoplantar skin due to suppression of melanocyte function and growth via the regulation of two important signaling factors, microphthalmia-associated transcription factor (MITF) and beta-catenin. We now report that treatment of keratinocytes with DKK1 increases their proliferation and decreases their uptake of melanin and that treatment of reconstructed skin with DKK1 induces a thicker and less pigmented epidermis. DNA microarray analysis revealed many genes regulated by DKK1, and several with critical expression patterns were validated by reverse transcriptase-polymerase chain reaction and Western blotting. DKK1 induced the expression of keratin 9 and alpha-Kelch-like ECT2 interacting protein (alphaKLEIP) but down-regulated the expression of beta-catenin, glycogen synthase kinase 3beta, protein kinase C, and proteinase-activated receptor-2 (PAR-2), which is consistent with the expression patterns of those proteins in human palmoplantar skin. Treatment of reconstructed skin with DKK1 reproduced the expression patterns of those key proteins observed in palmoplantar skin. These findings further elucidate why human skin is thicker and paler on the palms and soles than on the trunk through topographical and site-specific differences in the secretion of DKK1 by dermal fibroblasts that affects the overlying epidermis." 11741;"SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation.";"C. Bertolotto, R. Ballotti, T. Passeron";"Equipe 01, Team 01, Equipe 12, Team 12";17702866;"Proceedings of the National Academy of Sciences of the United States of America";"Passeron T, Valencia JC, Bertolotto C, Hoashi T, Le Pape E, Takahashi K, Ballotti R, Hearing VJ";;"08 2007";1185926400;;"SOX (SRY type HMG box) proteins are transcription factors that are predominantly known for their roles during development. During melanocyte development from the neural crest, SOX10 regulates microphthalmia-associated transcription factor, which controls a set of genes critical for pigment cell development and pigmentation, including dopachrome tautomerase and tyrosinase. We report here that another SOX factor, SOX9, is expressed by melanocytes in neonatal and adult human skin and is up-regulated by UVB exposure. We demonstrate that this regulation is mediated by cAMP and protein kinase. We also show that agouti signal protein, a secreted factor known to decrease pigmentation, down-regulates SOX9 expression. In adult and neonatal melanocytes, SOX9 regulates microphthalmia-associated transcription factor, dopachrome tautomerase, and tyrosinase promoters, leading to an increase in the expression of these key melanogenic proteins and finally to a stimulation of pigmentation. SOX9 completes the complex and tightly regulated process leading to the production of melanin by acting at a very upstream level. This role of SOX9 in pigmentation emphasizes the poorly understood impact of SOX proteins in adult tissues." 11739;"Treatment of oral erosive lichen planus with 1% pimecrolimus cream: a double-blind, randomized, prospective trial with measurement of pimecrolimus levels in the blood.";"T. Passeron";"Equipe 12, Team 12";17438179;"Archives of dermatology";"Passeron T, Lacour JP, Fontas E, Ortonne JP";;"Apr 2007";1176854400;;"To evaluate the efficacy of 1% pimecrolimus cream in treating oral erosive lichen planus and to assess its tolerance." 11737;"Sialylated core 1 O-glycans influence the sorting of Pmel17/gp100 and determine its capacity to form fibrils.";"T. Passeron";"Equipe 12, Team 12";17303571;"The Journal of biological chemistry";"Valencia JC, Rouzaud F, Julien S, Chen KG, Passeron T, Yamaguchi Y, Abu-Asab M, Tsokos M, Costin GE, Yamaguchi H, Jenkins LM, Nagashima K, Appella E, Hearing VJ";;"02 2007";1170288000;;"Pmel17 is a melanocyte/melanoma-specific protein that is essential for the maturation of melanosomes to form mature, fibrillar, and pigmented organelles. Recently, we reported that the less glycosylated form of Pmel17 (termed iPmel17) is sorted via the plasma membrane in a manner distinct from mature Pmel17 (termed mPmel17), which is sorted directly to melanosomes. To clarify the mechanism(s) underlying the distinct processing and sorting of Pmel17, we generated a highly specific antibody (termed alphaPEP25h) against an epitope within the repeat domain of Pmel17 that is sensitive to changes in O-glycosylation. alphaPEP25h recognizes only iPmel17 and allows analysis of the processing and sorting of iPmel17 when compared with alphaPEP13h, an antibody that recognizes both iPmel17 and mPmel17. Our novel findings using alphaPEP25h demonstrate that iPmel17 differs from mPmel17 not only in its sensitivity to endoglycosidase H, but also in the content of core 1 O-glycans modified with sialic acid. This evidence reveals that iPmel17 is glycosylated differently in the Golgi and that it is sorted through the secretory pathway. Analysis of Pmel17 processing in glycosylation-deficient mutant cells reveals that Pmel17 lacking the correct addition of sialic acid and galactose loses the ability to form fibrils. Furthermore, we show that addition of sialic acid affects the stability and sorting of Pmel17 and reduces pigmentation. Alterations in sialyltransferase activity and substrates differ between normal and transformed melanocytes and may represent a critical change during malignant transformation." 11735;"Immunohistochemistry and in situ hybridization in the study of human skin melanocytes.";"T. Passeron";"Equipe 12, Team 12";17286807;"Experimental dermatology";"Passeron T, Coelho SG, Miyamura Y, Takahashi K, Hearing VJ";;"Feb 2007";1170979200;;"Although keratinocytes are the most numerous type of cell in the skin, melanocytes are also key players as they produce and distribute melanin that protects the skin from ultraviolet (UV) radiation. In vitro experiments on melanocytic cell lines are useful to study melanogenesis and their progression towards melanoma. However, interactions of melanocytes with keratinocytes and with other types of cells in the skin, such as fibroblasts and Langerhans cells, are also crucial. We describe two techniques, immunohistochemistry (IHC) and tissue in situ hybridization (TISH), that can be used to identify and study melanocytes in the skin and their responses to UV or other stimuli in situ. We describe a practical method to localize melanocytic antigens on formalin-fixed, paraffin-embedded tissue sections and in frozen sections using indirect immunofluorescence with conjugated secondary antibodies. In addition, we detail the use of TISH and its combination with IHC to study mRNA levels of genes expressed in the skin at cellular resolution. This methodology, along with relevant tips and troubleshooting items, are important tools to identify and study melanocytes in the skin." 11733;"Regulation of human skin pigmentation and responses to ultraviolet radiation.";"T. Passeron";"Equipe 12, Team 12";17250543;"Pigment cell research";"Miyamura Y, Coelho SG, Wolber R, Miller SA, Wakamatsu K, Zmudzka BZ, Ito S, Smuda C, Passeron T, Choi W, Batzer J, Yamaguchi Y, Beer JZ, Hearing VJ";;"Jan 2007";1169769600;;"Pigmentation of human skin is closely involved in protection against environmental stresses, in particular exposure to ultraviolet (UV) radiation. It is well known that darker skin is significantly more resistant to the damaging effects of UV, such as photocarcinogenesis and photoaging, than is lighter skin. Constitutive skin pigmentation depends on the amount of melanin and its distribution in that tissue. Melanin is significantly photoprotective and epidermal cells in darker skin incur less DNA damage than do those in lighter skin. This review summarizes current understanding of the regulation of constitutive human skin pigmentation and responses to UV radiation, with emphasis on physiological factors that influence those processes. Further research is needed to characterize the role of skin pigmentation to reduce photocarcinogenesis and to develop effective strategies to minimize such risks." 11731;"The effects of dickkopf 1 on gene expression and Wnt signaling by melanocytes: mechanisms underlying its suppression of melanocyte function and proliferation.";"T. Passeron";"Equipe 12, Team 12";17159916;"The Journal of investigative dermatology";"Yamaguchi Y, Passeron T, Watabe H, Yasumoto K, Rouzaud F, Hoashi T, Hearing VJ";;"12 2006";1164931200;;"Dickkopf 1 (DKK1), which is expressed at high mRNA levels by fibroblasts in the dermis of human skin on the palms and soles, inhibits the function and proliferation of melanocytes in the epidermis of those areas via the suppression of beta-catenin and microphthalmia-associated transcription factor (MITF). In this study, we investigated the protein expression levels of DKK1 between palmoplantar and non-palmoplantar areas and the effects of DKK1 on melanocyte gene expression profiles and on Wnt signaling pathways using DNA microarray technology, reverse transcriptase-PCR, Western blot, 3-dimensional reconstructed skin, immunocytochemistry, and immunohistochemistry. DKK1-responsive genes included those encoding proteins involved in the regulation of melanocyte development, growth, differentiation, and apoptosis (including Kremen 1, G-coupled receptor 51, lipoprotein receptor-related protein 6, low-density lipoprotein receptor, tumor necrosis factor receptor super-family 10, growth arrest and DNA-damage-inducible gene 45beta, and MITF). Of special interest was the rapid decrease in expression of MITF in melanocytes treated with DKK1, which is concurrent with the decreased activities of beta-catenin and of glucose-synthase kinase 3beta via phosphorylation at Ser9 and with the upregulated expression of protein kinase C alpha. These results further clarify the mechanism by which DKK1 suppresses melanocyte density and differentiation, and help explain why DKK1-rich palmoplantar epidermis is paler than non-palmoplantar epidermis via mesenchymal-epithelial interactions." 11727;"Use of the 308-nm excimer laser for psoriasis and vitiligo.";"T. Passeron";"Equipe 12, Team 12";16427504;"Clinics in dermatology";"Passeron T, Ortonne JP";;"Feb Jan 2006";1136160000;;"The 308-nm excimer laser represents the latest advance in the concept of selective phototherapy. It emits a wavelength in the UV-B spectrum and thus shares the same indications as conventional phototherapy. Like other laser devices, the 308-nm excimer laser emits a monochromatic and coherent beam of light, can selectively treat a lesion while sparing surrounding healthy skin, and can deliver high fluencies. Clinicians have taken advantage of these properties to treat dermatologic disorders since 1997, with psoriasis and vitiligo attracting most attention. Initially, high fluencies (minimal erythemal dose, 8-16) were used, with excellent clinical results, to treat psoriasis vulgaris. The significance of side effects and the potential long-term carcinogenic risk associated with such fluencies have resulted in medium doses (about 3 minimal erythemal dose) being recommended, however. Interestingly, taking advantage of the selectivity of the laser, newer treatment protocols adapt the dose to the lesion and not to the minimal erythemal dose, as is the case for conventional phototherapies. Many prospective study series have also shown the efficacy and the good tolerance of the 308-nm excimer laser in the treatment of localized vitiligo. Induced rates of repigmentation seem to be higher than with narrowband UV-B. Moreover, the selectivity of the treatment prevents irradiation of healthy skin and limits unsightly tanning of surrounding skin. Aesthetically pleasing results are usually not achieved in extremities and bony prominences, which are not good indications for this technique. Combining the 308-nm excimer laser with 0.1% tacrolimus ointment has provided very interesting results, which need to be confirmed in larger series. The absence of actual data concerning the long-term risk for skin cancer after this treatment means that it should be considered with caution. Combination with topical steroids appears to be synergistic and potentially reduces long-term side effects; again, prospective data are lacking." 11728;"What's new in hypochromy.";"T. Passeron";"Equipe 12, Team 12";16766328;"The Journal of dermatological treatment";"Passeron T, Ortonne JP";;"Jun 2006";1150156800;;"Hypochromy is a common dermatological disorder. However, its treatment still gives unsatisfactory results. Interesting clues into the understanding of the pathophysiology of hypochromy have been recently brought about thanks to the pigmentary side effects reported with the new tyrosine kinase inhibition treatments. New therapeutic approaches to hypochromy are further discussed." 11725;"Lack of efficacy of tacrolimus in the treatment of vitiligo in the absence of UV-B exposure.";"T. Passeron";"Equipe 12, Team 12";16490866;"Archives of dermatology";"Ostovari N, Passeron T, Lacour JP, Ortonne JP";;"Feb 2006";1140739200;; 11721;"Melanin pigmentary disorders: treatment update.";"T. Passeron";"Equipe 12, Team 12";15837152;"Dermatologic clinics";"Ortonne JP, Passeron T";;"Apr 2005";1113955200;;"Most of the melanin pigmentary disorders are cosmetically important and have a strong impact on the quality of life of affected individuals. This article examines recent advances in the treatment of melanin pigmentary disorder including hypermelanosis and hypomelanosis. The development of laser technologies has completed the use of the increasing number of bleaching agents in treating hyperpigmented lesions. The treatment of hypomelanotic disorders is still often disappointing, but new therapeutic options provide encouraging results." 11722;"Physiopathology and genetics of vitiligo.";"T. Passeron";"Equipe 12, Team 12";16298511;"Journal of autoimmunity";"Passeron T, Ortonne JP";;"11 2005";1130803200;;"Generalized vitiligo is an acquired disorder in which white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. The autoimmune pathogenesis of vitiligo has become a rapidly evolving field of research. A humoral immune reaction has been implicated through the detection of circulating antibodies. However, recent research focuses on a melanocyte-specific cytotoxic-T-cell immune reaction in the melanocyte destruction. Several candidate genes have been proposed for vitiligo susceptibility. They include genes important for melanin biosynthesis, response to oxidative stress and/or regulation of autoimmunity. A recent genome-wide scan performed on families with numerous members presenting vitiligo has clearly revealed linkage of susceptibility loci." 11719;"[The 308 nm excimer laser in dermatology].";"T. Passeron";"Equipe 12, Team 12";15798552;"Presse medicale (Paris, France : 1983)";"Passeron T, Ortonne JP";;"Mar 2005";1112227200;;"THE EFFICACY OF THE 308 NM EXCIMER LASER in the treatment of common psoriasis has been demonstrated. THE DOSES USED have progressively decreased, hence, limiting the adverse events that appear redhibitory with high doses. THE ADAPTATION OF THE DOSES not to the patients themselves but to each of the plaques treated should reduce the number of sessions and the cumulated close necessary to obtain clinical remission. THE 308 NM EXCIMER LASER is effective and tolerance is good in the treatment of vitiligo. It should be proposed for limited vitiligo and essentially of the ""UV sensitive"" areas, which have shown aesthetically correct percentage of repigmentation. THE PLACE AND INTEREST of its association with other treatments, notably with topical tacrolimus, remains to be defined. Although the results obtained in the treatment of vitiligo are promising, they have to be confirmed in larger cohorts and ensure the absence of median and long term side effects. This therefore limits its use in combined treatments in the context of controlled clinical traits. THE 30 NM EXCIMER LASER IS AN EFFECTIVE AND WELL TOLERATED TREATMENT in localised and non-nodular forms of mycosis fungoid (MF). Although the number of patients treated is limited, the clinical and histological cure observed demonstrates the interest of this new technique in the treatment of MF. These results must be confirmed in a greater number of patients. THE 308 NM EXCIMER LASER is an interesting therapeutic alternative in the treatment of plaques of alopecia areata, erosive oral lichen planus, post-surgical hypopigmentation, vergetures and localised forms of atopic dermatitis. Because of the sparcity of data and in the absence of long term follow-up, it must not be proposed in first intention." 11717;"Genetic disorders of pigmentation.";"T. Passeron";"Equipe 12, Team 12";15708290;"Clinics in dermatology";"Passeron T, Mantoux F, Ortonne JP";;"Feb 2005";1108425600;;"More than 127 loci are actually known to affect pigmentation in mouse when they are mutated. From embryogenesis to transfer of melanin to the keratinocytes or melanocytes survival, any defect is able to alter the pigmentation process. Many gene mutations are now described, but the function of their product protein and their implication in melanogenesis are only partially understood. Each genetic pigmentation disorder brings new clues in the understanding of the pigmentation process. According to the main genodermatoses known to induce hypo- or hyperpigmentation, we emphasize in this review the last advances in the understanding of the physiopathology of these diseases and try to connect, when possible, the mutation to the clinical phenotype." 11714;"308-nm excimer laser therapy in alopecia areata.";"T. Passeron";"Equipe 12, Team 12";15523373;"Journal of the American Academy of Dermatology";"Zakaria W, Passeron T, Ostovari N, Lacour JP, Ortonne JP";;"Nov 2004";1099526400;; 11713;"Efficacy of the 308-nm excimer laser in the treatment of mycosis fungoides.";"T. Passeron";"Equipe 12, Team 12";15492207;"Archives of dermatology";"Passeron T, Zakaria W, Ostovari N, Perrin C, Larrouy JC, Lacour JP, Ortonne JP";;"Oct 2004";1098230400;; 11710;"Topical tacrolimus and the 308-nm excimer laser: a synergistic combination for the treatment of vitiligo.";"T. Passeron";"Equipe 12, Team 12";15381545;"Archives of dermatology";"Passeron T, Ostovari N, Zakaria W, Fontas E, Larrouy JC, Lacour JP, Ortonne JP";;"Sep 2004";1095984000;;"To compare the efficacy of combined tacrolimus and 308-nm excimer laser therapy vs 308-nm excimer laser monotherapy in treating vitiligo." 11709;"Invasive fungal dermatitis in a 770 gram neonate.";"T. Passeron";"Equipe 12, Team 12";15165208;"Pediatric dermatology";"Passeron T, Desruelles F, Gari-Toussaint M, Dageville C, Lacour JP";;"May 2004";1085788800;;"A 770 g birthweight, 25-weeks gestation infant girl was born from a bigeminal pregnancy. Six days later she developed erythematous ""diaper dermatitis"" and maceration of the flexural areas. Despite topical antifungal therapy, erythematous plaques appeared 2 days later on the back. Within less than 24 hours, skin erosions with crusting appeared and spread over the whole body. Candida albicans was found in cutaneous scales, and blood, umbilical catheter, and cerebrospinal fluid cultures. In spite of intravenous fluconazole therapy, her general condition deteriorated and she died 2 days later. This premature neonate had a typical case of invasive fungal dermatitis, which is characterized by diffuse erosive and crusting cutaneous lesions appearing several days after birth and a high rate of systemic fungal infection (mainly but not exclusively) due to Candida sp. Mortality is high and prompt diagnosis and initiation of antifungal therapy appears to be the most important factor for survival." 11707;"Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophilin/Slac2-a and actin association.";"C. Chiaverini, C. Bertolotto, K. Bille, P. Bahadoran, R. Ballotti, T. Passeron";"Equipe 12, Team 12, Equipe 01, Team 01";15059972;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Passeron T, Bahadoran P, Bertolotto C, Chiaverini C, Buscà R, Valony G, Bille K, Ortonne JP, Ballotti R";;"04 2004";1080777600;;"Melanosomes are melanin-containing organelles that belong to a recently individualized group of lysosome-related organelles. Recently, numerous reports have dissected the molecular mechanisms that control melanosome transport, but nothing was known about the possible regulation of melanosome distribution by exogenous physiological stimulus. In the present report, we demonstrate that a physiological melanocyte-differentiating agent such as alpha-melanocyte-stimulating hormone, through the stimulation of the cAMP pathway, induces a rapid centrifugal transport of melanosomes, leading to their accumulation at the dendrite tips of melanocytes. Interestingly, the small GTP binding proteins of the p21Rho family and one of their effectors, p160 Rho-associated kinase, but not PKA, play a key role in redistribution of melanosomes at the extremities of the dendrites. Further, we have investigated, at the molecular level, the effect of cAMP on the different proteins involved in the control of melanosome transport. We demonstrate that cAMP stimulates the expression of Rab27a and rapidly increases the interaction of the melanophilin/Slac2-a with actin. Thus, we propose that the stimulation of the interaction between melanophilin/Slac2-a and actin would allow the rapid accumulation of melanosomes in the actin-rich region of the dendrite extremities." 11705;"Drug rash with eosinophilia and systemic symptoms (DRESS) due to streptomycin.";"T. Passeron";"Equipe 12, Team 12";15040497;"Acta dermato-venereologica";"Passeron T, Ndir MC, Aubron C, Hovette P";;"Mar 2004";1080259200;; 11703;"[Skin ageing and its prevention].";"T. Passeron";"Equipe 12, Team 12";14534483;"Presse medicale (Paris, France : 1983)";"Passeron T, Ortonne JP";;"Oct 2003";1065744000;;"INTRINSIC AND EXTRINSIC FACTORS: Skin ageing is due to the conjunction of intrinsic (chronological ageing) and extrinsic factors (fundamentally photo-ageing). The physiopathological mechanisms of intrinsic ageing rejoin those of the ageing of all the other organs. Among the intrinsic causes, tobacco and above all ultra-violet radiation, UVB and also UVA, play a preponderant role. Photo-ageing is secondary to complex mechanisms that are increasingly known. The UVB directly interact with the DNA of the cutaneous cells. The deleterious effects of UVA are principally due to the formation of free radical oxygen, which result in an alteration in the nuclear and also mitochondrial DNA, but also an activation of the enzymes, metalloproteinase, capable of damaging the extra-cellular matrix. DELETERIOUS CONSEQUENCES: The phenomena of ageing provoke the decline in defence, healing and perception mechanisms and in the thermoregulation of the skin tissue. There are numerous and often unsightly clinical manifestations. Photo-ageing can be considered as a marker of risk of photo-carcinogenesis requiring increased clinical surveillance. PREVENTIVE AND CURATIVE MEASURES: The prevention of skin ageing must be based on the use of sunscreens protecting against both UVB and UVA, but, in order for them to be effective, they require a change in general life style. There are many efficient therapeutic means, but the possible side effects must be known and explained to the patient. Retinoids, in view of their innocuousness and efficacy not only in prevention but also treatment of skin ageing, should be considered as a therapeutic option of choice." 11701;"The new 940-nanometer diode laser: an effective treatment for leg venulectasia.";"T. Passeron";"Equipe 12, Team 12";12734507;"Journal of the American Academy of Dermatology";"Passeron T, Olivier V, Duteil L, Desruelles F, Fontas E, Ortonne JP";;"May 2003";1052352000;;"The 940-nm diode laser has been shown to be an effective treatment for leg veins." 11699;"Kawasaki disease with exceptional cutaneous manifestations.";"T. Passeron";"Equipe 12, Team 12";12014395;"European journal of pediatrics";"Passeron T, Olivier V, Sirvent N, Khalfi A, Boutté P, Lacour JP";;"May 2002";1021593600;; 11695;"Outdoor sunscreen testing with high-intensity solar exposure in a Chinese and Caucasian population.";"T. Passeron";"Equipe 12, Team 12";34157168;"Photodermatology, photoimmunology & photomedicine";"Granger C, Ong G, Andres P, Trullàs C, Hosenally M, Lai W, Liu W, Krutmann J, Passeron T, Lim HW";;"08 2021";1627776000;;"Currently, sunscreens' sun protection factor (SPF) and ultraviolet (UV) A protection are tested separately under indoor conditions, without considering external conditions that may affect performance. Studies are often conducted in Caucasian individuals; other racial groups may respond differently." 11693;"CLEC12B Decreases Melanoma Proliferation by Repressing Signal Transducer and Activator of Transcription 3.";"G. Beranger, H. Montaudie, M. Heim, M. Tulic, S. Rocchi, T. Passeron, Y. Cheli";"Equipe 12, Team 12, Equipe 01, Team 01";34310951;"The Journal of investigative dermatology";"Montaudié H, Sormani L, Dadone-Montaudié B, Heim M, Cardot-Leccia N, Tulic MK, Beranger G, Gay AS, Debayle D, Cheli Y, Raymond JH, Sohier P, Petit V, Rocchi S, Gesbert F, Larue L, Passeron T";;"Jul 2021";1627257600;;"The potential role of CLEC12B, a gene predominantly expressed by skin melanocytes discovered through transcriptomic analysis, in melanoma is unknown. In this study, we show that CLEC12B expression is lower in melanoma and melanoma metastases than in melanocytes and benign melanocytic lesions and that its decrease correlates with poor prognosis. We further show that CLEC12B recruits SHP2 phosphatase through its immunoreceptor tyrosine-based inhibition motif domain, inactivates signal transducer and activator of transcription 1/3/5, increases p53/p21/p27 expression/activity, and modulates melanoma cell proliferation. The growth of human melanoma cells overexpressing CLEC12B in nude mice after subcutaneous injection is significantly decreased compared with that in the vehicle control group and is associated with decreased signal transducer and activator of transcription 3 phosphorylation and increased p53 levels in the tumors. Reducing the level of CLEC12B had the opposite effect. We show that CLEC12B represses the activation of the signal transducer and activator of transcription pathway and negatively regulates the cell cycle, providing a proliferative asset to melanoma cells." 11694;"Editorial: Immunology of Vitiligo.";"T. Passeron";"Equipe 12, Team 12";34249018;"Frontiers in immunology";"Seneschal J, Harris JE, Le Poole IC, Passeron T, Speeckaert R, Boniface K";;"Jul 2021";1626048000;; 11687;"Allogeneic stem cell transplantation as a curative therapeutic approach for VEXAS syndrome: a case report.";"M. Loschi, T. Passeron, T. Cluzeau";"Equipe 02, Team 02, Equipe 12, Team 12";34999727;"Bone marrow transplantation";"Loschi M, Roux C, Sudaka I, Ferrero-Vacher C, Marceau-Renaut A, Duployez N, Passeron T, Cluzeau T";;"Jan 2022";1641686400;;"VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly described entity linked to somatic mutation of UBA1, encompassing inflammatory disorders and hematological malignancies. Patients experiments symptoms related to inflammatory manifestations on the skin, joints, lungs. Most patients are refractory to usual anti-inflammatory or immunosuppressive treatments. Half of them will develop hematological diseases, mostly myelodysplastic syndromes. VEXAS patients with hematological malignancies have a poor outcome and no curative option has been described so far. Because in the first reported cohort of VEXAS patients the UBA1 mutation was only found in hematopoietic stem cells but not in fibroblasts, we hypothesized that bone marrow transplantation would provide a cure for the disease. Here we report the case of a VEXAS patient who successfully received an allogeneic hematopoietic stem cell transplantation as a curative option." 11690;"HeaLED: Assessment of skin healing under light-emitting diode (LED) exposure-A randomized controlled study versus placebo.";"T. Passeron";"Equipe 12, Team 12";34529859;"Lasers in surgery and medicine";"Le Duff F, Fontas E, Guardoli D, Lacour JP, Passeron T";;"09 2021";1630454400;;"Light-emitting diodes (LEDs) in the visible or near-infrared spectrum have been reported to promote wound healing. However, despite being frequently proposed in daily clinical practice, the efficacy of photobiomodulation treatment after a laser procedure relies on very limited clinical data." 11685;"Efficacy of 308-nm excimer therapy in alopecia areata: A retrospective study with long-term follow-up.";"T. Passeron";"Equipe 12, Team 12, Equipe 07";35064603;"Photodermatology, photoimmunology & photomedicine";"Y DF, H M, Passeron T";;"Jan 2022";1642809600;; 11686;"CLEC12B Is a Melanocytic Gene Regulating the Color of the Skin.";"C. Regazzetti, E. Verhoeyen, H. Montaudie, L. Blot, M. Heim, M. Tulic, S. Rocchi, T. Passeron, Y. Cheli";"Equipe 12, Team 12, Team 03, Equipe 03, Equipe 01, Team 01";34896119;"The Journal of investigative dermatology";"Sormani L, Montaudie H, Blot L, Heim M, Cardot Leccia N, Mhaidly R, Verhoeyen E, Regazzetti C, Nottet N, Cheli Y, De Donatis GM, Dabert Gay AS, Debayle D, Taquin Martin H, Gesbert F, Rocchi S, Tulic MK, Passeron T";;"Dec 2021";1639353600;;"Pigmentation of the human skin is a complex process regulated by many genes. However, only a few have a profound impact on melanogenesis. Transcriptome analysis of pigmented skin compared with analysis of vitiligo skin devoid of melanocytes allowed us to unravel CLEC12B as a melanocytic gene. We showed that CLEC12B, a C-type lectin receptor, is highly expressed in melanocytes and that its expression is decreased in dark skin compared with that in white skin. CLEC12B directly recruits and activates SHP1 and SHP2 through its immunoreceptor tyrosine-based inhibitory motif domain and promotes CRE-binding protein degradation, leading to the downregulation of the downstream MITF pathway. CLEC12B ultimately controls melanin production and pigmentation in vitro and in a model of reconstructed human epidermis. The identification of CLEC12B in melanocytes shows that C-type lectin receptors exert function beyond immunity and inflammation. It also provides insights into the understanding of melanocyte biology and regulation of melanogenesis." 11679;"Self-applied topical interventions for melasma: a systematic review and meta-analysis of data from randomized, investigator-blinded clinical trials.";"T. Passeron";"Equipe 12, Team 12, Equipe 07";35290681;"The British journal of dermatology";"Pennitz A, Kinberger M, Avila Valle G, Passeron T, Nast A, Werner RN";;"Mar 2022";1647302400;;"Melasma is a frequent dermatological condition. Although its relevance as a skin condition is primarily of cosmetic nature, it may affect the patients' well-being and quality of life. A broad range of treatment options is available, which makes it difficult to choose the most appropriate treatment." 11680;"Clinicopathological and molecular analysis of cutaneous leiomyosarcoma: A retrospective multicenter study of 79 cases.";"H. Montaudie, T. Passeron";"Equipe 12, Team 12";35489551;"Journal of the American Academy of Dermatology";"Planet C, Dalle S, Dereure O, Stoebner PE, Picot MC, Soler M, Meunier L, Cardot-Leccia N, Kubiniek V, Di Mauro I, Delhorbe M, Lacour JP, Passeron T, Pedeutour F, Montaudié H, Dadone-Montaudié B";;"Apr 2022";1651276800;; 11677;"Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells.";"M. Tulic";"Equipe 12, Team 12";33650175;"Journal of pineal research";"Bilska B, Schedel F, Piotrowska A, Stefan J, Zmijewski M, Pyza E, Reiter RJ, Steinbrink K, Slominski AT, Tulic MK, Kleszczyński K";;"03 2021";1614556800;;"Melanoma is a leading cause of cancer deaths worldwide. Although immunotherapy has revolutionized the treatment for some patients, resistance towards therapy and unwanted side effects remain a problem for numerous individuals. Broad anti-cancer activities of melatonin are recognized; however, additional investigations still need to be elucidated. Herein, using various human melanoma cell models, we explore in vitro the new insights into the regulation of melanoma by melatonin and its metabolites which possess, on the other side, high safety profiles and biological meaningful. In this study, using melanotic (MNT-1) and amelanotic (A375, G361, Sk-Mel-28) melanoma cell lines, the comparative oncostatic responses, the impact on melanin content (for melanotic MNT-1 melanoma cells) as well as the mitochondrial function controlled by melatonin, its precursor (serotonin), a kynuric (N -acetyl-N -formyl-5-methoxykynuramine, AFMK) and indolic pathway (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) metabolites were assessed. Namely, significant disturbances were observed in bioenergetics as follows: (i) uncoupling of oxidative phosphorylation (OXPHOS), (ii) attenuation of glycolysis, (iii) dissipation of mitochondrial transmembrane potential (mtΔΨ) accompanied by (iv) massive generation of reactive oxygen species (ROS), and (v) decrease of glucose uptake. Collectively, these results together with previously published reports provide a new biological potential and make an imperative to consider using melatonin or its metabolites for complementary future treatments of melanoma-affected patients; however, these associations should be additionally investigated in clinical setting." 11674;"ITGBL1 is a new immunomodulator that favors development of melanoma tumors by inhibiting natural killer cells cytotoxicity.";"A. Jacquel, C. Bertolotto, H. Montaudie, K. Bille, M. Tulic, R. Ballotti, T. Passeron, T. Strub, Y. Cheli";"Equipe 02, Team 02, Equipe 01, Team 01, Equipe 12, Team 12";33413419;"Molecular cancer";"Cheli Y, Tulic MK, El Hachem N, Nottet N, Jacquel A, Gesson M, Strub T, Bille K, Picard-Gauci A, Montaudié H, Beranger GE, Passeron T, Close P, Bertolotto C, Ballotti R";;"01 2021";1609459200;;"Resistances to immunotherapies remains a major hurdle towards a cure for melanoma in numerous patients. An increase in the mesenchymal phenotype and a loss of differentiation have been clearly associated with resistance to targeted therapies. Similar phenotypes have been more recently also linked to resistance to immune checkpoint therapies. We demonstrated here that the loss of MIcrophthalmia associated Transcription Factor (MITF), a pivotal player in melanocyte differentiation, favors the escape of melanoma cells from the immune system. We identified Integrin beta-like protein 1 (ITGBL1), a secreted protein, upregulated in anti-PD1 resistant patients and in MITF melanoma cells, as the key immunomodulator. ITGBL1 inhibited immune cell cytotoxicity against melanoma cells by inhibiting NK cells cytotoxicity and counteracting beneficial effects of anti-PD1 treatment, both in vitro and in vivo. Mechanistically, MITF inhibited RUNX2, an activator of ITGBL1 transcription. Interestingly, VitaminD3, an inhibitor of RUNX2, improved melanoma cells to death by immune cells. In conclusion, our data suggest that inhibition of ITGBL1 might improve melanoma response to immunotherapies." 11521;"Ubiquitin-mediated proteasomal degradation of Rho proteins by the CNF1 toxin.";"A. Doye, L. Boyer";"Equipe 06, Team 06";16472677;"Methods in enzymology";"Doye A, Boyer L, Mettouchi A, Lemichez E";;"Feb 2006";1139875200;;"The CNF1 toxin is produced by uropathogenic and meningitis-causing Escherichia coli. CNF1 catalyzes the constitutive activation of Rho proteins by deamidation. The threshold of activation of Rho proteins by CNF1 is, however, attenuated because of a concomitant decrease of their cellular levels. Depletion of activated-Rac1 is catalyzed by ubiquitin-mediated proteasomal degradation. Consequently, we show by effector-binding pull-down that co-treatment of intoxicated cells with the MG132 proteasome-inhibitor results in a higher level of activation of Rac, as well as RhoA and Cdc42. We show that CNF1 induces the transient recruitment of Rho proteins to cellular membranes. Interestingly, at the difference of Rac and Cdc42, the inhibition of the proteasome during CNF1 treatment does not result in a significant accumulation of RhoA to cellular membranes. Using an in vivo ubiquitylation assay, we evidence that mutation of the geranylgeranyl acceptor cysteine of Rac1 (Rac1C189G) abolished the sensitivity of permanently activated-Rac1 to ubiquitylation, whereas Rac1C189G remained able to bind to the effector-binding domain of p21-PAK. Collectively, these results indicate that association with the cellular membranes is a necessary step for activated-Rac1 ubiquitylation." 11519;"Induction of transient macroapertures in endothelial cells through RhoA inhibition by Staphylococcus aureus factors.";"A. Doye, L. Boyer, P. Munro";"Equipe 06, Team 06";16754962;"The Journal of cell biology";"Boyer L, Doye A, Rolando M, Flatau G, Munro P, Gounon P, Clément R, Pulcini C, Popoff MR, Mettouchi A, Landraud L, Dussurget O, Lemichez E";;"Jun 2006";1149638400;;"The GTPase RhoA is a major regulator of the assembly of actin stress fibers and the contractility of the actomyosin cytoskeleton. The epidermal cell differentiation inhibitor (EDIN) and EDIN-like ADP-ribosyltransferases of Staphylococcus aureus catalyze the inactivation of RhoA, producing actin cable disruption. We report that purified recombinant EDIN and EDIN-producing S. aureus provoke large transcellular tunnels in endothelial cells that we have named macroapertures (MAs). These structures open transiently, followed by the appearance of actin-containing membrane waves extending over the aperture. Disruption of actin cables, either directly or indirectly, through rhoA RNAi knockdown also triggers the formation of MAs. Intoxication of endothelial monolayers by EDIN produces a loss of barrier function and provides direct access of the endothelium basement membrane to S. aureus." 11517;"alpha2beta1 integrin controls association of Rac with the membrane and triggers quiescence of endothelial cells.";"A. Doye, L. Boyer";"Equipe 06, Team 06";20592186;"Journal of cell science";"Cailleteau L, Estrach S, Thyss R, Boyer L, Doye A, Domange B, Johnsson N, Rubinstein E, Boucheix C, Ebrahimian T, Silvestre JS, Lemichez E, Meneguzzi G, Mettouchi A";;"Jul 2010";1278028800;;"Integrin receptors and their extracellular matrix ligands provide cues to cell proliferation, survival, differentiation and migration. Here, we show that alpha2beta1 integrin, when ligated to the basement membrane component laminin-1, triggers a proliferation arrest in primary endothelial cells. Indeed, in the presence of strong growth signals supplied by growth factors and fibronectin, alpha2beta1 engagement alters assembly of mature focal adhesions by alpha5beta1 and leads to impairment of downstream signaling and cell-cycle arrest in the G1 phase. Although the capacity of alpha5beta1 to signal for GTP loading of Rac is preserved, the joint engagement of alpha2beta1 interferes with membrane anchorage of Rac. Adapting the 'split-ubiquitin' sensor to screen for membrane-proximal alpha2 integrin partners, we identified the CD9 tetraspanin and further establish its requirement for destabilization of focal adhesions, control of Rac subcellular localization and growth arrest induced by alpha2beta1 integrin. Altogether, our data establish that alpha2beta1 integrin controls endothelial cell commitment towards quiescence by triggering a CD9-dependent dominant signaling." 11515;"Transient uptake and storage of serotonin in developing thalamic neurons.";"A. Doye";"Equipe 06, Team 06";8938116;Neuron;"Lebrand C, Cases O, Adelbrecht C, Doye A, Alvarez C, El Mestikawy S, Seif I, Gaspar P";;"Nov 1996";846806400;;"Serotonin (5-HT) has been shown to affect the development and patterning of the mouse barrelfield. We show that the dense transient 5-HT innervation of the somatosensory, visual, and auditory cortices originates in the thalamus rather than in the raphe: 5-HT is detected in thalamocortical fibers and most 5-HT cortical labeling disappears after thalamic lesions. Thalamic neurons do not synthesize 5-HT but take up exogenous 5-HT through 5-HT high affinity uptake sites located on thalamocortical axons and terminals. 3H-5-HT injected into the cortex is retrogradely transported to thalamic neurons. In situ hybridization shows a transient expression of the genes encoding the serotonin transporter and the vesicular monoamine transporter in thalamic sensory neurons. In these glutamatergic neurons, internalized 5-HT might thus be stored and used as a ""borrowed transmitter"" for extraneuronal signaling or could exert an intraneuronal control on thalamic maturation." 11513;"In vivo, villin is required for Ca(2+)-dependent F-actin disruption in intestinal brush borders.";"A. Doye";"Equipe 06, Team 06";10459016;"The Journal of cell biology";"Ferrary E, Cohen-Tannoudji M, Pehau-Arnaudet G, Lapillonne A, Athman R, Ruiz T, Boulouha L, El Marjou F, Doye A, Fontaine JJ, Antony C, Babinet C, Louvard D, Jaisser F, Robine S";;"Aug 1999";935539200;;"Villin is an actin-binding protein localized in intestinal and kidney brush borders. In vitro, villin has been demonstrated to bundle and sever F-actin in a Ca(2+)-dependent manner. We generated knockout mice to study the role of villin in vivo. In villin-null mice, no noticeable changes were observed in the ultrastructure of the microvilli or in the localization and expression of the actin-binding and membrane proteins of the intestine. Interestingly, the response to elevated intracellular Ca(2+) differed significantly between mutant and normal mice. In wild-type animals, isolated brush borders were disrupted by the addition of Ca(2+), whereas Ca(2+) had no effect in villin-null isolates. Moreover, increase in intracellular Ca(2+) by serosal carbachol or mucosal Ca(2+) ionophore A23187 application abolished the F-actin labeling only in the brush border of wild-type animals. This F-actin disruption was also observed in physiological fasting/refeeding experiments. Oral administration of dextran sulfate sodium, an agent that causes colonic epithelial injury, induced large mucosal lesions resulting in a higher death probability in mice lacking villin, 36 +/- 9.6%, compared with wild-type mice, 70 +/- 8.8%, at day 13. These results suggest that in vivo, villin is not necessary for the bundling of F-actin microfilaments, whereas it is necessary for the reorganization elicited by various signals. We postulate that this property might be involved in cellular plasticity related to cell injury." 11511;"The p21 Rho-activating toxin cytotoxic necrotizing factor 1 is endocytosed by a clathrin-independent mechanism and enters the cytosol by an acidic-dependent membrane translocation step.";"A. Doye";"Equipe 06, Team 06";10793151;"Molecular biology of the cell";"Contamin S, Galmiche A, Doye A, Flatau G, Benmerah A, Boquet P";;"May 2000";957398400;;"Cytotoxic necrotizing factor 1 (CNF1), a protein produced by pathogenic strains of Escherichia coli, activates the p21 Rho-GTP-binding protein, inducing a profound reorganization of the actin cytoskeleton. CNF1 binds to its cell surface receptor on HEp-2 cells with high affinity (K(d) = 20 pM). In HEp-2 cells the action of CNF1 is not blocked in the presence of filipin, a drug described to reduce cholera toxin internalization by the caveolae-like mechanism. Moreover, HEp-2 cells, which express a dominant negative form of proteins that impair the formation of clathrin coated-vesicles and internalization of transferrin (Eps15, dynamin or intersectin-Src homology 3), are still sensitive to CNF1. In this respect, the endocytosis of CNF1 is similar to the plant toxin ricin. However, unlike ricin toxin, CNF1 does not cross the Golgi apparatus and requires an acidic cell compartment to transfer its enzymatic activity into the cytosol in a manner similar to that required by diphtheria toxin. As shown for diphtheria toxin, the pH-dependent membrane translocation step of CNF1 could be mimicked at the level of the plasma membrane by a brief exposure to a pH of A in F7 and rs5355C>T in SELE modifies systolic blood pressure levels.";"M. Stathopoulou";"Equipe 10, Team 10";22815813;"PloS one";"El Shamieh S, Ndiaye NC, Stathopoulou MG, Murray HA, Masson C, Lamont JV, Fitzgerald P, Benetos A, Visvikis-Siest S";;"Jan 2012";1325376000;;"Although numerous genetic studies have been performed, only 0.9% of blood pressure phenotypic variance has been elucidated. This phenomenon could be partially due to epistatic interactions. Our aim was to identify epistatic interaction(s) associated with blood pressure levels in a pre-planned two-phase approach." 9768;"Alcohol Consumption, Beverage Preference, and Diet in Middle-Aged Men from the STANISLAS Study.";"M. Stathopoulou";"Equipe 10, Team 10";23056930;"Journal of nutrition and metabolism";"Herbeth B, Samara A, Stathopoulou M, Siest G, Visvikis-Siest S";;"Jan 2012";1325376000;;"The question about differences in dietary patterns associated with beer, wine, and spirits is still unresolved. We used diet data from 423 middle-aged males of the STANISLAS Study. Using adjusted values for covariates, we observed a negative significant association between increasing alcohol intakes and the consumption of milk, yogurt, and fresh/uncured cheese, sugar and confectionery, vegetables and fruits, and a significant positive relationship with cheese, meat and organs, pork-butcher's meat, and potatoes. In addition, the first dietary pattern identified by factor analysis (characterized a more prudent diet) was inversely related to alcohol intakes. Conversely, when analyzing daily consumption of specific food groups and diet patterns according to beverage preference (wine, beer, and spirits), no significant difference was observed. In conclusion, in this sample of middle-aged French males, there was a linear trend between increasing alcohol intakes and worsening of quality of diet, while no difference was observed according to beverage preference." 9766;"Associations of vascular endothelial growth factor (VEGF) with adhesion and inflammation molecules in a healthy population.";"M. Stathopoulou";"Equipe 10, Team 10";23201487;Cytokine;"Azimi-Nezhad M, Stathopoulou MG, Bonnefond A, Rancier M, Saleh A, Lamont J, Fitzgerald P, Ndiaye NC, Visvikis-Siest S";;"Feb 2013";1359676800;;"Vascular endothelial growth factor (VEGF) is implicated in numerous pathologies through complex relationships with cellular adhesion molecules (CAMs) and inflammation markers. These have not been assessed in non-pathological conditions. Our aim was the evaluation of associations between VEGF and CAM/inflammation molecules in a healthy population, and of possible genomic interplays in order to better apprehend the underlying mechanisms leading to the pathology. We examined the associations between VEGF and ICAM-1, VCAM-1, E-, L-, P-selectins, TNF-α, CRP and IL-6 plasma levels in 403 healthy individuals. Gene expression of CAM/inflammation molecules and VEGF isoforms (121, 145, 165, and 189) were quantified in peripheral blood mononuclear cells (PBMCs). The effect of four genetic variants (explaining ≈ 50% of the heritability of circulating VEGF levels) and of their interactions on plasma and mRNA levels of CAM/inflammation molecules was examined. VEGF was associated with ICAM-1 and E-selectin in plasma. In PBMCs, VEGF(145) mRNA was associated with ICAM-1, L-selectin and TNF-α expression. Interactions of the genetic variants were shown to affect ICAM-1, E-selectin, IL-6 and TNF-α plasma levels, while rs4416670 was associated with L-selectin expression. These findings propose a biological connection between VEGF and CAM/inflammation markers. Common genetic and transcriptional mechanisms may link these molecules and control their effect in healthy conditions." 9764;"A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C.";"M. Stathopoulou";"Equipe 10, Team 10";23204297;"Journal of lipid research";"Stathopoulou MG, Bonnefond A, Ndiaye NC, Azimi-Nezhad M, El Shamieh S, Saleh A, Rancier M, Siest G, Lamont J, Fitzgerald P, Visvikis-Siest S";;"Feb 2013";1359676800;;"Vascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (β = -0.08 mmol/l, P(overall) = 1.2 × 10(-7)) and LDL-C (β = 0.13 mmol/l, P(overall) = 1.5 × 10(-4)). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (P(overall) = 1.7 × 10(-5)). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA." 9762;"Common mutations and polymorphisms predicting adverse cardiovascular events: current view.";"M. Stathopoulou";"Equipe 10, Team 10";23215878;Pharmacogenomics;"Visvikis-Siest S, Stathopoulou MG, Ndiaye NC";;"Dec 2012";1354320000;; 9760;"Epistatic study reveals two genetic interactions in blood pressure regulation.";"M. Stathopoulou";"Equipe 10, Team 10";23298194;"BMC medical genetics";"Ndiaye NC, Said el S, Stathopoulou MG, Siest G, Tsai MY, Visvikis-Siest S";;"Jan 2013";1356998400;;"Although numerous candidate gene and genome-wide association studies have been performed on blood pressure, a small number of regulating genetic variants having a limited effect have been identified. This phenomenon can partially be explained by possible gene-gene/epistasis interactions that were little investigated so far." 9758;"What is the contribution of two genetic variants regulating VEGF levels to type 2 diabetes risk and to microvascular complications?";"M. Stathopoulou";"Equipe 10, Team 10";23405237;"PloS one";"Bonnefond A, Saulnier PJ, Stathopoulou MG, Grarup N, Ndiaye NC, Roussel R, Nezhad MA, Dechaume A, Lantieri O, Hercberg S, Lauritzen T, Balkau B, El-Sayed Moustafa JS, Hansen T, Pedersen O, Froguel P, Charpentier G, Marre M, Hadjadj S, Visvikis-Siest S";;"Jan 2013";1356998400;;"Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF-related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits.SNPs were genotyped in several case-control studies: French and Danish T2D studies (N(cases) = 6,920-N(controls) = 3,875 and N(cases) = 3,561-N(controls) = 2,623; respectively), two French studies one for diabetic nephropathy (N(cases) = 1,242-N(controls) = 860) and the other for diabetic retinopathy (N(cases) = 1,336-N(controls) = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population-based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions.In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7×10(-5)). Furthermore, the same allele was associated with higher glycated hemoglobin levels (β = 0.02%; P = 9.2×10(-3)). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients.In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected." 9756;"Newly identified synergy between clopidogrel and calcium-channel blockers for blood pressure regulation possibly involves CYP2C19 rs4244285.";"M. Stathopoulou";"Equipe 10, Team 10";23643422;"International journal of cardiology";"Stathopoulou MG, Monteiro P, Shahabi P, Peñas-Lledó E, El Shamieh S, Silva Santos L, Thilly N, Siest G, Llerena A, Visvikis-Siest S";;"Oct 2013";1380585600;; 9754;"Conference Scene: Systems biology and personalized health science and translation.";"M. Stathopoulou";"Equipe 10, Team 10";24279850;Pharmacogenomics;"Siest G, Ndiaye NC, El Shamieh S, Shahabi P, Stathopoulou M, Saleh AS, Godjo T, Albertini L, Visvikis-Siest S";;"Dec 2013";1385856000;;"After a 1-day advanced course on systems biology, the main themes of this 3-day colloquium were developed: from systems biology to systems medicine with special applications to cancer; pharmacogenomics in drug discovery and clinical application; and epigenomics and genome-wide association studies in cardiovascular diseases. In two roundtable discussions on pharmacogenomics and genome-wide association studies, the progress and the difficulties in the implementation of omics technologies in clinical practice were discussed. Three workshops were also organized on technical tools linked to the meeting themes. " 9752;"Pharmacogenomics: from cell to clinic (Part 1).";"M. Stathopoulou";"Equipe 10, Team 10";24798716;Pharmacogenomics;"Siest G, Medeiros R, Melichar B, Stathopoulou M, Van Schaik RH, Cacabelos R, Abt PM, Monteiro C, Gurwitz D, Queiroz J, Mota-Filipe H, Ndiaye NC, Visvikis-Siest S";;"Apr 2014";1396310400;;"The second international European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. The first part of this Conference Scene will focus on the pharmacogenomics and biomarkers used in medical oncology, and in particular solid tumors. In addition, this article covers the two keynote conference introductory lectures by Ann K Daly and Magnus Ingelman-Sundberg. The second part of this article will discuss the clinical implementation of pharmacogenomic tests; the role of transports and pharmacogenomics; how stem cells and other new tools are helping the development of pharmacogenomics and drug discovery; and an update on the clinical translation of pharmacogenomics to personalized medicine. Part two of this Conference Scene will be featured in the next issue of Pharmacogenomics. " 9750;"Conference scene: pharmacogenomics: from cell to clinic (part 2).";"M. Stathopoulou";"Equipe 10, Team 10";24897282;Pharmacogenomics;"Siest G, Medeiros R, Melichar B, Stathopoulou M, Van Schaik RH, Cacabelos R, Abt PM, Monteiro C, Gurwitz D, Queiroz J, Mota-Filipe H, Ndiaye NC, Visvikis-Siest S";;"Apr 2014";1396310400;;"Second International ESPT Meeting Lisbon, Portugal, 26-28 September 2013 The second European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. Part 1 of this Conference Scene was presented in the previous issue of Pharmacogenomics. This second part will focus on: clinical implementation of pharmacogenomics tests; transporters and pharmacogenomics; stem cells and other new tools for pharmacogenomics and drug discovery; from system pharmacogenomics to personalized medicine; and, finally, we will discuss the Posters and Awards that were presented at the conference. " 9748;"Genetic determinants of leucocyte telomere length in children: a neglected and challenging field.";"M. Stathopoulou";"Equipe 10, Team 10";25641522;"Paediatric and perinatal epidemiology";"Stathopoulou MG, Petrelis AM, Buxton JL, Froguel P, Blakemore AI, Visvikis-Siest S";;"Mar 2015";1425168000;;"Telomere length is associated with a large range of human diseases. Genome-wide association studies (GWAS) have identified genetic variants that are associated with leucocyte telomere length (LTL). However, these studies are limited to adult populations. Nevertheless, childhood is a crucial period for the determination of LTL, and the assessment of age-specific genetic determinants, although neglected, could be of great importance. Our aim was to provide insights and preliminary results on genetic determinants of LTL in children." 9746;"New genetic loci link adipose and insulin biology to body fat distribution.";"M. Stathopoulou";"Team 10, Equipe 10";25673412;Nature;"Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, Strawbridge RJ, Pers TH, Fischer K, Justice AE, Workalemahu T, Wu JMW, Buchkovich ML, Heard-Costa NL, Roman TS, Drong AW, Song C, Gustafsson S, Day FR, Esko T, Fall T, Kutalik Z, Luan J, Randall JC, Scherag A, Vedantam S, Wood AR, Chen J, Fehrmann R, Karjalainen J, Kahali B, Liu CT, Schmidt EM, Absher D, Amin N, Anderson D, Beekman M, Bragg-Gresham JL, Buyske S, Demirkan A, Ehret GB, Feitosa MF, Goel A, Jackson AU, Johnson T, Kleber ME, Kristiansson K, Mangino M, Leach IM, Medina-Gomez C, Palmer CD, Pasko D, Pechlivanis S, Peters MJ, Prokopenko I, Stančáková A, Sung YJ, Tanaka T, Teumer A, Van Vliet-Ostaptchouk JV, Yengo L, Zhang W, Albrecht E, Ärnlöv J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Blüher M, Böhringer S, Bonnet F, Böttcher Y, Bruinenberg M, Carba DB, Caspersen IH, Clarke R, Daw EW, Deelen J, Deelman E, Delgado G, Doney AS, Eklund N, Erdos MR, Estrada K, Eury E, Friedrich N, Garcia ME, Giedraitis V, Gigante B, Go AS, Golay A, Grallert H, Grammer TB, Gräßler J, Grewal J, Groves CJ, Haller T, Hallmans G, Hartman CA, Hassinen M, Hayward C, Heikkilä K, Herzig KH, Helmer Q, Hillege HL, Holmen O, Hunt SC, Isaacs A, Ittermann T, James AL, Johansson I, Juliusdottir T, Kalafati IP, Kinnunen L, Koenig W, Kooner IK, Kratzer W, Lamina C, Leander K, Lee NR, Lichtner P, Lind L, Lindström J, Lobbens S, Lorentzon M, Mach F, Magnusson PK, Mahajan A, McArdle WL, Menni C, Merger S, Mihailov E, Milani L, Mills R, Moayyeri A, Monda KL, Mooijaart SP, Mühleisen TW, Mulas A, Müller G, Müller-Nurasyid M, Nagaraja R, Nalls MA, Narisu N, Glorioso N, Nolte IM, Olden M, Rayner NW, Renstrom F, Ried JS, Robertson NR, Rose LM, Sanna S, Scharnagl H, Scholtens S, Sennblad B, Seufferlein T, Sitlani CM, Smith AV, Stirrups K, Stringham HM, Sundström J, Swertz MA, Swift AJ, Syvänen AC, Tayo BO, Thorand B, Thorleifsson G, Tomaschitz A, Troffa C, van Oort FV, Verweij N, Vonk JM, Waite LL, Wennauer R, Wilsgaard T, Wojczynski MK, Wong A, Zhang Q, Zhao JH, Brennan EP, Choi M, Eriksson P, Folkersen L, Franco-Cereceda A, Gharavi AG, Hedman ÅK, Hivert MF, Huang J, Kanoni S, Karpe F, Keildson S, Kiryluk K, Liang L, Lifton RP, Ma B, McKnight AJ, McPherson R, Metspalu A, Min JL, Moffatt MF, Montgomery GW, Murabito JM, Nicholson G, Nyholt DR, Olsson C, Perry JR, Reinmaa E, Salem RM, Sandholm N, Schadt EE, Scott RA, Stolk L, Vallejo EE, Westra HJ, Zondervan KT, , , , , , , , , , , , , , Amouyel P, Arveiler D, Bakker SJ, Beilby J, Bergman RN, Blangero J, Brown MJ, Burnier M, Campbell H, Chakravarti A, Chines PS, Claudi-Boehm S, Collins FS, Crawford DC, Danesh J, de Faire U, de Geus EJ, Dörr M, Erbel R, Eriksson JG, Farrall M, Ferrannini E, Ferrières J, Forouhi NG, Forrester T, Franco OH, Gansevoort RT, Gieger C, Gudnason V, Haiman CA, Harris TB, Hattersley AT, Heliövaara M, Hicks AA, Hingorani AD, Hoffmann W, Hofman A, Homuth G, Humphries SE, Hyppönen E, Illig T, Jarvelin MR, Johansen B, Jousilahti P, Jula AM, Kaprio J, Kee F, Keinanen-Kiukaanniemi SM, Kooner JS, Kooperberg C, Kovacs P, Kraja AT, Kumari M, Kuulasmaa K, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimäki T, Lyssenko V, Männistö S, Marette A, Matise TC, McKenzie CA, McKnight B, Musk AW, Möhlenkamp S, Morris AD, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Palmer LJ, Penninx BW, Peters A, Pramstaller PP, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ridker PM, Ritchie MD, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schwarz PE, Shuldiner AR, Staessen JA, Steinthorsdottir V, Stolk RP, Strauch K, Tönjes A, Tremblay A, Tremoli E, Vohl MC, Völker U, Vollenweider P, Wilson JF, Witteman JC, Adair LS, Bochud M, Boehm BO, Bornstein SR, Bouchard C, Cauchi S, Caulfield MJ, Chambers JC, Chasman DI, Cooper RS, Dedoussis G, Ferrucci L, Froguel P, Grabe HJ, Hamsten A, Hui J, Hveem K, Jöckel KH, Kivimaki M, Kuh D, Laakso M, Liu Y, März W, Munroe PB, Njølstad I, Oostra BA, Palmer CN, Pedersen NL, Perola M, Pérusse L, Peters U, Power C, Quertermous T, Rauramaa R, Rivadeneira F, Saaristo TE, Saleheen D, Sinisalo J, Slagboom PE, Snieder H, Spector TD, Stefansson K, Stumvoll M, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Veronesi G, Walker M, Wareham NJ, Watkins H, Wichmann HE, Abecasis GR, Assimes TL, Berndt SI, Boehnke M, Borecki IB, Deloukas P, Franke L, Frayling TM, Groop LC, Hunter DJ, Kaplan RC, O'Connell JR, Qi L, Schlessinger D, Strachan DP, Thorsteinsdottir U, van Duijn CM, Willer CJ, Visscher PM, Yang J, Hirschhorn JN, Zillikens MC, McCarthy MI, Speliotes EK, North KE, Fox CS, Barroso I, Franks PW, Ingelsson E, Heid IM, Loos RJ, Cupples LA, Morris AP, Lindgren CM, Mohlke KL";;"Feb 2015";1422748800;;"Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms. " 9744;"Genetic studies of body mass index yield new insights for obesity biology.";"M. Stathopoulou";"Team 10, Equipe 10";25673413;Nature;"Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, Ferreira T, Gustafsson S, Kutalik Z, Luan J, Mägi R, Randall JC, Winkler TW, Wood AR, Workalemahu T, Faul JD, Smith JA, Zhao JH, Zhao W, Chen J, Fehrmann R, Hedman ÅK, Karjalainen J, Schmidt EM, Absher D, Amin N, Anderson D, Beekman M, Bolton JL, Bragg-Gresham JL, Buyske S, Demirkan A, Deng G, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Goel A, Gong J, Jackson AU, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Leach IM, Medina-Gomez C, Medland SE, Nalls MA, Palmer CD, Pasko D, Pechlivanis S, Peters MJ, Prokopenko I, Shungin D, Stančáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet-Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Isaacs A, Albrecht E, Ärnlöv J, Arscott GM, Attwood AP, Bandinelli S, Barrett A, Bas IN, Bellis C, Bennett AJ, Berne C, Blagieva R, Blüher M, Böhringer S, Bonnycastle LL, Böttcher Y, Boyd HA, Bruinenberg M, Caspersen IH, Chen YI, Clarke R, Daw EW, de Craen AJM, Delgado G, Dimitriou M, Doney ASF, Eklund N, Estrada K, Eury E, Folkersen L, Fraser RM, Garcia ME, Geller F, Giedraitis V, Gigante B, Go AS, Golay A, Goodall AH, Gordon SD, Gorski M, Grabe HJ, Grallert H, Grammer TB, Gräßler J, Grönberg H, Groves CJ, Gusto G, Haessler J, Hall P, Haller T, Hallmans G, Hartman CA, Hassinen M, Hayward C, Heard-Costa NL, Helmer Q, Hengstenberg C, Holmen O, Hottenga JJ, James AL, Jeff JM, Johansson Å, Jolley J, Juliusdottir T, Kinnunen L, Koenig W, Koskenvuo M, Kratzer W, Laitinen J, Lamina C, Leander K, Lee NR, Lichtner P, Lind L, Lindström J, Lo KS, Lobbens S, Lorbeer R, Lu Y, Mach F, Magnusson PKE, Mahajan A, McArdle WL, McLachlan S, Menni C, Merger S, Mihailov E, Milani L, Moayyeri A, Monda KL, Morken MA, Mulas A, Müller G, Müller-Nurasyid M, Musk AW, Nagaraja R, Nöthen MM, Nolte IM, Pilz S, Rayner NW, Renstrom F, Rettig R, Ried JS, Ripke S, Robertson NR, Rose LM, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Scott WR, Seufferlein T, Shi J, Smith AV, Smolonska J, Stanton AV, Steinthorsdottir V, Stirrups K, Stringham HM, Sundström J, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Tayo BO, Thorand B, Thorleifsson G, Tyrer JP, Uh HW, Vandenput L, Verhulst FC, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Warren HR, Waterworth D, Weedon MN, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, , Brennan EP, Choi M, Dastani Z, Drong AW, Eriksson P, Franco-Cereceda A, Gådin JR, Gharavi AG, Goddard ME, Handsaker RE, Huang J, Karpe F, Kathiresan S, Keildson S, Kiryluk K, Kubo M, Lee JY, Liang L, Lifton RP, Ma B, McCarroll SA, McKnight AJ, Min JL, Moffatt MF, Montgomery GW, Murabito JM, Nicholson G, Nyholt DR, Okada Y, Perry JRB, Dorajoo R, Reinmaa E, Salem RM, Sandholm N, Scott RA, Stolk L, Takahashi A, Tanaka T, van 't Hooft FM, Vinkhuyzen AAE, Westra HJ, Zheng W, Zondervan KT, , , , , , , , , , , , , , Heath AC, Arveiler D, Bakker SJL, Beilby J, Bergman RN, Blangero J, Bovet P, Campbell H, Caulfield MJ, Cesana G, Chakravarti A, Chasman DI, Chines PS, Collins FS, Crawford DC, Cupples LA, Cusi D, Danesh J, de Faire U, den Ruijter HM, Dominiczak AF, Erbel R, Erdmann J, Eriksson JG, Farrall M, Felix SB, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Franco OH, Gansevoort RT, Gejman PV, Gieger C, Gottesman O, Gudnason V, Gyllensten U, Hall AS, Harris TB, Hattersley AT, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Homuth G, Hovingh GK, Humphries SE, Hunt SC, Hyppönen E, Illig T, Jacobs KB, Jarvelin MR, Jöckel KH, Johansen B, Jousilahti P, Jukema JW, Jula AM, Kaprio J, Kastelein JJP, Keinanen-Kiukaanniemi SM, Kiemeney LA, Knekt P, Kooner JS, Kooperberg C, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Marchand LL, Lehtimäki T, Lyssenko V, Männistö S, Marette A, Matise TC, McKenzie CA, McKnight B, Moll FL, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Madden PAF, Pasterkamp G, Peden JF, Peters A, Postma DS, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ridker PM, Rioux JD, Ritchie MD, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schunkert H, Schwarz PEH, Sever P, Shuldiner AR, Sinisalo J, Stolk RP, Strauch K, Tönjes A, Trégouët DA, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Völker U, Waeber G, Willemsen G, Witteman JC, Zillikens MC, Adair LS, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bornstein SR, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PIW, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hui J, Hunter DJ, Hveem K, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Metspalu A, Moebus S, Munroe PB, Njølstad I, Oostra BA, Palmer CNA, Pedersen NL, Perola M, Pérusse L, Peters U, Power C, Quertermous T, Rauramaa R, Rivadeneira F, Saaristo TE, Saleheen D, Sattar N, Schadt EE, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Thorsteinsdottir U, Stumvoll M, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Weir DR, Wichmann HE, Wilson JF, Zanen P, Borecki IB, Deloukas P, Fox CS, Heid IM, O'Connell JR, Strachan DP, Stefansson K, van Duijn CM, Abecasis GR, Franke L, Frayling TM, McCarthy MI, Visscher PM, Scherag A, Willer CJ, Boehnke M, Mohlke KL, Lindgren CM, Beckmann JS, Barroso I, North KE, Ingelsson E, Hirschhorn JN, Loos RJF, Speliotes EK";;"Feb 2015";1422748800;;"Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis. " 9742;"Genetic determined low response to thienopyridines is associated with higher systemic inflammation in smokers.";"M. Stathopoulou";"Equipe 10, Team 10";25916518;Pharmacogenomics;"Shahabi P, Cuisset T, Stathopoulou MG, Morange PE, Grosdidier C, Herbeth B, Siest G, Alessi MC, Visvikis-Siest S";;"Jan 2015";1420070400;;"To investigate whether the interactions of CYP2C19*2 and CYP2C19*17 with smoking are associated with the levels of P2Y12 receptor inhibition and CRP, in on-thienopyridine post-stenting patients." 9740;"Directional dominance on stature and cognition in diverse human populations.";"M. Stathopoulou";"Equipe 10, Team 10";26131930;Nature;"Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T, Jackson AU, Schurmann C, Smith AV, Zhang W, Okada Y, Stančáková A, Faul JD, Zhao W, Bartz TM, Concas MP, Franceschini N, Enroth S, Vitart V, Trompet S, Guo X, Chasman DI, O'Connel JR, Corre T, Nongmaithem SS, Chen Y, Mangino M, Ruggiero D, Traglia M, Farmaki AE, Kacprowski T, Bjonnes A, van der Spek A, Wu Y, Giri AK, Yanek LR, Wang L, Hofer E, Rietveld CA, McLeod O, Cornelis MC, Pattaro C, Verweij N, Baumbach C, Abdellaoui A, Warren HR, Vuckovic D, Mei H, Bouchard C, Perry JRB, Cappellani S, Mirza SS, Benton MC, Broeckel U, Medland SE, Lind PA, Malerba G, Drong A, Yengo L, Bielak LF, Zhi D, van der Most PJ, Shriner D, Mägi R, Hemani G, Karaderi T, Wang Z, Liu T, Demuth I, Zhao JH, Meng W, Lataniotis L, van der Laan SW, Bradfield JP, Wood AR, Bonnefond A, Ahluwalia TS, Hall LM, Salvi E, Yazar S, Carstensen L, de Haan HG, Abney M, Afzal U, Allison MA, Amin N, Asselbergs FW, Bakker SJL, Barr RG, Baumeister SE, Benjamin DJ, Bergmann S, Boerwinkle E, Bottinger EP, Campbell A, Chakravarti A, Chan Y, Chanock SJ, Chen C, Chen YI, Collins FS, Connell J, Correa A, Cupples LA, Smith GD, Davies G, Dörr M, Ehret G, Ellis SB, Feenstra B, Feitosa MF, Ford I, Fox CS, Frayling TM, Friedrich N, Geller F, Scotland G, Gillham-Nasenya I, Gottesman O, Graff M, Grodstein F, Gu C, Haley C, Hammond CJ, Harris SE, Harris TB, Hastie ND, Heard-Costa NL, Heikkilä K, Hocking LJ, Homuth G, Hottenga JJ, Huang J, Huffman JE, Hysi PG, Ikram MA, Ingelsson E, Joensuu A, Johansson Å, Jousilahti P, Jukema JW, Kähönen M, Kamatani Y, Kanoni S, Kerr SM, Khan NM, Koellinger P, Koistinen HA, Kooner MK, Kubo M, Kuusisto J, Lahti J, Launer LJ, Lea RA, Lehne B, Lehtimäki T, Liewald DCM, Lind L, Loh M, Lokki ML, London SJ, Loomis SJ, Loukola A, Lu Y, Lumley T, Lundqvist A, Männistö S, Marques-Vidal P, Masciullo C, Matchan A, Mathias RA, Matsuda K, Meigs JB, Meisinger C, Meitinger T, Menni C, Mentch FD, Mihailov E, Milani L, Montasser ME, Montgomery GW, Morrison A, Myers RH, Nadukuru R, Navarro P, Nelis M, Nieminen MS, Nolte IM, O'Connor GT, Ogunniyi A, Padmanabhan S, Palmas WR, Pankow JS, Patarcic I, Pavani F, Peyser PA, Pietilainen K, Poulter N, Prokopenko I, Ralhan S, Redmond P, Rich SS, Rissanen H, Robino A, Rose LM, Rose R, Sala C, Salako B, Salomaa V, Sarin AP, Saxena R, Schmidt H, Scott LJ, Scott WR, Sennblad B, Seshadri S, Sever P, Shrestha S, Smith BH, Smith JA, Soranzo N, Sotoodehnia N, Southam L, Stanton AV, Stathopoulou MG, Strauch K, Strawbridge RJ, Suderman MJ, Tandon N, Tang ST, Taylor KD, Tayo BO, Töglhofer AM, Tomaszewski M, Tšernikova N, Tuomilehto J, Uitterlinden AG, Vaidya D, van Hylckama Vlieg A, van Setten J, Vasankari T, Vedantam S, Vlachopoulou E, Vozzi D, Vuoksimaa E, Waldenberger M, Ware EB, Wentworth-Shields W, Whitfield JB, Wild S, Willemsen G, Yajnik CS, Yao J, Zaza G, Zhu X, Project TBJ, Salem RM, Melbye M, Bisgaard H, Samani NJ, Cusi D, Mackey DA, Cooper RS, Froguel P, Pasterkamp G, Grant SFA, Hakonarson H, Ferrucci L, Scott RA, Morris AD, Palmer CNA, Dedoussis G, Deloukas P, Bertram L, Lindenberger U, Berndt SI, Lindgren CM, Timpson NJ, Tönjes A, Munroe PB, Sørensen TIA, Rotimi CN, Arnett DK, Oldehinkel AJ, Kardia SLR, Balkau B, Gambaro G, Morris AP, Eriksson JG, Wright MJ, Martin NG, Hunt SC, Starr JM, Deary IJ, Griffiths LR, Tiemeier H, Pirastu N, Kaprio J, Wareham NJ, Pérusse L, Wilson JG, Girotto G, Caulfield MJ, Raitakari O, Boomsma DI, Gieger C, van der Harst P, Hicks AA, Kraft P, Sinisalo J, Knekt P, Johannesson M, Magnusson PKE, Hamsten A, Schmidt R, Borecki IB, Vartiainen E, Becker DM, Bharadwaj D, Mohlke KL, Boehnke M, van Duijn CM, Sanghera DK, Teumer A, Zeggini E, Metspalu A, Gasparini P, Ulivi S, Ober C, Toniolo D, Rudan I, Porteous DJ, Ciullo M, Spector TD, Hayward C, Dupuis J, Loos RJF, Wright AF, Chandak GR, Vollenweider P, Shuldiner A, Ridker PM, Rotter JI, Sattar N, Gyllensten U, North KE, Pirastu M, Psaty BM, Weir DR, Laakso M, Gudnason V, Takahashi A, Chambers JC, Kooner JS, Strachan DP, Campbell H, Hirschhorn JN, Perola M, Polašek O, Wilson JF";;"Jul 2015";1435708800;;"Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been. " 9738;"Angiogenesis related genes NOS3, CD14, MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults.";"M. Stathopoulou";"Equipe 10, Team 10";26437765;"BMC medical genetics";"Saleh A, Stathopoulou MG, Dadé S, Ndiaye NC, Azimi-Nezhad M, Murray H, Masson C, Lamont J, Fitzgerald P, Visvikis-Siest S";;"Oct 2015";1443657600;;"Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. The aim was to assess the genetic connections between the angiogenesis-related NOS3, CD14, MMP3, IL4R, IL4 genes and VEGF expression and plasma levels." 9736;"Beyond genome-wide association studies: identifying variants using -omics approaches.";"M. Stathopoulou";"Equipe 10, Team 10";29750611;"Personalized medicine";"Visvikis-Siest S, Stathopoulou MG";;"Nov 2015";1446336000;; 9734;"Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.";"M. Stathopoulou";"Equipe 10, Team 10";26910538;"PLoS genetics";"Choi SH, Ruggiero D, Sorice R, Song C, Nutile T, Vernon Smith A, Concas MP, Traglia M, Barbieri C, Ndiaye NC, Stathopoulou MG, Lagou V, Maestrale GB, Sala C, Debette S, Kovacs P, Lind L, Lamont J, Fitzgerald P, Tönjes A, Gudnason V, Toniolo D, Pirastu M, Bellenguez C, Vasan RS, Ingelsson E, Leutenegger AL, Johnson AD, DeStefano AL, Visvikis-Siest S, Seshadri S, Ciullo M";;"Feb 2016";1454284800;;"Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases." 9732;"Plasma VEGF-related polymorphisms are implied in autoimmune thyroid diseases.";"M. Stathopoulou";"Equipe 10, Team 10";26955881;Autoimmunity;"Zaaber I, Rancier M, Stathopoulou MG, Saleh A, Marmouch H, Masson C, Murray H, Kurth MJ, Lamont J, Fitzgerald P, Mahjoub S, Said K, Bel Hadj Jrad Tensaout B, Mestiri S, Visvikis-Siest S";;"06 2016";1464739200;;"Autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto thyroiditis (HT), are complex multifactorial diseases. Vascular endothelial growth factor (VEGF) is implicated in various inflammatory diseases, especially autoimmune diseases. Our aim was to elucidate the relationships between plasma VEGF levels and four genome-wide association study-identified single nucleotide polymorphisms (SNPs) related to VEGF with AITD in Tunisian patients. A total of 364 healthy controls and 389 patients with AITD were genotyped for the SNPs rs6921438, rs4416670, rs6993770 and rs10738760. Levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF after a period of six months of treatment. We found that the minor alleles of rs10738760 and rs6921438 are associated with the presence of GD. A allele of rs10738760 polymorphism is associated with increased plasma levels of free tri-iodothyronin (FT3) while no relationship was found with circulating VEGF plasma levels after six months of treatment. We also showed that the T allele of rs4416670 polymorphism was associated with increased risk of hyperthyroidism in patients treated for six months, independently of their initial diagnosis. There was no significant association between the SNPs and the risk for HT compared with controls. This study shows that AITD are influenced by 3 SNPs linked to VEGF circulating levels. Whereas rs10738760 appeared specific to GD and FT3 production after six months of treatment, rs6921438 and rs4416670 were implicated in the risk for GD. This study opens new ways to test pharmacogenomics concepts in the future especially in GD in which recurrence prognosis is still challenging." 9730;"A century of trends in adult human height.";"M. Stathopoulou";"Team 10, Equipe 10";27458798;eLife;" ";;"07 2016";1467331200;;"Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries." 9728;"Pro- and anti-angiogenic VEGF mRNAs in autoimmune thyroid diseases.";"M. Stathopoulou";"Equipe 10, Team 10";27494076;Autoimmunity;"Rancier M, Zaaber I, Stathopoulou MG, Chatelin J, Saleh A, Marmouch H, El Shamieh S, Masson C, Murray H, Lamont J, Fitzgerald P, Mahjoub S, Said K, Tensaout BB, Mestiri S, Visvikis-Siest S";;"09 2016";1472688000;;"The aim of this study was to assess the relationships between five different splice isoforms of VEGF mRNA and its plasma levels in individuals treated for autoimmune thyroid diseases (AITD); mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT). In a population from Tunisia, levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF and VEGF mRNA isoforms after a period of 6 months of patients' treatment. Plasma VEGF was measured in 110 AITD patients (21 GD and 89 HT patients). VEGF isoforms (VEGF121, VEGF165, VEGF145 and VEGF189 pro-angiogenic isoforms and VEGF165b anti-angiogenic isoform) in peripheral blood mononuclear cells were quantified in 71 patients (20 GD and 51 HT patients) and 86 healthy controls. Decreased levels of VEGF189 mRNA were observed in AITD compared to controls. VEGF165 was increased in GD patients compared to controls and the VEGF165b was increased in HT patients compared to GD. We observed increased levels of VEGF165b in hypothyroid AITD patients after treatment. We have also shown that the VEGF145 isoform levels were determined by FT4 in all patients and by the thyroid status after 6 months of treatment only in HT patients. An association was observed for VEGF165 mRNA levels with anti-TPO antibodies in all patients. Finally, FT4 was associated with VEGF plasma levels but only in healthy controls. In conclusion, this descriptive study highlights the specificity of VEGF mRNA isoforms in AITD, a fact underlining the need for novel clinical trials and the development of personalised theranostic approaches." 9726;"Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1 million participants.";"M. Stathopoulou";"Team 10, Equipe 10";27863813;"Lancet (London, England)";" ";;"01 2017";1483228800;;"Raised blood pressure is an important risk factor for cardiovascular diseases and chronic kidney disease. We estimated worldwide trends in mean systolic and mean diastolic blood pressure, and the prevalence of, and number of people with, raised blood pressure, defined as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher." 9724;"VEGF, the underlying factor for metabolic syndrome; fact or fiction?";"M. Stathopoulou";"Equipe 10, Team 10";28040466;"Diabetes & metabolic syndrome";"Mazidi M, Rezaie P, Kengne AP, Stathopoulou MG, Azimi-Nezhad M, Siest S";;"Nov 2017";1509494400;;"Metabolic syndrome (MetS) is currently diagnosed by the co-presence of at least three of the five following abnormalities: abdominal obesity, dysglycaemia, elevated serum triglycerides, low high-density cholesterol (HDL) and finally elevated blood pressure. Metabolic syndrome increases the risk of developing cardiovascular disease and diabetes. This review is on the associations between MetS and vascular endothelial growth factor (VEGF). VEGF induces migration and proliferation of endothelial cells (ECs), increases vascular permeability and has a role in tumor growth, adipose tissue expansion, age-related macular degeneration and diabetic retinopathy. Circulating levels of VEGFs are elevated in obese individuals and it has also been suggested that VEGF is secreted from adipose tissues, especially from intra-abdominal adipose tissue. There is abundant evidence to support that poor glycemic control in diabetic patients is associated with increased plasma VEGF, which in turn may cause hypertension and several vascular complications in diabetic patients. Circulating VEGF levels are increased in children and young adults with type 1 diabetes mellitus and middle-aged diabetic patients with proliferative retinopathy. It has been revealed that plasma VEGF increases in patients with hyperlipidemia and may trigger the development of atherosclerosis. It can be concluded that there is a positive association between VEGF and components of MetS. Because of the importance of this relationship, more investigations are needed in this field." 9722;"Pharmacogenomic Challenges in Cardiovascular Diseases: Examples of Drugs and Considerations for Future Integration in Clinical Practice.";"M. Stathopoulou";"Equipe 10, Team 10";28117005;"Current pharmaceutical biotechnology";"Chatelin J, Stathopoulou MG, Arguinano AA, Xie T, Visvikis-Siest S";;"Jan 2017";1483228800;;"Even if cardiovascular disease (CVD) drugs are supported by high level proofs, the results of CVD treatment present great disparities: there are still patients dying with supposed optimal treatment, patients facing adverse events and CVD remains the primary cause of death in the world. Pharmacogenomics is the basis of personalisation of the treatment able to allow higher medication success rates. In this review, we will present detailed examples of CVD drugs to highlight the complexity of this challenging field and we will discuss novel concepts that should be considered for a fastest integration of pharmacogenomics in clinical practice of CVD. Areas Covered: The complexity of pharmacogenetics and pharmacogenomics of CVD drugs are presented though examples of medications such as statins, with a focus on their effectiveness and adverse effects. Expert Opinion: The application of personalised medicine in the CVD medical practice requires the study of human genome with regard to drugs pharmacokinetics, pharmacodynamics, interactions and tolerance profile. The existing state -of-the-art of CVD drugs gives hopes for a future revolution in the drug development that will maximise cardiovascular patients benefit while decreasing their risks for adverse effects. Article Highlights Box: • Coronary heart disease (CHD) remains the first cause of death worldwide. • Cardiovascular treatment has a significant percentage of insufficient efficacy, poor tolerance and compliance. • Predicting the response to therapy while diminishing the side effects is the basis of personalised medicine; pharmacogenomics is leading towards this direction. • The response to CVD therapy and side effects are in the heart of CVD pharmacogenomics and significant progress has been noted. • The application of pharmacogenomics in the CVD medical practice is facing many methodological, technical, ethical, behavioral and financial issues, while cost-effectiveness is the main prerequisite. • The consideration of gene × gene × environment interactions and the inclusion of ""omics"" data in pharmacogenomic studies of CVD drugs will facilitate the generation of reliable results and will promote tailored treatments and new strategies of drug research and development." 9720;"8th Santorini Conference: Systems medicine and personalized health and therapy, Santorini, Greece, 3-5 October 2016.";"M. Stathopoulou";"Equipe 10, Team 10";28475488;"Drug metabolism and personalized therapy";"Visvikis-Siest S, Aldasoro Arguinano AA, Stathopoulou M, Xie T, Petrelis A, Weryha G, Froguel P, Meier-Abt P, Meyer UA, Mlakar V, Ansari M, Papassotiropoulos A, Dedoussis G, Pan B, Bühlmann RP, Noyer-Weidner M, Dietrich PY, Van Schaik R, Innocenti F, März W, Bekris LM, Deloukas P";;"05 2017";1493596800;; 9718;"TREM-1 SNP rs2234246 regulates TREM-1 protein and mRNA levels and is associated with plasma levels of L-selectin.";"M. Stathopoulou";"Equipe 10, Team 10";28771614;"PloS one";"Aldasoro Arguinano AA, Dadé S, Stathopoulou M, Derive M, Coumba Ndiaye N, Xie T, Masson C, Gibot S, Visvikis-Siest S";;"Jan 2017";1483228800;;"High levels of TREM-1 are associated with cardiovascular and inflammatory diseases risks and the most recent studies have showed that TREM-1 deletion or blockade is associated with up to 60% reduction of the development of atherosclerosis. So far, it is unknown whether the levels of TREM-1 protein are genetically regulated. Moreover, TREM family receptors have been suggested to regulate the cellular adhesion process. The goal of this study was to investigate whether polymorphisms within TREM-1 are regulating the variants of serum TREM-1 levels and the expression levels of their mRNA. Furthermore, we aimed to point out associations between polymorphisms on TREM-1 and blood levels of selectins. Among the 10 SNPs studied, the minor allele T of rs2234246, was associated with increased sTREM-1 in the discovery population (p-value = 0.003), explaining 33% of its variance, and with increased levels of mRNA (p-value = 0.007). The same allele was associated with increased soluble L-selectin levels (p-value = 0.011). The higher levels of sTREM-1 and L-selectin were confirmed in the replication population (p-value = 0.0007 and p-value = 0.018 respectively). We demonstrated for the first time one SNP on TREM-1, affecting its expression levels. These novel results, support the hypothesis that TREM-1 affects monocytes extravasation and accumulation processes leading to atherogenesis and atherosclerotic plaque progression, possibly through increased inflammation and subsequent higher expression of sL-selectin." 9716;"Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.";"M. Stathopoulou";"Team 10, Equipe 10";29029897;"Lancet (London, England)";" ";;"Dec 2017";1512086400;;"Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults." 9714;"A transnational collaborative network dedicated to the study and applications of the vascular endothelial growth factor-A in medical practice: the VEGF Consortium.";"M. Stathopoulou";"Equipe 10, Team 10";29087954;"Clinical chemistry and laboratory medicine";"Stathopoulou MG, Xie T, Ruggiero D, Chatelin J, Rancier M, Weryha G, Kurth MJ, Aldasoro Arguinano AA, Gorenjak V, Petrelis AM, Dagher G, Dedoussis G, Deloukas P, Lamont J, Marc J, Simmaco M, Schaik RHNV, Innocenti F, Merlin JL, Schneider J, Alizadeh BZ, Ciullo M, Seshadri S, Visvikis-Siest S, ";;"03 2018";1519862400;; 9712;"The future of telomere length in personalized medicine.";"M. Stathopoulou";"Equipe 10, Team 10";29293454;"Frontiers in bioscience (Landmark edition)";"Gorenjak V, Akbar S, Stathopoulou MG, Visvikis-Siest S";;"03 2018";1519862400;;"Telomere length has been subject of studies for many decades, aiming to elucidate its role in physiological processes, in process of aging and in diverse pathologies. Yet today, there is still no ""big title"" discovery that would lead to a practical use of telomeres as a reliable biomarker or target for a new drug. However, therapies for chronic disease patients are being tested and companies are already offering commercial tests for telomere length measurement. The strong genetic heritability of telomeres is opening the place for pharmacogenomics researches that could promote the personalized treatment of diverse diseases. In this article, we present the recent knowledge of telomeres genetic determination obtained by genome-wide association studies (GWAS), important biomarkers related to telomere length and review the possibilities of telomere's practical implementation in the medical treatment of diverse diseases and as a potential biomarker in personalized medicine. Furthermore, we summarise commercial offers of telomere length measurements available and we discuss the actions that should be taken to make steps forward into final application of the accumulated knowledge into practical use." 9710;"Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: a pooled analysis of 1018 population-based measurement studies with 88.6 million participants.";"M. Stathopoulou";"Team 10, Equipe 10";29579276;"International journal of epidemiology";" ";;"Jun 2018";1527811200;;"Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure." 9708;"The polymorphism rs6918289 located in the downstream region of the TREM2 gene is associated with TNF-α levels and IMT-F.";"M. Stathopoulou";"Equipe 10, Team 10";29740051;"Scientific reports";"Gorenjak V, Aldasoro Arguinano AA, Dadé S, Stathopoulou MG, Vance DR, Masson C, Visvikis-Siest S";;"05 2018";1525132800;;"Triggering receptor expressed on myeloid cells 2 (TREM2) is known for its anti-inflammatory properties during the immune response, and influences negatively on TNF-α expression levels. Genetic epidemiology studies have identified polymorphisms located in the TREM2 gene associated with neurodegenerative and chronic inflammatory diseases. TREM2 levels have been observed to affect plasma levels of TNF-α and plaque stability in symptomatic and asymptomatic patients with carotid stenosis. In this study, we investigated polymorphisms located in the TREM2 gene region and association with TNF-α levels and the intima media thickness of the femoral artery. The discovery population from the STANISLAS Family Study comprised of 809 individuals, whereas the replication population utilized an independent cohort of French origin (n = 916). Our results suggest that the minor allele (T) of SNP rs6918289 is positively associated with elevated plasma levels of TNF-α in discovery and replication populations (P = 0.0026, SE = 0.04 and P = 0.023, SE = 0.09, respectively), including femoral artery thickness in the discovery cohort (P = 0.026, SE = 0.009). Results indicate that rs6918289 may be considered as a risk factor for inflammatory diseases and could be used in stratified medicine with patients diagnosed with chronic inflammatory-related conditions, such as atherosclerosis." 9706;"Epistatic interaction of apolipoprotein E and lipolysis-stimulated lipoprotein receptor genetic variants is associated with Alzheimer's disease.";"M. Stathopoulou";"Equipe 10, Team 10";29858039;"Neurobiology of aging";"Xie T, Akbar S, Stathopoulou MG, Oster T, Masson C, Yen FT, Visvikis-Siest S";;"09 2018";1535760000;;"The ε4 allele of the apolipoprotein E (APOE) gene common polymorphism is the strongest genetic risk factor for Alzheimer's disease (AD). Human APOE gene is located on chromosome 19q13.1, a region linked to AD that also includes the LSR gene, which encodes the lipolysis-stimulated lipoprotein receptor (LSR). As an APOE receptor, LSR is involved in the regulation of lipid homeostasis in both periphery and brain. This study aimed to determine the potential interactions between 2 LSR genetic variants, rs34259399 and rs916147, and the APOE common polymorphism in 142 AD subjects (mean age: 73.16 ± 8.50 years) and 63 controls (mean age: 70.41 ± 8.49 years). A significant epistatic interaction was observed between APOE and both LSR variants, rs34259399 (beta = -0.95; p = 2 × 10) and rs916147 (beta = -0.83; p = 6.8 × 10). Interestingly, the interaction of LSR polymorphisms with APOE non-ε4 alleles increased AD risk. This indicates the existence of complex molecular interactions between these 2 neighboring genes involved in the pathogenesis of AD, which merits further investigation." 9704;"The Relationship Between Vascular Endothelial Growth Factor Cis- and Trans-Acting Genetic Variants and Metabolic Syndrome.";"M. Stathopoulou";"Equipe 10, Team 10";29891039;"The American journal of the medical sciences";"Azimi-Nezhad M, Mirhafez SR, Stathopoulou MG, Murray H, Ndiaye NC, Bahrami A, Varasteh A, Avan A, Bonnefond A, Rancier M, Mehrad-Majd H, Herbeth B, Lamont J, Fitzgerald P, Ferns GA, Visvikis-Siest S, Ghayour-Mobarhan M";;"06 2018";1527811200;;"We have investigated the association between 4 cis- and trans-genetic variants (rs6921438, rs4416670, rs6993770 and rs10738760) of the vascular endothelial growth factor (VEGF) gene and metabolic syndrome (MetS) and its individual components in an Iranian population." 9702;"Personalised Medicine: The Odyssey from Hope to Practice.";"M. Stathopoulou";"Equipe 10, Team 10";30248964;"Journal of personalized medicine";"Visvikis-Siest S, Gorenjak V, Stathopoulou MG";;"Sep 2018";1535760000;;"In this endeavour, inspired by the Odyssey, we aim to embark with the reader on a journey on a ship from Troy to Ithaca, coursing through the history of the momentous events and achievements that paved the way for personalised medicine. We will set sail amidst important genetic discoveries, beginning with the discovery of the first human genome, and voyage through the projects that contributed to the progress of pharmacogenomic studies. Concurrently, we will propose methods to overcome the obstacles that are slowing the potential full implementation of accumulated knowledge into everyday practice. This journey aims to reflect on the frontiers of current genetic knowledge and the practical use of this knowledge in preventive, diagnostic and pharmacogenomic approaches to directly impact the socio-economic aspects of public health." 9700;"Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.";"M. Stathopoulou";"Equipe 10, Team 10";30388399;"American journal of human genetics";"Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, Van der Most PJ, Tanaka T, Naderi E, Rose LM, Wu Y, Karlsson R, Barbalic M, Lin H, Pool R, Zhu G, Macé A, Sidore C, Trompet S, Mangino M, Sabater-Lleal M, Kemp JP, Abbasi A, Kacprowski T, Verweij N, Smith AV, Huang T, Marzi C, Feitosa MF, Lohman KK, Kleber ME, Milaneschi Y, Mueller C, Huq M, Vlachopoulou E, Lyytikäinen LP, Oldmeadow C, Deelen J, Perola M, Zhao JH, Feenstra B, , Amini M, , Lahti J, Schraut KE, Fornage M, Suktitipat B, Chen WM, Li X, Nutile T, Malerba G, Luan J, Bak T, Schork N, Del Greco M F, Thiering E, Mahajan A, Marioni RE, Mihailov E, Eriksson J, Ozel AB, Zhang W, Nethander M, Cheng YC, Aslibekyan S, Ang W, Gandin I, Yengo L, Portas L, Kooperberg C, Hofer E, Rajan KB, Schurmann C, den Hollander W, Ahluwalia TS, Zhao J, Draisma HHM, Ford I, Timpson N, Teumer A, Huang H, Wahl S, Liu Y, Huang J, Uh HW, Geller F, Joshi PK, Yanek LR, Trabetti E, Lehne B, Vozzi D, Verbanck M, Biino G, Saba Y, Meulenbelt I, O'Connell JR, Laakso M, Giulianini F, Magnusson PKE, Ballantyne CM, Hottenga JJ, Montgomery GW, Rivadineira F, Rueedi R, Steri M, Herzig KH, Stott DJ, Menni C, Frånberg M, St Pourcain B, Felix SB, Pers TH, Bakker SJL, Kraft P, Peters A, Vaidya D, Delgado G, Smit JH, Großmann V, Sinisalo J, Seppälä I, Williams SR, Holliday EG, Moed M, Langenberg C, Räikkönen K, Ding J, Campbell H, Sale MM, Chen YI, James AL, Ruggiero D, Soranzo N, Hartman CA, Smith EN, Berenson GS, Fuchsberger C, Hernandez D, Tiesler CMT, Giedraitis V, Liewald D, Fischer K, Mellström D, Larsson A, Wang Y, Scott WR, Lorentzon M, Beilby J, Ryan KA, Pennell CE, Vuckovic D, Balkau B, Concas MP, Schmidt R, Mendes de Leon CF, Bottinger EP, Kloppenburg M, Paternoster L, Boehnke M, Musk AW, Willemsen G, Evans DM, Madden PAF, Kähönen M, Kutalik Z, Zoledziewska M, Karhunen V, Kritchevsky SB, Sattar N, Lachance G, Clarke R, Harris TB, Raitakari OT, Attia JR, van Heemst D, Kajantie E, Sorice R, Gambaro G, Scott RA, Hicks AA, Ferrucci L, Standl M, Lindgren CM, Starr JM, Karlsson M, Lind L, Li JZ, Chambers JC, Mori TA, de Geus EJCN, Heath AC, Martin NG, Auvinen J, Buckley BM, de Craen AJM, Waldenberger M, Strauch K, Meitinger T, Scott RJ, McEvoy M, Beekman M, Bombieri C, Ridker PM, Mohlke KL, Pedersen NL, Morrison AC, Boomsma DI, Whitfield JB, Strachan DP, Hofman A, Vollenweider P, Cucca F, Jarvelin MR, Jukema JW, Spector TD, Hamsten A, Zeller T, Uitterlinden AG, Nauck M, Gudnason V, Qi L, Grallert H, Borecki IB, Rotter JI, März W, Wild PS, Lokki ML, Boyle M, Salomaa V, Melbye M, Eriksson JG, Wilson JF, Penninx BWJH, Becker DM, Worrall BB, Gibson G, Krauss RM, Ciullo M, Zaza G, Wareham NJ, Oldehinkel AJ, Palmer LJ, Murray SS, Pramstaller PP, Bandinelli S, Heinrich J, Ingelsson E, Deary IJ, Mägi R, Vandenput L, van der Harst P, Desch KC, Kooner JS, Ohlsson C, Hayward C, Lehtimäki T, Shuldiner AR, Arnett DK, Beilin LJ, Robino A, Froguel P, Pirastu M, Jess T, Koenig W, Loos RJF, Evans DA, Schmidt H, Smith GD, Slagboom PE, Eiriksdottir G, Morris AP, Psaty BM, Tracy RP, Nolte IM, Boerwinkle E, Visvikis-Siest S, Reiner AP, Gross M, Bis JC, Franke L, Franco OH, Benjamin EJ, Chasman DI, Dupuis J, Snieder H, Dehghan A, Alizadeh BZ";;"11 2018";1541030400;;"C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences." 9698;"The 9th Santorini Conference: Systems Medicine, Personalised Health and Therapy. ""The Odyssey from Hope to Practice"", Santorini, Greece, 30 September⁻3 October 2018.";"M. Stathopoulou";"Equipe 10, Team 10";30545130;"Journal of personalized medicine";"Visvikis-Siest S, Gorenjak V, Stathopoulou MG, Petrelis AM, Weryha G, Masson C, Hiegel B, Kumar S, Barouki R, Boerwinkle E, Dagher G, Deloukas P, Innocenti F, Lamont J, Marschler M, Meyer H, Meyer UA, Nofziger C, Paulmichl M, Vacher C, Webster L";;"12 2018";1543622400;;"The 9th traditional biannual conference on Systems Medicine, Personalised Health & Therapy-""The Odyssey from Hope to Practice"", inspired by the Greek mythology, was a call to search for practical solutions in cardio-metabolic diseases and cancer, to resolve and overcome the obstacles in modern medicine by creating more interactions among disciplines, as well as between academic and industrial research, directed towards an effective 'roadmap' for personalised health and therapy. The 9th Santorini Conference, under the Presidency of Sofia Siest, the director of the INSERM U1122; IGE-PCV (www.u1122.inserm.fr), University of Lorraine, France, offered a rich and innovative scientific program. It gathered 34 worldwide distinguished speakers, who shared their passion for personalised medicine with 160 attendees in nine specific sessions on the following topics: First day: The Odyssey from hope to practice: Personalised medicine-landmarks and challenges Second day: Diseases to therapeutics-genotype to phenotype an ""-OMICS"" approach: focus on personalised therapy and precision medicine Third day: Gene-environment interactions and pharmacovigilance: a pharmacogenetics approach for deciphering disease ""bench to clinic to reality"" Fourth day: Pharmacogenomics to drug discovery: a big data approach and focus on clinical data and clinical practice. In this article we present the topics shared among the participants of the conference and we highlight the key messages." 9696;"Association of TLR4 Polymorphisms, Expression, and Vitamin D with Helicobacter pylori Infection.";"M. Stathopoulou";"Equipe 10, Team 10";30641993;"Journal of personalized medicine";"Assaad S, Costanian C, Jaffal L, Tannous F, Stathopoulou MG, El Shamieh S";;"01 2019";1546300800;;"Helicobacter pylori () infection is the strongest recognized risk factor for gastric adenocarcinoma. Since previous observations have shown that polymorphisms in innate immune system genes, as well as vitamin D (VitD) levels, could modify the risk of infection with (), we analyzed the relation between single nucleotide polymorphisms (SNPs) in (, , ) , and VitD levels with infection. A case-control study on four hundred sixty Lebanese individuals was conducted. Eleven SNPs in total were genotyped and gene expression analysis using real-time PCR was performed in white blood cells of a subsample of eight individuals. A total of 49% of the participants were affected. Although no direct association was found between the SNPs and infection, rs4986790G>A and rs4986791T>C in were negatively associated with VitD levels (β = -0.371, = 5 × 10 and β = -0.4, = 2 × 10, respectively), which was negatively associated with infection (OR = 0.01, < 1 × 10). expression was 3× lower in individuals with compared with non-infected ( = 0.01). polymorphisms, expression, and VitD could be implicated in infection and further development of gastric adenocarcinoma." 9694;"Rising rural body-mass index is the main driver of the global obesity epidemic in adults.";"M. Stathopoulou";"Team 10, Equipe 10";31068725;Nature;" ";;"05 2019";1556668800;;"Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities. This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity. Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories." 9692;"National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio: a pooled analysis of 458 population-based studies in Asian and Western countries.";"M. Stathopoulou";"Team 10, Equipe 10";31321439;"International journal of epidemiology";" ";;"02 2020";1580515200;;"Although high-density lipoprotein (HDL) and non-HDL cholesterol have opposite associations with coronary heart disease, multi-country reports of lipid trends only use total cholesterol (TC). Our aim was to compare trends in total, HDL and non-HDL cholesterol and the total-to-HDL cholesterol ratio in Asian and Western countries." 9690;"Peripheral blood mononuclear cells extracts VEGF protein levels and VEGF mRNA: Associations with inflammatory molecules in a healthy population.";"M. Stathopoulou";"Equipe 10, Team 10";31419243;"PloS one";"Gorenjak V, Vance DR, Petrelis AM, Stathopoulou MG, Dadé S, El Shamieh S, Murray H, Masson C, Lamont J, Fitzgerald P, Visvikis-Siest S";;"Jan 2019";1546300800;;"Vascular endothelial growth factor (VEGF) is a signal protein, implicated in various physiological and pathophysiological processes together with other common inflammatory biomarkers. However, their associations have not yet been fully elucidated. In the present study, we investigated associations between VEGF and four specific VEGF mRNA isoforms with levels of 11 inflammation molecules, derived from peripheral blood mononuclear cells (PBMCs) extracts." 9688;"Telomere length determinants in childhood.";"M. Stathopoulou";"Equipe 10, Team 10";31465289;"Clinical chemistry and laboratory medicine";"Gorenjak V, Petrelis AM, Stathopoulou MG, Visvikis-Siest S";;"01 2020";1577836800;;"Telomere length (TL) is a dynamic marker that reflects genetic predispositions together with the environmental conditions of an individual. It is closely related to longevity and a number of pathological conditions. Even though the extent of telomere research in children is limited compared to that of adults, there have been a substantial number of studies providing first insights into child telomere biology and determinants. Recent discoveries revealed evidence that TL is, to a great extent, determined already in childhood and that environmental conditions in adulthood have less impact than first believed. Studies have demonstrated that large inter-individual differences in TL are present among newborns and are determined by diverse factors that influence intrauterine development. The first years of child growth are associated with high cellular turnover, which results in fast shortening of telomeres. The rate of telomere loss becomes stable in early adulthood. In this review article we summarise the existing knowledge on telomere dynamics during the first years of childhood, highlighting the conditions that affect newborn TL. We also warn about the knowledge gaps that should be filled to fully understand the regulation of telomeres, in order to implement them as biomarkers for use in diagnostics or treatment." 9686;"Obesity status modifies the association between rs7556897T>C in the intergenic region SLC19A3-CCL20 and blood pressure in French children.";"M. Stathopoulou";"Equipe 10, Team 10";32238601;"Clinical chemistry and laboratory medicine";"El Shamieh S, Stathopoulou MG, Bonnefond A, Ndiaye NC, Lecoeur C, Meyre D, Dadé S, Chedid P, Salami A, Shahabi P, Dedoussis GV, Froguel P, Visvikis-Siest S";;"10 2020";1601510400;;"Background Growing evidence reports an association between inflammatory markers, obesity and blood pressure (BP). Specifically, the intergenic single nucleotide polymorphism (SNP) rs7556897T > C (MAF = 0.34) located between SLC19A3 and the CCL20 was shown to be associated with chronic inflammatory diseases. In addition, CCL20 expression was found increased in pancreatic islets of obese rodents and human pancreatic β cells under the influence of inflammation. In this study, we hypothesized that SNP rs7556897 could affect BP levels, thus providing a link between inflammation, BP and obesity. Methods BP was measured under supine position with a manual sphygmomanometer; values reported were the means of three readings. We analyzed rs7556897 in 577 normal weight and 689 obese French children. Using real-time polymerase chain reaction (PCR), we quantified CCL20 and SLC19A3 expression in adipose tissue and peripheral blood mononuclear cells (PBMCs) of normal weight and overweight children. Results The rs7556897C allele was negatively associated with diastolic BP in normal weight children (β = -0.012 ± 0.004, p = 0.006) but positively associated in obese children (β = 2.178 ± 0.71, p = 0.002). A significant interaction between rs7556897T > C and the obesity status (obese or normal weight) was detected (β = 3.49, p = 9.79 × 10-5) for BP in a combined population analysis. CCL20 mRNA was only expressed in the adipose tissue of overweight children, and its expression levels were 10.7×  higher in PBMCs of overweight children than normal weight children. Finally, CCL20 mRNA levels were positively associated with rs7556897T > C in PBMCs of 58 normal weight children (β = 0.43, p = 0.002). SLC19A3 was not expressed in PBMCs, and in adipose tissue, it showed same levels of expression in normal weight and overweight children. The gene expression results may highlight a specific involvement of CCL20 via communicating obesity/inflammation pathways that regulate BP. Conclusions Childhood obesity reverses the effect of rs7556897T > C on diastolic BP, possibly via the modulation of CCL20 expression levels." 9684;"Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study.";"M. Stathopoulou";"Team 10, Equipe 10";32397738;"Circulation. Genomic and precision medicine";"Georgakis MK, Malik R, Gill D, Franceschini N, Sudlow CLM, Dichgans M, ";;"06 2020";1590969600;; 9682;"Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model.";"M. Stathopoulou";"Equipe 10, Team 10";32486379;Cells;"Toupance S, Stathopoulou MG, Petrelis AM, Gorenjak V, Labat C, Lai TP, Visvikis-Siest S, Benetos A";;"05 2020";1588291200;;"Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort ( = 0.027 and = 0.025, respectively). These SNPs, both located on the gene, were associated with the LTL/MTL ratio ( = 0.007 and = 0.037, respectively), but not with MTL ( = 0.78 and = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD." 9680;"Repositioning of the global epicentre of non-optimal cholesterol.";"M. Stathopoulou";"Team 10, Equipe 10";32494083;Nature;" ";;"06 2020";1590969600;;"High blood cholesterol is typically considered a feature of wealthy western countries. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular risk-changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world." 9678;"Epigenome-wide association study in healthy individuals identifies significant associations with DNA methylation and PBMC extract VEGF-A concentration.";"M. Stathopoulou";"Equipe 10, Team 10";32503626;"Clinical epigenetics";"Gorenjak V, Vance DR, Dade S, Stathopoulou MG, Doherty L, Xie T, Murray H, Masson C, Lamont J, Fitzgerald P, Visvikis-Siest S";;"06 2020";1590969600;;"Vascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis. It is known for its high heritability (> 60%) and involvement in most common morbidities, which makes it a potentially interesting biomarker. Large GWAS studies have already assessed polymorphisms related to VEGF-A. However, no previous research has provided epigenome-wide insight in regulation of VEGF-A." 9676;"Increased risk of hypercholesterolemia in a French and Lebanese population due to an interaction between rs2569190 in CD14 and gender.";"M. Stathopoulou";"Equipe 10, Team 10";32544432;"Clinica chimica acta; international journal of clinical chemistry";"El Shamieh S, Salami A, Stathopoulou MG, Chedid P, Visvikis-Siest S";;"Oct 2020";1601510400;;"Since identifying gender-specific genetic associations may have a significant impact on public health, we studied the interaction between rs2569190 in CD14 (cluster of differentiation 14) and gender in relation to the lipid traits in two independent populations." 9674;"Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants.";"M. Stathopoulou";"Team 10, Equipe 10";33160572;"Lancet (London, England)";" ";;"11 2020";1604188800;;"Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents." 9672;"Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.";"M. Stathopoulou";"Equipe 10, Team 10";33402679;"Nature communications";"Lagou V, Mägi R, Hottenga JJ, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, Dimas AS, Ulrich A, Zudina L, Gådin JR, Jiang L, Faggian A, Bonnefond A, Fadista J, Stathopoulou MG, Isaacs A, Willems SM, Navarro P, Tanaka T, Jackson AU, Montasser ME, O'Connell JR, Bielak LF, Webster RJ, Saxena R, Stafford JM, Pourcain BS, Timpson NJ, Salo P, Shin SY, Amin N, Smith AV, Li G, Verweij N, Goel A, Ford I, Johnson PCD, Johnson T, Kapur K, Thorleifsson G, Strawbridge RJ, Rasmussen-Torvik LJ, Esko T, Mihailov E, Fall T, Fraser RM, Mahajan A, Kanoni S, Giedraitis V, Kleber ME, Silbernagel G, Meyer J, Müller-Nurasyid M, Ganna A, Sarin AP, Yengo L, Shungin D, Luan J, Horikoshi M, An P, Sanna S, Boettcher Y, Rayner NW, Nolte IM, Zemunik T, Iperen EV, Kovacs P, Hastie ND, Wild SH, McLachlan S, Campbell S, Polasek O, Carlson O, Egan J, Kiess W, Willemsen G, Kuusisto J, Laakso M, Dimitriou M, Hicks AA, Rauramaa R, Bandinelli S, Thorand B, Liu Y, Miljkovic I, Lind L, Doney A, Perola M, Hingorani A, Kivimaki M, Kumari M, Bennett AJ, Groves CJ, Herder C, Koistinen HA, Kinnunen L, Faire U, Bakker SJL, Uusitupa M, Palmer CNA, Jukema JW, Sattar N, Pouta A, Snieder H, Boerwinkle E, Pankow JS, Magnusson PK, Krus U, Scapoli C, de Geus EJCN, Blüher M, Wolffenbuttel BHR, Province MA, Abecasis GR, Meigs JB, Hovingh GK, Lindström J, Wilson JF, Wright AF, Dedoussis GV, Bornstein SR, Schwarz PEH, Tönjes A, Winkelmann BR, Boehm BO, März W, Metspalu A, Price JF, Deloukas P, Körner A, Lakka TA, Keinanen-Kiukaanniemi SM, Saaristo TE, Bergman RN, Tuomilehto J, Wareham NJ, Langenberg C, Männistö S, Franks PW, Hayward C, Vitart V, Kaprio J, Visvikis-Siest S, Balkau B, Altshuler D, Rudan I, Stumvoll M, Campbell H, van Duijn CM, Gieger C, Illig T, Ferrucci L, Pedersen NL, Pramstaller PP, Boehnke M, Frayling TM, Shuldiner AR, Peyser PA, Kardia SLR, Palmer LJ, Penninx BW, Meneton P, Harris TB, Navis G, Harst PV, Smith GD, Forouhi NG, Loos RJF, Salomaa V, Soranzo N, Boomsma DI, Groop L, Tuomi T, Hofman A, Munroe PB, Gudnason V, Siscovick DS, Watkins H, Lecoeur C, Vollenweider P, Franco-Cereceda A, Eriksson P, Jarvelin MR, Stefansson K, Hamsten A, Nicholson G, Karpe F, Dermitzakis ET, Lindgren CM, McCarthy MI, Froguel P, Kaakinen MA, Lyssenko V, Watanabe RM, Ingelsson E, Florez JC, Dupuis J, Barroso I, Morris AP, Prokopenko I, ";;"01 2021";1609459200;;"Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes." 9670;"Genome-wide association study of circulating interleukin 6 levels identifies novel loci.";"M. Stathopoulou";"Equipe 10, Team 10";33517400;"Human molecular genetics";"Ahluwalia TS, Prins BP, Abdollahi M, Armstrong NJ, Aslibekyan S, Bain L, Jefferis B, Baumert J, Beekman M, Ben-Shlomo Y, Bis JC, Mitchell BD, de Geus E, Delgado GE, Marek D, Eriksson J, Kajantie E, Kanoni S, Kemp JP, Lu C, Marioni RE, McLachlan S, Milaneschi Y, Nolte IM, Petrelis AM, Porcu E, Sabater-Lleal M, Naderi E, Seppälä I, Shah T, Singhal G, Standl M, Teumer A, Thalamuthu A, Thiering E, Trompet S, Ballantyne CM, Benjamin EJ, Casas JP, Toben C, Dedoussis G, Deelen J, Durda P, Engmann J, Feitosa MF, Grallert H, Hammarstedt A, Harris SE, Homuth G, Hottenga JJ, Jalkanen S, Jamshidi Y, Jawahar MC, Jess T, Kivimaki M, Kleber ME, Lahti J, Liu Y, Marques-Vidal P, Mellström D, Mooijaart SP, Müller-Nurasyid M, Penninx B, Revez JA, Rossing P, Räikkönen K, Sattar N, Scharnagl H, Sennblad B, Silveira A, Pourcain BS, Timpson NJ, Trollor J, , van Dongen J, Van Heemst D, Visvikis-Siest S, Vollenweider P, Völker U, Waldenberger M, Willemsen G, Zabaneh D, Morris RW, Arnett DK, Baune BT, Boomsma DI, Chang YC, Deary IJ, Deloukas P, Eriksson JG, Evans DM, Ferreira MA, Gaunt T, Gudnason V, Hamsten A, Heinrich J, Hingorani A, Humphries SE, Jukema JW, Koenig W, Kumari M, Kutalik Z, Lawlor DA, Lehtimäki T, März W, Mather KA, Naitza S, Nauck M, Ohlsson C, Price JF, Raitakari O, Rice K, Sachdev PS, Slagboom E, Sørensen TIA, Spector T, Stacey D, Stathopoulou MG, Tanaka T, Wannamethee SG, Whincup P, Rotter JI, Dehghan A, Boerwinkle E, Psaty BM, Snieder H, Alizadeh BZ";;"04 2021";1617235200;;"Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology." 9668;"Effect of Mastiha supplementation on NAFLD: The MAST4HEALTH Randomised, Controlled Trial.";"M. Stathopoulou";"Equipe 10, Team 10";33629536;"Molecular nutrition & food research";"Amerikanou C, Kanoni S, Kaliora AC, Barone A, Bjelan M, D'Auria G, Gioxari A, Gosalbes MJ, Mouchti S, Stathopoulou MG, Soriano B, Stojanoski S, Banerjee R, Halabalaki M, Mikropoulou EV, Kannt A, Lamont J, Llorens C, Marascio F, Marascio M, Roig FJ, Smyrnioudis I, Varlamis I, Visvikis-Siest S, Vukic M, Milic N, Medic-Stojanoska M, Cesarini L, Campolo J, Gastaldelli A, Deloukas P, Trivella MG, Francino MP, Dedoussis GV, ";;"05 2021";1619827200;;"Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with poor therapeutic strategies. Mastiha possesses antioxidant/anti-inflammatory and lipid-lowering properties. The authors investigate the effectiveness of Mastiha as a nonpharmacological intervention in NAFLD." 9662;"Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight.";"M. Stathopoulou";"Team 10, Equipe 10";33685583;eLife;" ";;"Mar 2021";1614556800;;"From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions." 9660;"Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD.";"M. Stathopoulou";"Equipe 10, Team 10";34025683;"Frontiers in immunology";"Kanoni S, Kumar S, Amerikanou C, Kurth MJ, Stathopoulou MG, Bourgeois S, Masson C, Kannt A, Cesarini L, Kontoe MS, Milanović M, Roig FJ, Beribaka M, Campolo J, Jiménez-Hernández N, Milošević N, Llorens C, Smyrnioudis I, Francino MP, Milić N, Kaliora AC, Trivella MG, Ruddock MW, Medić-Stojanoska M, Gastaldelli A, Lamont J, Deloukas P, Dedoussis GV, Visvikis-Siest S";;"Jan 2021";1609459200;;"Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene ( associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene ( and the sphingolipid transporter-1 gene () associated with hemoglobin levels, the transforming growth factor-beta-induced gene () and the micro-RNA 129-1 ( associated with IL-6 and the granzyme B gene () associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD." 9658;"Epigenome-wide association study detects a novel loci associated with central obesity in healthy subjects.";"M. Stathopoulou";"Equipe 10, Team 10";34556110;"BMC medical genomics";"Xie T, Gorenjak V, Stathopoulou MG, Dadé S, Marouli E, Masson C, Murray H, Lamont J, Fitzgerald P, Deloukas P, Visvikis-Siest S";;"09 2021";1630454400;;"Central obesity is a condition that poses a significant risk to global health and requires the employment of novel scientific methods for exploration. The objective of this study is to use DNA methylation analysis to detect DNA methylation loci linked to obesity phenotypes, i.e. waist circumference and waist-to-hip ratio adjusted for BMI." 9656;"A genetic determinant of VEGF-A levels is associated with telomere attrition.";"M. Stathopoulou";"Equipe 10, Team 10";34661551;Aging;"Gorenjak V, Petrelis AM, Stathopoulou MG, Toupance S, Kumar S, Labat C, Masson C, Murray H, Lamont J, Fitzgerald P, Benetos A, Visvikis-Siest S, ";;"10 2021";1633046400;;"Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, β=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications." 9654;"Prediction of coronary heart disease incidence in a general male population by circulating non-coding small RNA sRNY1-5p in a nested case-control study.";"C. Mauduit, M. Stathopoulou, M. Trabucchi, M. Benahmed, V. Grandjean";"Equipe 10, Team 10";33469068;"Scientific reports";"Costa VL, Ruidavets JB, Bongard V, Perret B, Repetto E, Stathopoulou MG, Serra F, Benahmed M, Mauduit C, Grandjean V, Ferrières J, Martinez LO, Trabucchi M";;"01 2021";1609459200;;"During the development of atherosclerotic lesion, s-RNYs (small RNAs of about 24/34 nucleotides) are derived by the processing of long Ro-associated non-coding RNAs (RNYs) in macrophages. The levels of serum s-RNYs have been found significantly upregulated in patients with coronary heart disease (CHD) compared to age-matched CHD-free individuals. The present study aimed to examine the predictive value of serum s-RNYs for CHD events in the general male population. Within the frame of nested-case-control study, the GENES study, we measured the absolute expression of a RNY-derived small RNA, the s-RNY1-5p, in the serum of individuals (without CHD at baseline) who encountered a CHD event within 12 years of follow-up (n = 30) (Cases) and compared them to individuals who remained event-free (Controls) (n = 30). The expression of s-RNY1-5p in serum was significantly upregulated in Cases compared to Controls (p = 0.027). The proportion of CHD event-free was significantly higher among individuals with serum s-RNY1-5p below the median value (631 molecules/mL). In a multivariable model adjusted for age, smoking, hypertension, diabetes and dyslipidemia, the risk of CHD events increased more than fourfold in individuals with serum s-RNY1-5p above the median value (HR, 4.36; 95% CI 1.22-15.60). A positive association with CHD events was also observed when considering s-RNY1-5p as a continuous variable (p = 0.022). Based on our results, we conclude that serum s-RNY1-5p is an independent predictor of CHD events in a general male population and might be a relevant biomarker for early detection of cardiovascular diseases." 9652;"Systemic CLIP-seq analysis and game theory approach to model microRNA mode of binding.";"C. Mauduit, M. Stathopoulou, M. Trabucchi, M. Benahmed, V. Grandjean";"Equipe 10, Team 10";33823551;"Nucleic acids research";"Serra F, Bottini S, Pratella D, Stathopoulou MG, Sebille W, El-Hami L, Repetto E, Mauduit C, Benahmed M, Grandjean V, Trabucchi M";;"06 2021";1622505600;;"microRNAs (miRNAs) associate with Ago proteins to post-transcriptionally silence gene expression by targeting mRNAs. To characterize the modes of miRNA-binding, we developed a novel computational framework, called optiCLIP, which considers the reproducibility of the identified peaks among replicates based on the peak overlap. We identified 98 999 binding sites for mouse and human miRNAs, from eleven Ago2 CLIP-seq datasets. Clustering the binding preferences, we found heterogeneity of the mode of binding for different miRNAs. Finally, we set up a quantitative model, named miRgame, based on an adaptation of the game theory. We have developed a new algorithm to translate the miRgame into a score that corresponds to a miRNA degree of occupancy for each Ago2 peak. The degree of occupancy summarizes the number of miRNA-binding sites and miRNAs targeting each binding site, and binding energy of each miRNA::RNA heteroduplex in each peak. Ago peaks were stratified accordingly to the degree of occupancy. Target repression correlates with higher score of degree of occupancy and number of miRNA-binding sites within each Ago peak. We validated the biological performance of our new method on miR-155-5p. In conclusion, our data demonstrate that miRNA-binding sites within each Ago2 CLIP-seq peak synergistically interplay to enhance target repression." 9650;"Paternal High-Protein Diet Programs Offspring Insulin Sensitivity in a Sex-Specific Manner.";"M. Stathopoulou, V. Grandjean";"Equipe 10, Team 10";34069853;Biomolecules;"Gong P, Bailbé D, Bianchi L, Pommier G, Liu J, Tolu S, Stathopoulou MG, Portha B, Grandjean V, Movassat J";;"05 2021";1619827200;;"The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity ( < 0.05) and decreased GIIS ( < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood." 9581;"High Prevalence of Acquired Thrombophilia Without Prognosis Value in Patients With Coronavirus Disease 2019.";"E. Ferrari, J. Contenti";"Equipe 09, Team 09, Equipe 05, Team 05";32972320;"Journal of the American Heart Association";"Ferrari E, Sartre B, Squara F, Contenti J, Occelli C, Lemoel F, Levraut J, Doyen D, Dellamonica J, Mondain V, Chirio D, Risso K, Cua E, Orban JC, Ichai C, Labbaoui M, Mossaz B, Moceri P, Appert-Flory A, Fischer F, Toulon P";;"11 2020";1604188800;;"Background Recent literature reports a strong thrombotic tendency in patients hospitalized for a coronavirus disease 2019 (COVID-19) infection. This characteristic is unusual and seems specific to COVID-19 infections, especially in their severe form. Viral infections can trigger acquired thrombophilia, which can then lead to thrombotic complications. We investigate for the presence of acquired thrombophilia, which could participate in this phenomenon, and report its prevalence. We also wonder if these thrombophilias participate in the bad prognosis of severe COVID-19 infections. Methods and Results In 89 consecutive patients hospitalized for COVID-19 infection, we found a 20% prevalence of PS (protein S) deficiency and a high (ie, 72%) prevalence of antiphospholipid antibodies: mainly lupus anticoagulant. The presence of PS deficiency or antiphospholipid antibodies was not linked with a prolonged activated partial thromboplastin time nor with D-dimer, fibrinogen, or CRP (C-reactive protein) concentrations. These coagulation abnormalities are also not linked with thrombotic clinical events occurring during hospitalization nor with mortality. Conclusions We assess a high prevalence of positive tests detecting thrombophilia in COVID-19 infections. However, in our series, these acquired thrombophilias are not correlated with the severity of the disease nor with the occurrence of thrombotic events. Albeit the strong thrombotic tendency in COVID-19 infections, the presence of frequent acquired thrombophilia may be part of the inflammation storm of COVID-19 and should not systematically modify our strategy on prophylactic anticoagulant treatment, which is already revised upwards in this pathological condition. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT04335162." 9579;"Characteristics of Cardiac Injury in Critically Ill Patients With Coronavirus Disease 2019.";"E. Ferrari";"Equipe 09, Team 09";33129792;Chest;"Doyen D, Dupland P, Morand L, Fourrier E, Saccheri C, Buscot M, Hyvernat H, Ferrari E, Bernardin G, Cariou A, Mira JP, Jamme M, Dellamonica J, Jozwiak M";;"05 2021";1619827200;;"Cardiac injury has been reported in up to 30% of coronavirus disease 2019 (COVID-19) patients. However, cardiac injury is defined mainly by troponin elevation without description of associated structural abnormalities and its time course has not been studied." 9577;"Active compression versus standard anterior-posterior defibrillation for external cardioversion of atrial fibrillation: A prospective randomized study.";"E. Ferrari";"Equipe 09, Team 09";33181323;"Heart rhythm";"Squara F, Elbaum C, Garret G, Liprandi L, Scarlatti D, Bun SS, Mossaz B, Rocher M, Bateau J, Moceri P, Ferrari E";;"03 2021";1614556800;;"Electrical cardioversion is the first-line rhythm control therapy for symptomatic persistent atrial fibrillation (AF). Contemporary use of biphasic shock waveforms and anterior-posterior positioning of defibrillation electrodes have improved cardioversion efficacy; however, it remains unsuccessful in >10% of patients." 9575;"New Road to Septal Pacing Using Patient-Tailored Fluoroscopy Criteria: A Prospective Comparative Study of the Individualized Left Anterior Oblique Projection With Caudal Angulation.";"E. Ferrari";"Equipe 09, Team 09";33320701;"Circulation. Arrhythmia and electrophysiology";"Squara F, Poulard A, Scarlatti D, Bun SS, Moceri P, Ferrari E";;"12 2020";1606780800;; 9573;"Does Unidirectional Block Exist after a Radiofrequency Line Creation? Insights from Ultra-High-Density Mapping (The UNIBLOCK Study).";"E. Ferrari";"Equipe 09, Team 09";34204104;"Journal of clinical medicine";"Bun SS, Da Costa A, Guichard JB, Khoueiry Z, Squara F, Scarlatti D, Taghji P, Moceri P, Ferrari E";;"Jun 2021";1622505600;;"Whether unidirectional conduction block (UB) can be observed after creation of a radiofrequency (RF) line is still debated. Previous studies reported a prevalence of 9 to 33% of UB, but the assessment was performed using a point-by-point recording across the line. Ultra-high-density (UHD) system may bring some new insights on the exact prevalence of UB." 9571;"Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.";"E. Ferrari";"Equipe 09, Team 09";34363769;"The Lancet. Haematology";"Klok FA, Toenges G, Mavromanoli AC, Barco S, Ageno W, Bouvaist H, Brodmann M, Cuccia C, Couturaud F, Dellas C, Dimopoulos K, Duerschmied D, Empen K, Faggiano P, Ferrari E, Galiè N, Galvani M, Ghuysen A, Giannakoulas G, Huisman MV, Jiménez D, Kozak M, Lang IM, Lankeit M, Meneveau N, Münzel T, Palazzini M, Petris AO, Piovaccari G, Salvi A, Schellong S, Schmidt KH, Verschuren F, Schmidtmann I, Meyer G, Konstantinides SV, ";;"Sep 2021";1630454400;;"Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe." 9569;"Cohort study: ""Outcomes of kidney transplantation in patients with prosthetic heart valves"".";"E. Ferrari";"Equipe 09, Team 09";34425020;"Transplant international : official journal of the European Society for Organ Transplantation";"Ouahmi H, Moceri P, Zorzi K, Albano L, Durand M, Karimi F, Morelon E, Buron F, Le Quintrec M, Pernin V, Ladriere M, Girerd S, Dantal J, Loupy A, Couzi L, Ferrari E, Esnault V, Merville P, Legendre C, Giral M, Sicard A, ";;"Nov 2021";1635724800;;"The number of kidney transplant candidates with prosthetic heart valves (PHVs) is increasing. Yet, outcomes of kidney transplantation in these patients are still unclear. This is the first report of post-transplant outcomes in patients with PHVs at time of kidney transplantation. We conducted a matched cohort study among recipients from the multicentric and prospective DIVAT cohort to compare the outcomes in patients with left-sided PHVs at time of transplantation and a group of recipients without PHV matched according to age, dialysis time, initial disease, pretransplant DSA, diabetes, and cardiovascular events. Of 23 018 patients, 92 patients with PHVs were included and compared to 276 patients without PHV. Delayed graft function and postoperative bleeding occurred more frequently in patients with PHVs. Kidney graft survival was similar between groups. 5-year overall survival was 68.5% in patients with PHV vs. 87.9% in patients without PHV [HR, 2.72 (1.57-4.70), P = 0.0004]. Deaths from infection, endocarditis, and bleeding were more frequent in patients with PHV. Mechanical valves, but not bioprosthetic valves, were independent risk factors for mortality [HR, 2.89 (1.68-4.97), P = 0.0001]. Patients with PHV have high mortality rates after kidney transplantation. These data suggest that mechanical valves, but not biological valves, increase risks of post-transplant mortality." 9567;"Is pulmonary embolism recurrence linked with the severity of the first event? A French retrospective cohort study.";"E. Ferrari";"Equipe 09, Team 09";34588255;"BMJ open";"Ferrari E, Fourrier E, Asarisi F, Heme N, Redjimi N, Berkane N, Labbaoui M, Breittmayer JP, Bun SS, Moceri P, Squara F";;"09 2021";1630454400;;"Severity of a first pulmonary embolism (PE) is sometimes proposed as a criterion for prolonging anticoagulant treatment. However, little evidence supports this idea. We attempted to determine the connection between severity of first PE and the risk of recurrence." 9565;"Value of 3D right ventricular function over 2D assessment in acute pulmonary embolism.";"E. Ferrari";"Equipe 09, Team 09";34672394;"Echocardiography (Mount Kisco, N.Y.)";"Moceri P, Duchateau N, Sartre B, Baudouy D, Squara F, Sermesant M, Ferrari E";;"10 2021";1633046400;;"Pulmonary embolism (PE) is a common life-threatening disease, with mortality related to right ventricular (RV) dysfunction." 9563;"Prevalence and Clinical Characteristics of Patients with Pause-Dependent Atrioventricular Block.";"E. Ferrari";"Equipe 09, Team 09, Equipe 07, Team 07, Equipe 12";35054143;"Journal of clinical medicine";"Bun SS, Asarisi F, Heme N, Squara F, Scarlatti D, Taghji P, Deharo JC, Moceri P, Ferrari E";;"Jan 2022";1640995200;;"In patients with complete atrioventricular block (AVB), the prevalence and clinical characteristics of patients with pause-dependent AVB (PD-AVB) is not known. Our objective was to assess the prevalence of PD-AVB in a population of patients with complete (or high-grade) AVB." 9561;"Radial artery deviation and reimplantation inhibits venous juxta-anastomotic stenosis and increases primary patency of radial-cephalic fistulas for hemodialysis.";"E. Jean-Baptiste, N. Sadaghianloo, R. Hassen-Khodja";"Equipe 09, Team 09";27432198;"Journal of vascular surgery";"Sadaghianloo N, Declemy S, Jean-Baptiste E, Haudebourg P, Robino C, Islam MS, Hassen-Khodja R, Dardik A";;"09 2016";1472688000;;"Although the end cephalic vein-to-side radial artery arteriovenous fistula is the ""gold standard"" procedure for primary hemodialysis access, it is associated with high rates of primary failure because of the development of neointimal hyperplasia and juxta-anastomotic stenosis. We report initial results of a new approach to perform radial-cephalic fistulas, radial artery deviation and reimplantation (RADAR), designed to avoid juxta-anastomotic stenosis." 9559;"Increased Oxidative Stress and Hypoxia Inducible Factor-1 Expression during Arteriovenous Fistula Maturation.";"N. Sadaghianloo, R. Hassen-Khodja";"Equipe 09, Team 09";28163173;"Annals of vascular surgery";"Sadaghianloo N, Yamamoto K, Bai H, Tsuneki M, Protack CD, Hall MR, Declemy S, Hassen-Khodja R, Madri J, Dardik A";;"May 2017";1493596800;;"The poor clinical results that are frequently reported for arteriovenous fistulae (AVF) for hemodialysis are typically due to failure of AVF maturation. We hypothesized that early AVF maturation is associated with generation of reactive oxygen species and activation of the hypoxia-inducible factor-1 (HIF-1) pathway, potentially promoting neointimal hyperplasia. We tested this hypothesis using a previously reported mouse AVF model that recapitulates human AVF maturation." 9557;"Cerebral Infarct Topography and Early Outcome after Surgery for Symptomatic Carotid Stenosis: A Multicentre Study.";"E. Jean-Baptiste, F. Lareyre, R. Hassen-Khodja";"Equipe 09, Team 09";28910807;"Cerebrovascular diseases (Basel, Switzerland)";"Kazandjian C, Settembre N, Lareyre F, Kretz B, Soudry-Faure A, Béjot Y, Malikov S, Hassen-Khodja R, Jean-Baptiste E, Steinmetz E";;"Jan 2017";1483228800;;"Although carotid stenosis can cause both territorial and border-zone (BZ) cerebral infarcts (CI), the influence of CI topography on postoperative complications after surgery remains unclear. We compared early outcomes after endarterectomy on the basis of CI location: territorial (T group) or BZ group." 9555;"Late Outcomes of Carotid Artery Stenting for Radiation Therapy-Induced Carotid Stenosis.";"N. Sadaghianloo, R. Hassen-Khodja";"Equipe 09, Team 09";35012391;"Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists";"Nasr B, Crespy V, Penasse E, Gaudry M, Rosset E, Feugier P, Gouëffic Y, Maurel B, Hostalrich A, Alric P, Sadaghianloo N, Settembre N, Chevallier J, Ben Ahmed S, Gouny P, Steinmetz E, ";;"Jan 2022";1640995200;;"Carotid artery stenting (CAS) appears as a promising alternative treatment to carotid endarterectomy for radiation therapy (RT)-induced carotid stenosis. However, this is based on a poor level of evidence studies (small sample size, primarily single institution reports, few long-term data). The purpose of this study was to report the long-term outcomes of a multicentric series of CAS for RT-induced stenosis." 9553;"Comparison of Cryopreserved Arterial Allografts Versus Heparin-bonded Vascular Grafts in Infragenicular Bypass for Chronic Limb Threatening Ischemia.";"E. Jean-Baptiste, N. Sadaghianloo, R. Hassen-Khodja";"Equipe 09, Team 09";31629123;"Annals of vascular surgery";"Hirth-Voury A, Massiot N, Giauffret E, Behets C, Duprey A, Hassen-Khodja R, Jean-Baptiste E, Sadaghianloo N";;"Apr 2020";1585699200;;"The purpose of this study was to compare cryopreserved arterial allograft (CAA) to heparin-bonded prosthesis (HBP) in infragenicular bypasses for patients with chronic limb-threatening ischemia (CLTI)." 9548;"TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";28912363;"Arteriosclerosis, thrombosis, and vascular biology";"Lareyre F, Clément M, Raffort J, Pohlod S, Patel M, Esposito B, Master L, Finigan A, Vandestienne M, Stergiopulos N, Taleb S, Trachet B, Mallat Z";;"11 2017";1509494400;;"Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture." 9549;"Micro-RNAs in abdominal aortic aneurysms: insights from animal models and relevance to human disease.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";26965051;"Cardiovascular research";"Raffort J, Lareyre F, Clement M, Mallat Z";;"Mar 2016";1457740800;;"Abdominal aortic aneurysm (AAA) is a major health concern and may be associated with high rates of mortality linked to acute complications. Diagnosis and treatment are, respectively, based on imaging and surgical techniques. Drug-based therapies are still mostly ineffective, which highlight a real unmet need. Major pathophysiological mechanisms leading to aneurysm formation involve inflammatory processes, degradation of the extracellular matrix, and loss of smooth muscle cells. However, the precise cellular and molecular pathways are still poorly understood. Recently, microRNAs have emerged as major intracellular players in a wide range of biological processes, and their stability in extracellular medium within microvesicles has led to propose them as mediators of intercellular crosstalk and as potential biomarkers and therapeutic targets in a variety of disease settings. To date, several studies have been performed to address the involvement of micro-RNAs (miRs) in aneurysm formation and complications. Here, we discuss the roles and implications of miRs in animal models and their relevance to human AAA. " 9547;"Regarding 'Diabetes mellitus increases the risk of ruptured abdominal aortic aneurysms'.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";29081238;"Diabetes & vascular disease research";"Raffort J, Lareyre F";;"01 2018";1514764800;;"Abdominal aortic aneurysm (AAA) is a life-threatening disease, associated with high rates of mortality in case of aortic rupture. While the disease is often associated with atherosclerosis and cardiovascular risk factors, the majority of epidemiological studies published so far have highlighted a negative association between diabetes and AAA. However, a recent publication from epidemiological data of the National Health Fund in Poland reported a higher incidence of AAA and rupture in diabetic patients compared to non-diabetics. Here, we discuss issues and methodological considerations hoping to shed light on these unexpected results." 9545;"Angiographic Analysis of Vascular Integrity After Percutaneous Closure Using Prostar XL Device During Transcatheter Aortic Valve Implantation.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";28474978;"Vascular and endovascular surgery";"Lareyre F, Raffort J, Dommerc C, Benhammamia M, Bourlon F, Habib Y, Mialhe C";;"May 2017";1494028800;;"Percutaneous closure devices are commonly used to achieve hemostasis during endovascular procedures including transcatheter aortic valve implantation (TAVI). The aim of our study was to investigate the quality of the percutaneous femoral arterial closure by Prostar XL device using a systematic peroperative angiographic control at the end of TAVI procedure." 9542;"A Fatal Aortic Arch Rupture Due to Descending Necrotizing Mediastinitis in a 24-year-old Woman.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";28618847;"Vascular and endovascular surgery";"Lareyre F, Cohen C, Declemy S, Raffort J, Quintard H";;"Jun 2017";1497657600;;"Descending necrotizing mediastinitis (DNM) is a life-threatening disease which often develops from a purulent infection of the oral cavity and is associated with high rates of mortality. Here we report the case of a young patient who died from an aortic arch rupture in context of DNM developed from an odontogenic infection caused by Prevotella buccae. Based on the current knowledge on this very rare vascular complication, we discuss factors that may have contributed to this fatal issue and future issues to optimize care provided to patients." 9541;"Patterns of Acute Ischemic Strokes After Carotid Endarterectomy and Therapeutic Implications.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";28845749;"Vascular and endovascular surgery";"Lareyre F, Raffort J, Weill C, Marsé C, Suissa L, Chikande J, Hassen-Khodja R, Jean-Baptiste E";;"Aug 2017";1503964800;;"Acute ischemic strokes following surgical treatment of carotid stenosis lead to substantial disability and mortality, and vascular mechanisms underlying their development are not fully elucidated. The goal of this study was to analyze the topographic patterns of acute ischemic stroke following carotid endarterectomy (CEA) on diffusion-weighted and perfusion-weighted magnetic resonance imaging (MRI)." 9539;"Sexual Dysfunction After Abdominal Aortic Aneurysm Surgical Repair: Current Knowledge and Future Directions.";"F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";29292207;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Regnier P, Lareyre F, Hassen-Khodja R, Durand M, Touma J, Raffort J";;"Jan 2018";1514937600;;"Abdominal aortic aneurysm (AAA) represents a major health concern and the curative treatment relies on surgical approaches including open and endovascular aortic repair (EVAR). While epidemiological studies have addressed the major outcomes including mortality and life threatening complications, the impact of surgical intervention on sexual function has been less well described. The aim of this review was to summarise current knowledge on the occurrence of sexual dysfunction in the context of AAA surgical repair and to explore whether surgical techniques could have differential impact." 9535;"High Neutrophil to Lymphocyte Ratio Is Associated With Symptomatic and Ruptured Thoracic Aortic Aneurysm.";"D. Lê, F. Lareyre, J. Raffort";"Equipe 09, Team 09";29334754;Angiology;"Lareyre F, Raffort J, Le D, Chan HL, Houerou TL, Cochennec F, Touma J, Desgranges P";;"Jan 2018";1516147200;;"The predictive value of the neutrophil to lymphocyte ratio (NLR) has been demonstrated in several cardiovascular diseases. The aim of our study was to investigate the association between the preoperative NLR and aneurysm characteristics as well as 30-day postoperative morbidity and mortality in patients with thoracic aortic aneurysm (TAA) undergoing aortic surgical repair. Consecutive patients (n = 75) with TAA were retrospectively included over a 10-year period. Clinical characteristics, aneurysm characteristics, and 30-day postoperative outcome were recorded. The median age of patients was 71 (67-80) years. The median preoperative NLR was 3.5 (2.3-5.8). The proportion of asymptomatic TAA was significantly lower in patients with an NLR > 3.5 compared with those with an NLR < 3.5 (52.6% vs 75.7%; P = .054). The proportion of patients with pain or with ruptured TAA was significantly higher in patients with an NLR > 3.5 compared with those with NLR < 3.5 (42.1% vs 16.2%; P = .022 and 26.3% vs 2.7%; P = .007, respectively). No significant difference was observed regarding the 30-day overall postoperative mortality and morbidity. The preoperative NLR did not correlate with TAA diameter. A high preoperative NLR is significantly associated with symptomatic and ruptured TAA, suggesting a potential interest as a marker and/or player in the disease." 9536;"Deletion of IRF8 (Interferon Regulatory Factor 8)-Dependent Dendritic Cells Abrogates Proatherogenic Adaptive Immunity.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";29436389;"Circulation research";"Clément M, Haddad Y, Raffort J, Lareyre F, Newland SA, Master L, Harrison J, Ozsvar-Kozma M, Bruneval P, Binder CJ, Taleb S, Mallat Z";;"Feb 2018";1518566400;;"Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood." 9531;"Medicine, science and family: find the right mix to make a good cocktail.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31690207;"Acta chirurgica Belgica";"Raffort J, Lareyre F";;"Apr 2020";1585699200;; 9532;"Impaired Autophagy in CD11b Dendritic Cells Expands CD4 Regulatory T Cells and Limits Atherosclerosis in Mice.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31610723;"Circulation research";"Clement M, Raffort J, Lareyre F, Tsiantoulas D, Newland S, Lu Y, Masters L, Harrison J, Saveljeva S, Ma MKL, Ozsvar-Kozma M, Lam BYH, Yeo GSH, Binder CJ, Kaser A, Mallat Z";;"Oct 2019";1571184000;;"Atherosclerosis is a chronic inflammatory disease. Recent studies have shown that dysfunctional autophagy in endothelial cells, smooth muscle cells, and macrophages, plays a detrimental role during atherogenesis, leading to the suggestion that autophagy-stimulating approaches may provide benefit." 9529;"Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30657332;"Circulation. Genomic and precision medicine";"Paige E, Clément M, Lareyre F, Sweeting M, Raffort J, Grenier C, Finigan A, Harrison J, Peters JE, Sun BB, Butterworth AS, Harrison SC, Bown MJ, Lindholt JS, Badger SA, Kullo IJ, Powell J, Norman PE, Scott DJA, Bailey MA, Rose-John S, Danesh J, Freitag DF, Paul DS, Mallat Z";;"02 2019";1548979200;;"The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection." 9527;"High Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio are Associated with Symptomatic Internal Carotid Artery Stenosis.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30268367;"Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association";"Massiot N, Lareyre F, Voury-Pons A, Pelletier Y, Chikande J, Carboni J, Umbdenstock E, Jean-Baptiste E, Hassen-Khodja R, Raffort J";;"Oct 2018";1538352000;;"The neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) have been identified as predictive factors in several cardiovascular diseases but their significance in patients with internal carotid artery (ICA) stenosis is still poorly known. The aim of this study was to determine the clinical significance of the preoperative NLR and PLR in patients with ICA stenosis undergoing carotid endarterectomy." 9524;"Mycotic Aortic Aneurysm and Infected Aortic Graft After Intravesical Bacillus Calmette-Guérin Treatment for Bladder Cancer.";"F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30213242;"Vascular and endovascular surgery";"Lareyre F, Reverso-Meinietti J, Carboni J, Gaudart A, Hassen-Khodja R, Raffort J";;"Sep 2018";1536969600;;"Although intravesical therapy with bacillus Calmette-Guérin (BCG) has proven its efficiency in the treatment of early-stage bladder cancer, infectious complications can occur and mycotic aneurysms represent a rare but life-threatening complication. Here, we report the case of an aortic graft infection in a patient with abdominal aortic aneurysm who received BCG instillations for the treatment of bladder cancer. Based on the current knowledge on this rare vascular complication, we discuss factors that may have contributed to its occurrence and review issues to optimize its management and early detection." 9523;"Endovascular Treatment of Transplant Renal Artery Stenosis: Evaluation of Postoperative Outcomes and Risk Factors for Recurrence.";"E. Jean-Baptiste, F. Lareyre, J. Raffort";"Equipe 09, Team 09";30009628;Angiology;"Roustan FR, Lareyre F, Bentellis I, Haider R, Torrino S, Sedat J, Albano L, Jean-Baptiste E, Raffort J, Durand M";;"Jul 2018";1531785600;;"Angioplasty with or without stenting has become a well-established procedure to treat transplant renal artery stenosis (TRAS). We evaluated our experience on postoperative outcomes following the intervention and identified potential predictive factors of TRAS recurrence. Consecutive patients who underwent endovascular treatment of TRAS were retrospectively reviewed. The study end points were the technical success, 30-day postoperative complications, and the estimated glomerular filtration rate (eGFR). Thirty-two patients underwent endovascular treatment for TRAS. The technical success rate was 96.6%. Complications were observed for 7 (21.9%) patients: 4 had a dissection, 2 a pseudoaneurysm, and 1 (3.1%) patient developed an acute pulmonary edema. The mean eGFR significantly increased at 7 days, 3 months, and 6 months postintervention (43.1, 44.9, and 44.3 vs 33.9 mL/min/1.73 m preoperatively, < .05). The TRAS recurrence was observed in 7 (21.9%) patients. These patients had significantly higher preoperative peak systolic velocity and systolic rise time (5 vs 4 m/s, = .0383 and 103 vs 80 milliseconds, = .0148, respectively). Endovascular treatment of TRAS is associated with high technical success and significant improvement in renal function. Further studies are required to confirm predictive factors of TRAS recurrence following endovascular treatment." 9519;"Reply to ""Inflammation Parameters in Aortic Aneurysm"".";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30270636;Angiology;"Raffort J, Lareyre F";;"Oct 2018";1538438400;; 9520;"Coverage of Accessory Renal Arteries During Endovascular Aortic Aneurysm Repair: What Are the Consequences and the Implications for Clinical Practice?";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";29682989;Angiology;"Lareyre F, Panthier F, Jean-Baptiste E, Hassen-Khodja R, Raffort J";;"Apr 2018";1524528000;;"An accessory renal artery (ARA) represents an anatomic variation which can challenge endovascular aortic aneurysm repair (EVAR). The aim of this review was to summarize the current knowledge on postoperative outcomes following ARA coverage during EVAR. We performed a systematic literature review. The MEDLINE database was searched on September 2017, and 8 relevant studies were included. The frequency of ARA in patients undergoing EVAR varied between 9.5% and 16.2%, and the frequency of ARA coverage varied between 5.2% and 9.4%. Four reports did not observe any significant changes on postoperative renal function, whereas 1 study reported an early transient increase in creatinine after ARA coverage. The occurrence of renal infarct varied from 20% to 84%. Five studies did not observe endoleaks related to ARA coverage, whereas one reported the occurrence of type II endoleaks in 3 of 18 patients who had ARA coverage. No significant change in blood pressure, mortality, and mean length of hospital stay was observed. The ARA coverage can potentially have renal and vascular consequences, but none of them were critical. Further studies may be useful to identify preoperative criteria that may help to choose the most appropriate surgical approach before ARA coverage." 9517;"High Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio are Associated with Symptomatic Internal Carotid Artery Stenosis.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30268367;"Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association";"Massiot N, Lareyre F, Voury-Pons A, Pelletier Y, Chikande J, Carboni J, Umbdenstock E, Jean-Baptiste E, Hassen-Khodja R, Raffort J";;"Oct 2018";1538352000;;"The neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) have been identified as predictive factors in several cardiovascular diseases but their significance in patients with internal carotid artery (ICA) stenosis is still poorly known. The aim of this study was to determine the clinical significance of the preoperative NLR and PLR in patients with ICA stenosis undergoing carotid endarterectomy." 9513;"From bedside to bench: an evaluation of expectations and challenges encountered by young surgeons facing basic science.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30909846;"Acta chirurgica Belgica";"Lareyre F, Allaire E, Raffort J";;"Mar 2019";1553644800;;" The evolution of surgical practice may lead to increasing difficulties for surgeons to perform fundamental research. The aim of this study was to evaluate the expectations and the challenges encountered by young surgeons when starting basic science. A qualitative study was conducted in France. A written questionnaire was anonymously filled by the participants attending to the Master Degree in surgical science. The study included 47 participants (median age: 28 years, 59.6% of men); 37 (78.7%) participants had applied for a grant for their salary and 32 (68.1%) had obtained it. Nine (19.1%) participants had planned to keep their usual clinical activity. The main motivations were the perspective to embark on an academic career (55.3%) and improvement of knowledge in science (38.3%). The main barriers encountered were the lack of time (70.2%), the lack of interest (27.7%), the lack of financial support (23.4%) and administrative difficulties (12.8%). This study identified main barriers that young surgeons have to face when getting involved in basic science underlining the need to improve institutional and financial support to ensure involvement of new generations of surgeons in surgical research." 9511;"Impact of Polar Renal Artery Coverage after Fenestrated Endovascular Aortic Repair for Juxtarenal and Type IV Thoracoabdominal Aortic Aneurysms.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30738151;"Annals of vascular surgery";"Lareyre F, Raffort J, Carboni J, Chikande J, Massiot N, Voury-Pons A, Umbdenstock E, Hassen-Khodja R, Jean-Baptiste E";;"Feb 2019";1549756800;;"Fenestrated endovascular aortic repair (FEVAR) of complex aneurysm can require the coverage of polar renal artery. The aim of this study was to investigate the impact of the procedure on postoperative outcomes in patients with juxtarenal or thoracoabdominal aortic aneurysms." 9512;"Platelet to lymphocyte ratio as a predictive factor of 30-day mortality in patients with acute mesenteric ischemia.";"F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";31314768;"PloS one";"Augène E, Lareyre F, Chikande J, Guidi L, Ballaith A, Bossert JN, Pelletier Y, Caradu C, Hassen-Khodja R, Raffort J";;"Jul 2019";1563408000;;"Acute mesenteric ischemia is associated with high rates of mortality. The aim of this study was to investigate the prognostic value of the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) on 30-day outcomes in patients with acute mesenteric ischemia." 9509;"Translational applications of glucose metabolism in abdominal aortic aneurysm.";"F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";31147135;"Journal of vascular surgery";"Lareyre F, Hassen-Khodja R, Raffort J";;"Jun 2019";1559347200;;"Even though diabetes mellitus is a major risk for cardiovascular events and atherosclerosis-related diseases, it is negatively associated with abdominal aortic aneurysm. The understanding of the mechanisms underlying this negative association could bring new insights to identify prognostic and therapeutic targets. Here we summarize current knowledge of the relationship between glycemic parameters and clinical outcomes of patients with abdominal aortic aneurysm. Translational applications of glucose-targeted approaches as well as their potential interest for clinical practice are discussed in this context." 9505;"Evaluation of the Impact of Sarcopenia in Patients with Acute Mesenteric Ischemia.";"F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";31629853;"Annals of vascular surgery";"Lareyre F, Augène E, Chikande J, Guidi L, Ballaith A, Caradu C, Hassen-Khodja R, Raffort J";;"Oct 2019";1571616000;;"Sarcopenia has been identified as a prognostic factor in several diseases. The aim of this study was to investigate the impact of sarcopenia in patients with acute mesenteric ischemia." 9506;"Options to achieve proximal sealing zone during endovascular repair of abdominal aortic aneurysm and correlated classification.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31335295;Vascular;"Mialhe C, Lareyre F, Raffort J";;"Jul 2019";1563926400;; 9503;"Relationship between metformin and abdominal aortic aneurysm.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";31727461;"Journal of vascular surgery";"Raffort J, Hassen-Khodja R, Jean-Baptiste E, Lareyre F";;"Nov 2019";1573862400;;"Abdominal aortic aneurysm (AAA) is a life-threatening disease and pharmacologic agents to treat the disease remain lacking for clinical practice. Epidemiologic studies have highlighted a negative association between the use of antidiabetic drugs, including metformin, and AAA. Metformin is well-known for its blood glucose-lowering effect, but its action on both metabolism and inflammatory response has led to propose it as a potential therapeutic target in several cardiovascular diseases. In this review, we summarize the current knowledge on the link between metformin and AAA. Based on the known effects of the drug on the aortic wall, translational applications and clinical trials investigating the interest of metformin in the management of patients with AAA are discussed." 9501;"Virtual assistants for vascular surgeons.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32711917;"Journal of vascular surgery";"Lareyre F, Adam C, Carrier M, Raffort J";;"08 2020";1596240000;; 9499;"Vascular Calcifications are Associated with Increased Mortality in Patients with Acute Mesenteric Ischemia.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";32866577;"Annals of vascular surgery";"Lareyre F, Augène E, Massalou D, Chikande J, Guidi L, Jean-Baptiste E, Hassen-Khodja R, Raffort J";;"Sep 2020";1598918400;;"Vascular calcifications have been identified as predictors of mortality in several cardiovascular diseases but have not been investigated in context of acute mesenteric ischemia. The aim of this study was to investigate the impact of vascular calcifications in patients with acute mesenteric ischemia." 9495;"The role of the vascular surgeon to optimize the management of vascular complications during transcatheter aortic valve implantation.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32611280;Vascular;"Lareyre F, Raffort J";;"Jul 2020";1593734400;; 9496;"Artificial Intelligence for Education of Vascular Surgeons.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32279982;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Adam C, Carrier M, Chakfé N, Raffort J";;"Apr 2020";1586822400;; 9492;"Management of accessory renal arteries during aneurysm repair in a patient with end-stage renal failure.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32224095;"Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie";"Lareyre F, Carlier M, Raffort J";;"Apr 2020";1585699200;;"The presence of accessory renal artery is a frequent anatomic variation that can challenge abdominal aortic aneurysm (AAA) repair. Here, we show an image of an abdominal aortic aneurysm extended to multiple accessory renal arteries in a patient known for an end-stage renal failure. This case raises the questions of the criteria that should be taken in consideration for an optimal management of accessory renal artery during AAA repair." 9491;"Artificial intelligence in abdominal aortic aneurysm.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";32093909;"Journal of vascular surgery";"Raffort J, Adam C, Carrier M, Ballaith A, Coscas R, Jean-Baptiste E, Hassen-Khodja R, Chakfé N, Lareyre F";;"Feb 2020";1582675200;;"Abdominal aortic aneurysm (AAA) is a life-threatening disease, and the only curative treatment relies on open or endovascular repair. The decision to treat relies on the evaluation of the risk of AAA growth and rupture, which can be difficult to assess in practice. Artificial intelligence (AI) has revealed new insights into the management of cardiovascular diseases, but its application in AAA has so far been poorly described. The aim of this review was to summarize the current knowledge on the potential applications of AI in patients with AAA." 9489;"Artificial Intelligence in Vascular Surgery: Moving from Big Data to Smart Data.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32339687;"Annals of vascular surgery";"Lareyre F, Adam C, Carrier M, Raffort J";;"Apr 2020";1588032000;; 9485;"Deciphering the Role of Interleukin-1β in the Development of Dissecting Thoracic Aortic Aneurysm.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33281025;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Raffort J";;"Dec 2020";1607299200;; 9486;"Reduced Abdominal Aortic Aneurysm Growth Rate in Diabetic Patients Treated by Metformin: A Potential Role of Chemokines?";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32736029;"Annals of vascular surgery";"Raffort J, Lareyre F";;"Aug 2020";1596240000;; 9483;"Management of Vascular Complications during Anterior Lumbar Spinal Surgery Using Mini-Open Retroperitoneal Approach.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33549783;"Annals of vascular surgery";"Pelletier Y, Lareyre F, Cointat C, Raffort J";;"Feb 2021";1612656000;;"Anterior retroperitoneal spine exposure has become increasingly performed for the surgical treatment of various spinal disorders. Despite its advantages, the procedure is not riskless and can expose to potentially life-threatening vascular lesions. The aim of this review is to report the vascular lesions that can happen during anterior lumbar spinal surgery using mini-open retroperitoneal approach and to describe their management." 9481;"Applications of Head-Mounted Displays and Smart Glasses in Vascular Surgery.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33823254;"Annals of vascular surgery";"Lareyre F, Chaudhuri A, Adam C, Carrier M, Mialhe C, Raffort J";;"Apr 2021";1617667200;;"Advances in virtual, augmented and mixed reality have led to the development of wearable technologies including head mounted displays (HMD) and smart glasses. While there is a growing interest on their potential applications in health, only a few studies have addressed so far their use in vascular surgery. The aim of this review was to summarize the fundamental notions associated with these technologies and to discuss potential applications and current limits for their use in vascular surgery." 9477;"Feasibility of the Application of Holographic Augmented Reality in Endovascular Surgery Using Microsoft HoloLens Head-Mounted Display.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34182109;"Annals of vascular surgery";"Mialhe C, Chaudhuri A, Raffort J, Lareyre F";;"Jun 2021";1624838400;;"Advances in virtual, augmented (AR) and mixed reality have led to the development of wearable technologies including head mounted displays (HMD). The aim of this study was to investigate the feasibility to use HMD during endovascular surgery." 9478;"Nationwide study in France investigating the impact of diabetes on mortality in patients undergoing abdominal aortic aneurysm repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34588565;"Scientific reports";"Raffort J, Lareyre F, Fabre R, Mallat Z, Pradier C, Bailly L";;"Sep 2021";1632960000;;"The aim of this nationwide study was to analyze the impact of diabetes on post-operative mortality in patients undergoing AAA repair in France. This 10-year retrospective, multicenter study based on the French National electronic health data included patients undergoing AAA repair between 2010 and 2019. In-hospital post-operative mortality was analyzed using Kaplan-Meier curve survival and Log-Rank tests. A multivariate regression analysis was performed to calculate Hazard Ratios. Over 79,935 patients who underwent AAA repair, 61,146 patients (76.5%) had at least one hospital-readmission after the AAA repair, for a mean follow-up of 3.5 ± 2.5 years. Total in-hospital mortality over the 10-year study was 16,986 (21.3%) and 4581 deaths (5.8%) occurred during the first hospital stay for AAA repair. Age over 64 years old, the presence of AAA rupture and hospital readmission at 30-day were predictors of post-operative mortality (AdjHR = 1.59 CI 95% 1.51-1.67; AdjHR = 1.49 CI 95% 1.36-1.62 and AdjHR = 1.92, CI 95% 1.84-2.00). The prevalence of diabetes was significantly lower in ruptured AAA compared to unruptured AAA (14.8% vs 20.9%, P < 0.001 for type 2 diabetes and 2.5% vs 4.0%, P < 0.001 for type 1 diabetes). Type 1 diabetes was significantly associated with post-operative mortality (AdjHR = 1.30 CI 95% 1.20-1.40). For type 2 diabetes, the association was not statistically significant (Adj HR = 0.96, CI 95% 0.92-1.01). Older age, AAA rupture and hospital readmission were associated with deaths that occurred after discharge from the first AAA repair. Type 1 diabetes was identified as a risk factor of post-operative mortality. This study highlights the complex association between diabetes and AAA and should encourage institutions to report long-term follow-up after AAA repair to better understand its impact." 9472;"Contrast-induced Nephropathy in Non-cardiac Vascular Procedures, A Narrative Review: Part 2.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34238195;"Current vascular pharmacology";"Raffort J, Lareyre F, Katsiki N, Mikhailidis DP";;"Jul 2021";1625788800;;"This is Part 2 of a narrative review summarizing the literature on CIN after non-cardiac vascular diagnostic or therapeutic procedures, focusing on Peripheral Artery Disease (PAD) and Renal Artery Stenosis (RAS). Part 1 discussed CIN in relation to aortic aneurysms and carotid stenosis. We comment on the incidence, biomarkers, risk factors and consequences of CIN in patients with PAD or RAS, as well as on strategies to prevent CIN. Future perspectives in the field of CIN in relation to non-cardiac vascular procedures are also considered." 9473;"Artificial intelligence and automatic segmentation of abdominal aortic aneurysm: Past, present, and future.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34172198;"Journal of vascular surgery";"Lareyre F, Adam C, Carrier M, Raffort J";;"07 2021";1625097600;; 9471;"Holographic Imaging with the HoloLens Head Mounted System to Enhance Angio Suite Ergonomics During an Endovascular Procedure.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33632612;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Mialhe C, Raffort J, Lareyre F";;"Feb 2021";1614297600;; 9466;"Applications of Artificial Intelligence in Non-cardiac Vascular Diseases: A Bibliographic Analysis.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09, Equipe 07, Team 07, Equipe 12";34996315;Angiology;"Lareyre F, Lê CD, Ballaith A, Adam C, Carrier M, Amrani S, Caradu C, Raffort J";;"Jan 2022";1641600000;;"Research output related to artificial intelligence (AI) in vascular diseases has been poorly investigated. The aim of this study was to evaluate scientific publications on AI in non-cardiac vascular diseases. A systematic literature search was conducted using the PubMed database and a combination of keywords and focused on three main vascular diseases (carotid, aortic and peripheral artery diseases). Original articles written in English and published between January 1995 and December 2020 were included. Data extracted included the date of publication, the journal, the identity, number, affiliated country of authors, the topics of research, and the fields of AI. Among 171 articles included, the three most productive countries were USA, China, and United Kingdom. The fields developed within AI included: machine learning (n = 90; 45.0%), vision (n = 45; 22.5%), robotics (n = 42; 21.0%), expert system (n = 15; 7.5%), and natural language processing (n = 8; 4.0%). The applications were mainly new tools for: the treatment (n = 52; 29.1%), prognosis (n = 45; 25.1%), the diagnosis and classification of vascular diseases (n = 38; 21.2%), and imaging segmentation (n = 38; 21.2%). By identifying the main techniques and applications, this study also pointed to the current limitations and may help to better foresee future applications for clinical practice." 9467;"Automated Segmentation of the Human Abdominal Vascular System Using a Hybrid Approach Combining Expert System and Supervised Deep Learning.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34362129;"Journal of clinical medicine";"Lareyre F, Adam C, Carrier M, Raffort J";;"Aug 2021";1628294400;;"Computed tomography angiography (CTA) is one of the most commonly used imaging technique for the management of vascular diseases. Here, we aimed to develop a hybrid method combining a feature-based expert system with a supervised deep learning (DL) algorithm to enable a fully automatic segmentation of the abdominal vascular tree." 9465;"Impact of Metformin Treatment on Outcomes after Abdominal Aortic Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34648860;"Annals of vascular surgery";"Lareyre F, Lê CD, Amrani S, Raffort J";;"Oct 2021";1634169600;; 9463;"Assessment of Access-Related Injury During Transcatheter Aortic Valve Implantation: Current Issues and Future Directions.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";28786712;Angiology;"Lareyre F, Raffort J, Bourlon F, Mialhe C";;"Aug 2017";1502236800;; 9457;"Surgical Management of Percutaneous Transfemoral Access to Minimize Vascular Complications Related to Transcatheter Aortic Valve' Implantation.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";28569069;Angiology;"Lareyre F, Raffort J, Dommerc C, Habib Y, Bourlon F, Mialhe C";;"Jun 2017";1496361600;;"Transcatheter aortic valve implantation (TAVI) is associated with substantial rates of vascular complications. The aim of our study is to describe the surgical management of percutaneous transfemoral access by a vascular surgeon and to report the 30-day postoperative vascular complications and mortality. Perioperative procedures to manage the femoral access site were recorded retrospectively from 220 consecutive patients who underwent TAVI. Postoperative vascular complications related to the main access were categorized according to the Valve Academic Research Consortium 2 classification. Perioperative procedures related to vascular access were performed for 56 (25.4%) patients: 6 patients required open surgical repair, 48 patients underwent endovascular stenting, and 2 patients had both procedures. The all-cause mortality was 3.6%, but no death related to a vascular complication was reported during the 30-day postoperative follow-up period. Ten (4.5%) patients developed postoperative hematomas; 2 (0.9%) of them were retroperitoneal and led to major bleeding requiring an unplanned surgical intervention. Our study underlines the utility of a multidisciplinary approach to manage the percutaneous access in TAVI for managing postoperative vascular complications." 9458;"Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet.";"J. Raffort";"Equipe 09, Team 09";28414328;"Nature medicine";"Nus M, Sage AP, Lu Y, Masters L, Lam BYH, Newland S, Weller S, Tsiantoulas D, Raffort J, Marcus D, Finigan A, Kitt L, Figg N, Schirmbeck R, Kneilling M, Yeo GSH, Binder CJ, de la Pompa JL, Mallat Z";;"Apr 2017";1492473600;;"Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (T) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-T cells, leading to PDL1-mediated suppression of T cell motility, alteration of T cell differentiation, reduced T abundance and suppression of the proatherogenic T response. Our findings reveal a previously unsuspected role for MZB cells in controlling the T-germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response." 9459;"Angiographic Analysis of Vascular Integrity After Percutaneous Closure Using Prostar XL Device During Transcatheter Aortic Valve Implantation.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";28474978;"Vascular and endovascular surgery";"Lareyre F, Raffort J, Dommerc C, Benhammamia M, Bourlon F, Habib Y, Mialhe C";;"May 2017";1494028800;;"Percutaneous closure devices are commonly used to achieve hemostasis during endovascular procedures including transcatheter aortic valve implantation (TAVI). The aim of our study was to investigate the quality of the percutaneous femoral arterial closure by Prostar XL device using a systematic peroperative angiographic control at the end of TAVI procedure." 9455;"TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";28912363;"Arteriosclerosis, thrombosis, and vascular biology";"Lareyre F, Clément M, Raffort J, Pohlod S, Patel M, Esposito B, Master L, Finigan A, Vandestienne M, Stergiopulos N, Taleb S, Trachet B, Mallat Z";;"Sep 2017";1505520000;;"Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture." 9451;"Changes in Ocular Subfoveal Choroidal Thickness After Carotid Endarterectomy Using Enhanced Depth Imaging Optical Coherence Tomography: A Pilot Study.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";29082746;Angiology;"Lareyre F, Nguyen E, Raffort J, Carboni J, Doyen J, Hassen-Khodja R, Gastaud P, Chofflet J, Jean-Baptiste E";;"Oct 2017";1509408000;;"The influence of both severe chronic carotid stenosis and carotid endarterectomy (CEA) on ocular tissue has been poorly evaluated. The goal of this study was to measure subfoveal choroidal thickness (SFCT), before and after CEA, in patients with severe carotid stenosis. Consecutive patients (n = 36) with severe carotid stenosis were prospectively included. Patients (n = 19) were followed up at 1 and 3 months after CEA. The SFCT was measured bilaterally using enhanced depth imaging optical coherence tomography (EDI-OCT). Preoperatively, the median SFCT of the ipsilateral eye did not differ significantly from the contralateral eye (223 vs 236 µm; P = .75). In the ipsilateral eye, the mean SFCT was significantly higher at 1 month postsurgery and the effect was maintained at 3 months (226.3 ± 17.1 at 3 months vs 210.8 ± 16.5 µm at baseline; P < .001). For the contralateral eye, the increase in SFCT reached statistical significance at 3 months (220.1 ± 11.3 at 3 months vs 214.8 ± 11.5 µm at baseline; P = .04). The mean SFCT significantly increased bilaterally after CEA, with a more noticeable effect in the ipsilateral eye. Further studies are required to determine whether EDI-OCT could be useful as a potential marker of ophthalmologic outcomes." 9452;"A 7-Year Single-Center Experience of Transfemoral TAVI: Evolution of Surgical Activity and Impact on Vascular Outcome.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";29105493;Angiology;"Lareyre F, Raffort J, Dommerc C, Habib Y, Bourlon F, Mialhe C";;"Jul 2018";1530403200;;"Transcatheter aortic valve implantation (TAVI) has become a well-established alternative to open surgery to treat aortic stenosis. We describe our 7-year TAVI experience using transfemoral access and identity changes in surgical activity and evaluate its impact on postoperative vascular outcomes. Consecutive patients (N = 340) who underwent TAVI with percutaneous transfemoral access were retrospectively included and divided into 4 quartiles according to the date of intervention. Vascular outcomes were classified according to the Valve Academic Research Consortium 2 classification. The number of patients who underwent transfemoral TAVI increased over time and their clinical characteristics evolved, with a lower Society of Thoracic Surgeons score and less comorbidities. The material used evolved and TAVI could be performed despite higher iliac calcification and tortuosity scores. With experience, the procedural time, the postoperative length of stay at hospital, and the 30-day postoperative mortality significantly decreased. No significant change was observed for vascular outcome, except for minor hematoma. We witnessed an increase in transfemoral TAVI procedure, with changes in clinical and procedural characteristics associated with an improvement in postoperative outcomes." 9449;"Sexual Dysfunction After Abdominal Aortic Aneurysm Surgical Repair: Current Knowledge and Future Directions.";"F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";29292207;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Regnier P, Lareyre F, Hassen-Khodja R, Durand M, Touma J, Raffort J";;"Jan 2018";1514937600;;"Abdominal aortic aneurysm (AAA) represents a major health concern and the curative treatment relies on surgical approaches including open and endovascular aortic repair (EVAR). While epidemiological studies have addressed the major outcomes including mortality and life threatening complications, the impact of surgical intervention on sexual function has been less well described. The aim of this review was to summarise current knowledge on the occurrence of sexual dysfunction in the context of AAA surgical repair and to explore whether surgical techniques could have differential impact." 9447;"Pelvi-ureteric junction obstruction related to crossing vessels: vascular anatomic variations and implication for surgical approaches.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";29302903;"International urology and nephrology";"Panthier F, Lareyre F, Audouin M, Raffort J";;"Mar 2018";1519862400;;"Pelvi-ureteric junction obstruction corresponds to an impairment of urinary transport that can lead to renal dysfunction if not treated. Several mechanisms can cause the obstruction of the ureter including intrinsic factors or extrinsic factors such as the presence of crossing vessels. The treatment of the disease relies on surgical approaches, pyeloplasty being the standard reference. The technique consists in removing the pathologic ureteric segment and renal pelvis and transposing associated crossing vessels if present. The vascular anatomy of the pelvi-ureteric junction is complex and varies among individuals, and this can impact on the disease development and its surgical treatment. In this review, we summarize current knowledge on vascular anatomic variations in the pelvi-ureteric junction. Based on anatomic characteristics, we discuss implications for surgical approaches during pyeloplasty and vessel transposition." 9443;"Association of Platelet to Lymphocyte Ratio and Risk of 30-Day Postoperative Complications in Patients Undergoing Abdominal Aortic Surgical Repair.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30021492;"Vascular and endovascular surgery";"Lareyre F, Carboni J, Chikande J, Massiot N, Voury-Pons A, Umbdenstock E, Jean-Baptiste E, Hassen-Khodja R, Raffort J";;"Jan 2019";1546300800;;"The predictive value of the platelet to lymphocyte ratio (PLR) has been demonstrated in several cardiovascular diseases. The aim of this study was to investigate the interest of the preoperative PLR as a predictor of 30-day postoperative outcome in patients with abdominal aortic aneurysm (AAA) undergoing open or endovascular surgical repair." 9444;"Coverage of Accessory Renal Arteries During Endovascular Aortic Aneurysm Repair: What Are the Consequences and the Implications for Clinical Practice?";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";29682989;Angiology;"Lareyre F, Panthier F, Jean-Baptiste E, Hassen-Khodja R, Raffort J";;"Apr 2018";1524528000;;"An accessory renal artery (ARA) represents an anatomic variation which can challenge endovascular aortic aneurysm repair (EVAR). The aim of this review was to summarize the current knowledge on postoperative outcomes following ARA coverage during EVAR. We performed a systematic literature review. The MEDLINE database was searched on September 2017, and 8 relevant studies were included. The frequency of ARA in patients undergoing EVAR varied between 9.5% and 16.2%, and the frequency of ARA coverage varied between 5.2% and 9.4%. Four reports did not observe any significant changes on postoperative renal function, whereas 1 study reported an early transient increase in creatinine after ARA coverage. The occurrence of renal infarct varied from 20% to 84%. Five studies did not observe endoleaks related to ARA coverage, whereas one reported the occurrence of type II endoleaks in 3 of 18 patients who had ARA coverage. No significant change in blood pressure, mortality, and mean length of hospital stay was observed. The ARA coverage can potentially have renal and vascular consequences, but none of them were critical. Further studies may be useful to identify preoperative criteria that may help to choose the most appropriate surgical approach before ARA coverage." 9441;"Diabetes mellitus is not associated with worse vascular outcome following percutaneous transfemoral transcatheter aortic valve implantation.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30642229;"Acta cardiologica";"Lareyre F, Mialhe C, Bourlon F, Habib Y, Dommerc C, Raffort J";;"Dec 2019";1575158400;;" Transcatheter aortic valve implantation (TAVI) is an alternative to open surgical aortic valve replacement and the impact of diabetes on vascular outcomes is worth of investigation. The aim of our study was to determine if diabetic patients had distinct pre-operative characteristics compared to non-diabetics and to evaluate the impact of the disease on vascular outcomes. Four hundred consecutive patients who underwent TAVI with percutaneous transfemoral access were retrospectively included. Vascular outcomes were classified according to the Valve Academic Research Consortium 2 classification. Seventy-eight (19.5%) patients were diabetics. Compared to non-diabetics, diabetic patients were younger and had significantly higher body mass index (29.7+/- 0.7 kg/m vs 26.8+/- 0.3,  < .0001), higher proportion of associated dyslipidemia (34.6% vs 11.5%,  < .0001) and arterial hypertension (60% vs 38.2%,  = .0009). Anatomical characteristics of the vascular access and procedural characteristics did not differ among the groups. No significant difference was observed in the incidence of major and minor vascular complications and 30-day post-operative mortality between diabetic and non-diabetic patients (2.6% vs 1.9%,  = .6916). Diabetes is not associated with worse vascular outcome following TAVI suggesting that the vascular access can be managed safely in these patients." 9439;"Management of Accessory Renal Artery During Abdominal Aortic Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30621434;Angiology;"Lareyre F, Mialhe C, Dommerc C, Raffort J";;"Jul 2019";1561939200;; 9437;"Endovascular Aneurysm Sealing of a Collapsed and Thrombosed Aortic Stent-Graft With Renovisceral Chimney Stent-Grafts.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30395489;"Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists";"Lareyre F, Mialhe C, Dommerc C, Raffort J";;"02 2019";1548979200;;"To report the use of the Nellix endovascular aneurysm sealing (EVAS) system in the management of proximal stent-graft collapse associated with thrombosis following endovascular aneurysm repair (EVAR)." 9432;"Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30943775;"Arteriosclerosis, thrombosis, and vascular biology";"Clément M, Chappell J, Raffort J, Lareyre F, Vandestienne M, Taylor AL, Finigan A, Harrison J, Bennett MR, Bruneval P, Taleb S, Jørgensen HF, Mallat Z";;"06 2019";1559347200;;"Objective- Recent studies suggested the occurrence of phenotypic switching of vascular smooth muscle cells (VSMCs) during the development of aortic aneurysm (AA). However, lineage-tracing studies are still lacking, and the behavior of VSMCs during the formation of dissecting AA is poorly understood. Approach and Results- We used multicolor lineage tracing of VSMCs to track their fate after injury in murine models of Ang II (angiotensin II)-induced dissecting AA. We also addressed the direct impact of autophagy on the response of VSMCs to AA dissection. Finally, we studied the relevance of these processes to human AAs. Here, we show that a subset of medial VSMCs undergoes clonal expansion and that VSMC outgrowths are observed in the adventitia and borders of the false channel during Ang II-induced development of dissecting AA. The clonally expanded VSMCs undergo phenotypic switching with downregulation of VSMC differentiation markers and upregulation of phagocytic markers, indicative of functional changes. In particular, autophagy and endoplasmic reticulum stress responses are activated in the injured VSMCs. Loss of autophagy in VSMCs through deletion of autophagy protein 5 gene ( Atg5) increases the susceptibility of VSMCs to death, enhances endoplasmic reticulum stress activation, and promotes IRE (inositol-requiring enzyme) 1α-dependent VSMC inflammation. These alterations culminate in increased severity of aortic disease and higher incidence of fatal AA dissection in mice with VSMC-restricted deletion of Atg5. We also report increased expression of autophagy and endoplasmic reticulum stress markers in VSMCs of human dissecting AAs. Conclusions- VSMCs undergo clonal expansion and phenotypic switching in Ang II-induced dissecting AAs in mice. We also identify a critical role for autophagy in regulating VSMC death and endoplasmic reticulum stress-dependent inflammation with important consequences for aortic wall homeostasis and repair." 9435;"A fully automated pipeline for mining abdominal aortic aneurysm using image segmentation.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31551507;"Scientific reports";"Lareyre F, Adam C, Carrier M, Dommerc C, Mialhe C, Raffort J";;"Sep 2019";1569456000;;"Imaging software have become critical tools in the diagnosis and the treatment of abdominal aortic aneurysms (AAA). The aim of this study was to develop a fully automated software system to enable a fast and robust detection of the vascular system and the AAA. The software was designed from a dataset of injected CT-scans images obtained from 40 patients with AAA. Pre-processing steps were performed to reduce the noise of the images using image filters. The border propagation based method was used to localize the aortic lumen. An online error detection was implemented to correct errors due to the propagation in anatomic structures with similar pixel value located close to the aorta. A morphological snake was used to segment 2D or 3D regions. The software allowed an automatic detection of the aortic lumen and the AAA characteristics including the presence of thrombus and calcifications. 2D and 3D reconstructions visualization were available to ease evaluation of both algorithm precision and AAA properties. By enabling a fast and automated detailed analysis of the anatomic characteristics of the AAA, this software could be useful in clinical practice and research and be applied in a large dataset of patients." 9431;"Impact of Polar Renal Artery Coverage on Early Renal Function after Chimney Endovascular Aortic Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";30910175;"Journal of vascular and interventional radiology : JVIR";"Lareyre F, Mialhe C, Dommerc C, Raffort J";;"Apr 2019";1554076800;;"To evaluate impact of polar renal artery coverage on early renal function after chimney endovascular aneurysm repair (EVAR)." 9429;"Endovascular Aneurysm Sealing and Chimney Endovascular Aneurysm Sealing in the Treatment of Type Ia and Type III Endoleaks After Endovascular Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31394252;"Annals of vascular surgery";"Lareyre F, Mialhe C, Dommerc C, Raffort J";;"Aug 2019";1565308800;;"The aim of this study was to report the treatment of type Ia and type III endoleaks after endovascular aneurysm repair (EVAR) or chimney EVAR using endovascular aneurysm sealing (EVAS) and chimney EVAS." 9427;"Regarding ""The association between platelet/lymphocyte ratio, neutrophil/lymphocyte ratio, and carotid artery stenosis and stroke following carotid endarterectomy"".";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31584349;Vascular;"Raffort J, Lareyre F";;"Oct 2019";1570233600;; 9423;"Endovascular aneurysm sealing as an alternative for the treatment of failed endovascular aneurysm repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31896300;Vascular;"Lareyre F, Mialhe C, Dommerc C, Mbeutcha A, Raffort J";;"Jan 2020";1578096000;;"The Nellix EndoVascular Aneurysm Sealing (EVAS) system has offered a novel approach in the treatment of abdominal aortic aneurysm (AAA). While it is currently indicated as a primary procedure in patients with infrarenal AAA with suitable anatomy according to the indications for use, a few studies aimed to address its potential interest in failed endovascular aneurysm repair (EVAR). The aim of this systematic review was to analyze the postoperative outcomes of patients with prior EVAR who underwent EVAS." 9424;"Fundamentals in Artificial Intelligence for Vascular Surgeons.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31857229;"Annals of vascular surgery";"Raffort J, Adam C, Carrier M, Lareyre F";;"Dec 2019";1576886400;;"Artificial intelligence (AI) corresponds to a broad discipline that aims to design systems, which display properties of human intelligence. While it has led to many advances and applications in daily life, its introduction in medicine is still in its infancy. AI has created interesting perspectives for medical research and clinical practice but has been sometimes associated with hype leading to a misunderstanding of its real capabilities. Here, we aim to introduce the fundamental notions of AI and to bring an overview of its potential applications for medical and surgical practice. In the limelight of current knowledge, limits and challenges to face as well as future directions are discussed." 9421;"Impact of diabetes on long-term survival and morbidity following aortic aneurysm repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";31864657;"Journal of vascular surgery";"Lareyre F, Raffort J";;"Dec 2019";1577059200;; 9415;"Looking for the Optimal Evaluation of Abdominal Aortic Aneurysm Risk of Rupture.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32186259;"Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists";"Lareyre F, Raffort J";;"Mar 2020";1584576000;; 9416;"Link between Hyperglycaemia, Insulin resistance, and Lower Extremity Weakness Following Complex Endovascular Aortic Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32169335;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Raffort J";;"Mar 2020";1584230400;; 9417;"Prediction of Abdominal Aortic Aneurysm Growth and Risk of Rupture in the Era of Machine Learning.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32242452;Angiology;"Lareyre F, Adam C, Carrier M, Raffort J";;"Apr 2020";1585958400;; 9411;"Artificial Intelligence for Education of Vascular Surgeons.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32279982;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Adam C, Carrier M, Chakfé N, Raffort J";;"Apr 2020";1586822400;; 9412;"Mycotic aortic and left iliac ruptured aneurysm due to : a case report and literature overview.";"E. Jean-Baptiste, F. Lareyre, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";32253984;"Acta chirurgica Belgica";"Ballaith A, Raffort J, Rajhi K, Salucki B, Drai C, Jean-Baptiste E, Hassen-Khodja R, Lareyre F";;"Apr 2020";1586304000;;"Mycotic aneurysm is a life-threatening disease often caused by and species. Interestingly, () is described as a rare causative agent. We report the case of a patient who developed a mycotic aortic and ruptured left iliac aneurysm due to The patient developed a secondary aortic graft infection due to a mesenteric ischemia with fecal peritonitis. A literature overview of the current knowledge on mycotic aortic aneurysms specifically due to is discussed including the clinical characteristics of patients, the management of the disease and the post-operative outcomes." 9409;"Using Digital Twins for Precision Medicine in Vascular Surgery.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32417283;"Annals of vascular surgery";"Lareyre F, Adam C, Carrier M, Raffort J";;"May 2020";1589760000;; 9405;"Reduced Abdominal Aortic Aneurysm Growth Rate in Diabetic Patients Treated by Metformin: A Potential Role of Chemokines?";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32736029;"Annals of vascular surgery";"Raffort J, Lareyre F";;"Aug 2020";1596240000;; 9406;"Vascular Remodeling and Immune Cell Infiltration in Splenic Artery Aneurysms.";"E. Jean-Baptiste, F. Lareyre, J. Raffort";"Equipe 09, Team 09";32851875;Angiology;"Clément M, Lareyre F, Loste A, Sannier A, Burel-Vandenbos F, Massiot N, Carboni J, Jean-Baptiste E, Caligiuri G, Nicoletti A, Raffort J";;"Jul 2021";1625097600;;"Rupture of splenic artery aneurysms (SAAs) is associated with a high mortality rate. The aim of this study was to identify the features of SAAs. Tissue sections from SAAs were compared to nonaneurysmal splenic arteries using various stains. The presence of intraluminal thrombus (ILT), vascular smooth muscle cells (VSMCs), cluster of differentiation (CD)-68+ phagocytes, myeloperoxidase+ neutrophils, CD3+, and CD20+ adaptive immune cells were studied using immunofluorescence microscopy. Analysis of SAAs revealed the presence of atherosclerotic lesions, calcifications, and ILT. Splenic artery aneurysms were characterized by a profound vascular remodeling with a dramatic loss of VSMCs, elastin degradation, adventitial fibrosis associated with enhanced apoptosis, and increased matrix metalloproteinase 9 expression. We observed an infiltration of immune cells comprising macrophages, neutrophils, T, and B cells. The T and B cells were found in the adventitial layer of SAAs, but their organization into tertiary lymphoid organs was halted. We failed to detect germinal centers even in the most organized T/B cell follicles and these lymphoid clusters lacked lymphoid stromal cells. This detailed histopathological characterization of the vascular remodeling during SAA showed that lymphoid neogenesis was incomplete, suggesting that critical mediators of their development must be missing." 9403;"Investigation of the diagnostic and prognostic value of miR-637 in atherosclerosis.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33461433;Vascular;"Lareyre F, Raffort J";;"Jan 2021";1611014400;; 9399;"Update on the Management of Accessory Renal Arteries During Endovascular Aortic Aneurysm Repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";32990033;Angiology;"Lareyre F, Carlier M, Raffort J";;"Sep 2020";1601337600;; 9400;"Measurement of Aneurysm Volumes After Endovascular Aortic Aneurysm Repair as a Predictive Factor of Postoperative Complications.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33475028;"Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists";"Raffort J, Lareyre F";;"Jan 2021";1611187200;; 9397;"Aorto-pulmonary and aorto-digestive fistula after hybrid aortic arch aneurysm repair.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33752845;"Journal de medecine vasculaire";"Augène E, Berthet JP, Lareyre F, Raffort J";;"Mar 2021";1616457600;; 9393;"Metformin to Limit Abdominal Aortic Aneurysm Expansion: Time for Clinical Trials.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33836975;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Raffort J";;"Apr 2021";1618012800;; 9394;"[Autophagy in dendritic cells promotes atheroprotective regulatory T cells].";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";33739265;"Medecine sciences : M/S";"Clément M, Raffort J, Lareyre F, Mallat Z";;"Mar 2021";1616112000;; 9391;"Contrast-induced Nephropathy in Non-cardiac Vascular Procedures, A Narrative Review: Part 1.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34238194;"Current vascular pharmacology";"Raffort J, Lareyre F, Katsiki N, Mikhailidis DP";;"Jul 2021";1625788800;;"Contrast-induced Nephropathy (CIN) is animportant complication of iodinated Contrast Medium (CM) administration, being associated with both short- and long-term adverse outcomes (e.g., cardiorenal events, longer hospital stay and mortality). CIN has been mainly studied in relation to cardiac procedures but it can also occur following non-cardiac vascular interventions. This is Part 1 of a narrative review summarizing the available literature on CIN after non-cardiac vascular diagnostic or therapeutic procedures for aortic aneurysm and carotid stenosis. We discuss the definition, pathophysiology, incidence, risk factors, biomarkers and consequences of CIN in these settings, as well as preventive strategies and alternatives to limit iodinated CM use. Physicians and vascular surgeons should be aware of CM-related adverse events and the potential strategies to avoid it. Clearly, more research in this important field is required." 9388;"Biomarkers of Contrast-Induced Nephropathy After Non-cardiac Vascular Procedures: An Under-explored Area.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34461743;Angiology;"Lareyre F, Raffort J";;"Aug 2021";1630368000;; 9387;"Short-term outcomes and survival of pyrocarbon hemiarthroplasty in the young arthritic shoulder.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34280573;"Journal of shoulder and elbow surgery";"Cointat C, Raynier JL, Vasseur H, Lareyre F, Raffort J, Gauci MO, Boileau P";;"Jul 2021";1626652800;;"The purpose was to report the short-term outcomes and survival of hemiarthroplasty with a pyrocarbon head (HA-PYC) for the treatment of shoulder osteoarthritis in patients aged ≤ 60 years. We hypothesized that HA-PYC could be an alternative to hemi-metal (avoiding the risk of rapid glenoid erosion) and total shoulder arthroplasty (TSA) (avoiding the risk of rapid glenoid loosening) in an active patient population." 9385;"Incidence of contrast-induced acute kidney injury in patients with acute mesenteric ischemia and identification of potential predictive factors.";"E. Jean-Baptiste, F. Lareyre, J. Raffort";"Equipe 09, Team 09";34645315;Vascular;"Augène E, Lareyre F, Chikande J, Guidi L, Mutambayi G, Lê CD, Jean-Baptiste E, Katsiki N, Mikhailidis DP, Raffort J";;"Oct 2021";1634169600;;"Contrast-enhanced computed tomography angiography (CTA) is commonly used to investigate acute abdominal conditions, but the risk of contrast-induced acute kidney injury (CI-AKI) has been poorly investigated in patients with acute mesenteric ischemia. The aim of the present study was to evaluate the incidence of CI-AKI in these patients and identify potential predictive factors." 9379;"Automatic Segmentation of Maximum Aortic Diameter to Standardize Methods of Measurements on Computed Tomography Angiography.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";35038496;"Annals of vascular surgery";"Lareyre F, Lê CD, Adam C, Carrier M, Raffort J";;"Jan 2022";1642377600;; 9380;"Automatic Measurement of Maximal Diameter of Abdominal Aortic Aneurysm on Computed Tomography Angiography Using Artificial Intelligence.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34954034;"Annals of vascular surgery";"Lareyre F, Chaudhuri A, Flory V, Augène E, Adam C, Carrier M, Amrani S, Chikande J, Lê CD, Raffort J";;"Dec 2021";1640476800;;"The treatment of abdominal aortic aneurysm relies on surgical repair and the indication mainly depends on its size evaluated by the maximal diameter (Dmax). The aim of this study was to evaluate a new automatic method based on artificial intelligence to measure the Dmax on computed tomography angiography." 9381;"Automatic Measurement of Abdominal Aortic Aneurysm Maximum Diameter Using Artificial Intelligence.";"F. Lareyre, J. Raffort";"Equipe 09, Team 09";34857446;"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery";"Lareyre F, Adam C, Raffort J";;"Dec 2021";1638489600;; 9373;"Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy.";"G. Chinetti";"Equipe 09, Team 09";15780828;"Current opinion in pharmacology";"Chinetti-Gbaguidi G, Fruchart JC, Staels B";;"Mar 2005";1111536000;;"Several conditions and risk factors predispose to cardiovascular disease, including visceral obesity, type 2 diabetes, insulin resistance, hypertension and dyslipidemia, and are collectively called the metabolic syndrome. Different pharmacological approaches are under development to address these risk factors and improve the cardiovascular risk profile. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Thus PPARs appear good drug targets for the correction of the global risk profile that predisposes an individual to cardiovascular disease." 9374;"Measuring biomarkers to assess the therapeutic effects of PPAR agonists?";"G. Chinetti";"Equipe 09, Team 09";18034622;Pharmacogenomics;"Chinetti-Gbaguidi G, Staels B";;"Nov 2007";1195862400;;"The metabolic syndrome is defined as a clustering of cardiovascular risk factors with insulin resistance, including dyslipidemia, coagulation disturbances and hypertension. Activators of the peroxisome proliferator-activated receptors (PPARs) modulate several of the metabolic risk factors predisposing to atherosclerosis. Fibrates are hypolipidemic drugs acting through activation of PPARalpha, whereas glitazones are insulin sensitizers activating PPARgamma. In addition, these drugs exert pleiotropic anti-inflammatory actions. In this review, we will focus on the effects of fibrates and glitazones on biomarker modulation and their usefulness in the treatment of cardiovascular disease." 9375;"Pleiotropic effects of fibrates.";"G. Chinetti";"Equipe 09, Team 09";16105484;"Current atherosclerosis reports";"Chinetti-Gbaguidi G, Fruchart JC, Staels B";;"Aug 2005";1124323200;;"Fibrates are a widely used class of hypolipidemic drugs. The effects of fibrates are mediated through the activation of the transcription factor peroxisome proliferator-activated receptor a (PPARa). Fibrates act to modulate the transcription of genes that encode proteins controlling lipid transport and metabolism. Fibrates also exert pleiotropic anti-inflammatory effects by down regulating expression of genes encoding inflammatory cytokines and acute phase response proteins. These combined actions translate into clinical benefit as demonstrated by the reduction in cardiovascular morbidity and mortality in primary and secondary intervention trials." 9371;"Peroxisome proliferator-activated receptor alpha controls cellular cholesterol trafficking in macrophages.";"G. Chinetti";"Equipe 09, Team 09";16162941;"Journal of lipid research";"Chinetti-Gbaguidi G, Rigamonti E, Helin L, Mutka AL, Lepore M, Fruchart JC, Clavey V, Ikonen E, Lestavel S, Staels B";;"Sep 2005";1126828800;;"The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant that governs its availability for efflux to extracellular acceptors. NPC1 and NPC2 are proteins localized in the late endosome and control cholesterol transport from the lysosome to the plasma membrane. Here, we report that NPC1 and NPC2 gene expression is induced by oxidized LDL (OxLDL) in human macrophages. Because OxLDLs contain natural activators of peroxisome proliferator-activated receptor alpha (PPARalpha), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPARalpha and the consequences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPARalpha ligands in human macrophages. Furthermore, PPARalpha activation leads to an enrichment of cholesterol in the plasma membrane. By contrast, incubation with progesterone, which blocks postlysosomal cholesterol trafficking, as well as NPC1 and NPC2 mRNA depletion using small interfering RNA, abolished ABCA1-dependent cholesterol efflux induced by PPARalpha activators. These observations identify a novel regulatory role for PPARalpha in the control of cholesterol availability for efflux that, associated with its ability to inhibit cholesterol esterification and to stimulate ABCA1 and scavenger receptor class B type I expression, may contribute to the stimulation of reverse cholesterol transport." 9368;"Therapeutical effects of PPAR agonists assessed by biomarker modulation.";"G. Chinetti";"Equipe 09, Team 09";16298909;"Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals";"Chinetti-Gbaguidi G, Fruchart JC, Staels B";;"Nov 2005";1130803200;;"The metabolic syndrome is defined as the clustering of cardiovascular risk factors, such as glucose intolerance, hyperinsulinemia, dyslipidemia, coagulation disturbances and hypertension. Activators of the nuclear receptors peroxisome proliferator-activated receptors (PPARs) modulate several of the metabolic risk factors pre-disposing to atherosclerosis. Fibrates are hypolipidemic drugs operating through activation of PPARalpha, whereas glitazones are insulin sensitizers activating PPARgamma. In addition, these drugs exert pleiotropic and anti-inflammatory actions. This review will focus on the different effects of fibrates and glitazones, as measured by biomarker modulation, on the development of atherosclerosis and cardiovascular disease." 9367;"Induction of CXCR2 receptor by peroxisome proliferator-activated receptor gamma in human macrophages.";"G. Chinetti";"Equipe 09, Team 09";18292390;"Arteriosclerosis, thrombosis, and vascular biology";"Rigamonti E, Fontaine C, Lefebvre B, Duhem C, Lefebvre P, Marx N, Staels B, Chinetti-Gbaguidi G";;"Feb 2008";1203724800;;"Macrophages play a central role in the immune response against infectious organisms. Once activated, macrophages secrete proinflammatory cytokines and chemokines. Interleukin (IL)-8 and related CXC chemokines play a role in the recruitment and activation of phagocytes acting through CXCR1 and CXCR2 receptors. The nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma exerts antiinflammatory properties in macrophages, by inhibiting cytokine and CC chemokine production. In this study, we investigated whether PPAR-gamma also plays a role in the regulation of the CXC chemokine pathway." 9363;"PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.";"G. Chinetti";"Equipe 09, Team 09";17681149;"Cell metabolism";"Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G";;"Aug 2007";1186531200;;"Th1 cytokines promote monocyte differentiation into proatherogenic M1 macrophages, while Th2 cytokines lead to an ""alternative"" anti-inflammatory M2 macrophage phenotype. Here we show that in human atherosclerotic lesions, the expression of M2 markers and PPARgamma, a nuclear receptor controlling macrophage inflammation, correlate positively. Moreover, PPARgamma activation primes primary human monocytes into M2 differentiation, resulting in a more pronounced anti-inflammatory activity in M1 macrophages. However, PPARgamma activation does not influence M2 marker expression in resting or M1 macrophages, nor does PPARgamma agonist treatment influence the expression of M2 markers in atherosclerotic lesions, indicating that only native monocytes can be primed by PPARgamma activation to an enhanced M2 phenotype. Furthermore, PPARgamma activation significantly increases expression of the M2 marker MR in circulating peripheral blood mononuclear cells. These data demonstrate that PPARgamma activation skews human monocytes toward an anti-inflammatory M2 phenotype." 9364;"Peroxisome proliferator-activated receptors--from active regulators of macrophage biology to pharmacological targets in the treatment of cardiovascular disease.";"G. Chinetti";"Equipe 09, Team 09";18042221;"Journal of internal medicine";"Bouhlel MA, Staels B, Chinetti-Gbaguidi G";;"Nov 2007";1196294400;;"Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes. Pharmacological modulation of macrophage activities therefore represents an important strategy for the prevention and treatment of inflammation-related diseases, such as atherosclerosis. This review focuses on recent advances on the role of the peroxisome proliferator-activated receptor transcription factor family in the modulation of lipid homeostasis and the inflammatory response in macrophages and the potential participation of these actions in the modulation of metabolic and cardiovascular disease." 9359;"Liver X receptor activation induces the uptake of cholesteryl esters from high density lipoproteins in primary human macrophages.";"G. Chinetti";"Equipe 09, Team 09";18802017;"Arteriosclerosis, thrombosis, and vascular biology";"Bultel S, Helin L, Clavey V, Chinetti-Gbaguidi G, Rigamonti E, Colin M, Fruchart JC, Staels B, Lestavel S";;"Dec 2008";1228089600;;"Liver X receptors (LXRs) are oxysterol-activated nuclear receptors regulating reverse cholesterol transport, in part by modulating cholesterol efflux from macrophages to apoAI and HDL via the ABCA1 and ABCG1/ABCG4 pathways. Moreover, LXR activation increases intracellular cholesterol trafficking via the induction of NPC1 and NPC2 expression. However, implication of LXRs in the selective uptake of cholesteryl esters from lipoproteins in human macrophages has never been reported." 9357;"Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages.";"G. Chinetti";"Equipe 09, Team 09";21145308;"Biochemical and biophysical research communications";"Mayi TH, Rigamonti E, Pattou F, Staels B, Chinetti-Gbaguidi G";;"Dec 2010";1292371200;;"Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR)γ are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPARγ target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD(+) concentration was observed. Interestingly, LXR activation decreased the PPARγ-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPARγ pathways in human macrophages." 9358;"The nuclear receptor Rev-erbalpha is a liver X receptor (LXR) target gene driving a negative feedback loop on select LXR-induced pathways in human macrophages.";"G. Chinetti";"Equipe 09, Team 09";18511497;"Molecular endocrinology (Baltimore, Md.)";"Fontaine C, Rigamonti E, Pourcet B, Duez H, Duhem C, Fruchart JC, Chinetti-Gbaguidi G, Staels B";;"May 2008";1212192000;;"A role of the nuclear receptor Rev-erbalpha in the regulation of transcription pathways involving other nuclear receptors is emerging. Indeed, Rev-erbalpha is a negative regulator of transcription by binding to overlapping response elements shared with various nuclear receptors, including the peroxisome proliferator-activated receptors and the retinoid-related orphan receptor alpha (RORalpha). Here, we show that Rev-erbalpha is expressed in primary human macrophages and that its expression is induced by synthetic ligands for the liver X receptors (LXRs), which control cholesterol homeostasis, inflammation, and the immune response in macrophages. LXRalpha binds to a specific response element in the human Rev-erbalpha promoter, thus inducing Rev-erbalpha transcriptional expression. Interestingly, Rev-erbalpha does not influence basal or LXR-regulated cholesterol homeostasis. However, Rev-erbalpha overexpression represses the induction of toll-like receptor (TLR)-4 by LXR agonists, whereas Rev-erbalpha silencing by short interfering RNA results in enhanced TLR-4 expression upon LXR activation. Electrophoretic mobility shift, chromatin immunoprecipitation, and transient transfection experiments demonstrate that Rev-erbalpha represses human TLR-4 promoter activity by binding as a monomer to a RevRE site overlapping with the LXR response element site in the TLR-4 promoter. These data identify Rev-erbalpha as a new LXR target gene, inhibiting LXR-induction of TLR-4 in a negative transcriptional feedback loop, but not cholesterol homeostasis gene expression." 9355;"Unlike PPARgamma, PPARalpha or PPARbeta/delta activation does not promote human monocyte differentiation toward alternative macrophages.";"G. Chinetti";"Equipe 09, Team 09";19527689;"Biochemical and biophysical research communications";"Bouhlel MA, Brozek J, Derudas B, Zawadzki C, Jude B, Staels B, Chinetti-Gbaguidi G";;"Jun 2009";1245196800;;"Macrophages adapt their response to micro-environmental signals. While Th1 cytokines promote pro-inflammatory M1 macrophages, Th2 cytokines promote an ""alternative"" anti-inflammatory M2 macrophage phenotype. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in macrophages where they control the inflammatory response. It has been shown that PPARgamma promotes the differentiation of monocytes into anti-inflammatory M2 macrophages in humans and mice, while a role for PPARbeta/delta in this process has been reported only in mice and no data are available for PPARalpha. Here, we show that in contrast to PPARgamma, expression of PPARalpha and PPARbeta/delta overall does not correlate with the expression of M2 markers in human atherosclerotic lesions, whereas a positive correlation with genes of lipid metabolism exists. Moreover, unlike PPARgamma, PPARalpha or PPARbeta/delta activation does not influence human monocyte differentiation into M2 macrophages in vitro. Thus, PPARalpha and PPARbeta/delta do not appear to modulate the alternative differentiation of human macrophages." 9353;"Visfatin is induced by peroxisome proliferator-activated receptor gamma in human macrophages.";"G. Chinetti";"Equipe 09, Team 09";20608974;"The FEBS journal";"Mayi TH, Duhem C, Copin C, Bouhlel MA, Rigamonti E, Pattou F, Staels B, Chinetti-Gbaguidi G";;"Aug 2010";1280620800;;"Obesity is a low-grade chronic inflammatory disease associated with an increased number of macrophages (adipose tissue macrophages) in adipose tissue. Within the adipose tissue, adipose tissue macrophages are the major source of visfatin/pre-B-cell colony-enhancing factor/nicotinamide phosphoribosyl transferase. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) exerts anti-inflammatory effects in macrophages by inhibiting cytokine production and enhancing alternative differentiation. In this study, we investigated whether PPARgamma modulates visfatin expression in murine (bone marrow-derived macrophage) and human (primary human resting macrophage, classical macrophage, alternative macrophage or adipose tissue macrophage) macrophage models and pre-adipocyte-derived adipocytes. We show that synthetic PPARgamma ligands increase visfatin gene expression in a PPARgamma-dependent manner in primary human resting macrophages and in adipose tissue macrophages, but not in adipocytes. The threefold increase of visfatin mRNA was paralleled by an increase of protein expression (30%) and secretion (30%). Electrophoretic mobility shift assay experiments and transient transfection assays indicated that PPARgamma induces visfatin promoter activity in human macrophages by binding to a DR1-PPARgamma response element. Finally, we show that PPARgamma ligands increase NAD(+) production in primary human macrophages and that this regulation is dampened in the presence of visfatin small interfering RNA or by the visfatin-specific inhibitor FK866. Taken together, our results suggest that PPARgamma regulates the expression of visfatin in macrophages, leading to increased levels of NAD(+)." 9351;"Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways.";"G. Chinetti";"Equipe 09, Team 09";21350215;"Circulation research";"Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y, Derudas B, Mayi T, Bories G, Tailleux A, Haulon S, Zawadzki C, Jude B, Staels B";;"Apr 2011";1301616000;;"A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an ""alternative"" M2 phenotype." 9349;"PPARα activation differently affects microparticle content in atherosclerotic lesions and liver of a mouse model of atherosclerosis and NASH.";"G. Chinetti";"Equipe 09, Team 09";21529810;Atherosclerosis;"Baron M, Leroyer AS, Majd Z, Lalloyer F, Vallez E, Bantubungi K, Chinetti-Gbaguidi G, Delerive P, Boulanger CM, Staels B, Tailleux A";;"Sep 2011";1314835200;;"Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are complex pathologies characterized by lipid accumulation, chronic inflammation and extensive tissue remodelling. Microparticles (MPs), small membrane vesicles produced by activated and apoptotic cells, might not only be biomarkers, but also functional actors in these pathologies. The apoE2-KI mouse is a model of atherosclerosis and NAFLD. Activation of the nuclear receptor PPARα decreases atherosclerosis and components of non-alcoholic steatohepatitis (NASH) in the apoE2-KI mouse." 9347;"Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype.";"G. Chinetti";"Equipe 09, Team 09";21968977;Diabetologia;"Fuentes L, Wouters K, Hannou SA, Cudejko C, Rigamonti E, Mayi TH, Derudas B, Pattou F, Chinetti-Gbaguidi G, Staels B, Paumelle R";;"Dec 2011";1322697600;;"Human adipose tissue macrophages (ATMs) display an alternatively activated (M2) phenotype, but are still able to produce excessive inflammatory mediators. However, the processes driving this particular ATM phenotype are not understood. Genome-wide association studies associated the CDKN2A locus, encoding the tumour suppressor p16(INK4A), with the development of type 2 diabetes. In the present study, p16(INK4A) levels in human ATMs and the role of p16(INK4A) in acquiring the ATM phenotype were assessed." 9344;"p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages.";"G. Chinetti";"Equipe 09, Team 09";21636855;Blood;"Cudejko C, Wouters K, Fuentes L, Hannou SA, Paquet C, Bantubungi K, Bouchaert E, Vanhoutte J, Fleury S, Remy P, Tailleux A, Chinetti-Gbaguidi G, Dombrowicz D, Staels B, Paumelle R";;"Sep 2011";1314835200;;"The CDKN2A locus, which contains the tumor suppressor gene p16(INK4a), is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMϕ) or alternatively (AAMϕ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16(INK4a) deficiency (p16(-/-)) modulates the macrophage phenotype. Transcriptome analysis revealed that p16(-/-) BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4-induced macrophage polarization. In line with this observation, p16(-/-) BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16(-/-) BM displayed higher hepatic AAMϕ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMϕ phenotype skewing. Surprisingly, p16(-/-) BMDMs did not display increased IL-4-induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)-induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16(INK4a) as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases." 9343;"Macrophage polarization in metabolic disorders: functions and regulation.";"G. Chinetti";"Equipe 09, Team 09";21825981;"Current opinion in lipidology";"Chinetti-Gbaguidi G, Staels B";;"Oct 2011";1317427200;;"To discuss recent findings on the role and regulation of macrophage polarization in obesity and atherosclerosis." 9341;"Impaired expression of the inducible cAMP early repressor accounts for sustained adipose CREB activity in obesity.";"G. Chinetti";"Equipe 09, Team 09";21998402;Diabetes;"Favre D, Le Gouill E, Fahmi D, Verdumo C, Chinetti-Gbaguidi G, Staels B, Caiazzo R, Pattou F, Lê KA, Tappy L, Regazzi R, Giusti V, Vollenweider P, Waeber G, Abderrahmani A";;"Dec 2011";1322697600;;"Increase in adipose cAMP-responsive element binding protein (CREB) activity promotes adipocyte dysfunction and systemic insulin resistance in obese mice. This is achieved by increasing the expression of activating transcription factor 3 (ATF3). In this study, we investigated whether impaired expression of the inducible cAMP early repressor (ICER), a transcriptional antagonist of CREB, is responsible for the increased CREB activity in adipocytes of obese mice and humans." 9337;"Impaired alternative macrophage differentiation of peripheral blood mononuclear cells from obese subjects.";"G. Chinetti";"Equipe 09, Team 09";22192929;"Diabetes & vascular disease research";"Bories G, Caiazzo R, Derudas B, Copin C, Raverdy V, Pigeyre M, Pattou F, Staels B, Chinetti-Gbaguidi G";;"Jul 2012";1341100800;;"Visceral obesity is a chronic, low-grade inflammatory disease that predisposes people to the metabolic syndrome, type 2 diabetes and its cardiovascular complications. Adipose tissue is not a passive storehouse for fat, but an endocrine organ synthesizing and releasing a variety of bioactive molecules, some of which are produced by infiltrated immune-inflammatory cells including macrophages. Two different subpopulations of macrophages have been identified in adipose tissue: pro-inflammatory 'classical' M1 and anti-inflammatory 'alternative' M2 macrophages, and their ratio is suggested to influence the metabolic complications of obesity. These macrophages derive primarily from peripheral blood mononuclear cells (PBMCs). We hypothesised that obesity and the metabolic syndrome modulate PBMC functions. Therefore, alteration of the monocyte response, and more specifically their ability to differentiate toward alternative anti-inflammatory macrophages, was assessed in PBMCs isolated from lean and obese subjects with or without alterations in glucose homeostasis. Our results indicate that PBMCs from obese subjects have an altered expression of M2 markers and that their monocytes are less susceptible to differentiate toward an alternative phenotype. Thus PBMCs in obesity are programmed, which may contribute to the inflammatory dysregulation and increased susceptibility to inflammatory diseases in these patients." 9339;"Human adipose tissue macrophages display activation of cancer-related pathways.";"G. Chinetti";"Equipe 09, Team 09";22511784;"The Journal of biological chemistry";"Mayi TH, Daoudi M, Derudas B, Gross B, Bories G, Wouters K, Brozek J, Caiazzo R, Raverdi V, Pigeyre M, Allavena P, Mantovani A, Pattou F, Staels B, Chinetti-Gbaguidi G";;"Apr 2012";1334793600;;"Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype." 9335;"Peroxisome proliferator-activated receptor-γ activation induces 11β-hydroxysteroid dehydrogenase type 1 activity in human alternative macrophages.";"G. Chinetti";"Equipe 09, Team 09";22207732;"Arteriosclerosis, thrombosis, and vascular biology";"Chinetti-Gbaguidi G, Bouhlel MA, Copin C, Duhem C, Derudas B, Neve B, Noel B, Eeckhoute J, Lefebvre P, Seckl JR, Staels B";;"Mar 2012";1330560000;;"11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome proliferator- activated receptor-γ (PPARγ) is a nuclear receptor controlling inflammation, lipid metabolism, and the macrophage polarization state. In this study, we investigated the impact of macrophage polarization on the expression and activity of 11β-HSD1 and the role of PPARγ therein." 9331;"11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.";"G. Chinetti";"Equipe 09, Team 09";23303209;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Kipari T, Hadoke PW, Iqbal J, Man TY, Miller E, Coutinho AE, Zhang Z, Sullivan KM, Mitic T, Livingstone DE, Schrecker C, Samuel K, White CI, Bouhlel MA, Chinetti-Gbaguidi G, Staels B, Andrew R, Walker BR, Savill JS, Chapman KE, Seckl JR";;"Apr 2013";1364774400;;"11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages." 9332;"Role of proinflammatory CD68(+) mannose receptor(-) macrophages in peroxiredoxin-1 expression and in abdominal aortic aneurysms in humans.";"G. Chinetti";"Equipe 09, Team 09";23241402;"Arteriosclerosis, thrombosis, and vascular biology";"Boytard L, Spear R, Chinetti-Gbaguidi G, Acosta-Martin AE, Vanhoutte J, Lamblin N, Staels B, Amouyel P, Haulon S, Pinet F";;"Feb 2013";1359676800;;"Abdominal aortic aneurysms (AAAs), dilations of the infrarenal aorta, are characterized by inflammation and oxidative stress. We previously showed increased levels of peroxiredoxin-1 (PRDX-1) in macrophages cultured from AAA patients. The purpose of the study was to determine which subpopulation of macrophages is present in AAAs and is involved in upregulation of PRDX-1 in aneurysmal disease." 9329;"Macrophage function and polarization in cardiovascular disease: a role of estrogen signaling?";"G. Chinetti";"Equipe 09, Team 09";23640494;"Arteriosclerosis, thrombosis, and vascular biology";"Bolego C, Cignarella A, Staels B, Chinetti-Gbaguidi G";;"May 2013";1367625600;;"Macrophages are plastic and versatile cells adapting their function/phenotype to the microenvironment. Distinct macrophage subpopulations with different functions, including classically (M1) and (M2) activated macrophages, have been described. Reciprocal skewing of macrophage polarization between the M1 and M2 state is a process modulated by transcription factors, such as the nuclear peroxisome proliferator-activated receptors. However, whether the estrogen/estrogen receptor pathways control the balance between M1/M2 macrophages is only partially understood. Estrogen-dependent effects on the macrophage system may be regarded as potential targets of pharmacological approaches to protect postmenopausal women from the elevated risk of cardiovascular disease." 9327;"Free leptin, carotid plaque phenotype and relevance to related symptomatology: insights from the OPAL-Lille carotid endarterectomy study.";"G. Chinetti";"Equipe 09, Team 09";23890921;"International journal of cardiology";"Elkalioubie A, Zawadzki C, Roma-Lavisse C, Chinetti-Gbaguidi G, Tagzirt M, Corseaux D, Juthier F, Vaast B, Vanhoutte J, Vincentelli A, Jude B, Haulon S, Staels B, Susen S, Van Belle E, Dupont A";;"Oct 2013";1380585600;; 9325;"Adipose tissue macrophages (ATM) of obese patients are releasing increased levels of prolactin during an inflammatory challenge: a role for prolactin in diabesity?";"G. Chinetti";"Equipe 09, Team 09";24361460;"Biochimica et biophysica acta";"Bouckenooghe T, Sisino G, Aurientis S, Chinetti-Gbaguidi G, Kerr-Conte J, Staels B, Fontaine P, Storme L, Pattou F, Vambergue A";;"Apr 2014";1396310400;;"Obesity, characterized by low grade inflammation, induces adipose tissue macrophage (ATM) infiltration in white adipose tissue (AT) in both humans and rodents, thus contributing to insulin resistance. Previous studies have shown altered prolactin secretion in obesity, however, studies linking ATM infiltration and prolactin (PRL) secretion to the pathogenesis of the metabolic syndrome, obesity and diabetes are lacking." 9323;"Liver X receptor activation stimulates iron export in human alternative macrophages.";"G. Chinetti";"Equipe 09, Team 09";24036496;"Circulation research";"Bories G, Colin S, Vanhoutte J, Derudas B, Copin C, Fanchon M, Daoudi M, Belloy L, Haulon S, Zawadzki C, Jude B, Staels B, Chinetti-Gbaguidi G";;"Nov 2013";1383264000;;"In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities." 9321;"HDL does not influence the polarization of human monocytes toward an alternative phenotype.";"G. Chinetti";"Equipe 09, Team 09";24456889;"International journal of cardiology";"Colin S, Fanchon M, Belloy L, Bochem AE, Copin C, Derudas B, Stroes ES, Hovingh GK, Kuivenhoven JA, Dallinga-Thie GM, Staels B, Chinetti-Gbaguidi G";;"Mar 2014";1393632000;;"Macrophages are crucial cells in the pathogenesis of atherosclerosis. Macrophages are plastic cells which can switch from a classical pro-inflammatory M1 to an alternative anti-inflammatory M2 macrophage phenotype, depending on the environmental stimuli. Because high-density lipoprotein (HDL) cholesterol levels are inversely correlated to cardiovascular disease and since HDL displays anti-inflammatory properties, we investigated whether HDL can affect alternative macrophage differentiation of primary human monocytes in the presence of interleukin (IL)-4, a M2 macrophage polarization driver, in vitro and ex vivo." 9319;"miR-206 controls LXRα expression and promotes LXR-mediated cholesterol efflux in macrophages.";"G. Chinetti";"Equipe 09, Team 09";24603323;"Biochimica et biophysica acta";"Vinod M, Chennamsetty I, Colin S, Belloy L, De Paoli F, Schaider H, Graier WF, Frank S, Kratky D, Staels B, Chinetti-Gbaguidi G, Kostner GM";;"Jun 2014";1401580800;;"Liver X receptors (LXRα and LXRβ) are key transcription factors in cholesterol metabolism that regulate cholesterol biosynthesis/efflux and bile acid metabolism/excretion in the liver and numerous organs. In macrophages, LXR signaling modulates cholesterol handling and the inflammatory response, pathways involved in atherosclerosis. Since regulatory pathways of LXR transcription control are well understood, in the present study we aimed at identifying post-transcriptional regulators of LXR activity. MicroRNAs (miRs) are such post-transcriptional regulators of genes that in the canonical pathway mediate mRNA inactivation. In silico analysis identified miR-206 as a putative regulator of LXRα but not LXRβ. Indeed, as recently shown, we found that miR-206 represses LXRα activity and expression of LXRα and its target genes in hepatic cells. Interestingly, miR-206 regulates LXRα differently in macrophages. Stably overexpressing miR-206 in THP-1 human macrophages revealed an up-regulation and miR-206 knockdown led to a down-regulation of LXRα and its target genes. In support of these results, bone marrow-derived macrophages (BMDMs) from miR-206 KO mice also exhibited lower expression of LXRα target genes. The physiological relevance of these findings was proven by gain- and loss-of-function of miR-206; overexpression of miR-206 enhanced cholesterol efflux in human macrophages and knocking out miR-206 decreased cholesterol efflux from MPMs. Moreover, we show that miR-206 expression in macrophages is repressed by LXRα activation, while oxidized LDL and inflammatory stimuli profoundly induced miR-206 expression. We therefore propose a feed-back loop between miR-206 and LXRα that might be part of an LXR auto-regulatory mechanism to fine tune LXR activity. " 9317;"HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype.";"G. Chinetti";"Equipe 09, Team 09";24854267;"Journal of the American Society of Nephrology : JASN";"Shroff R, Speer T, Colin S, Charakida M, Zewinger S, Staels B, Chinetti-Gbaguidi G, Hettrich I, Rohrer L, O'Neill F, McLoughlin E, Long D, Shanahan CM, Landmesser U, Fliser D, Deanfield JE";;"Nov 2014";1414800000;;"Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2-5 (HDL(CKD)), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL(CKD) strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation. " 9315;"Macrophage phenotypes and their modulation in atherosclerosis.";"G. Chinetti";"Equipe 09, Team 09";24998279;"Circulation journal : official journal of the Japanese Circulation Society";"De Paoli F, Staels B, Chinetti-Gbaguidi G";;"Jan 2014";1388534400;;"Atherosclerosis is the result of a chronic inflammatory response in the arterial wall related to uptake of low-density lipoprotein by macrophages and their subsequent transformation in foam cells. Monocyte-derived macrophages are the principal mediators of tissue homeostasis and repair, response to pathogens and inflammation. However, macrophages are a homogeneous cell population presenting a continuum phenotypic spectrum with, at the extremes, the classically Th-1 polarized M1 and alternatively Th-2 polarized M2 macrophage phenotypes, which have been well described. Moreover, M2 macrophages also present several subtypes often termed M2a, b, c and d, each of them expressing specific markers and exhibiting specialized properties. Macrophage plasticity is mirrored also in the atherosclerotic lesions, where different stimuli can influence the phenotype giving rise to a complex system of subpopulations, such as Mox, Mhem, M(Hb) and M4 macrophages. An abundant literature has described the potential modulators of the reciprocal skewing between pro-inflammatory M1 and anti-inflammatory M2 macrophages including lesion stage and localization, miRNA, transcription factors such as PPARγ, KLF4 and NR4A family members, high-density lipoproteins and plaque lipid content, pathways such as the rapamycin-mTOR1 pathway, molecules such as thioredoxin-1, infection by helminths and irradiation. We hope to provide an overview of the macrophage phenotype complexity in cardiovascular diseases, particularly atherosclerosis." 9313;"Macrophage phenotypes in atherosclerosis.";"G. Chinetti";"Equipe 09, Team 09";25319333;"Immunological reviews";"Colin S, Chinetti-Gbaguidi G, Staels B";;"Oct 2014";1413504000;;"Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype. " 9311;"Macrophage subsets in atherosclerosis.";"G. Chinetti";"Equipe 09, Team 09";25367649;"Nature reviews. Cardiology";"Chinetti-Gbaguidi G, Colin S, Staels B";;"Jan 2015";1420070400;;"Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. In atherosclerotic lesions, macrophages respond to various environmental stimuli, such as modified lipids, cytokines, and senescent erythrocytes, which can modify their functional phenotypes. The results of studies on human atherosclerotic plaques demonstrate that the relative proportions of macrophage subsets within a plaque might be a better indicator of plaque phenotype and stability than the total number of macrophages. Understanding the function of specific macrophage subsets and their contribution to the composition and growth of atherosclerotic plaques would aid the identification of novel strategies to delay or halt the development of the disease and its associated pathophysiological consequences. However, most studies aimed at characterizing the phenotypes of human macrophages are performed in vitro and, therefore, their functional relevance to human pathology remains uncertain. In this Review, the diverse range of macrophage phenotypes in atherosclerotic lesions and their potential roles in both plaque progression and stability are discussed, with an emphasis on human pathology. " 9307;"Emerging small molecule drugs.";"G. Chinetti";"Equipe 09, Team 09";25523004;"Handbook of experimental pharmacology";"Colin S, Chinetti-Gbaguidi G, Kuivenhoven JA, Staels B";;"Dec 2014";1419033600;;"Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208. " 9308;"The neuron-derived orphan receptor 1 (NOR1) is induced upon human alternative macrophage polarization and stimulates the expression of markers of the M2 phenotype.";"G. Chinetti";"Equipe 09, Team 09";25941992;Atherosclerosis;"De Paoli F, Eeckhoute J, Copin C, Vanhoutte J, Duhem C, Derudas B, Dubois-Chevalier J, Colin S, Zawadzki C, Jude B, Haulon S, Lefebvre P, Staels B, Chinetti-Gbaguidi G";;"Jul 2015";1435708800;;"Atherosclerosis is an inflammatory disease in which macrophages play a crucial role. Macrophages are present in different phenotypes, with at the extremes of the spectrum the classical M1 pro-inflammatory and the alternative M2 anti-inflammatory macrophages. The neuron-derived orphan receptor 1 (NOR1), together with Nur77 and Nurr1, are members of the NR4A orphan nuclear receptor family, expressed in human atherosclerotic lesion macrophages. However, the role of NOR1 in human macrophages has not been studied yet." 9305;"The coronary artery disease-associated gene C6ORF105 is expressed in human macrophages under the transcriptional control of PPARγ.";"G. Chinetti";"Equipe 09, Team 09";25595457;"FEBS letters";"Chinetti-Gbaguidi G, Copin C, Derudas B, Vanhoutte J, Zawadzki C, Jude B, Haulon S, Pattou F, Marx N, Staels B";;"Feb 2015";1422748800;;"Coronary artery disease (CAD) is a major cause of morbidity and mortality. Mutations in C6ORF105, associated with decreased gene expression, positively correlate with the risk of CAD in Chinese populations. Moreover, the C6ORF105-encoded protein may play a role in coagulation. Here, we report that C6ORF105 gene expression is lower in circulating mononuclear cells from obese diabetic than lean subjects. Moreover, C6ORF105 is expressed in human macrophages and atherosclerotic lesions, where its expression positively correlates with expression of the transcription factor Peroxisome Proliferator-Activated Receptor (PPAR)γ. Activation of PPARγ increases, in a PPARγ-dependent manner, the expression of C6ORF105 in human macrophages and atherosclerotic lesions. " 9303;"M1 and M2 macrophage proteolytic and angiogenic profile analysis in atherosclerotic patients reveals a distinctive profile in type 2 diabetes.";"G. Chinetti";"Equipe 09, Team 09";25966737;"Diabetes & vascular disease research";"Roma-Lavisse C, Tagzirt M, Zawadzki C, Lorenzi R, Vincentelli A, Haulon S, Juthier F, Rauch A, Corseaux D, Staels B, Jude B, Van Belle E, Susen S, Chinetti-Gbaguidi G, Dupont A";;"Jul 2015";1435708800;;"This study aimed to investigate atherosclerotic mediators' expression levels in M1 and M2 macrophages and to focus on the influence of diabetes on M1/M2 profiles. Macrophages from 36 atherosclerotic patients (19 diabetics and 17 non-diabetics) were cultured with interleukin-1β (IL-1β) or IL-4 to induce M1 or M2 phenotype, respectively. The atherosclerotic mediators' expression was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that M1 and M2 macrophages differentially expressed mediators involved in proteolysis and angiogenesis processes. The proteolytic balance (matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1), MMP-9/plasminogen activator inhibitor-1 (PAI-1) and MMP-9/tissue factor pathway inhibitor-2 (TFPI-2) ratios) was higher in M1 versus M2, whereas M2 macrophages presented higher angiogenesis properties (increased vascular endothelial growth factor/TFPI-2 and tissue factor/TFPI-2 ratios). Moreover, M1 macrophages from diabetics displayed more important proangiogenic and proteolytic activities than non-diabetics. This study reveals that M1 and M2 macrophages could differentially modulate major atherosclerosis-related pathological processes. Moreover, M1 macrophages from diabetics display a deleterious phenotype that could explain the higher plaque vulnerability observed in these subjects. " 9301;"Transducin-like enhancer of split-1 is expressed and functional in human macrophages.";"G. Chinetti";"Equipe 09, Team 09";26763127;"FEBS letters";"De Paoli F, Copin C, Vanhoutte J, Derudas B, Vinod M, Zawadzki C, Susen S, Pattou F, Haulon S, Staels B, Eeckhoute J, Chinetti-Gbaguidi G";;"Jan 2016";1451606400;;"Macrophages display heterogeneous phenotypes, including the classical M1 proinflammatory and the alternative M2 anti-inflammatory polarization states. The transducin-like enhancer of split-1 (TLE1) is a transcriptional corepressor whose functions in macrophages have not been studied yet. We report that TLE1 is highly expressed in human alternative macrophages in vitro and in atherosclerotic plaques as well as in adipose tissue M1/M2 mixed macrophages. TLE1 silencing in alternative macrophages decreases the expression of the M2 markers IL-1Ra and IL-10, while it exacerbates TNFα and CCL3 induction by lipopolysaccharide. Hence, TLE1 is expressed in human macrophages where it has potential anti-inflammatory and alternative phenotype promoting properties. " 9299;"Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function.";"G. Chinetti";"Equipe 09, Team 09";27900262;"Molecular metabolism";"Bricambert J, Favre D, Brajkovic S, Bonnefond A, Boutry R, Salvi R, Plaisance V, Chikri M, Chinetti-Gbaguidi G, Staels B, Giusti V, Caiazzo R, Pattou F, Waeber G, Froguel P, Abderrahmani A";;"12 2016";1480550400;;"The goal of the study was to investigate the role of histone deacetylases (HDACs) in adipocyte function associated with obesity and hypoxia." 9297;"DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose-dependently modulate the inflammatory response in human macrophages: Putative mechanisms through PPAR activation.";"G. Chinetti";"Equipe 09, Team 09";27988338;"Free radical biology & medicine";"Bosviel R, Joumard-Cubizolles L, Chinetti-Gbaguidi G, Bayle D, Copin C, Hennuyer N, Duplan I, Staels B, Zanoni G, Porta A, Balas L, Galano JM, Oger C, Mazur A, Durand T, Gladine C";;"02 2017";1485907200;;"Whereas the anti-inflammatory properties and mechanisms of action of long chain ω3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. We conducted a dose-dependent and comparative study in human primary macrophages aiming to compare the anti-inflammatory activity of two types of DHA-derived oxylipins including the well-described protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A- and 4-F-NeuroP) formed through free-radical mediated oxygenation and expected to be new anti-inflammatory mediators. Considering the potential ability of these DHA-derived oxylipins to bind PPARs and knowing the central role of these transcription factors in the regulation of macrophage inflammatory response, we performed transactivation assays to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced mRNA levels of cytokines such as IL-6 and TNF-α, however not at the same doses. NPD1 showed the most effect at 0.1µM (-14.9%, p<0.05 for IL-6 and -26.7%, p<0.05 for TNF-α) while the three other molecules had greater effects at 10µM, with the strongest result due to the cyclopentenone neuroprostane, 14-A-NeuroP (-49.8%, p<0.001 and -40.8%, p<0.001, respectively). Part of the anti-inflammatory properties of the DHA-derived oxylipins investigated could be linked to their activation of PPARs. Indeed, all tested oxylipins significantly activated PPARγ, with 14-A-NeuroP leading to the strongest activation, and NPD1 and PDX also activated PPARα. In conclusion, our results show that neuroprostanes and more especially cyclopentenone neuroprostanes have potent anti-inflammatory activities similar or even more pronounced than protectins supporting that neuroprostanes should be considered as important contributors to the anti-inflammatory effects of DHA." 9295;"PPARβ in macrophages and atherosclerosis.";"G. Chinetti";"Equipe 09, Team 09";28011212;Biochimie;"Chinetti-Gbaguidi G, Staels B";;"May 2017";1493596800;;"Macrophages are central cells in the genesis and development of atherosclerosis, one of the major causes of cardiovascular diseases. Macrophages take up lipids (mainly cholesterol and triglycerides) from lipoproteins thus transforming into foam cells. Moreover, through the efflux pathway, macrophages are the main actors of the elimination of excessive tissue cholesterol toward extra-cellular acceptors. Macrophages participate in the control of inflammation by displaying different functional phenotypes, from the M1 pro-inflammatory to the M2 anti-inflammatory state. The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)β (also called PPARδ or PPARβ/δ) is expressed in macrophages where it plays a different role in the control of lipid metabolism, inflammation and phagocytosis of apoptotic cells. This review will summarize our current understanding of how PPARβ regulates macrophage biology and its impact on atherosclerosis. Differences between studies and species-specific macrophage gene regulation will be discussed." 9293;"Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis.";"G. Chinetti";"Equipe 09, Team 09";28077943;"PPAR research";"Ferret-Sena V, Maia E Silva A, Sena A, Cavaleiro I, Vale J, Derudas B, Chinetti-Gbaguidi G, Staels B";;"Jan 2016";1451606400;;"Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPAR, PPAR/, PPAR, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPAR/ mRNA ( = 0.009) in comparison to baseline, while mRNA expression of PPAR and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls ( = 0.026 and = 0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients ( = 0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy." 9291;"Peroxisome Proliferator-Activated Receptor Induces the Expression of Tissue Factor Pathway Inhibitor-1 (TFPI-1) in Human Macrophages.";"G. Chinetti";"Equipe 09, Team 09";28115923;"PPAR research";"Chinetti-Gbaguidi G, Copin C, Derudas B, Marx N, Eechkoute J, Staels B";;"Jan 2016";1451606400;;"Tissue factor (TF) is the initiator of the blood coagulation cascade after interaction with the activated factor VII (FVIIa). Moreover, the TF/FVIIa complex also activates intracellular signalling pathways leading to the production of inflammatory cytokines. The TF/FVIIa complex is inhibited by the tissue factor pathway inhibitor-1 (TFPI-1). Peroxisome proliferator-activated receptor gamma (PPAR) is a transcription factor that, together with PPAR and PPAR/, controls macrophage functions. However, whether PPAR activation modulates the expression of TFP1-1 in human macrophages is not known. Here we report that PPAR activation increases the expression of TFPI-1 in human macrophages in vitro as well as in vivo in circulating peripheral blood mononuclear cells. The induction of TFPI-1 expression by PPAR ligands, an effect shared by the activation of PPAR and PPAR/, occurs also in proinflammatory M1 and in anti-inflammatory M2 polarized macrophages. As a functional consequence, treatment with PPAR ligands significantly reduces the inflammatory response induced by FVIIa, as measured by variations in the IL-8, MMP-2, and MCP-1 expression. These data identify a novel role for PPAR in the control of TF the pathway." 9289;"Human Alternative Macrophages Populate Calcified Areas of Atherosclerotic Lesions and Display Impaired RANKL-Induced Osteoclastic Bone Resorption Activity.";"G. Chinetti";"Equipe 09, Team 09";28438779;"Circulation research";"Chinetti-Gbaguidi G, Daoudi M, Rosa M, Vinod M, Louvet L, Copin C, Fanchon M, Vanhoutte J, Derudas B, Belloy L, Haulon S, Zawadzki C, Susen S, Massy ZA, Eeckhoute J, Staels B";;"Jun 2017";1496275200;;"Vascular calcification is a process similar to bone formation leading to an inappropriate deposition of calcium phosphate minerals in advanced atherosclerotic plaques. Monocyte-derived macrophages, located in atherosclerotic lesions and presenting heterogeneous phenotypes, from classical proinflammatory M1 to alternative anti-inflammatory M2 macrophages, could potentially display osteoclast-like functions." 9287;"[Inflammation and metabolic and vascular diseases: pharmacologic approaches].";"G. Chinetti";"Equipe 09, Team 09";17051858;"Journees annuelles de diabetologie de l'Hotel-Dieu";"Chinetti G, Staels B";;"Jan 2006";1136073600;; 9285;"Transcriptional regulation of macrophage cholesterol trafficking by PPARalpha and LXR.";"G. Chinetti";"Equipe 09, Team 09";17073767;"Biochemical Society transactions";"Chinetti G, Fruchart JC, Staels B";;"Dec 2006";1164931200;;"PPARs (peroxisome-proliferator-activated receptors) and LXRs (liver X receptors) are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Since the macrophage plays an important role in host defence and immuno-inflammatory pathologies, particular attention has been paid to the role of PPARs and LXRs in the control of macrophage gene expression and function. Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes, including atherosclerosis. Research over the last few years has revealed important roles for PPARs and LXRs in macrophage inflammation and cholesterol homoeostasis with consequences in atherosclerosis development. This review will discuss the role of these transcription factors in the control of cholesterol trafficking in macrophages." 9283;"Association between liver X receptor alpha gene polymorphisms and risk of metabolic syndrome in French populations.";"G. Chinetti";"Equipe 09, Team 09";18209740;"International journal of obesity (2005)";"Legry V, Cottel D, Ferrières J, Chinetti G, Deroide T, Staels B, Amouyel P, Meirhaeghe A";;"Mar 2008";1204329600;;"The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor alpha (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome." 9281;"PPARs/RXRs in Cardiovascular Physiology and Disease.";"G. Chinetti";"Equipe 09, Team 09";18389071;"PPAR research";"Finck BN, Chinetti G, Staels B";;"Jan 2008";1199145600;; 9279;"Association between a thyroid hormone receptor-α gene polymorphism and blood pressure but not with coronary heart disease risk.";"G. Chinetti";"Equipe 09, Team 09";21654857;"American journal of hypertension";"Goumidi L, Gauthier K, Legry V, Mayi TH, Houzet A, Cottel D, Montaye M, Proust C, Kee F, Ferrières J, Arveiler D, Ducimetière P, Staels B, Dallongeville J, Chinetti G, Flamant F, Amouyel P, Meirhaeghe A";;"Sep 2011";1314835200;;"Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor-β whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-α (TR-α) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-α (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk." 9277;"Nur77turing macrophages in atherosclerosis.";"G. Chinetti";"Equipe 09, Team 09";22302751;"Circulation research";"Lefebvre P, Chinetti G, Staels B";;"Feb 2012";1328054400;; 9275;"Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone.";;;22592557;"American journal of physiology. Regulatory, integrative and comparative physiology";"Wolowczuk I, Hennart B, Leloire A, Bessede A, Soichot M, Taront S, Caiazzo R, Raverdy V, Pigeyre M, , Guillemin GJ, Allorge D, Pattou F, Froguel P, Poulain-Godefroy O";;"Jul 2012";1341100800;;"Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension." 9273;"Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production.";"G. Chinetti";"Equipe 09, Team 09";22843443;"European heart journal";"Colin S, Briand O, Touche V, Wouters K, Baron M, Pattou F, Hanf R, Tailleux A, Chinetti G, Staels B, Lestavel S";;"Aug 2013";1375315200;;"Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor controlling lipid metabolism in liver, heart, muscle, and macrophages. Peroxisome proliferator-activated receptor-α activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver. However, the intestine expresses PPAR-α, produces HDL and chylomicrons, and is exposed to diet-derived PPAR-α ligands. Therefore, we examined the effects of PPAR-α activation on intestinal lipid and lipoprotein metabolism." 9271;"Von Willebrand factor as a biological sensor of blood flow to monitor percutaneous aortic valve interventions.";"G. Chinetti";"Equipe 09, Team 09";25670067;"Circulation research";"Van Belle E, Rauch A, Vincentelli A, Jeanpierre E, Legendre P, Juthier F, Hurt C, Banfi C, Rousse N, Godier A, Caron C, Elkalioubie A, Corseaux D, Dupont A, Zawadzki C, Delhaye C, Mouquet F, Schurtz G, Deplanque D, Chinetti G, Staels B, Goudemand J, Jude B, Lenting PJ, Susen S";;"Mar 2015";1425168000;;"Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis. Residual gradient and residual aortic regurgitation are major predictors of midterm and long-term outcome after percutaneous aortic valve procedures. We hypothesized that (1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor defect could be instantaneous after acute changes in blood flow, (2) a bedside point-of-care assay (platelet function analyzer-closure time adenine DI-phosphate [PFA-CADP]), reflecting HMW multimers changes, could be used to monitor in real-time percutaneous aortic valve procedures." 9269;"Structural and functional changes in HDL with low grade and chronic inflammation.";"G. Chinetti";"Equipe 09, Team 09";25919891;"International journal of cardiology";"O'Neill F, Riwanto M, Charakida M, Colin S, Manz J, McLoughlin E, Khan T, Klein N, Kay CW, Patel K, Chinetti G, Staels B, D'Aiuto F, Landmesser U, Deanfield J";;"Jun 2015";1433116800;;"HDL functionality has been shown to be impaired in inflammatory conditions, including coronary artery disease. The present study aims to determine the impact of low grade and acute inflammation on HDL function and structure." 9267;"The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation.";"G. Chinetti";"Equipe 09, Team 09";26347385;"Obesity (Silver Spring, Md.)";"Favennec M, Hennart B, Caiazzo R, Leloire A, Yengo L, Verbanck M, Arredouani A, Marre M, Pigeyre M, Bessede A, Guillemin GJ, Chinetti G, Staels B, Pattou F, Balkau B, Allorge D, Froguel P, Poulain-Godefroy O";;"Oct 2015";1443657600;;"This study characterized the kynurenine pathway (KP) in human obesity by evaluating circulating levels of kynurenines and the expression of KP enzymes in adipose tissue." 9265;"Insights on glicentin, a promising peptide of the proglucagon family.";"F. Lareyre, G. Chinetti, J. Raffort";"Equipe 09, Team 09";28736498;"Biochemia medica";"Raffort J, Lareyre F, Massalou D, Fénichel P, Panaïa-Ferrari P, Chinetti G";;"Jun 2017";1496275200;;"Glicentin is a proglucagon-derived peptide mainly produced in the L-intestinal cells. While the roles of other members of the proglucagon family including glucagon-like peptide 1, glucagon-like peptide 2 and oxyntomodulin has been well studied, the functions and variation of glicentin in human are not fully understood. Experimental and clinical studies have highlighted its role in both intestinal physiology and glucose metabolism, pointing to its potential interest in a wide range of pathological states including gastrointestinal and metabolic disorders. Due to its structure presenting many similarities with the other proglucagon-derived peptides, its measurement is technically challenging. The recent commercialization of specific detection methods has offered new opportunities to go further in the understanding of glicentin physiology. Here we summarize the current knowledge on glicentin biogenesis and physiological roles. In the limelight of clinical studies investigating glicentin variation in human, we discuss future directions for potential applications in clinical practice." 9263;"Diabetes and aortic aneurysm: current state of the art.";"F. Lareyre, G. Chinetti, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30052821;"Cardiovascular research";"Raffort J, Lareyre F, Clément M, Hassen-Khodja R, Chinetti G, Mallat Z";;"11 2018";1541030400;;"Aortic aneurysm is a life-threatening disease due to the risk of aortic rupture. The only curative treatment available relies on surgical approaches; drug-based therapies are lacking, highlighting an unmet need for clinical practice. Abdominal aortic aneurysm (AAA) is frequently associated with atherosclerosis and cardiovascular risk factors including male sex, age, smoking, hypertension, and dyslipidaemia. Thoracic aortic aneurysm (TAA) is more often linked to genetic disorders of the extracellular matrix and the contractile apparatus but also share similar cardiovascular risk factors. Intriguingly, a large body of evidence points to an inverse association between diabetes and both AAA and TAA. A better understanding of the mechanisms underlying the negative association between diabetes and aortic aneurysm could help the development of innovative diagnostic and therapeutic approaches to tackle the disease. Here, we summarize current knowledge on the relationship between glycaemic parameters, diabetes, and the development of aortic aneurysm. Cellular and molecular pathways that underlie the protective effect of diabetes itself and its treatment are reviewed and discussed, along with their potential implications for clinical translation." 9261;"IL-1β- and IL-4-polarized macrophages have opposite effects on adipogenesis of intramuscular fibro-adipogenic progenitors in humans.";"G. Chinetti, J. Raffort";"Equipe 09, Team 09";30451963;"Scientific reports";"Moratal C, Raffort J, Arrighi N, Rekima S, Schaub S, Dechesne CA, Chinetti G, Dani C";;"11 2018";1541030400;;"Intramuscular fat deposition represents a negative prognostic factor for several myopathies, metabolic diseases and aging. Fibro-adipogenic progenitors (FAPs) are considered as the main source of intramuscular adipocytes, but the mechanisms controlling their adipogenic potential are still not elucidated in humans. The aim of this study was to explore the regulation of human FAP adipogenesis by macrophages. We found that CD140a-expressing FAPs were located close to CD68 positive macrophages in muscles from patients with Duchenne muscular dystrophy (DMD). This strongly suggests a potential interaction between FAPs and macrophages in vivo. Isolated human primary FAPs were then differentiated in the presence of conditioned media obtained from primary blood monocyte-polarized macrophages. Molecules released by IL-1β-polarized macrophages (M(IL-1β)) drastically reduced FAP adipogenic potential as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic markers. This was associated with an increased gene expression of pro-inflammatory cytokines in FAPs. Conversely, factors secreted by IL-4-polarized macrophages (M(IL-4)) enhanced FAP adipogenesis. Finally, the inhibition of FAP adipocyte differentiation by M(IL-1β) macrophages requires the stimulation of Smad2 phosphorylation of FAPs. Our findings identify a novel potential crosstalk between FAPs and M(IL-1β) and M(IL-4) macrophages in the development of adipocyte accumulation in human skeletal muscles." 9259;"Regarding ""Outcomes associated with hyperglycemia after abdominal aortic aneurysm repair"".";"F. Lareyre, G. Chinetti, J. Raffort";"Equipe 09, Team 09";30579453;"Journal of vascular surgery";"Lareyre F, Chinetti G, Raffort J";;"01 2019";1546300800;; 9257;"Differential micro-RNA expression in diabetic patients with abdominal aortic aneurysm.";"E. Jean-Baptiste, F. Lareyre, G. Chinetti, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30922869;Biochimie;"Lareyre F, Clément M, Moratal C, Loyer X, Jean-Baptiste E, Hassen-Khodja R, Chinetti G, Mallat Z, Raffort J";;"Jul 2019";1561939200;;"The potential implication of micro-RNAs (miRs) in the negative association between diabetes and abdominal aortic aneurysm (AAA) has so far never been addressed. The aim of this study was to compare miR expression between diabetic and non-diabetic patients with AAA." 9255;"First family case of haemoglobinopathy Titusville in France and literature overview.";"C. Ruetsch, G. Chinetti, J. Raffort";"Equipe 11, Team 11, Equipe 09, Team 09";30940650;"Journal of clinical pathology";"Ruetsch C, Raffort J, Panaia-Ferrari P, Deconde C, Caruba-Bafghi C, Naimi M, Kavafyan J, Suissa L, Chinetti G";;"Jul 2019";1561939200;;"Normal haemoglobin is a tetramer molecule, consisting of two α and β haemoglobin chains. Haemoglobinopathies occur when abnormalities in these proteins are present. More than 1000 naturally occurring human haemoglobin variants with single amino acid substitution throughout the molecule have been identified and can be discovered through their clinical and biological manifestations. Here, we report the case of a 60-year-old woman for whom no oximetry results were obtained during blood gas analysis (BGA) and the values of oxygen saturation obtained from pulse oximetry (73%) and co-oximetry (90%) differed. Haemoglobin analysis demonstrated the presence of a variant in the alpha chain. Clinical history of the patient and her family revealed they carry a haemoglobin variant (Titusville type), thus representing the first French family case reported. Those results raised the question whether the presence of this variant could be the cause of the errors encountered during BGA." 9251;"Does iron overload in metabolic syndrome affect macrophage profile? A case control study.";"G. Chinetti";"Equipe 09, Team 09";34022567;"Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)";"Lahaye C, Gladine C, Pereira B, Berger J, Chinetti-Gbaguidi G, Lainé F, Mazur A, Ruivard M";;"Sep 2021";1630454400;;"Dysmetabolic iron overload syndrome (DIOS) is common but the clinical relevance of iron overload is not understood. Macrophages are central cells in iron homeostasis and inflammation. We hypothesized that iron overload in DIOS could affect the phenotype of monocytes and impair macrophage gene expression." 9241;"cAMP signaling by anthrax edema toxin induces transendothelial cell tunnels, which are resealed by MIM via Arp2/3-driven actin polymerization.";"A. Doye, P. Munro";"Equipe 06, Team 06";22100162;"Cell host & microbe";"Maddugoda MP, Stefani C, Gonzalez-Rodriguez D, Saarikangas J, Torrino S, Janel S, Munro P, Doye A, Prodon F, Aurrand-Lions M, Goossens PL, Lafont F, Bassereau P, Lappalainen P, Brochard F, Lemichez E";;"Nov 2011";1320105600;;"RhoA-inhibitory bacterial toxins, such as Staphylococcus aureus EDIN toxin, induce large transendothelial cell macroaperture (TEM) tunnels that rupture the host endothelium barrier and promote bacterial dissemination. Host cells repair these tunnels by extending actin-rich membrane waves from the TEM edges. We reveal that cyclic-AMP signaling produced by Bacillus anthracis edema toxin (ET) also induces TEM formation, which correlates with increased vascular permeability. We show that ET-induced TEM formation resembles liquid dewetting, a physical process of nucleation and growth of holes within a thin liquid film. We also identify the cellular mechanisms of tunnel closure and reveal that the I-BAR domain protein Missing in Metastasis (MIM) senses de novo membrane curvature generated by the TEM, accumulates at the TEM edge, and triggers Arp2/3-dependent actin polymerization, which induces actin-rich membrane waves that close the TEM. Thus, the balance between ET-induced TEM formation and resealing likely determines the integrity of the host endothelium barrier." 9239;"Pseudomonas aeruginosa Exolysin promotes bacterial growth in lungs, alveolar damage and bacterial dissemination.";"P. Munro";"Equipe 06, Team 06";28522850;"Scientific reports";"Bouillot S, Munro P, Gallet B, Reboud E, Cretin F, Golovkine G, Schoehn G, Attrée I, Lemichez E, Huber P";;"05 2017";1493596800;;"Exolysin (ExlA) is a recently-identified pore-forming toxin secreted by a subset of Pseudomonas aeruginosa strains identified worldwide and devoid of Type III secretion system (T3SS), a major virulence factor. Here, we characterized at the ultrastructural level the lesions caused by an ExlA-secreting strain, CLJ1, in mouse infected lungs. CLJ1 induced necrotic lesions in pneumocytes and endothelial cells, resulting in alveolo-vascular barrier breakdown. Ectopic expression of ExlA in an exlA-negative strain induced similar tissue injuries. In addition, ExlA conferred on bacteria the capacity to proliferate in lungs and to disseminate in secondary organs, similar to bacteria possessing a functional T3SS. CLJ1 did not promote a strong neutrophil infiltration in the alveoli, owing to the weak pro-inflammatory cytokine reaction engendered by the strain. However, CLJ1 was rapidly eliminated from the blood in a bacteremia model, suggesting that it can be promptly phagocytosed by immune cells. Together, our study ascribes to ExlA-secreting bacteria the capacity to proliferate in the lung and to damage pulmonary tissues, thereby promoting metastatic infections, in absence of substantial immune response exacerbation." 9237;"Disease susceptibility in the Zig-Zag model of host-microbe interactions: only a consequence of immune suppression?";"L. Boyer";"Equipe 06, Team 06";26788791;"Molecular plant pathology";"Keller H, Boyer L, Abad P";;"May 2016";1462060800;; 9235;"Virulence Analysis of Bacillus cereus Isolated after Death of Preterm Neonates, Nice, France, 2013.";"L. Boyer, R. Ruimy, R. Lotte";"Equipe 06, Team 06";28418291;"Emerging infectious diseases";"Lotte R, Hérissé AL, Berrouane Y, Lotte L, Casagrande F, Landraud L, Herbin S, Ramarao N, Boyer L, Ruimy R";;"05 2017";1493596800;;"After the deaths of 2 preterm neonates with Bacillus cereus systemic infection in the same intensive care unit, we investigated the pathogenic potential of this bacterium. Genetic and virulence analysis indicated the neonates were infected with 2 different strains with a virulence potential similar to environmental strains, indicating likely patient immune response failure." 9233;"Multiplexed Anti-Toxoplasma IgG, IgM, and IgA Assay on Plasmonic Gold Chips: towards Making Mass Screening Possible with Dye Test Precision.";"C. Pomares";"Equipe 06, Team 06";27008879;"Journal of clinical microbiology";"Li X, Pomares C, Gonfrier G, Koh B, Zhu S, Gong M, Montoya JG, Dai H";;"07 2016";1467331200;;"Toxoplasmosis is an infection caused by the protozoan parasite Toxoplasma gondii that can lead to severe sequelae in the fetus during pregnancy. Definitive serologic diagnosis of the infection during gestation is made mostly by detecting T. gondii-specific antibodies, including IgG and IgM, individually in a single serum sample by using commercially available kits. The IgA test is used by some laboratories as an additional marker of acute infection. Most of the commercial tests have failed to reach 100% correlation with the reference method, the Sabin-Feldman dye test for the detection of Toxoplasma IgG antibodies. For Toxoplasma IgM and IgA antibodies, there is no reference method and their evaluation is done by comparing the results of one assay to those of another. There is a need for multiplexed assay platforms, as the serological diagnosis of T. gondii infection does not rely on the detection of a single Ig subtype. Here we describe the development of a plasmonic gold chip with vast fluorescence enhancement in the near-infrared region for simultaneous detection of IgG, IgM, and IgA antibodies against T. gondii in an ∼1-μl serum or whole-blood sample. When 168 samples were tested on this platform, IgG antibody detection sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were all 100%. IgM antibody detection achieved 97.6% sensitivity and 96.9% specificity with a 90.9% PPV and a 99.2% NPV. Thus, the nanoscience-based plasmonic gold platform enables a high-performance, low-cost, multiplexed assay requiring ultrasmall blood volumes, paving the way for the implementation of universal screening for toxoplasmosis infection during gestation." 9231;"Laboratory Diagnosis of Congenital Toxoplasmosis.";"C. Pomares";"Equipe 06, Team 06";27147724;"Journal of clinical microbiology";"Pomares C, Montoya JG";;"10 2016";1475280000;;"Recent studies have demonstrated that screening and treatment for toxoplasmosis during gestation result in a decrease of vertical transmission and clinical sequelae. Early treatment was associated with improved outcomes. Thus, laboratory methods should aim for early identification of infants with congenital toxoplasmosis (CT). Diagnostic approaches should include, at least, detection of Toxoplasma IgG, IgM, and IgA and a comprehensive review of maternal history, including the gestational age at which the mother was infected and treatment. Here, we review laboratory methods for the diagnosis of CT, with emphasis on serological tools. A diagnostic algorithm that takes into account maternal history is presented." 9229;"Prevalence, risk factors for infection and subtype distribution of the intestinal parasite Blastocystis sp. from a large-scale multi-center study in France.";"C. Pomares";"Equipe 06, Team 06";27566417;"BMC infectious diseases";"El Safadi D, Cian A, Nourrisson C, Pereira B, Morelle C, Bastien P, Bellanger AP, Botterel F, Candolfi E, Desoubeaux G, Lachaud L, Morio F, Pomares C, Rabodonirina M, Wawrzyniak I, Delbac F, Gantois N, Certad G, Delhaes L, Poirier P, Viscogliosi E";;"Aug 2016";1470009600;;"Blastocystis sp. is the most common intestinal parasite of humans. Despite its potential public health impact, epidemiological data regarding the prevalence and molecular subtype distribution of Blastocystis sp. in Europe are rarely reported. Therefore, the first multi-center epidemiological survey performed in Europe was conducted in France to diagnose and subtype Blastocystis sp. and to identify risk factors for infection." 9227;"Cytokine profiles in patients with toxoplasmic lymphadenitis in the setting of pregnancy.";"C. Pomares";"Equipe 06, Team 06";27744174;Cytokine;"Pomares C, Holmes TH, Estran R, Press CJ, Ramirez R, Talucod J, Maecker H, Rosenberg-Hasson Y, Montoya JG";;"02 2017";1485907200;;"Majority of Toxoplasma gondii infections are benign and asymptomatic; however, some patients experience toxoplasmic lymphadenitis (TL). Factors associated as to whether infection will be symptomatic or not are unknown." 9225;"Evaluation of a new multiplex PCR assay (ParaGENIE G-Amoeba Real-Time PCR kit) targeting Giardia intestinalis, Entamoeba histolytica and Entamoeba dispar/Entamoeba moshkovskii from stool specimens: evidence for the limited performances of microscopy-based approach for amoeba species identification.";"C. Pomares";"Equipe 06, Team 06";29454845;"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases";"Morio F, Valot S, Laude A, Desoubeaux G, Argy N, Nourrisson C, Pomares C, Machouart M, Le Govic Y, Dalle F, Botterel F, Bourgeois N, Cateau E, Leterrier M, Jeddi F, Gaboyard M, Le Pape P";;"Nov 2018";1541030400;;"Besides the potential to identify a wide variety of gastrointestinal parasites, microscopy remains the reference standard in clinical microbiology for amoeba species identification and, especially when coupled with adhesin detection, to discriminate the pathogenic Entamoeba histolytica from its sister but non-pathogenic species Entamoeba dispar/Entamoeba moshkovskii. However, this approach is time-consuming, requires a high-level of expertise that can be jeopardized considering the low prevalence of gastrointestinal parasites in non-endemic countries. Here, we evaluated the CE-IVD-marked multiplex PCR (ParaGENIE G-Amoeba, Ademtech) targeting E. histolytica and E. dispar/E. moshkovskii and Giardia intestinalis." 9223;"Genetic Characterization of Toxoplasma gondii DNA Samples Isolated From Humans Living in North America: An Unexpected High Prevalence of Atypical Genotypes.";"C. Pomares";"Equipe 06, Team 06";29982713;"The Journal of infectious diseases";"Pomares C, Devillard S, Holmes TH, Olariu TR, Press CJ, Ramirez R, Talucod J, Estran R, Su C, Dubey JP, Ajzenberg D, Montoya JG";;"10 2018";1538352000;;"Whereas in Europe most of Toxoplasma gondii genotypes belong to the type II lineage, in Latin America, type II is rare and atypical strains predominate. In North America, data on T. gondii genotypes in humans are scarce." 9221;"Rapid diagnostic tests relying on antigen detection from stool as an efficient point of care testing strategy for giardiasis and cryptosporidiosis? Evaluation of a new immunochromatographic duplex assay.";"C. Pomares";"Equipe 06, Team 06";30122511;"Diagnostic microbiology and infectious disease";"Goudal A, Laude A, Valot S, Desoubeaux G, Argy N, Nourrisson C, Pomares C, Machouart M, Le Govic Y, Dalle F, Botterel F, Bourgeois N, Cateau E, Leterrier M, Lavergne RA, Beser J, Le Pape P, Morio F";;"Jan 2019";1546300800;;"Microscopy is the gold standard for the diagnosis of gastrointestinal parasites but is time-consuming and dependent on operator skills. Rapid diagnostic tests represent alternative methods but most evaluations have been conducted on a limited number of samples preventing their implementation in the clinical setting. We evaluated a new CE-IVD marked immunochromatographic assay (Crypto/Giardia K-SeT®, Coris Bioconcept) for the detection of G. intestinalis and Cryptosporidium spp. in 2 phases (retrospective and prospective) on a set of 482 stool samples including rare Cryptosporidium species. Besides G. intestinalis, this test could represent a rapid and reliable alternative to the modified Ziehl-Neelsen staining for the diagnosis of cryptosporidiosis (sensitivity/specificity were 89.2%/99.3% and 86.7%/100% for G. intestinalis and Cryptosporidium resp.), reducing diagnostic delays. Such strategy would also be time-saving by avoiding wet mount microscopy and concentrations steps, being particularly appropriate for laboratories having little expertise in microscopy or not able to implement molecular diagnostic methods." 9219;"Plasmonic gold chips for the diagnosis of Toxoplasma gondii, CMV, and rubella infections using saliva with serum detection precision.";"C. Pomares";"Equipe 06, Team 06";30701339;"European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology";"Li X, Pomares C, Peyron F, Press CJ, Ramirez R, Geraldine G, Cannavo I, Chapey E, Levigne P, Wallon M, Montoya JG, Dai H";;"May 2019";1556668800;;"Sampling the blood compartment by an invasive procedure such as phlebotomy is the most common approach used for diagnostic purposes. However, phlebotomy has several drawbacks including pain, vasovagal reactions, and anxiety. Therefore, alternative approaches should be tested to minimize patient's discomfort. Saliva is a reasonable compartment; when obtained, it generates little or no anxiety. We setup a multiplexed serology assay for detection of Toxoplasma gondii IgG and IgM, rubella IgG, and CMV IgG, in serum, whole blood, and saliva using novel plasmonic gold (pGOLD) chips. pGOLD test results in serum, whole blood, and saliva were compared with commercial kits test results in serum. One hundred twenty serum/saliva sets (Lyon) and 28 serum/whole blood/saliva sets (Nice) from France were tested. In serum and whole blood, sensitivity and specificity of multiplex T. gondii, CMV, and rubella IgG were 100% in pGOLD when compared to commercial test results in serum. In saliva, sensitivity and specificity for T. gondii and rubella IgG were 100%, and for CMV IgG, sensitivity and specificity were 92.9% and 100%, respectively, when compared to commercial test results in serum. We were also able to detect T. gondii IgM in saliva with sensitivity and specificity of 100% and 95.4%, respectively, when compared to serum test results. Serological testing by multiplex pGOLD assay for T. gondii, rubella, and CMV in saliva is reliable and likely to be more acceptable for systematic screening of pregnant women, newborn, and immunocompromised patients." 9217;"Assessment of the first commercial multiplex PCR kit (ParaGENIE Crypto-Micro Real-Time PCR) for the detection of Cryptosporidium spp., Enterocytozoon bieneusi, and Encephalitozoon intestinalis from fecal samples.";"C. Pomares";"Equipe 06, Team 06";31079868;"Diagnostic microbiology and infectious disease";"Morio F, Poirier P, Le Govic Y, Laude A, Valot S, Desoubeaux G, Argy N, Nourrisson C, Pomares C, Machouart M, Dalle F, Botterel F, Bourgeois N, Cateau E, Leterrier M, Beser J, Lavergne RA, Le Pape P";;"Sep 2019";1567296000;;"Cryptosporidium spp. Enterocytozoon bieneusi and Encephalitozoon intestinalis are opportunistic pathogens responsible for gastrointestinal diseases. We evaluated the ParaGENIE Crypto-Micro Real-Time PCR kit (Ademtech, France), the first CE-IVD compliant PCR assay available for these pathogens. This study was conducted blindly against a reference panel of 115 stool specimens including positive samples for Cryptosporidium spp. (n = 48) and E. bieneusi (n = 38) as well as negative or positive samples for other parasites to test for cross-reactivity. An additional set of samples corresponding to 8 rare Cryptosporidium species was also included. Discrepancies were evaluated with external in-house PCR tests. The ParaGENIE Crypto-Micro PCR assay displayed a sensitivity/specificity of 91.7%/100% and 97.3%/98.7% for Cryptosporidium spp. and E. bieneusi, respectively, and was able to detect all 12 Cryptosporidium species of the reference panel, including rare species. This new CE-IVD assay will facilitate the diagnosis of intestinal cryptosporidiosis and microsporidiosis, a major concern in immunocompromised patients and travelers." 9215;"Is Real-Time PCR Targeting Rep 529 Suitable for Diagnosis of Toxoplasmosis in Patients Infected with Non-Type II Strains in North America?";"C. Pomares";"Equipe 06, Team 06";31694976;"Journal of clinical microbiology";"Pomares C, Estran R, Press CJ, Bera A, Ramirez R, Montoya JG, Robert Gangneux F";;"01 2020";1577836800;;" DNA detection is essential to antenatally diagnose a congenital infection and reactivation of a past infection in an immunocompromised patient. Initially, PCR methods targeted the 35-fold repetitive B1 gene, and more recently, coding sequence Rep 529 has been preferred, as it was reported to be repeated 200- to 300-fold and yielded far better sensitivity than amplification of the B1 sequence. To date, few data are available in regard to the efficacy of Rep 529 for non-type II genotypes. In this study, we compared the results of B1 quantitative PCR (qPCR) with those of two different Rep 529 qPCRs performed on 111 samples in two different laboratories (Rep 529-1 and Rep 529-2). The performances of the 3 qPCRs were also compared according to the genotypes of the isolates for 13 type II and 21 non-type II samples. The performance of the Rep 529 target was superior to that of the B1 target regardless of the genotype (threshold cycle [ ] values for the Rep 529-1 and Rep 529-2 qPCRs were lower than those for the B1 qPCR [ < 0.001 and  < 0.01, respectively]). The same results were observed when a comparison was made according to the genotype of the strain (type II and non-type II genotypes). To our knowledge, these results provide the first relative quantitative data revealing that the efficiency of Rep 529 qPCR does not depend on the genotype of isolates and that, in fact, it is superior to B1 qPCR." 9213;"Toxoplasmosis Outbreak Associated With Toxoplasma gondii-Contaminated Venison-High Attack Rate, Unusual Clinical Presentation, and Atypical Genotype.";"C. Pomares";"Equipe 06, Team 06";32412062;"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America";"Schumacher AC, Elbadawi LI, DeSalvo T, Straily A, Ajzenberg D, Letzer D, Moldenhauer E, Handly TL, Hill D, Dardé ML, Pomares C, Passebosc-Faure K, Bisgard K, Gomez CA, Press C, Smiley S, Montoya JG, Kazmierczak JJ";;"05 2021";1619827200;;"During 2017, in response to a physician's report, the Wisconsin Department of Health Services, Division of Public Health, began investigating an outbreak of febrile illness among attendees of a retreat where never frozen, intentionally undercooked, locally harvested venison was served. Preliminary testing tentatively identified the illness as toxoplasmosis." 9211;"Characteristics and outcome according to underlying disease in non-AIDS patients with acute respiratory failure due to Pneumocystis pneumonia.";"C. Pomares";"Equipe 06, Team 06";33411170;"European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology";"Burghi G, Biard L, Roux A, Valade S, Robert-Gangneux F, Hamane S, Maubon D, Debourgogne A, Le Gal S, Dalle F, Leterrier M, Toubas D, Pomares C, Bellanger AP, Bonhomme J, Berry A, Iriart X, Durand-Joly I, Magne D, Pons D, Hennequin C, Maury E, Azoulay E, Lemiale V";;"Jun 2021";1622505600;;"In the non-AIDS group, several underlying conditions and immune defects could lead to different PCP presentations. This study compared PCP presentation and outcome according to the underlying disease. A secondary analysis of a previously published prospective observational study including 544 PCP patients was done. Only non-AIDS patients were included. Underlying disease was defined as chronic lymphocytic leukemia (CLL), organ transplantation, solid cancer, allogeneic hematopoietic stem cell transplant (AHSCT), other hematological diseases, and immunosuppressive treatment. Clinical characteristics and outcomes were compared between groups. Multiple correspondent analyses compared clinical characteristics at diagnosis. Day 30 mortality was analyzed. Three hundred and twenty-one patients were included in the study. The underlying diseases were hematological malignancy (n = 75), AHSCT (n = 14), CLL (n = 19), solid organ transplant (n = 94), solid tumor (n = 39), and immunosuppressive treatment (n = 57). Compared with other underlying diseases, PCP related to CLL was closer to PCP related to AIDS presentation (long duration of symptoms before diagnosis, high level of dyspnea, and low oxygen saturation at diagnosis). Day 30 mortality was associated with underlying disease, oxygen flow, and shock at ICU admission. PCP presentations may vary according to the underlying reason for immunosuppression. Response to treatment and adjuvant steroid therapy should be analyzed regarding this result." 9209;"Epidemiology of candidemia in NICE area, France: A five-year study of antifungal susceptibility and mortality.";"C. Pomares";"Equipe 06, Team 06";34768155;"Journal de mycologie medicale";"Vannini M, Emery S, Lieutier-Colas F, Legueult K, Mondain V, Retur N, Gastaud L, Pomares C, Hasseine L";;"Oct 2021";1633046400;;"The aim of this study was to investigate the epidemiology of candidemia, the fungal susceptibility, the first-line therapy and the morality rate over 5 years. Knowing the differences of the yeasts in the candidemia local epidemiology, is essential to obtain information on fungal epidemiology to adapt antifungal strategies." 9207;"The C-terminal segment of Leishmania major HslU: Toward potential inhibitors of LmHslVU activity.";"C. Pomares, G. MICHEL";"Equipe 06, Team 06";34894575;"Bioorganic chemistry";"Singh P, Samanta K, Kebe NM, Michel G, Legrand B, Sitnikova VE, Kajava AV, Pagès M, Bastien P, Pomares C, Coux O, Hernandez JF";;"02 2022";1643673600;;"It is urgent to develop less toxic and more efficient treatments for leishmaniases and trypanosomiases. We explore the possibility to target the parasite mitochondrial HslVU protease, which is essential for growth and has no analogue in the human host. For this, we develop compounds potentially inhibiting the complex assembly by mimicking the C-terminal (C-ter) segment of the ATPase HslU. We previously showed that a dodecapeptide derived from Leishmania major HslU C-ter segment (LmC12-U2, Cpd 1) was able to bind to and activate the digestion of a fluorogenic substrate by LmHslV. Here, we present the study of its structure-activity relationships. By replacing each essential residue with related non-proteinogenic residues, we obtained more potent analogues. In particular, a cyclohexylglycine residue at position 11 (cpd 24) allowed a more than three-fold gain in potency while reducing the size of compound 24 from twelve to six residues (cpd 50) without significant loss of potency, opening the way toward short HslU C-ter peptidomimetics as potential inhibitors of HslV proteolytic function. Finally, conjugates constituted of LmC6-U2 analogues and a mitochondrial penetrating peptide were found to penetrate into the promastigote form of L. infantum and to inhibit the parasite growth without showing toxicity toward human THP-1 cells at the same concentration (i.e. 30 μM)." 9205;"[Management of ocular toxoplasmosis in France: Results of a modified Delphi study].";"C. Pomares";"Equipe 06, Team 06";35109988;"Journal francais d'ophtalmologie";"Schaeffer M, Ballonzoli L, Gaucher D, Arndt C, Angioi-Duprez K, Baudonnet R, Bodaghi B, Bron A, Chiambaretta F, Cimon B, Chiquet C, Creuzot-Garcher C, Daien V, Deleplanque AS, Fricker-Hidalgo H, Hadjadj E, Houze S, Ifrah T, Korobelnik JF, Labalette P, Le Lez ML, L'Ollivier C, Mercie M, Mouriaux F, Paris L, Pelloux H, Pomares C, Quintyn JC, Rougier MB, Rousseau A, Soler V, Talmud M, Villena I, Villard O, Speeg-Schatz C, Bourcier T, Sauer A";;"Jan 2022";1640995200;;"To evaluate diagnostic and therapeutic practices and then establish a consensus on the management of ocular toxoplasmosis in France through a Delphi study." 9203;"Case Report: Autoimmune Hemolysis Anemia After Dihydroartemisinin and Piperaquine for Uncomplicated Malaria.";"C. Pomares, J. Courjon, L. Simon, M. Carles";"Equipe 06, Team 06, Equipe 12, Team 12";35111773;"Frontiers in medicine";"Louvois M, Simon L, Pomares C, Jeandel PY, Demonchy E, Carles M, Delaunay P, Courjon J";;"Jan 2021";1609459200;;"Malaria is still an endemic disease in Africa, with many imported cases in Europe. The standard treatment is intravenous artesunate for severe malaria and oral artemisinin-based combination therapy (ACT) for uncomplicated malaria. Delayed hemolytic anemia (DHA) after intravenous artesunate has been extensively described, and guidelines recommend biological monitoring until 1 month after the end of the treatment. A link with an autoimmune process is still unsure. Nevertheless, cases with positive direct antiglobulin test (DAT) have been reported. Conversely, DHA is not recognized as an adverse effect of oral ACT. Previously, only few cases of DHA occurring after oral ACT without intravenous artesunate administration have been reported. We report the case of a 42-year-old man returning from Togo. He was treated with dihydroartemisinin/piperaquine combination for uncomplicated malaria, with low parasitemia. Nine days after the end of the treatment, the patient developed hemolytic anemia with positive DAT. Eventually, the patient recovered after corticotherapy. After excluding common causes of autoimmune hemolytic anemia, we considered that dihydroartemisinin/piperaquine treatment was involved in this side effect." 9201;"[Fight against neglected parasitic tropical diseases gets the Nobel prize].";"P. Marty";"Equipe 06, Team 06";26742550;"Medecine et sante tropicales";"Marty P";;"Dec Oct 2015";1444608000;; 9199;"[Visceral leishmaniasis without splenomegaly. A pediatric case report].";"P. Marty";"Equipe 06, Team 06";26776600;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Leblanc C, Nouar D, Izri A, Brun S, Marty P, Gaudelus J, De Pontual L";;"Apr 2016";1459468800;;"Pediatric visceral leishmaniasis is caused by Leishmania infantum, a dog parasite transmitted to humans by the bite of the female phlebotomine sand fly. The well-known clinical triad is fever, pallor, and splenomegaly. A secondary macrophage activation syndrome (MAS) can complicate this infection, which is lethal when not treated. When MAS is observed without any explanation, a visceral leishmaniasis is highly recommended. We report a case of visceral leishmaniasis in a 21-month-old child complicated by a macrophage activation syndrome without splenomegaly. No immunodeficiency was diagnosed that could explain this unusual clinical condition. To our knowledge, this is the first case of visceral leishmaniasis without splenomegaly reported to date. " 9197;"Genetic Diversity and Population Structure of Leishmania infantum from Southeastern France: Evaluation Using Multi-Locus Microsatellite Typing.";"C. Pomares, G. MICHEL, P. Marty";"Equipe 06, Team 06";26808522;"PLoS neglected tropical diseases";"Pomares C, Marty P, Bañuls AL, Lemichez E, Pratlong F, Faucher B, Jeddi F, Moore S, Michel G, Aluru S, Piarroux R, Hide M";;"Jan 2016";1451606400;;"In the south of France, Leishmania infantum is responsible for numerous cases of canine leishmaniasis (CanL), sporadic cases of human visceral leishmaniasis (VL) and rare cases of cutaneous and muco-cutaneous leishmaniasis (CL and MCL, respectively). Several endemic areas have been clearly identified in the south of France including the Pyrénées-Orientales, Cévennes (CE), Provence (P), Alpes-Maritimes (AM) and Corsica (CO). Within these endemic areas, the two cities of Nice (AM) and Marseille (P), which are located 150 km apart, and their surroundings, concentrate the greatest number of French autochthonous leishmaniasis cases. In this study, 270 L. infantum isolates from an extended time period (1978-2011) from four endemic areas, AM, P, CE and CO, were assessed using Multi-Locus Microsatellite Typing (MLMT). MLMT revealed a total of 121 different genotypes with 91 unique genotypes and 30 repeated genotypes. Substantial genetic diversity was found with a strong genetic differentiation between the Leishmania populations from AM and P. However, exchanges were observed between these two endemic areas in which it seems that strains spread from AM to P. The genetic differentiations in these areas suggest strong epidemiological structuring. A model-based analysis using STRUCTURE revealed two main populations: population A (consisting of samples primarily from the P and AM endemic areas with MON-1 and non-MON-1 strains) and population B consisting of only MON-1 strains essentially from the AM endemic area. For four patients, we observed several isolates from different biological samples which provided insight into disease relapse and re-infection. These findings shed light on the transmission dynamics of parasites in humans. However, further data are required to confirm this hypothesis based on a limited sample set. This study represents the most extensive population analysis of L. infantum strains using MLMT conducted in France. " 9195;"Detection of Pneumocystis jirovecii by Quantitative PCR To Differentiate Colonization and Pneumonia in Immunocompromised HIV-Positive and HIV-Negative Patients.";"C. Pomares";"Equipe 06, Team 06";27008872;"Journal of clinical microbiology";"Fauchier T, Hasseine L, Gari-Toussaint M, Casanova V, Marty PM, Pomares C";;"06 2016";1464739200;;"Pneumocystis jirovecii pneumonia (PCP) is an acute and life-threatening lung disease caused by the fungus Pneumocystis jirovecii The presentation of PCP in HIV-positive patients is well-known and consists of a triad of dyspnea, fever, and cough, whereas the presentation of PCP in HIV-negative patients is atypical and consists of a sudden outbreak, O2 desaturation, and a rapid lethal outcome without therapy. Despite the availability of direct and indirect identification methods, the diagnosis of PCP remains difficult. The cycle threshold (CT) values obtained by quantitative PCR (qPCR) allow estimation of the fungal burden. The more elevated that the fungal burden is, the higher the probability that the diagnosis is pneumonia. The purposes of the present study were to evaluate the CT values to differentiate colonization and pneumonia in a population of immunocompromised patients overall and patients stratified on the basis of their HIV infection status. Testing of bronchoalveolar lavage (BAL) fluid samples from the whole population of qPCR-positive patients showed a mean CT value for patients with PCP of 28 (95% confidence interval [CI], 26 to 30) and a mean CT value for colonized patients of 35 (95% CI, 34 to 36) (P < 10(-3)). For the subgroup of HIV-positive patients, we demonstrated that a CT value below 27 excluded colonization and a CT value above 30 excluded PCP with a specificity of 100% and a sensitivity of 80%, respectively. In the subgroup of HIV-negative patients, we demonstrated that a CT value below 31 excluded colonization and a CT value above 35 excluded PCP with a specificity of 80% and a sensitivity of 80%, respectively. Thus, qPCR of BAL fluid samples is an important tool for the differentiation of colonization and pneumonia in P. jirovecii-infected immunocompromised patients and patients stratified on the basis of HIV infection status with different CT values." 9193;"Immunoadjuvant Properties of the Rho Activating Factor CNF1 in Prophylactic and Curative Vaccination against Leishmania infantum.";"G. MICHEL, L. Boyer, P. Munro, P. Marty";"Equipe 06, Team 06";27257862;"PloS one";"Michel G, Ferrua B, Munro P, Boyer L, Mathal N, Gillet D, Marty P, Lemichez E";;"Jan 2016";1451606400;;"There is a need to develop new effective immunoadjuvants for prophylactic or therapeutic vaccines against intracellular pathogens. The activation of Rho GTPases by bacterial cytotoxic necrotizing factor 1 (CNF1) elicits humoral protective responses against protein antigens. Here, we set out to investigate whether CNF1 activity initiates humoral immunity against co-administered parasite antigens and anti-microbial immune signaling. We report that co-administration of wild-type (WT) CNF1 with Leishmania (L.) promastigote antigens at the nasal mucosa triggered prophylactic and curative vaccine responses against this parasite. Vaccination of the mucosa with promastigote lysate antigens combined with WT CNF1 conferred protection against high inoculum L. infantum infection, which reached 82% in the spleen. Immune parameter analysis by antigen recall indicated robust T-helper (Th)1 polarization of immune memory cells, with high IL-2 and IFN-γ production combined with decreased IL-4 production. Additionally, we explored the curative effect of WT CNF1 on previously infected animals. We observed that PL combined with WT CNF1, but not the inactive C866S mutant CNF1 (mCNF1), induced a 58% decrease in the parasite burden in the spleen. " 9191;"Performance assessment of two lysis methods for direct identification of yeasts from clinical blood cultures using MALDI-TOF mass spectrometry.";"P. Marty";"Equipe 06, Team 06";27281814;"Medical mycology";"Jeddi F, Yapo-Kouadio GC, Normand AC, Cassagne C, Marty P, Piarroux R";;"Feb 2017";1485907200;;"In cases of fungal infection of the bloodstream, rapid species identification is crucial to provide adapted therapy and thereby ameliorate patient outcome. Currently, the commercial Sepsityper kit and the sodium-dodecyl sulfate (SDS) method coupled with MALDI-TOF mass spectrometry are the most commonly reported lysis protocols for direct identification of fungi from positive blood culture vials. However, the performance of these two protocols has never been compared on clinical samples. Accordingly, we performed a two-step survey on two distinct panels of clinical positive blood culture vials to identify the most efficient protocol, establish an appropriate log score (LS) cut-off, and validate the best method. We first compared the performance of the Sepsityper and the SDS protocols on 71 clinical samples. For 69 monomicrobial samples, mass spectrometry LS values were significantly higher with the SDS protocol than with the Sepsityper method (P < .0001), especially when the best score of four deposited spots was considered. Next, we established the LS cut-off for accurate identification at 1.7, based on specimen DNA sequence data. Using this LS cut-off, 66 (95.6%) and 46 (66.6%) isolates were correctly identified at the species level with the SDS and the Sepsityper protocols, respectively. In the second arm of the survey, we validated the SDS protocol on an additional panel of 94 clinical samples. Ninety-two (98.9%) of 93 monomicrobial samples were correctly identified at the species level (median LS = 2.061). Overall, our data suggest that the SDS method yields more accurate species identification of yeasts, than the Sepsityper protocol." 9187;"Inadequate labeling of pork sausages prepared in Corsica causing a trichinellosis outbreak in France.";"C. Ruetsch, P. Marty";"Equipe 11, Team 11, Equipe 06, Team 06";27317463;"Parasite (Paris, France)";"Ruetsch C, Delaunay P, Armengaud A, Peloux-Petiot F, Dupouy-Camet J, Vallée I, Polack B, Boireau P, Marty P";;"Jan 2016";1451606400;;"Three cases of human trichinellosis due to Trichinella britovi were reported in 2015 in the Southeast of France resulting from consumption of raw pork sausages (figatelli) prepared in Corsica. Fourteen other people ate figatelli from the same batch but were not infected due to the figatelli being well cooked. This is the first reported human trichinellosis outbreak due to consumption of Corsican sausages prepared from uncontrolled pork. Consumption of raw figatelli is a common tradition in Corsica. As a result, the health recommendation to cook the product well is not always applied. In the present case, the figatelli product label was not sufficiently visible to advise consumers of the risks associated with uncooked pork." 9185;"Spinal cord compression due to a primary vertebral hydatid disease: A rare case report in metropolitan France and a literature review.";"P. Marty";"Equipe 06, Team 06";27339831;Neuro-Chirurgie;"Gennari A, Almairac F, Litrico S, Albert C, Marty P, Paquis P";;"Aug 2016";1470009600;;"Bone echinococcosis or bone hydatidosis is mainly caused by the larva of a dog taenia, Echinococcus granulosus. We described a rare imported case in metropolitan France of spinal cord compression from a primary vertebral hydatidosis." 9183;"Experimental infection of Phlebotomus perniciosus by bioluminescent Leishmania infantum using murine model and artificial feeder.";"G. MICHEL, P. Marty";"Equipe 06, Team 06";27439032;"Memorias do Instituto Oswaldo Cruz";"Cannet A, Akhoundi M, Michel G, Marty P, Delaunay P";;"Jul 2016";1467331200;;"Leishmaniasis is a vector-borne disease that is transmitted by sandflies and caused by obligate intracellular protozoa of the genus Leishmania. In the present study, we carried out a screening on the experimental infection of Phlebotomus pernioucus by bioluminescent Leishmania infantum using murine model and artificial feeder. We developed a real-time polymerase chain reaction (RT-PCR)-based method to determine individually the number of Leishmania promastigotes fed by infected flies. Among 1840 new emerged female sand flies, 428 were fed on the infected mice. After their death, they were analysed individually by RT-PCR. Our results demonstrated just a single Leishmania positive female at sixth day post meal. A total of 1070 female sand flies were exposed in contact with artificial feeder containing the human blood with two different quantities of Leishmania parasites: 2.106/mL and 1.107/mL. A blood meal including 1.107/mL LUC-promastigotes was proposed to 270 females and 75 (28%) flies were engorged. Among them, 44 (59%) were positive by RT-PCR analysis, with a relative average of 50551 Leishmania parasites. In case of blood feeding of females with 2.106/mL promastigotes, 57 out of 800 (7%) females succeed to feed from artificial feeder which 22 (39%) were positive with a relative average of 6487 parasites. " 9181;"Molecular characterization of Wolbachia infection in bed bugs (Cimex lectularius) collected from several localities in France.";"C. Loubatier, P. Marty";"Equipe 06, Team 06";27492563;"Parasite (Paris, France)";"Akhoundi M, Cannet A, Loubatier C, Berenger JM, Izri A, Marty P, Delaunay P";;"Jan 2016";1451606400;;"Wolbachia symbionts are maternally inherited intracellular bacteria that have been detected in numerous insects including bed bugs. The objective of this study, the first epidemiological study in Europe, was to screen Wolbachia infection among Cimex lectularius collected in the field, using PCR targeting the surface protein gene (wsp), and to compare obtained Wolbachia strains with those reported from laboratory colonies of C. lectularius as well as other Wolbachia groups. For this purpose, 284 bed bug specimens were caught and studied from eight different regions of France including the suburbs of Paris, Bouches-du-Rhône, Lot-et-Garonne, and five localities in Alpes-Maritimes. Among the samples, 166 were adults and the remaining 118 were considered nymphs. In all, 47 out of 118 nymphs (40%) and 61 out of 166 adults (37%) were found positive on wsp screening. Among the positive cases, 10 samples were selected randomly for sequencing. The sequences had 100% homology with wsp sequences belonging to the F-supergroup strains of Wolbachia. Therefore, we confirm the similarity of Wolbachia strains detected in this epidemiological study to Wolbachia spp. reported from laboratory colonies of C. lectularius. " 9179;"Comparison of Toxoplasma gondii IgG avidity Architect and Vidas assays with the estimated date of infection in pregnant women.";"C. Pomares, G. MICHEL, P. Marty";"Equipe 06, Team 06";27762213;"Parasite (Paris, France)";"Smets A, Fauchier T, Michel G, Marty P, Pomares C";;"Jan 2016";1451606400;;"A maternal Toxoplasma gondii infection during pregnancy is a risk for congenital infection through maternal-fetal transplacental transmission. Estimation of the date of infection is of the utmost importance for management and treatment recommendations. In this setting, IgG avidity has been shown to be useful as high avidity rules out an infection dating less than 4 months. The estimated date of infection can also be obtained by the ratio of T. gondii IgG titers measured by the Vidas (bioMérieux) assay versus T. gondii IgG titers measured by the Architect (Abbott Laboratories) test, together with T. gondii IgM and IgA antibody responses. In this study, using 117 serum samples from pregnant women, we compared the IgG avidity values obtained by Architect and Vidas with the presumed date of T. gondii infection established by the T. gondii IgG ratio of IgG Vidas and IgG Architect plus the IgM and IgA results. To date, IgG avidity Vidas seems to exhibit better performance than Architect. For both assays, gray zone results were most likely obtained from patients infected more than 4 months before sampling. These data should be taken into account for a possible reconsideration of the interpretation of avidity results in the gray zone." 9177;"Epidemiology of the outbreak, vectors and reservoirs of cutaneous leishmaniasis in Mali: A systematic review and meta-analysis.";"P. Marty";"Equipe 06, Team 06";27794393;"Asian Pacific journal of tropical medicine";"Kone AK, Niare DS, Thera MA, Kayentao K, Djimde A, Delaunay P, Kouriba B, Giudice PD, Izri A, Marty P, Doumbo OK";;"10 2016";1475280000;;"To compile available data and to estimate the burden, characteristics and risks factors of cutaneous leishmaniasis (CL) in Mali." 9175;"Validation of IgG, IgM multiplex plasmonic gold platform in French clinical cohorts for the serodiagnosis and follow-up of Toxoplasma gondii infection.";"C. Pomares, P. Marty";"Equipe 06, Team 06";28040304;"Diagnostic microbiology and infectious disease";"Pomares C, Zhang B, Arulkumar S, Gonfrier G, Marty P, Zhao S, Cheng S, Tang M, Dai H, Montoya JG";;"Mar 2017";1488326400;;"We report the use of the multiplexed T. gondii IgG, IgM test on plasmonic gold (pGOLD) platform in the setting of T. gondii infection by analyzing 244 sera from Nice, France (seroconversion, chronically infected, non-infected and newborns serum samples). Results were compared with commercial tests for the detection of IgG and IgM and their overall clinical final interpretation of a complete serological profile. The IgG and IgM test results on the platform were in agreement in, respectively, 95% and 93% with the commercial kits. When comparing with the overall clinical interpretation of the serological profile, the agreement reached 99.5% and 97.7% for IgG and IgM, respectively. This innovative pGOLD platform allows detection of both IgG and IgM simultaneously with only ~1 microliter of serum. The multiplexed IgG/IgM test on pGOLD platform is a strong candidate for its use in the massive screening programs for toxoplasmosis during pregnancy." 9173;"Leishmania infections: Molecular targets and diagnosis.";"P. Marty";"Equipe 06, Team 06";28159546;"Molecular aspects of medicine";"Akhoundi M, Downing T, Votýpka J, Kuhls K, Lukeš J, Cannet A, Ravel C, Marty P, Delaunay P, Kasbari M, Granouillac B, Gradoni L, Sereno D";;"Oct 2017";1506816000;;"Progress in the diagnosis of leishmaniases depends on the development of effective methods and the discovery of suitable biomarkers. We propose firstly an update classification of Leishmania species and their synonymies. We demonstrate a global map highlighting the geography of known endemic Leishmania species pathogenic to humans. We summarize a complete list of techniques currently in use and discuss their advantages and limitations. The available data highlights the benefits of molecular markers in terms of their sensitivity and specificity to quantify variation from the subgeneric level to species complexes, (sub) species within complexes, and individual populations and infection foci. Each DNA-based detection method is supplied with a comprehensive description of markers and primers and proposal for a classification based on the role of each target and primer in the detection, identification and quantification of leishmaniasis infection. We outline a genome-wide map of genes informative for diagnosis that have been used for Leishmania genotyping. Furthermore, we propose a classification method based on the suitability of well-studied molecular markers for typing the 21 known Leishmania species pathogenic to humans. This can be applied to newly discovered species and to hybrid strains originating from inter-species crosses. Developing more effective and sensitive diagnostic methods and biomarkers is vital for enhancing Leishmania infection control programs." 9171;"Diagnostic performance of ELISA, IFAT and Western blot for the detection of anti-Leishmania infantum antibodies in cats using a Bayesian analysis without a gold standard.";"P. Marty";"Equipe 06, Team 06";28285598;"Parasites & vectors";"Persichetti MF, Solano-Gallego L, Vullo A, Masucci M, Marty P, Delaunay P, Vitale F, Pennisi MG";;"Mar 2017";1488326400;;"Anti-Leishmania antibodies are increasingly investigated in cats for epidemiological studies or for the diagnosis of clinical feline leishmaniosis. The immunofluorescent antibody test (IFAT), the enzyme-linked immunosorbent assay (ELISA) and western blot (WB) are the serological tests more frequently used. The aim of the present study was to assess diagnostic performance of IFAT, ELISA and WB to detect anti-L. infantum antibodies in feline serum samples obtained from endemic (n = 76) and non-endemic (n = 64) areas and from cats affected by feline leishmaniosis (n = 21) by a Bayesian approach without a gold standard." 9169;"Severe intestinal obstruction due to Strongyloides stercoralis in a pregnant woman.";"J. Courjon, P. Marty";"Equipe 06, Team 06";28651833;"Medecine et maladies infectieuses";"Malézieux-Picard A, Saint-Paul MC, Dellamonica J, Courjon J, Tieulié N, Marty P, Fuzibet JG, Collomp R, Marinho JA, Queyrel V";;"10 2017";1506816000;; 9167;"Immunodetection and molecular determination of visceral and cutaneous Leishmania infection using patients' urine.";"P. Marty";"Equipe 06, Team 06";29847780;"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases";"Mirzaei A, Ahmadipour F, Cannet A, Marty P, Delaunay P, Perrin P, Dorkeld F, Sereno D, Akhoundi M";;"09 2018";1535760000;;"The diagnosis of leishmaniasis relies mainly on the use of invasive processes, to collect the biological material for detecting Leishmania parasites. Body fluids, which can be collected by non-invasive process, would greatly facilitate the leishmaniasis diagnosis. In the present study, we investigated the potency of urine immunoblotting to diagnose cutaneous and visceral leishmaniasis and we compared with routine molecular methods. A total of 80 samples, including 40 sera and their 40 corresponding urine samples were collected from 37 suspected patients with cutaneous and visceral leishmaniasis, and 3 healthy individuals (as control), in Ilam and Ardabil provinces of Iran. All sera and urine samples were analyzed, using immunoblotting. The confirmation of leishmaniasis infection was performed, using conventional and quantitative PCRs as well as by sequencing the amplicons. Among 37 suspected patients, 23 patients presented cutaneous lesions (CL) and 14 exhibited clinical symptoms reminiscent of visceral leishmaniasis (L. infantum). Among cutaneous patients, 15 were positive for zoonotic cutaneous leishmaniasis (L. major), and eight for anthroponotic cutaneous leishmaniasis (L. tropica). Molecular quantification of Leishmania parasites was performed on sera, urines and cutaneous biopsies of CL and VL patients, demonstrating that parasite load is lower in urines, compared to sera or biopsy. DNA can be detected in 20 out of 23 (86.9%) CL urine samples and in 13 out of 14 (92.8%) VL urine samples. Immunodetection analysis demonstrates that 22 out of 23 (95.6%) sera from CL patients and all patients suspected with VL are positive. For urine samples, 18 out of 23 (78.2%) urine of CL patients and 13 out of 14 (92.8%) urine of VL patients were positive, using Western blot. Therefore, immunodetection and molecular analysis using urine samples can be used as a diagnostic tool for surveying cutaneous and visceral leishmaniasis." 9165;"Management of toxoplasmosis in transplant recipients: an update.";"C. Pomares, P. Marty";"Equipe 06, Team 06";29855213;"Expert review of anti-infective therapy";"Dard C, Marty P, Brenier-Pinchart MP, Garnaud C, Fricker-Hidalgo H, Pelloux H, Pomares C";;"06 2018";1527811200;;"Toxoplasmosis is a life-threatening parasitic disease for hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The risk of toxoplasmosis in transplant patients mainly depends on the degree of immunosuppression, the tropism of Toxoplasma gondii for the grafted tissue, and the seroprevalence in the general population. Although transplant recipients with toxoplasmosis have a high mortality rate, there are neither well-defined recommendations nor a consensus for the management of this disease in these patients. Areas covered. This review focuses on the management of toxoplasmosis in transplant recipients and discusses the various strategies for diagnosis, prevention, treatment, and follow-up in clinical practice. The literature search was conducted on publications in English and French using the search terms 'Toxoplasma gondii,' 'organ transplant,' and 'transplant recipients.' Expert commentary. The diagnosis of toxoplasmosis has greatly improved over the last two decades, but it is still a fatal illness. Non-specificity of the symptoms, resulting in a delay before diagnosis, and therapeutic failure are the main causes of death. The development of active treatments against cysts is one of the current challenges that will considerably improve the management of toxoplasmosis in transplant recipients by clearing chronic infection to avoid T. gondii reactivation." 9163;"Subclinical Leishmania infection in patients with rheumatic diseases under biological drugs.";"G. MICHEL, P. Marty";"Equipe 06, Team 06";30097989;Infection;"Maritati M, Trentini A, Michel G, Bellini T, Almugadam S, Hanau S, Govoni M, Marty P, Contini C";;"Dec 2018";1543622400;;"Climate changes and immunosuppression are influencing the spread of leishmaniasis and re-emergence in Northern Italy, respectively. We evaluated the prevalence of subclinical leishmaniasis in patients from a Northern Italian region with chronic inflammatory rheumatism (CIRD) receiving biological drugs (BD) and correlated it to the area of residence." 9161;"Progressive dysphonia in a man living in an endemic area for Leishmania infantum.";"P. Marty";"Equipe 06, Team 06";30528067;"Medecine et maladies infectieuses";"Sevestre J, Reverso-Meinietti J, Butet V, Inedjian JM, Marty P";;"May 2019";1556668800;; 9159;"Visceral Leishmaniasis in West Africa: Clinical Characteristics, Vectors, and Reservoirs.";"P. Marty";"Equipe 06, Team 06";31565426;"Journal of parasitology research";"Kone AK, Niaré DS, Piarroux M, Izri A, Marty P, Laurens MB, Piarroux R, Thera MA, Doumbo OK";;"Jan 2019";1546300800;;"Visceral leishmaniasis (VL) is the most serious form of human leishmaniasis. VL is understudied in West Africa. The increasing number of patients at-risk, including persons living with HIV and other chronic immunosuppressive diseases, and likely underreporting of VL related to diagnostic challenges advocate for review of existing data to understand VL regional epidemiology. Our review aims to describe the clinical characteristics and epidemiology of Human VL (HVL) in West Africa. We conducted a literature search to identify peer-reviewed articles and grey literature sources using the search terms ""Visceral leishmaniasis West Africa"", "" West Africa""; and "" West Africa"". Thirty published articles report HVL from seven countries, including The Gambia, Niger, Nigeria, Ivory Coast, Togo, Burkina Faso, and Guinea Bissau. Three countries report cases of Canine Visceral Leishmaniasis (CVL), including The Gambia, Senegal, and Burkina Faso. Niger, Nigeria, and Ivory Coast report the greatest number of HVL cases. As VL is present in West Africa, active surveillance, increased diagnostic capacity, and studies of vectors and reservoirs are essential to better understand VL epidemiology in the region." 9157;"[Epidemiology of Cutaneous Leishmaniasis in West Africa: a Systematic Review].";"P. Marty";"Equipe 06, Team 06";32881442;"Bulletin de la Societe de pathologie exotique (1990)";"Cissé M, Zida A, Diallo AH, Marty P, Aoun K";;"Jan 2020";1577836800;;"Cutaneous leishmaniasis (CL) has been described in West Africa (WA) since the beginning of the 20th century. The incidence of cases has markedly increased during the last decades in several countries of the region. Despite that, data remain scarce and fragmentary. The current incidence and geographic distribution of the disease as well as the involved vectors and reservoirs remain poorly documented. The objective of this review was to collect and analyze available data about CL in WA in order to improve the management of cases and the control of the disease transmission. A systematic literature review was performed using the Pubmed, Google Scholar and Hinari databases. Publications focusing on epidemiological aspects of CL, involved parasite species, sand flies and potential reservoir hosts were searched without any restrictions. Unpublished studies were extracted from Google. Manuscripts without full text or summary available were excluded as well as those whose summaries did not contain any usable data. One hundred and fifteen studies were recorded. Among them, 93 filled selection criteria. CL has been reported in 10 West African countries with outbreaks described in five countries. Burkina Faso, where the average incidence of the disease is around 928 cases per year, and Ghana seem to be the most affected. Cases have been confirmed in the majority of studies by microscopy sometimes associated with culture or histology. The exposure rate to Leishmania infection based on leishmanin skin test was relatively high with an overall average of 30.2%. Leishmania major was the only species identified with a predominance of MON-74 (62%) and MON-26 (30.6%) zymodemes. Phlebotomus duboscqi is retained as the vector whereas Sergentomyia darlingi and Sergentomyia ingrami were found naturally infected. Rodents including Arvicanthis niloticus, Gerbilliscus gambiana and Mastomys spp. are reported as the main reservoir hosts. Additional studies are needed to better characterize CL in WA in order to optimize the management of cases and to organize the control of the disease transmission." 9155;"PCR and culture for diagnosis of keratitis.";"P. Marty";"Equipe 06, Team 06";33099504;"The British journal of ophthalmology";"Yera H, Ok V, Lee Koy Kuet F, Dahane N, Ariey F, Hasseine L, Delaunay P, Martiano D, Marty P, Bourges JL";;"09 2021";1630454400;;" keratitis (AK) is a rare but sight-threatening infection. Molecular diagnosis of corneal scraping has improved the diagnosis of AK. Different molecular targets and conditions have been used in diagnosis thus far. In this study, we prospectively compared the performance of five PCR assays on corneal samples for the diagnosis of AK." 9153;"Acquisition of multidrug-resistant bacteria and colistin resistance genes in French medical students on internships abroad.";"P. Marty";"Equipe 06, Team 06";33248262;"Travel medicine and infectious disease";"Dao TL, Hoang VT, Magmoun A, Ly TDA, Baron SA, Hadjadj L, Canard N, Drali T, Gouriet F, Raoult D, Parola P, Marty P, Rolain JM, Gautret P";;"Feb Jan 2021";1609545600;;"Acquisition of multidrug resistant bacteria (MDR) and colistin resistance genes by international travellers has been demonstrated. Studies conducted in medical students during internships abroad are scant." 9151;"Sputum proteomic analysis for distinguishing between pulmonary tuberculosis and non-tuberculosis using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS): preliminary results.";"J. Courjon, P. Marty";"Equipe 06, Team 06";33711448;"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases";"Dao TL, Hoang VT, Ly TDA, Lagier JC, Baron SA, Raoult D, Parola P, Courjon J, Marty P, Chaudet H, Gautret P";;"Nov 2021";1635724800;;"The aim was to evaluate the feasibility and diagnostic contribution of protein profiling using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) applied to sputum to diagnose pulmonary tuberculosis." 9149;"Post-mortem diagnosis of imported malaria in France: a case report.";"C. Pomares, P. Marty";"Equipe 06, Team 06";34126991;"Malaria journal";"Sevestre J, Bernardi C, Gillet M, Delaunay P, Fanjat Y, Toni G, Marty P, Alunni V, Pomares C";;"Jun 2021";1622505600;;"Malaria is a potentially lethal parasitic disease due to infection by Plasmodium parasites, transmitted by Anopheles mosquito vectors. Various preventative measures may be recommended for travellers who visit endemic areas. The diagnosis is generally evoked in the context of a febrile patient returning from an endemic zone. Nevertheless, symptoms and clinical signs may be difficult to interpret, and fatal cases may only be diagnosed retrospectively with laboratory techniques, specific pathological features and patient history. The present work reports a case of fatal cerebral malaria diagnosed post-mortem, along with the techniques that allowed identification of the causative agent." 9147;"Epidemiology and genomic characterisation of travel-associated and locally-acquired influenza, Marseille, France.";"P. Marty";"Equipe 06, Team 06";34921995;"Travel medicine and infectious disease";"Dao TL, Levasseur A, Tall ML, Hoang VT, Colson P, Caputo A, Ly TDA, Ninove L, Grimaldier C, Jardot P, Marty P, La Scola B, Gautret P";;"Feb Jan 2022";1641081600;;"The purpose of the study was to challenge the hypothesis of an introduction of influenza viruses by international travellers and subsequent local circulation in Marseille, France." 9145;"Disseminated feline leishmaniosis due to Leishmania infantum in Southern France.";"P. Marty";"Equipe 06, Team 06";9637231;"Veterinary parasitology";"Ozon C, Marty P, Pratlong F, Breton C, Blein M, Lelièvre A, Haas P";;"Feb 1998";886291200;;"A fortuitously discovered case of feline leishmaniosis is reported. The parasites were found in the skin and the bone marrow of a domestic female cat that spontaneously died after a few weeks of evolution. Serological tests for FeLV, FIV and PIF virus detection gave negative results. By using Western blot serology, a characteristic pattern of leishmaniosis was obtained and by performing an isoenzyme electrophoresis, a Leishmania infantum MON-1 strain was identified. The same zymodeme is implicated in most of the canine and human leishmaniosis in Southern Europe. A study on the prevalence of asymptomatic feline leismaniosis is foreseen." 9143;"Visceral leishmaniosis in HIV-positive patients: primary infection, reactivation and latent infection. Impact of the CD4+ T-lymphocyte counts.";"P. Marty";"Equipe 06, Team 06";9833855;"AIDS (London, England)";"Kubar J, Marty P, Lelièvre A, Quaranta JF, Staccini P, Caroli-Bosc C, Le Fichoux Y";;"Nov 1998";909878400;;"To discriminate cases of visceral leishmaniosis (VL) following a primary infection from cases originating in a reactivation of a latent Leishmania infection and to assess the impact of CD4+ T-cell counts on the occurrence of VL in patients with HIV disease." 9141;"The biological diagnosis of leishmaniasis in HIV-infected patients.";"P. Marty";"Equipe 06, Team 06";14678639;"Annals of tropical medicine and parasitology";"Deniau M, Cañavate C, Faraut-Gambarelli F, Marty P";;"Oct 2003";1064966400;;"This review emphasises the particular difficulties encountered in confirming a suspected case of cutaneous or visceral leishmaniasis when that case is co-infected with HIV. HIV infection appears to have a more profound impact on the development of visceral leishmaniasis than on the evolution of the purely cutaneous disease. The various techniques available for immunological, parasitological and molecular diagnosis are presented and evaluated. The value of serodiagnosis for the detection of antileishmanial antibodies is in part dependent on the antigens used. Western blots may have a use not only in diagnosis but also in predicting the cases of HIV infection that are at most risk of developing symptomatic leishmaniasis. The presence of leishmanial parasites may still only be demonstrated incontrovertibly by the microscopical examination of smears or the culture of blood or biopsy samples. The use of cultures not only permits diagnosis but also detailed study of the parasites. The potential use of PCR in diagnosis is explored and related to other possible tests. A recommended, standardized procedure for the diagnosis of leishmaniasis in HIV-infected patients is presented." 9139;"Visceral leishmaniasis in organ transplant recipients: 11 new cases and a review of the literature.";"P. Marty";"Equipe 06, Team 06";16046170;"Microbes and infection";"Basset D, Faraut F, Marty P, Dereure J, Rosenthal E, Mary C, Pratlong F, Lachaud L, Bastien P, Dedet JP";;"Oct 2005";1128124800;;"Eleven new cases of visceral leishmaniasis (VL) are reported in organ transplant patients in France. The epidemiological, clinical, biological, diagnostic and therapeutic features are reviewed, based on these cases and 46 cases reported in the literature. VL was most commonly associated with renal transplantation (77% of the cases). Most patients were from Southern European countries. The main clinical symptom was fever. Leucopoenia and anaemia were the most frequent haematological disorders. Diagnosis was by direct finding of the parasite in smears of bone marrow (85.2%) or, by positive serology (90.9%). Without antileishmanial treatment, VL in transplant recipients was fatal. Treatment using either antimonials or amphotericine B gave similar cure rates of around 80% of the cases. But toxicity was higher for antimonials. Relapses occurred in 14.3%." 9137;"[Mediterranean leishmaniasis caused by Leishmania infantum. Update on the utility of the IT-Leish and ID-Pagia leishmaniasis tests].";"P. Marty";"Equipe 06, Team 06";17506280;"Medecine tropicale : revue du Corps de sante colonial";"Marty P, Delaunay P, Fissore C, Le Fichoux Y";;"Feb 2007";1170288000;;"The purpose of this article is to update information about Mediterranean leishmaniasis caused by Leishmania infantum in man and about the canine reservoir. Special emphasis is placed on laboratory diagnosis tests for Mediterranean visceral leishmaniasis (MVL) in humans. In addition two rapid diagnostic tests for human leishmaniasis are compared based on indirect immunofluorescence and Western blot. Findings show that the overall sensitivity of the two tests in immunocompetent and immunodepressed patients ranged from 54% to 97%, a specificity of 97%, with positive predictive value ranging from 75% to 97% and a negative predictive value of around 95%. For diagnosis of cutaneous leishmaniasis, positivity of these tests in one case out of 2 underscores the predictive value of a positive test." 9133;"[Mediterranean visceral leishmaniasis].";"C. Pomares, G. MICHEL, P. Marty";"Equipe 06, Team 06";22039711;"Bulletin de l'Academie nationale de medecine";"Marty P, Pomares C, Michel G, Delaunay P, Ferrua B, Rosenthal E";;"Jan 2011";1293840000;;"Mediterranean visceral leishmaniasis is a parasitic zoonosis due to Leishmania infantum. The dog is the reservoir species and also the main victim. The vector is the female Phlebotomus sand fly. In the southern Mediterranean region the disease is most frequent in children, whereas in Europe, and particularly in France, it is mostly an opportunistic infection associated with immunosuppression. Frequent asymptomatic carriage has been detected in southern Europe. The classic symptom triad consists of fever, pallor and splenomegaly. Biological signs include low cell blood counts (anemia, leukoneutropenia, and thrombocytopenia) and an inflammatory syndrome. Commercial serologic tests such as those based on immunoblotting are very useful. The gold standard for diagnosis is parasite detection in bone marrow or blood. PCR is useful for therapeutic follow-up. Treatment is currently based on liposomal amphotericin B (AmBisome)." 9134;"Importance of worldwide asymptomatic carriers of Leishmania infantum (L. chagasi) in human.";"C. Pomares, G. MICHEL, P. Marty";"Equipe 06, Team 06";21679680;"Acta tropica";"Michel G, Pomares C, Ferrua B, Marty P";;"Jun 2011";1308355200;;"Leishmaniasis due to Leishmania infantum (syn. L. chagasi) infection is a zoonotic disease present mainly in Mediterranean basin, central Asia and Brazil. Besides a limited number of human cases of clinical visceral leishmaniasis, a great number of infections remains asymptomatic. In this review, the prevalence of asymptomatic carriers of L. infantum was evaluated worldwide using parasitological methods or indirect testing such as a skin test or serology. The consequences of the presence of asymptomatic carriers on parasite transmission by blood donation or the development of clinical visceral leishmaniasis in immunocompromised individuals and its possible role as reservoir are discussed." 9131;"[Epidemiology of cutaneous leishmaniasis in five villages of Dogon country, Mali].";"P. Marty";"Equipe 06, Team 06";22246557;"Bulletin de la Societe de pathologie exotique (1990)";"Kone AK, Delaunay P, Djimdé AA, Thera MA, Giudice PD, Coulibaly D, Traoré K, Goita SM, Abathina A, Izri A, Marty P, Doumbo OK";;"Feb 2012";1328054400;;"The epidemiology of the cutaneous leishmaniasis (CL) with Leishmania major is poorly documented in Mali. Following reports of CL in the tourist areas of the Dogon country (Bandiagara Escarpment), a joint French and Malian bio-clinical team conducted a field study from 16 to 27 January, 2010. The population of 5 villages has been examined by a dermato-infectiologist and cases were selected by visual inspection of skin lesions. Smears and biopsies (from the lesions) and venous blood were obtained from suspected cases of CL. Diagnosis was performed by light microscopy, in vitro cultures, serology and molecular biology. Fifty patients with skin lesions have been examined. Twenty-one have been suspected as CL. At least one sample was obtained from 18 patients. The lesions were predominantly old, more or less scarring and secondary infected. A skin smear was performed for 15 patients, a skin biopsy for 14 patients: smears and cultures were all negative. The PCR (Leishmania spp.) made on 14 biopsies was positive for 12 patients (86%). The low amount of amplified DNA obtained did not allow the sequencing and identification of the species of Leishmania. Western blot (WB) serology was positive in 11 cases out of 12 (92%). This investigation showed the presence of cutaneous leishmaniasis in Bandiagara. A further investigation is required during transmission period (September-October) to confirm the presence of Leishmania major epidemic in Dogon country." 9129;"Anthrenus sp. and an Uncommon Cluster of Dermatitis.";"C. Pomares, L. Simon, P. Marty";"Equipe 06, Team 06";34152950;"Emerging infectious diseases";"Simon L, Boukari F, Oumarou HA, Hubiche T, Marty P, Pomares C, Delaunay P";;"07 2021";1625097600;;"We report patients in their homes in France who had cutaneous lesions caused by Anthrenus sp. larvae during the end of winter and into spring. These lesions mimic bites but are allergic reactions to larvae hairs pegged in the skin. These lesions should be distinguished from bites of bed bugs or fleas." 9127;"Place of Serology in the Diagnosis of Zoonotic Leishmaniases With a Focus on Visceral Leishmaniasis Due to .";"C. Pomares, L. Simon, P. Marty";"Equipe 06, Team 06";32158704;"Frontiers in cellular and infection microbiology";"Lévêque MF, Lachaud L, Simon L, Battery E, Marty P, Pomares C";;"Jan 2020";1577836800;;"Leishmaniases are a group of parasitic diseases transmitted through the bite of female phlebotomine sandflies. Depending on the species, the reservoirs can be humans (anthroponosis) or different animals (zoonosis). Zoonotic leishmaniasis present several clinical forms in function of the species involved: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and muco-cutaneous leishmaniasis (MCL). The biological diagnosis is of utmost importance because the clinical features are not specific. In addition to parasitological and molecular biology (polymerase chain reaction, PCR) assays, serology is routinely used for the diagnosis of leishmaniasis. Indeed, although PCR is more sensitive than serological assays, its implementation is limited to referral laboratories and research centers. Therefore, serology is still a key element for their diagnosis. Here, we discuss the different serological assays available for the diagnosis of zoonotic leishmaniasis. We will review the enzyme-linked immunosorbent assay, immunofluorescence antibody test, immunochromatography test (ICT), direct agglutination test, and western blot as well as the different diagnostic strategies in function of the clinical form (VL, CL, and MCL). We will also discuss the place of serology for detecting asymptomatic carriers and for the follow-up of VL. Depending on the laboratory, different assays can be used, from ICT, which is appropriate for field testing, to a combination of serological tests to improve the sensitivity." 9125;"Serological diagnosis of Toxoplasma gondii: analysis of false-positive IgG results and implications.";"C. Pomares, L. Simon, P. Marty";"Equipe 06, Team 06";32031519;"Parasite (Paris, France)";"Simon L, Fillaux J, Guigon A, Lavergne RA, Villard O, Villena I, Marty P, Pomares C, ";;"Jan 2020";1577836800;;"Primary infection by Toxoplasma gondii in pregnant women can result in serious outcomes for the foetus. A false-positive IgG result during pregnancy can lead to a misdiagnosis of past infection and to stopping preventive measures. We collected 189 sera with positive Architect Toxo IgG assay (Abbott Laboratories) and negative IgG results with at least two other serological tests, in order to find an explanation for the suspected false-positive IgG results. We used the recomLine Toxoplasma IgG immunoblot (Mikrogen Diagnostik) to search for specific antigenic reactivities of the sera, and the LDBio Toxo II IgG immunoblot (LDBio Diagnostics) as a confirmatory test." 9121;"Late clinical failure associated with cytochrome b codon 268 mutation during treatment of falciparum malaria with atovaquone-proguanil in traveller returning from Congo.";"A. Chevalier, C. Pomares, P. Marty";"Equipe 06, Team 06";31964401;"Malaria journal";"Massamba L, Madamet M, Benoit N, Chevalier A, Fonta I, Mondain V, Jeandel PY, Amalvict R, Delaunay P, Mosnier J, Marty P, Pomares C, Pradines B";;"Jan 2020";1577836800;;"The drug combination atovaquone-proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone-proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb)." 9119;"Evaluation of six commercial kits for the serological diagnosis of Mediterranean visceral leishmaniasis.";"C. Pomares";"Equipe 06, Team 06";32210438;"PLoS neglected tropical diseases";"Lévêque MF, Battery E, Delaunay P, Lmimouni BE, Aoun K, L'Ollivier C, Bastien P, Mary C, Pomares C, Fillaux J, Lachaud L";;"03 2020";1583020800;;"Zoonotic visceral leishmaniasis (VL) is endemic in the Mediterranean basin. However, large-scale comparative analyses of the commercial kits for the serological diagnosis of this neglected disease are lacking. This study compared the performances of four enzyme-linked immunosorbent assays (ELISA) and two immunochromatographic tests (ICT) as screening tests for the serodiagnosis of human VL in the Mediterranean region." 9117;"A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies.";"P. Marty";"Equipe 06, Team 06";26937644;"PLoS neglected tropical diseases";"Akhoundi M, Kuhls K, Cannet A, Votýpka J, Marty P, Delaunay P, Sereno D";;"Mar 2016";1456790400;;"The aim of this study is to describe the major evolutionary historical events among Leishmania, sandflies, and the associated animal reservoirs in detail, in accordance with the geographical evolution of the Earth, which has not been previously discussed on a large scale." 9115;"Bed Bugs (Hemiptera, Cimicidae): Overview of Classification, Evolution and Dispersion.";"P. Marty";"Equipe 06, Team 06";32630433;"International journal of environmental research and public health";"Akhoundi M, Sereno D, Durand R, Mirzaei A, Bruel C, Delaunay P, Marty P, Izri A";;"06 2020";1590969600;;"The bed bugs ( and ) have undergone a significant resurgence worldwide since the 1990s. A compilation of findings from a database, including 2650 scientific publications from seven major medical databases, allowed us to document main evolutionary events, from fossil evidence, dating from 11,000 years ago, until the present that has led to the current worldwide expansion of species. We present the hypotheses on the possible dispersion pathways of bed bugs in light of the major historical and evolutionary events. A detailed classification of the Cimicidae family and finally, an illustrative map displaying the current distribution of known species in each geographical ecozone of Asia, Europe, Africa, the Americas, and Australia are presented." 9113;"Painful Awakening due to Stings.";"L. Simon, P. Marty";"Equipe 06, Team 06";33269682;"The American journal of tropical medicine and hygiene";"Simon L, Delaunay P, Marty P";;"10 2020";1601510400;; 9111;"Risk factors for symptoms of infection and microbial carriage among French medical students abroad.";"P. Marty";"Equipe 06, Team 06";32890724;"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases";"Dao TL, Canard N, Hoang VT, Ly TDA, Drali T, Ninove L, Fenollar F, Raoult D, Parola P, Marty P, Gautret P";;"Nov 2020";1604188800;;"To investigate symptoms of infections and their risk factors among French medical students undertaking an internship abroad." 9109;"Ultrasound features of fetal toxoplasmosis: A contemporary multicenter survey in 88 fetuses.";"C. Pomares";"Equipe 06, Team 06";32506432;"Prenatal diagnosis";"Codaccioni C, Picone O, Lambert V, Maurice P, Pomar L, Winer N, Guibaud L, Lavergne RA, Saliou AH, Quinio D, Benachi A, Noel C, Ville Y, Cuillier F, Pomares C, Ferret N, Filisetti D, Weingertner AS, Vequeau-Goua V, Cateau E, Benoist G, Wallon M, Dommergues M, Villena I, Mandelbrot L";;"12 2020";1606780800;;"To describe the lesions detected by prenatal ultrasound examination in congenital toxoplasmosis (CT)." 9107;"A case of congenital toxoplasmosis-associated miscarriage with maternal infection four months prior to conception.";"C. Pomares, L. Simon, P. Marty";"Equipe 06, Team 06";32589941;"Parasitology international";"Simon L, Trastour C, Soler A, Jeannet F, Durieux MF, Passebosc-Faure K, Marty P, Pomares C";;"Dec 2020";1606780800;;"We report a case of fatal congenital toxoplasmosis with maternal infection dated four months before pregnancy in the absence of any specific immunosuppressive condition." 9105;"Fatal pulmonary infection related to in a patient with chronic obstructive pulmonary disease.";"R. Ruimy, R. Lotte";"Equipe 06, Team 06";32226629;"New microbes and new infections";"Scussel R, Lotte R, Gillon J, Chassang M, Boudoumi D, Ruimy R";;"May 2020";1588291200;;" are aerobic, gram-positive, non-acid fast rods isolated from soil, waters, and animals. They are opportunistic human pathogens, but very few cases have been published so far. We report the first case of fatal pulmonary infection related to in an immunocompetent patient with chronic obstructive pulmonary disease." 9103;"Tuberculosis trends in a hot-spot region in Paris, France.";"R. Ruimy";"Equipe 06, Team 06";32317068;"The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease";"Pierre-Audigier C, Talla C, Alame-Emane AK, Audigier B, Grall N, Ruimy R, Andremont A, Cadet-Daniel V, Sola C, Takiff H, Gicquel B, Vray M, Armand-Lefevre L";;"04 2020";1585699200;;" Tuberculosis (TB) incidence is declining overall in France, but not in Paris where some areas remain relative hot spots for TB. To obtain a better knowledge of local TB epidemiology in order to facilitate control measures. Analysis of demographic data of TB patients diagnosed at the Bichat-Claude Bernard Hospital from 2007 to 2016, with spoligotyping of complex isolates. During the study period, 1096 TB patients were analysed. The incidence of TB diagnosis was stable, averaging 115 patients per year, predominantly males (71%), foreign-born (81%), with pulmonary TB (77%) and negative HIV serology (88%). The mean age of foreign-born TB patients decreased over the study period, most significantly in recent arrivals in France, whose average age decreased by two years ( = 0.001). The time period between arrival in France and being diagnosed with active TB decreased annually significantly by 0.75 years ( = 0.02). The proportion of L4.6.2/Cameroon and L2/Beijing sub-lineages increased annually by 0.7% ( < 0.05). Multi-drug resistant strains, representing 4% of all strains, increased annually by 0.75% ( = 0.03) The number of TB patients remained high in northern Paris and the surrounding suburbs, suggesting the need for increased control measures." 9101;"Staphylococcus capitis isolated from bloodstream infections: a nationwide 3-month survey in 38 neonatal intensive care units.";"R. Ruimy";"Equipe 06, Team 06";32519215;"European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology";"Decalonne M, Dos Santos S, Gimenes R, Goube F, Abadie G, Aberrane S, Ambrogi V, Baron R, Barthelemy P, Bauvin I, Belmonte O, Benabid E, Ammar RB, Yahia SBH, Berrouane Y, Berthelot P, Beuchee A, Bille E, Bolot P, Bordes-Couecou S, Bouissou A, Bourdon S, Bourgeois-Nicolaos N, Boyer S, Cattoen C, Cattoir V, Chaplain C, Chatelet C, Claudinon A, Chautemps N, Cormier H, Coroller-Bec C, Cotte B, De Chillaz C, Dauwalder O, Davy A, Delorme M, Demasure M, Desfrere L, Drancourt M, Dupin C, Faraut-Derouin V, Florentin A, Forget V, Fortineau N, Foucan T, Frange P, Gambarotto K, Gascoin G, Gibert L, Gilquin J, Glanard A, Grando J, Gravet A, Guinard J, Hery-Arnaud G, Huart C, Idri N, Jellimann JM, Join-Lambert O, Joron S, Jouvencel P, Kempf M, Ketterer-Martinon S, Khecharem M, Klosowski S, Labbe F, Lacazette A, Lapeyre F, Larche J, Larroude P, Le Pourhiennec A, Le Sache N, Ledru S, Lefebvre A, Legeay C, Lemann F, Lesteven C, Levast-Raffin M, Leyssene D, Ligi I, Lozniewski A, Lureau P, Mallaval FO, Malpote E, Marret S, Martres P, Menard G, Menvielle L, Mereghetti L, Merle V, Minery P, Morange V, Mourdie J, Muggeo A, Nakhleh J, Noulard MN, Olive C, Patural H, Penn P, Petitfrere M, Pozetto B, Riviere B, Robine A, Ceschin CR, Ruimy R, Siali A, Soive S, Slimani S, Trentesaux AS, Trivier D, Vandenbussche C, Villeneuve L, Werner E, Le Vu S, Van Der Mee-Marquet N";;"Nov 2020";1604188800;;"To increase the knowledge about S. capitis in the neonatal setting, we conducted a nationwide 3-month survey in 38 neonatal intensive care units (NICUs) covering 56.6% of French NICU beds. We demonstrated 14.2% of S. capitis BSI (S.capBSI) among nosocomial BSIs. S.capBSI incidence rate was 0.59 per 1000 patient-days. A total of 55.0% of the S.capBSIs were late onset catheter-related BSIs. The S. capitis strains infected preterm babies (median gestational age 26 weeks, median birth weight 855 g). They were resistant to methicillin and aminoglycosides and belonged to the NRCS-A clone. Evolution was favorable in all but one case, following vancomycin treatment." 9099;"An unusual Staphylococcus saccharolyticus spondylodiscitis post kyphoplasty: a case report.";"B. Lamy, R. Ruimy";"Equipe 06, Team 06";32703263;"BMC infectious diseases";"Trojani MC, Lamy B, Ruimy R, Amoretti N, Risso K, Roux C";;"Jul 2020";1593561600;;"Staphylococcus saccharolyticus is a rarely encountered coagulase-negative, which grows slowly and its strictly anaerobic staphylococcus from the skin. It is usually considered a contaminant, but some rare reports have described deep-seated infections. Virulence factors remain poorly known, although, genomic analysis highlights pathogenic potential." 9096;"A Population Pharmacokinetic Analysis of Continuous Infusion of Cloxacillin during Bone and Joint Infections.";"J. Courjon, R. Ruimy";"Equipe 06, Team 06";32988822;"Antimicrobial agents and chemotherapy";"Courjon J, Garzaro M, Roger PM, Ruimy R, Lavrut T, Chelli M, Raynier JL, Chirio D, Demonchy E, Cabane L, Jehl F, Trojani C, Grillon A, Goutelle S";;"11 2020";1604188800;;"Intravenous administration of antibiotics is recommended during the early phase of methicillin-susceptible (MSSA) bone and joint infection (BJI). We sought to compare the plasma concentrations of cloxacillin administered alternately by continuous and intermittent infusion (CI and ItI) in patients with MSSA BJI. In this prospective crossover trial, patients were randomly assigned to receive either 3 days of CI (two 75-mg/kg 12-h cloxacillin infusions per day) and then 3 days of ItI (four 37.5-mg/kg 1-h cloxacillin infusions per day) or vice versa. The drug concentration measurement was performed on day 3 of each type of administration at 1, 6, and 11 h and at 1, 2, 3, 4, and 6 h after the beginning of CI and ItI, respectively. We used the nonparametric algorithm NPAG to estimate population pharmacokinetic (PK) parameters. The final model was used to perform pharmacokinetic/pharmacodynamic (PK/PD) simulations and calculate the probabilities of target attainment (PTA) for several ItI and CI dosing regimens. We considered two PK/PD targets of time spent above the MIC for free cloxacillin concentrations ( ): 50 and 100%. Eighty-four concentrations from 11 patients were analyzed. A two-compartment model adequately described the data. ItI with q6h regimens and short 1-h infusions of 2,000 or 3,000 mg were associated with low PTA, even for the low target (50% ) while 3-h infusions and continuous infusions (6 to 12 g/day) were associated with a PTA of >90% for an MIC up to 0.5 mg/liter. These results support the use of prolonged or continuous infusion of cloxacillin in patients with BJI." 9094;"Dalbavancin treatment for prosthetic joint infections in real-life: a national cohort study and literature review.";"J. Courjon, R. Lotte";"Equipe 06, Team 06";33962065;"Journal of global antimicrobial resistance";"Matt M, Duran C, Courjon J, Lotte R, Moing VL, Monnin B, Pavese P, Chavanet P, Khatchatourian L, Tattevin P, Cattoir V, Lechiche C, Illes G, Lacassin-Beller F, Senneville E, Dinh A, ";;"06 2021";1622505600;;"Dalbavancin is a long-lasting lipoglycopeptide active against Gram-positive bacteria, especially methicillin-resistant staphylococci. Few data are available on dalbavancin use for treatment of prosthetic joint infections (PJIs). We describe a cohort of patients treated for PJI with dalbavancin and review the literature regarding this condition." 9092;"Case Report: A New Mycobacterium ulcerans Genotype Causing Buruli Ulcer in Côte d'Ivoire.";"R. Ruimy";"Equipe 06, Team 06";33819173;"The American journal of tropical medicine and hygiene";"Bahadoran P, Hammoudi N, Gaudart A, Saad J, Di Filippo Y, Drancourt M, Ruimy R";;"Apr 2021";1617235200;;"Mycobacterium ulcerans, the opportunistic pathogen causing Buruli ulcer, is reported to affect rural populations in 36 tropical countries. We report one case of Buruli ulcer in a peri-urban area in Côte d'Ivoire, confirmed by whole genome sequencing which indicated a M. ulcerans genotype previously unreported in Côte d'Ivoire." 9090;"Real-world evaluation of ceftolozane/tazobactam therapy and clinical outcomes in France.";"R. Ruimy";"Equipe 06, Team 06";34015539;"Infectious diseases now";"Castan B, Akrich B, Levy-Bachelot L, Amode A, Berthelot A, Mackosso C, Mathis L, Mootien J, Ruimy R, Ruiz F, Timsit JF, Boutoille D";;"Sep 2021";1630454400;;"To describe the real-world clinical use of ceftolozane/tazobactam (C/T) and associated outcomes in France." 9088;"Proteinuria as a Biomarker for COVID-19 Severity.";"J. Courjon";"Equipe 06, Team 06";33767630;"Frontiers in physiology";"Ouahmi H, Courjon J, Morand L, François J, Bruckert V, Lombardi R, Esnault V, Seitz-Polski B, Demonchy E, Dellamonica J, Boyer-Suavet S";;"Jan 2021";1609459200;;"Renal involvement in syndrome coronavirus 2 (SARS-CoV-2) infection has been retrospectively described, especially acute kidney injury (AKI). However, quantitative proteinuria assessment and its implication in coronavirus disease 2019 (COVID-19) remain unknown." 9086;"Management of prosthetic joint infections in France: a national audit to identify key situations requiring innovation and homogenization.";"J. Courjon";"Equipe 06, Team 06";33933020;"BMC infectious diseases";"Le Maréchal M, Cavalli Z, Batailler C, Gonzalez JF, Ferreira A, Lustig S, Ferry T, Courjon J";;"May 2021";1619827200;;"Prosthetic joint infections (PJI) are one of the most serious complication of arthroplasty. The management of PJI needs a multidisciplinary collaboration between orthopaedic surgeon, infectious disease specialist and microbiologist. In France, the management of PJI is organized around reference centres (CRIOACs). Our main objective was to perform an audit through a questionnaire survey based on clinical cases, to evaluate how French physicians manage PJI. Eligible participants were all physicians involved in care of patients presenting a PJI. Physicians could answer individually, or collectively during a multidisciplinary team meeting dedicated to PJI. The survey consisted as three questionnaires organized in a total of six clinical cases." 9084;"Cotrimoxazole for community-acquired urinary tract infections leads to more adverse effects than fluoroquinolones.";"J. Courjon";"Equipe 06, Team 06";33975674;"Infectious diseases now";"Michelangeli C, Courjon J, Curlier E, Roger PM";;"Jun 2021";1622505600;;"For several years, we applied an internal guideline for community-acquired urinary tract infections (cUTI), targeting the reduction of fluoroquinolone use (FQ) and thereby favouring cotrimoxazole (CTM) prescription. Our aim was to report adverse effects (AE) and outcome for patients presenting with cUTI and treated with these compounds." 9082;"An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19.";"J. Courjon";"Equipe 06, Team 06";34048876;"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases";"Ader F, Peiffer-Smadja N, Poissy J, Bouscambert-Duchamp M, Belhadi D, Diallo A, Delmas C, Saillard J, Dechanet A, Mercier N, Dupont A, Alfaiate T, Lescure FX, Raffi F, Goehringer F, Kimmoun A, Jaureguiberry S, Reignier J, Nseir S, Danion F, Clere-Jehl R, Bouiller K, Navellou JC, Tolsma V, Cabié A, Dubost C, Courjon J, Leroy S, Mootien J, Gaci R, Mourvillier B, Faure E, Pourcher V, Gallien S, Launay O, Lacombe K, Lanoix JP, Makinson A, Martin-Blondel G, Bouadma L, Botelho-Nevers E, Gagneux-Brunon A, Epaulard O, Piroth L, Wallet F, Richard JC, Reuter J, Staub T, Lina B, Noret M, Andrejak C, Lê MP, Peytavin G, Hites M, Costagliola D, Yazdanpanah Y, Burdet C, Mentré F, ";;"Dec 2021";1638316800;;"We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support." 9080;"COVID-19 patients age, comorbidity profiles and clinical presentation related to the SARS-CoV-2 UK-variant spread in the Southeast of France.";"J. Courjon, J. Contenti, M. Carles, V. Giordanengo";"Equipe 06, Team 06, Equipe 05, Team 05";34531412;"Scientific reports";"Courjon J, Contenti J, Demonchy E, Levraut J, Barbry P, Rios G, Dellamonica J, Chirio D, Bonnefoy C, Giordanengo V, Carles M";;"09 2021";1630454400;;"The variant 20I/501Y.V1, associated to a higher risk of transmissibility, emerged in Nice city (Southeast of France, French Riviera) during January 2021. The pandemic has resumed late December 2020 in this area. A high incidence rate together with a fast turn-over of the main circulating variants, provided us the opportunity to analyze modifications in clinical profile and outcome traits. We performed an observational study in the University hospital of Nice from December 2020 to February 2021. We analyzed data of sequencing of SARS-CoV-2 from the sewage collector and PCR screening from all positive samples at the hospital. Then, we described the characteristics of all COVID-19 patients admitted in the emergency department (ED) (n = 1247) and those hospitalized in the infectious diseases ward or ICU (n = 232). The UK-variant was absent in this area in December, then increasingly spread in January representing 59% of the PCR screening performed mid-February. The rate of patients over 65 years admitted to the ED decreased from 63 to 50% (p = 0.001). The mean age of hospitalized patients in the infectious diseases ward decreased from 70.7 to 59.2 (p < 0.001) while the proportion of patients without comorbidity increased from 16 to 42% (p = 0.007). Spread of the UK-variant in the Southeast of France affects younger and healthier patients." 9075;"Obesity, diabetes, hypertension and severe outcomes among inpatients with coronavirus disease 2019: a nationwide study.";"J. Courjon, M. Carles";"Equipe 06, Team 06";34537362;"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases";"Bailly L, Fabre R, Courjon J, Carles M, Dellamonica J, Pradier C";;"Jan 2022";1640995200;;"Initial studies of individuals with coronavirus disease 2019 (COVID-19) revealed that obesity, diabetes and hypertension were associated with severe outcomes. Subsequently, some authors showed that the risk could vary according to age, gender, co-morbidities and medical history. In a nationwide retrospective cohort, we studied the association between these co-morbidities and patients' requirement for invasive mechanical ventilation (IMV) or their death." 9059;"Ubiquitin-related processes and innate immunity in C. elegans.";"O. Visvikis, JA. Garcia-Sanchez";"Equipe 06, Team 06";33630111;"Cellular and molecular life sciences : CMLS";"Garcia-Sanchez JA, Ewbank JJ, Visvikis O";;"May 2021";1619827200;;"Innate immunity is an evolutionary ancient defence strategy that serves to eliminate infectious agents while maintaining host health. It involves a complex network of sensors, signaling proteins and immune effectors that detect the danger, then relay and execute the immune programme. Post-translational modifications relying on conserved ubiquitin and ubiquitin-like proteins are an integral part of the system. Studies using invertebrate models of infection, such as the nematode Caenorhabditis elegans, have greatly contributed to our understanding of how ubiquitin-related processes act in immune sensing, regulate immune signaling pathways, and participate to host defence responses. This review highlights the interest of working with a genetically tractable model organism and illustrates how C. elegans has been used to identify ubiquitin-dependent immune mechanisms, discover novel ubiquitin-based resistance strategies that mediate pathogen clearance, and unravel the role of ubiquitin-related processes in tolerance, preserving host fitness during pathogen attack. Special emphasis is placed on processes that are conserved in mammals." 9057;"Escherichia coli producing CNF1 toxin hijacks Tollip to trigger Rac1-dependent cell invasion.";"A. Doye, L. Boyer, O. Visvikis";"Equipe 06, Team 06";21291504;"Traffic (Copenhagen, Denmark)";"Visvikis O, Boyer L, Torrino S, Doye A, Lemonnier M, Lorès P, Rolando M, Flatau G, Mettouchi A, Bouvard D, Veiga E, Gacon G, Cossart P, Lemichez E";;"Feb 2011";1296864000;;"Rho GTPases, which are master regulators of both the actin cytoskeleton and membrane trafficking, are often hijacked by pathogens to enable their invasion of host cells. Here we report that the cytotoxic necrotizing factor-1 (CNF1) toxin of uropathogenic Escherichia coli (UPEC) promotes Rac1-dependent entry of bacteria into host cells. Our screen for proteins involved in Rac1-dependent UPEC entry identifies the Toll-interacting protein (Tollip) as a new interacting protein of Rac1 and its ubiquitinated forms. We show that knockdown of Tollip reduces CNF1-induced Rac1-dependent UPEC entry. Tollip depletion also reduces the Rac1-dependent entry of Listeria monocytogenes expressing InlB invasion protein. Moreover, knockdown of Tollip, Tom1 and clathrin, decreases CNF1 and Rac1-dependent internalization of UPEC. Finally, we show that Tollip, Tom1 and clathrin associate with Rac1 and localize at the site of bacterial entry. Collectively, these findings reveal a new link between Rac1 and Tollip, Tom1 and clathrin membrane trafficking components hijacked by pathogenic bacteria to allow their efficient invasion of host cells." 9055;"The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1.";"A. Doye, L. Boyer, O. Visvikis, P. Munro";"Equipe 06, Team 06";22036506;"Developmental cell";"Torrino S, Visvikis O, Doye A, Boyer L, Stefani C, Munro P, Bertoglio J, Gacon G, Mettouchi A, Lemichez E";;"Nov 2011";1320105600;;"Rac1 small GTPase controls essential aspects of cell biology and is a direct target of numerous bacterial virulence factors. The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation. HACE1 expression increases the ubiquitylation of Rac1, when the GTPase is activated by point mutations or by the GEF-domain of Dbl. RNAi-mediated depletion of HACE1 blocks the ubiquitylation of active Rac1 and increases GTP-bound Rac1 cellular levels. HACE1 antagonizes cell isotropic spreading, a hallmark of Rac1 activation, and is required for endothelial cell monolayer invasion by bacteria. Together, these data establish the role of the HACE1 E3 ubiquitin-ligase in controlling Rac1 ubiquitylation and activity." 9053;"Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis.";"L. Boyer";"Equipe 06, Team 06";26492464;"Small GTPases";"Boyer L, Lemichez E";;"10 2015";1443657600;;"The monitoring of the activation state of Rho GTPases has emerged as a potent innate immune mechanism for detecting pathogens. In the March issue of PLOS Pathogens, we show that the activation of Rho GTPases by the CNF1 toxin during E. coli-triggered bacteremia leads to a GR1(+)cell-mediated efficient bacterial clearing and improves host survival. Host alarm requires the Caspase-1/IL-1beta signaling axis. Furthermore, we discover that pathogenic bacteria have the capacity to block immune responses via the expression of the α-hemolysin pore-forming toxin. In this commentary, we will comment on these findings and highlight the questions raised by this example of attack-defense mechanisms used alternatively by the pathogen and the host during blood infection." 9051;"EDIN-B Promotes the Translocation of Staphylococcus aureus to the Bloodstream in the Course of Pneumonia.";"A. Doye, J. Courjon, L. Boyer, O. Visvikis, P. Munro";"Equipe 06, Team 06";26501320;Toxins;"Courjon J, Munro P, Benito Y, Visvikis O, Bouchiat C, Boyer L, Doye A, Lepidi H, Ghigo E, Lavigne JP, Vandenesch F, Lemichez E";;"Oct 2015";1443657600;;"It is crucial to define risk factors that contribute to host invasion by Staphylococcus aureus. Here, we demonstrate that the chromosomally encoded EDIN-B isoform from S. aureus contributes to the onset of bacteremia during the course of pneumonia. Deletion of edinB in a European lineage community-acquired methicillin resistant S. aureus (CA-MRSA) strain (ST80-MRSA-IV) dramatically decreased the frequency and magnitude of bacteremia in mice suffering from pneumonia. This deletion had no effect on the bacterial burden in both blood circulation and lung tissues. Re-expression of wild-type EDIN-B, unlike the catalytically inactive mutant EDIN-R185E, restored the invasive characteristics of ST80-MRSA-IV. " 9049;"Escherichia coli K1 meningitis: Analysis of the effects of CNF1 toxin in newborn mice questions its virulence function.";"L. Boyer";"Equipe 06, Team 06";27432618;Virulence;"Boyer L";;"10 2016";1475280000;; 9047;"Chemical Composition, Antimicrobial and Insecticidal Activities of Flowers Essential Oils of Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm. from Martinique Island.";"L. Boyer";"Equipe 06, Team 06";27935668;"Chemistry & biodiversity";"Kerdudo A, Ellong EN, Burger P, Gonnot V, Boyer L, Chandre F, Adenet S, Rochefort K, Michel T, Fernandez X";;"Apr 2017";1491004800;;"Alpinia species, used as ornamental plants and flavoring agents, are renowned for their therapeutic properties and their subsequent use in traditional medicines throughout the world. Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm. is the most common Alpinia species encountered in Martinique. Several essential oils (EOs) obtained by hydrodistillation of A. zerumbet flowers collected in various locations on the island at different seasons were analysed to evaluate the influence of the collection period and area on the EOs' chemical compositions and to assess their bioactivity. A combination of GC-FID and GC/MS techniques was used to examine the volatile constituents, leading to the identification of a total of 71 components accounting for 97.8 - 99.3% of the respective total GC-FID areas: among them, nineteen compounds were characterized for the first time in A. zerumbet EOs. The antimicrobial activity of these EOs was assessed against eight bacterial, yeast and fungal strains and two multi-resistant strains: some significant bacteriostatic and fungistatic activities of A. zerumbet flower oils were evidenced. Finally, an interesting insecticidal activity of the flower EO was highlighted for the first time against Aedes aegypti." 9045;"UHPLC-HRMS/MS Based Profiling of Algerian Lichens and Their Antimicrobial Activities.";"C. Pomares, G. MICHEL, L. Boyer";"Equipe 06, Team 06";29505125;"Chemistry & biodiversity";"Brakni R, Ali Ahmed M, Burger P, Schwing A, Michel G, Pomares C, Hasseine L, Boyer L, Fernandez X, Landreau A, Michel T";;"Apr 2018";1522540800;;"Lichens are complex symbiotic organisms able to produce a vast array of compounds. The Algerian lichen diversity has only prompted little interest even given the 1085 species listed. Herein, the chemodiversity of four Algerian lichens including Cladonia rangiformis, Ramalina farinaceae, R. fastigiata, and Roccella phycopsis was investigated. A dereplication strategy, using ultra high performance liquid chromatography-high resolution-electrospray ionization-mass spectrometry (UHPLC-HRMS/MS), was carried out for a comprehensive characterization of their substances including phenolics, depsides, depsidones, depsones, dibenzofurans, and aliphatic acids. Some known compounds were identified for the first time in some species. Additionally, the lichenic extracts were evaluated for their antifungal and antimicrobial activities on human pathogenic strains (Candida albicans, C. glabrata, Aspergillus fumigatus, Staphylococcus aureus, and Escherichia coli). Cyclohexane extracts were found particularly active against human pathogenic fungi with MIC values ranging from 8 to 62.5 μg/mL, without cytotoxicity. This study highlights the therapeutic and prophylactic potential of lichenic extracts as antibacterial and antifungal agents." 9043;"Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production.";"L. Boyer, L. Yvan-Charvet, S. Marchetti, T. Barouillet";"Equipe 06, Team 06, Equipe 13, Team 13, Team 03, Equipe 03";29523554;"Circulation research";"Viaud M, Ivanov S, Vujic N, Duta-Mare M, Aira LE, Barouillet T, Garcia E, Orange F, Dugail I, Hainault I, Stehlik C, Marchetti S, Boyer L, Guinamard R, Foufelle F, Bochem A, Hovingh KG, Thorp EB, Gautier EL, Kratky D, Dasilva-Jardine P, Yvan-Charvet L";;"05 2018";1525132800;;"Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment." 9041;"Leishmania infection: Misdiagnosis as cancer and tumor-promoting potential.";"A. Majoor, C. Pomares, G. MICHEL, L. Boyer, P. Marty";"Equipe 06, Team 06";30529443;"Acta tropica";"Schwing A, Pomares C, Majoor A, Boyer L, Marty P, Michel G";;"Sep 2019";1567296000;;"Given the prevalence of cancer and leishmaniasis worldwide, the presence of these two pathologies in the same tissue sample may be merely fortuitous. The clinical outcome of both diseases is under the control of innate and adaptive immunity, and in both cases these progressive diseases are characterized by an impaired host Th1 response. As a consequence, the Th2 cytokine microenvironment occurring in progressive leishmaniasis may potentially promote tumor cell proliferation and vice versa. On the other hand, clinical aspects of subclinical cutaneous or visceral leishmaniasis sometimes closely resemble those observed in various neoplasms thus leading to misdiagnosis. In this review, we present recent findings on the association between leishmaniasis and malignant disorders. Our review includes HIV positive, HIV negative subjects and patients whose HIV status has not been established. Leishmaniasis mimicking a malignant disorder was confirmed and extended to unreported neoplastic disorders including squamous cell carcinoma, T-cell and B-cell lymphoma, oral and intranasal tumors and granulomas. Thus, leishmaniasis should be considered in the differential diagnosis and course of various cancers in Leishmania endemic areas or in patients with travel history to these areas. We also listed recent reports showing that Leishmania can promote cancer development in immunocompromised as well as in immunocompetent patients. The potential mechanisms supporting this promoting effect are discussed." 9039;"Diet Supplementation in ω3 Polyunsaturated Fatty Acid Favors an Anti-Inflammatory Basal Environment in Mouse Adipose Tissue.";"L. Boyer, O. Dufies, P. Munro";"Equipe 06, Team 06";30791540;Nutrients;"Colson C, Ghandour RA, Dufies O, Rekima S, Loubat A, Munro P, Boyer L, Pisani DF";;"Feb 2019";1548979200;;"Oxylipins are metabolized from dietary ω3 and ω6 polyunsaturated fatty acids and are involved in an inflammatory response. Adipose tissue inflammatory background is a key factor of metabolic disorders and it is accepted that dietary fatty acids, in terms of quality and quantity, modulate oxylipin synthesis in this tissue. Moreover, it has been reported that diet supplementation in ω3 polyunsaturated fatty acids resolves some inflammatory situations. Thus, it is crucial to assess the influence of dietary polyunsaturated fatty acids on oxylipin synthesis and their impact on adipose tissue inflammation. To this end, mice fed an ω6- or ω3-enriched standard diet ( ratio of 30 and 3.75, respectively) were analyzed for inflammatory phenotype and adipose tissue oxylipin content. Diet enrichment with an ω3 polyunsaturated fatty acid induced an increase in the oxylipins derived from ω6 linoleic acid, ω3 eicosapentaenoic, and ω3 docosahexaenoic acids in brown and white adipose tissues. Among these, the level of pro-resolving mediator intermediates, as well as anti-inflammatory metabolites, were augmented. Concomitantly, expressions of M2 macrophage markers were increased without affecting inflammatory cytokine contents. In vitro, these metabolites did not activate macrophages but participated in macrophage polarization by inflammatory stimuli. In conclusion, we demonstrated that an ω3-enriched diet, in non-obesogenic non-inflammatory conditions, induced synthesis of oxylipins which were involved in an anti-inflammatory response as well as enhancement of the M2 macrophage molecular signature, without affecting inflammatory cytokine secretion." 9037;"It takes two to tango: two Aeromonas isolates combine virulence and multidrug resistance in flap infection following leech therapy.";"A. Robert, B. Lamy, L. Boyer, R. Ruimy";"Equipe 06, Team 06";31927115;"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases";"Barraud O, Robert A, Laval L, Ruimy R, Morquin D, Boyer L, Lamy B";;"Jun 2020";1590969600;; 9034;"Nocardia takedensis: a newly recognized pathogen responsible for skin and soft tissue infections.";"A. Chevalier, L. Boyer, R. Ruimy, R. Lotte";"Equipe 06, Team 06";32819355;"Annals of clinical microbiology and antimicrobials";"Lotte R, Chevalier A, Dantas S, Degand N, Gaudart A, Rörhlich PS, Boyer L, Rodriguez-Nava V, Del Giudice P, Ruimy R";;"Aug 2020";1596240000;;"Nocardia takedensis was first isolated in 2005, from soil in Japan. We report here two cases of lymphangitis in France (2012-2017) caused by N. takedensis both occurring after skin injury while gardening, which enabled its inoculation. The two patients were immunocompromised and successfully treated by an antimicrobial agent active on the isolated strain, trimethoprim-sulfamethoxazole and amoxicillin-clavulanic acid for patient one and patient two, respectively. Our study along with previous ones supports the idea of a newly recognized cutaneous opportunistic pathogen and reinforces the recommendation of using gloves during soil exposure for immunocompromised patients. Lastly, according to data found in the literature, we would recommend trimethoprim-sulfamethoxazole as an efficient empirical antibiotic therapy in case of cutaneous infection caused by N. takedensis." 9033;"Modulation of the inflammatory response to LPS by the recruitment and activation of brown and brite adipocytes in mice.";"L. Boyer, O. Dufies, P. Munro";"Equipe 06, Team 06";32954821;"American journal of physiology. Endocrinology and metabolism";"Munro P, Dufies O, Rekima S, Loubat A, Duranton C, Boyer L, Pisani DF";;"11 2020";1604188800;;"Numerous studies have shown that the recruitment and activation of thermogenic adipocytes, which are brown and beige/brite, reduce the mass of adipose tissue and normalize abnormal glycemia and lipidemia. However, the impact of these adipocytes on the inflammatory state of adipose tissue is still not well understood, especially in response to endotoxemia, which is a major aspect of obesity and metabolic diseases. First, we analyzed the phenotype and metabolic function of white and brite primary adipocytes in response to lipopolysaccharide (LPS) treatment in vitro. Then, 8-wk-old male BALB/c mice were treated for 1 wk with a β3-adrenergic receptor agonist (CL316,243, 1 mg/kg/day) to induce recruitment and activation of brown and brite adipocytes and were subsequently injected with LPS ( lipopolysaccharide, 100 μg/mouse ip) to generate acute endotoxemia. The metabolic and inflammatory parameters of the mice were analyzed 6 h later. Our results showed that in response to LPS, thermogenic activity promoted a local anti-inflammatory environment with high secretion of IL-1 receptor antagonist (IL-1RA) without affecting other anti- or proinflammatory cytokines. Interestingly, activation of brite adipocytes reduced the LPS-induced secretion of leptin. However, thermogenic activity and adipocyte function were not altered by LPS treatment in vitro or by acute endotoxemia in vivo. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes specifically in response to endotoxemia. This encourages potential therapy involving brown and brite adipocytes for the treatment of obesity and associated metabolic diseases. Recruitment and activation of brown and brite adipocytes in the adipose tissue of mice lead to a local low-grade anti-inflammatory phenotype in response to acute endotoxemia without alteration of adipocyte phenotype and function." 9031;"Gene expression kinetics of Exaiptasia pallida innate immune response to Vibrio parahaemolyticus infection.";"L. Boyer";"Equipe 06, Team 06";33167855;"BMC genomics";"Seneca F, Davtian D, Boyer L, Czerucka D";;"Nov 2020";1604188800;;"Recent sequencing projects on early-diverging metazoans such as cnidarians, have unveiled a rich innate immunity gene repertoire; however, little is known about immunity gene regulation in the host's early response against marine bacterial pathogens over time. Here, we used RNA-seq on the sea anemone Exaiptasia pallida (Ep) strain CC7 as a model to depict the innate immune response during the onset of infection with the marine pathogenic bacteria Vibrio parahaemolyticus (Vp) clinical strain O3:K6, and lipopolysaccharides (LPS) exposure. Pairwise and time series analyses identified the genes responsive to infection as well as the kinetics of innate immune genes over time. Comparisons between the responses to live Vp and purified LPS was then performed." 9029;"RhoGTPases and inflammasomes: Guardians of effector-triggered immunity.";"L. Boyer, O. Dufies";"Equipe 06, Team 06";33914853;"PLoS pathogens";"Dufies O, Boyer L";;"04 2021";1617235200;;"Pathogens have evolved smart strategies to invade hosts and hijack their immune responses. One such strategy is the targeting of the host RhoGTPases by toxins or virulence factors to hijack the cytoskeleton dynamic and immune processes. In response to this microbial attack, the host has evolved an elegant strategy to monitor the function of virulence factors and toxins by sensing the abnormal activity of RhoGTPases. This innate immune strategy of sensing bacterial effector targeting RhoGTPase appears to be a bona fide example of effector-triggered immunity (ETI). Here, we review recently discovered mechanisms by which the host can sense the activity of these toxins through NOD and NOD-like receptors (NLRs)." 9027;"Impact of thermogenesis induced by chronic β3-adrenergic receptor agonist treatment on inflammatory and infectious response during bacteremia in mice.";"L. Boyer, P. Munro";"Equipe 06, Team 06";34437647;"PloS one";"Munro P, Rekima S, Loubat A, Duranton C, Pisani DF, Boyer L";;"Jan 2021";1609459200;;"White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response. We treated mice for one week with a β3-adrenergic receptor agonist to induce activation of brown adipose tissue and brite adipocytes within white adipose tissue. Mice were then injected intraperitoneally with E. coli to generate acute infection. The metabolic, infectious and inflammatory parameters of the mice were analysed during 48 hours after infection. Our results shown that in response to bacteria, thermogenic activity promoted a discrete and local anti-inflammatory environment in white adipose tissue characterized by the increase of the IL-1RA secretion. More generally, activation of brown and brite adipocytes did not modify the host response to infection including no additive effect with fever and an equivalent bacteria clearance and inflammatory response. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes in response to acute bacterial infection and open a way to characterize their effect along more chronic infection as septicaemia." 9025;"NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly.";"L. Boyer, O. Visvikis";"Equipe 06, Team 06";34615873;"Nature communications";"Niu T, De Rosny C, Chautard S, Rey A, Patoli D, Groslambert M, Cosson C, Lagrange B, Zhang Z, Visvikis O, Hacot S, Hologne M, Walker O, Wong J, Wang P, Ricci R, Henry T, Boyer L, Petrilli V, Py BF";;"10 2021";1633046400;;"NLRP3 controls the secretion of inflammatory cytokines IL-1β/18 and pyroptosis by assembling the inflammasome. Upon coordinated priming and activation stimuli, NLRP3 recruits NEK7 within hetero-oligomers that nucleate ASC and caspase-1 filaments, but the apical molecular mechanisms underlying inflammasome assembly remain elusive. Here we show that NEK7 recruitment to NLRP3 is controlled by the phosphorylation status of NLRP3 S803 located within the interaction surface, in which NLRP3 S803 is phosphorylated upon priming and later dephosphorylated upon activation. Phosphomimetic substitutions of S803 abolish NEK7 recruitment and inflammasome activity in macrophages in vitro and in vivo. In addition, NLRP3-NEK7 binding is also essential for NLRP3 deubiquitination by BRCC3 and subsequently inflammasome assembly, with NLRP3 phosphomimetic mutants showing enhanced ubiquitination and degradation than wildtype NLRP3. Finally, we identify CSNK1A1 as the kinase targeting NLRP3 S803. Our findings thus reveal NLRP3 S803 phosphorylation status as a druggable apical molecular mechanism controlling inflammasome assembly." 9023;"Complete Circular Genome Sequences of Three Bacillus cereus Group Strains Isolated from Positive Blood Cultures from Preterm and Immunocompromised Infants Hospitalized in France.";"A. Chevalier, L. Boyer, R. Ruimy, R. Lotte";"Equipe 06, Team 06";34647805;"Microbiology resource announcements";"Ben Khedher M, Nindo F, Chevalier A, Bonacorsi S, Dubourg G, Fenollar F, Casagrande F, Lotte R, Boyer L, Gallet A, Rolain JM, Croce O, Ruimy R";;"Oct 2021";1633046400;;"We report here the complete genome sequences of three Bacillus cereus group strains isolated from blood cultures from premature and immunocompromised infants hospitalized in intensive care units in three French hospitals. These complete genome sequences were obtained from a combination of Illumina HiSeq X Ten short reads and Oxford Nanopore MinION long reads." 9000;"Fasting Circulating Glicentin Increases After Bariatric Surgery.";"F. Lareyre, G. Chinetti, J. Raffort";"Equipe 09, Team 09";27987137;"Obesity surgery";"Raffort J, Panaïa-Ferrari P, Lareyre F, Bayer P, Staccini P, Fénichel P, Chinetti G";;"Dec 2016";1482019200;;"Bariatric surgery including the Roux-en-Y gastric bypass (RYGB) and the laparoscopic sleeve gastrectomy (LSG) is a well-established therapeutic option for patients with morbid or severe obesity. Metabolic modifications observed after bariatric surgery are thought to be, at least partly, linked to hormonal changes. While variation of several proglucagon-derived peptides during bariatric surgery is well documented, little is known about glicentin. The aim of this study was to investigate circulating glicentin variations after bariatric surgery." 8994;"Decreased serum glicentin concentration in patients with severe and morbid obesity.";"F. Lareyre, G. Chinetti, J. Raffort";"Equipe 09, Team 09";28661200;"Annals of clinical biochemistry";"Raffort J, Panaïa-Ferrari P, Lareyre F, Blois M, Bayer P, Staccini P, Fénichel P, Chinetti G";;"Jun 2017";1498780800;;"Background Proglucagon-derived hormones represent a family of peptides mainly produced in the pancreas and the intestine. While several proglucagon-derived peptides play key roles in metabolic diseases, little is known about glicentin. The aim of the present study was to investigate serum glicentin concentrations in individuals with adult obesity and to study its potential link with various metabolic parameters. Methods Fifty-two individuals with normal body mass index (BMI < 25 kg/m) and 39 patients with severe or morbid obesity (BMI > 35 kg/m) were prospectively included at the University Hospital of Nice between January 2014 and April 2016. Clinical data were recorded, and a fasting blood sample was collected to measure glicentin, glucose, insulin, C-peptide, total cholesterol, triglyceride, LDL and HDL-cholesterol. In addition, a homeostasis model assessment for insulin resistance (HOMA2-IR) was also calculated. Results Patients with severe and morbid obesity had significantly higher plasma glucose, together with higher serum concentrations of insulin, C-peptide, HOMA2-IR, triglyceride, LDL-cholesterol and lower serum concentrations of HDL-cholesterol compared with individuals with a normal body mass index. The obese patients displayed significantly lower fasting serum concentrations of glicentin compared with subjects with a normal body mass index (12 pmol/L vs. 24 pmol/L, P < 0.0001). In the total population, fasting glicentin concentrations did not correlate with BMI, glycaemic parameters (glucose, insulin, C-peptide, HOMA-IR) or lipid parameters (total cholesterol, triglyceride, LDL and HDL-cholesterol). Conclusion To the best of our knowledge, this is the first study reporting serum glicentin concentrations in healthy lean and obese adult subjects. We found that fasting serum glicentin concentrations are decreased in patients with severe or morbid obesity suggesting the potential interest of this peptide in obesity and metabolic-related disorders." 8995;"Monocytes and macrophages in abdominal aortic aneurysm.";"F. Lareyre, G. Chinetti, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";28406184;"Nature reviews. Cardiology";"Raffort J, Lareyre F, Clément M, Hassen-Khodja R, Chinetti G, Mallat Z";;"Apr 2017";1492128000;;"Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity, and high mortality in the event of aortic rupture. Major advances in open surgical and endovascular repair of AAA have been achieved during the past 2 decades. However, drug-based therapies are still lacking, highlighting a real need for better understanding of the molecular and cellular mechanisms involved in AAA formation and progression. The main pathological features of AAA include extracellular matrix remodelling associated with degeneration and loss of vascular smooth muscle cells and accumulation and activation of inflammatory cells. The inflammatory process has a crucial role in AAA and substantially influences many determinants of aortic wall remodelling. In this Review, we focus specifically on the involvement of monocytes and macrophages, summarizing current knowledge on the roles, origin, and functions of these cells in AAA development and its complications. Furthermore, we show and propose that distinct monocyte and macrophage subsets have critical and differential roles in initiation, progression, and healing of the aneurysmal process. On the basis of experimental and clinical studies, we review potential translational applications to detect, assess, and image macrophage subsets in AAA, and discuss the relevance of these applications for clinical practice." 8996;"Diabetes and aortic aneurysm: current state of the art.";"F. Lareyre, G. Chinetti, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30052821;"Cardiovascular research";"Raffort J, Lareyre F, Clément M, Hassen-Khodja R, Chinetti G, Mallat Z";;"Jul 2018";1532736000;;"Aortic aneurysm is a life-threatening disease due to the risk of aortic rupture. The only curative treatment available relies on surgical approaches; drug-based therapies are lacking, highlighting an unmet need for clinical practice. Abdominal aortic aneurysm (AAA) is frequently associated with atherosclerosis and cardiovascular risk factors including male sex, age, smoking, hypertension, and dyslipidaemia. Thoracic aortic aneurysm (TAA) is more often linked to genetic disorders of the extracellular matrix and the contractile apparatus but also share similar cardiovascular risk factors. Intriguingly, a large body of evidence points to an inverse association between diabetes and both AAA and TAA. A better understanding of the mechanisms underlying the negative association between diabetes and aortic aneurysm could help the development of innovative diagnostic and therapeutic approaches to tackle the disease. Here, we summarize current knowledge on the relationship between glycaemic parameters, diabetes, and the development of aortic aneurysm. Cellular and molecular pathways that underlie the protective effect of diabetes itself and its treatment are reviewed and discussed, along with their potential implications for clinical translation." 8991;"Regarding ""Diabetes-Related Factors and Abdominal Aortic Aneurysm Events: The Atherosclerotic Risk in Communities Study"".";"F. Lareyre, G. Chinetti, J. Raffort";"Equipe 09, Team 09";30482433;"Annals of epidemiology";"Raffort J, Chinetti G, Lareyre F";;"Nov 2018";1543449600;; 8987;"Glucagon-Like peptide-1: A new therapeutic target to treat abdominal aortic aneurysm?";"F. Lareyre, G. Chinetti, J. Raffort";"Equipe 09, Team 09";30103898;Biochimie;"Raffort J, Chinetti G, Lareyre F";;"Sep 2018";1535760000;;"Recent antidiabetic drugs including GLP-1 receptor agonists and DPP-IV inhibitors have demonstrated protective effects in several cardiovascular diseases but their effect in abdominal aortic aneurysm (AAA) is far less known. AAA can be associated with extremely high rates of mortality and pharmacological treatments are still lacking underlining the real need to identify new therapeutic targets. The aim of this review was to summarize current knowledge on the role of GLP-1 pathway in AAA. A systematic literature review was performed and 6 relevant studies (2 clinical and 4 experimental) were included. Experimental studies demonstrated a protective effect of both GLP-1 receptor agonists and DPP-IV inhibitors through targeting the main pathophysiological mechanisms underlying AAA formation. The effects of these drugs in human AAA are still poorly known. In the limelight of clinical and experimental studies, we discuss current limits and future directions." 8988;"Transforming growth factor β neutralization finely tunes macrophage phenotype in elastase-induced abdominal aortic aneurysm and is associated with an increase of arginase 1 expression in the aorta.";"E. Jean-Baptiste, F. Lareyre, G. Chinetti, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30792060;"Journal of vascular surgery";"Raffort J, Lareyre F, Clément M, Moratal C, Jean-Baptiste E, Hassen-Khodja R, Burel-Vandenbos F, Bruneval P, Chinetti G, Mallat Z";;"08 2019";1564617600;;"Macrophages play a critical role in the initiation and progression of abdominal aortic aneurysm (AAA) and are classically distinguished into M1 ""proinflammatory"" and M2 ""anti-inflammatory"" macrophages. Topical application of elastase associated with transforming growth factor β (TGF-β) systemic neutralization reproduces the main pathologic features of human AAA, offering a new model to investigate their role. The aim of this study was to investigate whether macrophages contribute to the expression of canonical M1/M2 markers in the aorta in the AAA model induced by elastase and systemic blockade of TGF-β and whether blocking of TGF-β activity affects macrophage phenotype and the expression of the M2 marker arginase 1 (ARG1)." 8986;"Association of abdominal aortic aneurysm diameter with insulin resistance index.";"E. Jean-Baptiste, F. Lareyre, G. Chinetti, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";30429669;"Biochemia medica";"Lareyre F, Moratal C, Zereg E, Carboni J, Panaïa-Ferrari P, Bayer P, Jean-Baptiste E, Hassen-Khodja R, Chinetti G, Raffort J";;"Oct 2018";1538352000;;"Epidemiological studies have highlighted a negative association between diabetes and abdominal aortic aneurysm (AAA). The aim of this study was to investigate the association between insulin resistance and AAA size." 8984;"TREM-1 orchestrates angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm.";"F. Lareyre, G. Chinetti, J. Raffort";"Equipe 09, Team 09";33258804;"The Journal of clinical investigation";"Vandestienne M, Zhang Y, Santos-Zas I, Al-Rifai R, Joffre J, Giraud A, Laurans L, Esposito B, Pinet F, Bruneval P, Raffort J, Lareyre F, Vilar J, Boufenzer A, Guyonnet L, Guerin C, Clauser E, Silvestre JS, Lang S, Soulat-Dufour L, Tedgui A, Mallat Z, Taleb S, Boissonnas A, Derive M, Chinetti G, Ait-Oufella H";;"Dec 2020";1606780800;;"The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans." 8982;"Activation of factor IX zymogen results in exposure of a binding site for low-density lipoprotein receptor-related protein.";"J. Neels";"Equipe 09, Team 09";11071642;Blood;"Neels JG, van Den Berg BM, Mertens K, ter Maat H, Pannekoek H, van Zonneveld AJ, Lenting PJ";;"Nov 2000";973036800;;"The interaction between the endocytic receptor low density lipoprotein receptor-related protein (LRP) and either coagulation factor IX or its active derivative factor IXa was studied. Purified factor IX was unable to associate with LRP when analyzed by surface plasmon resonance. By contrast, factor XIa-mediated conversion of factor IX into factor IXa resulted in reversible dose- and calcium-dependent binding to LRP. Active-site blocking of factor IXa did not affect binding to LRP, whereas LRP binding was efficiently inhibited in the presence of heparin or antibodies against factor IX or LRP. The factor IXa-LRP interaction could be described by a 2-site binding model with equilibrium dissociation constants of 27 nmol/L and 69 nmol/L. Consistent with this model, it was observed that factor IXa binds to 2 different recombinant receptor fragments of LRP (denoted cluster II and cluster IV) with equilibrium dissociation constants of 227 nmol/L and 53 nmol/L, respectively. The amount of factor IXa degraded by LRP-deficient cells was 35% lower than by LRP-expressing cells, demonstrating that LRP contributes to the transport of factor IXa to the intracellular degradation pathway. Because ligand binding to LRP is often preceded by binding to proteoglycans, the contribution of proteoglycans to the catabolism of factor IXa was addressed by employing proteoglycan-deficient cells. Degradation of factor IXa by proteoglycan-deficient cells proceeded at a 83% lower rate than wild-type cells. In conclusion, the data presented here indicate that both LRP and proteoglycans have the potential to contribute to the catabolism of factor IXa." 8980;"Interaction between factor VIII and LDL receptor-related protein. Modulation of coagulation?";"J. Neels";"Equipe 09, Team 09";11150722;"Trends in cardiovascular medicine";"Neels JG, Bovenschen N, van Zonneveld AJ, Lenting PJ";;"Jan 2000";946684800;;"Recent reports suggest that the multifunctional receptor low-density lipoprotein receptor-related protein (LRP) may contribute to the regulation of blood coagulation by mechanisms that differ from the simple removal of protease/inhibitor complexes from the circulation. This possibility became apparent from the observation that LRP is involved in down-regulation of Tissue Factor expression at the surface of monocytes and fibroblasts. Furthermore, coagulation Factor VIII and activated Factor IX (Factor IXa) have been identified as proteins that are able to bind to LRP. In the present review, the potential contribution of LRP to the regulation of the coagulation cascade through these novel pathways is discussed, with particular reference to the interaction between LRP and coagulation Factor VIII." 8978;"The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1.";"J. Neels";"Equipe 09, Team 09";15001579;"The Journal of biological chemistry";"Degryse B, Neels JG, Czekay RP, Aertgeerts K, Kamikubo Y, Loskutoff DJ";;"May 2004";1083369600;;"Although plasminogen activator inhibitor-1 (PAI-1) is known to stimulate cell migration, little is known about underlying mechanisms. We show that both active and inactive (e.g. cleaved) PAI-1 can activate the Jak/Stat signaling system and stimulate cell migration in chemotaxis, haptotaxis, chemokinesis, and wound healing assays. Moreover, antibodies to the LDL receptor-related protein (LRP) and an LRP antagonist (RAP) blocked these motogenic effects of PAI-1, while a PAI-1 mutant that did not bind to LRP failed to activate the Jak/Stat signaling pathway or to stimulate cell migration. PAI-1 had no chemotactic effect on LRP-deficient cells. These results indicate that LRP is a signaling molecule, that it mediates the migration-promoting activity of PAI-1, and that this activity does not require intact, biologically active PAI-1. Activation of this LRP-dependent signaling pathway by PAI-1 may begin to explain how the inhibitor stimulates cell migration in a variety of normal and pathological processes." 8976;"Disulfide bonding arrangements in active forms of the somatomedin B domain of human vitronectin.";"J. Neels";"Equipe 09, Team 09";15157085;Biochemistry;"Kamikubo Y, De Guzman R, Kroon G, Curriden S, Neels JG, Churchill MJ, Dawson P, Ołdziej S, Jagielska A, Scheraga HA, Loskutoff DJ, Dyson HJ";;"Jun 2004";1086048000;;"The N-terminal cysteine-rich somatomedin B (SMB) domain (residues 1-44) of the human glycoprotein vitronectin contains the high-affinity binding sites for plasminogen activator inhibitor-1 (PAI-1) and the urokinase receptor (uPAR). We previously showed that the eight cysteine residues of recombinant SMB (rSMB) are organized into four disulfide bonds in a linear uncrossed pattern (Cys(5)-Cys(9), Cys(19)-Cys(21), Cys(25)-Cys(31), and Cys(32)-Cys(39)). In the present study, we use an alternative method to show that this disulfide bond arrangement remains a major preferred one in solution, and we determine the solution structure of the domain using NMR analysis. The solution structure shows that the four disulfide bonds are tightly packed in the center of the domain, replacing the traditional hydrophobic core expected for a globular protein. The few noncysteine hydrophobic side chains form a cluster on the outside of the domain, providing a distinctive binding surface for the physiological partners PAI-1 and uPAR. The hydrophobic surface consists mainly of side chains from the loop formed by the Cys(25)-Cys(31) disulfide bond, and is surrounded by conserved acidic and basic side chains, which are likely to contribute to the specificity of the intermolecular interactions of this domain. Interestingly, the overall fold of the molecule is compatible with several arrangements of the disulfide bonds. A number of different disulfide bond arrangements were able to satisfy the NMR restraints, and an extensive series of conformational energy calculations performed in explicit solvent confirmed that several disulfide bond arrangements have comparable stabilization energies. An experimental demonstration of the presence of alternative disulfide conformations in active rSMB is provided by the behavior of a mutant in which Asn(14) is replaced by Met. This mutant has the same PAI-1 binding activity as rVN1-51, but its fragmentation pattern following cyanogen bromide treatment is incompatible with the linear uncrossed disulfide arrangement. These results suggest that active forms of the SMB domain may have a number of allowed disulfide bond arrangements as long as the Cys(25)-Cys(31) disulfide bond is preserved." 8974;"Inhibition of endogenous leptin protects mice from arterial and venous thrombosis.";"J. Neels";"Equipe 09, Team 09";15458978;"Arteriosclerosis, thrombosis, and vascular biology";"Konstantinides S, Schäfer K, Neels JG, Dellas C, Loskutoff DJ";;"Nov 2004";1099267200;;"Human obesity is associated with an increased risk for arterial and venous thrombosis and with elevated levels of leptin in the blood. Leptin administration promotes arterial thrombosis in mice, and leptin-deficient ob/ob mice have an attenuated thrombotic response to injury. Thus, endogenous leptin may regulate arterial and venous thrombosis in vivo. Experiments were performed to test this hypothesis." 8972;"Cell signaling. A new way to burn fat.";"J. Neels";"Equipe 09, Team 09";16794069;"Science (New York, N.Y.)";"Neels JG, Olefsky JM";;"Jun 2006";1149120000;; 8970;"Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance.";"J. Neels";"Equipe 09, Team 09";17351624;"Nature medicine";"Lesniewski LA, Hosch SE, Neels JG, de Luca C, Pashmforoush M, Lumeng CN, Chiang SH, Scadeng M, Saltiel AR, Olefsky JM";;"Apr 2007";1175385600;;"Cbl-associated protein (Cap) is a member of a phosphatidylinositol 3-kinase-independent pathway for insulin-stimulated translocation of the glucose transporter GLUT4. Despite this positive role of Cap in glucose uptake, here we show that deletion of the gene encoding Cap (official gene name: Sorbs1) protects against high-fat diet (HFD)-induced insulin resistance in mice while also having an opposite, insulin-sensitizing effect, accompanied by reduced tissue markers of inflammation. Given the emerging role of chronic inflammation in insulin resistance and the macrophage in initiating this inflammatory process, we considered that Sorbs1 deletion from macrophages may have resulted in the observed protection from HFD-induced insulin resistance. Using bone marrow transplantation to generate functional Sorbs1-null macrophages, we show that the insulin-sensitive phenotype can be transferred to wild-type mice by transplantation of Sorbs1-null bone marrow. These studies show that macrophages are an important cell type in the induction of insulin resistance and that Cap has a modulatory role in this function." 8968;"Blockade of alpha4 integrin signaling ameliorates the metabolic consequences of high-fat diet-induced obesity.";"J. Neels";"Equipe 09, Team 09";18426864;Diabetes;"Féral CC, Neels JG, Kummer C, Slepak M, Olefsky JM, Ginsberg MH";;"Jul 2008";1214870400;;"Many prevalent diseases of advanced societies, such as obesity-induced type 2 diabetes, are linked to indolent mononuclear cell-dependent inflammation. We previously proposed that blockade of alpha4 integrin signaling can inhibit inflammation while limiting mechanism-based toxicities of loss of alpha4 function. Thus, we hypothesized that mice bearing an alpha4(Y991A) mutation, which blocks signaling, would be protected from development of high-fat diet-induced insulin resistance." 8966;"Vitronectin inhibits plasminogen activator inhibitor-1-induced signalling and chemotaxis by blocking plasminogen activator inhibitor-1 binding to the low-density lipoprotein receptor-related protein.";"J. Neels";"Equipe 09, Team 09";18703159;"The international journal of biochemistry & cell biology";"Kamikubo Y, Neels JG, Degryse B";;"Mar 2009";1235865600;;"We have previously reported that the serpin plasminogen activator inhibitor-1 activates the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) signalling pathway and stimulates cell migration by binding to the low-density lipoprotein receptor-related protein. All the free forms (cleaved, latent or active) of this inhibitor were shown to be motogenic. However, the plasminogen activator inhibitor-1 can also interact with vitronectin which acts as a cofactor by increasing the half-life of the active form of the serpin. Since vitronectin influences most of the biological functions of the plasminogen activator inhibitor-1, we explored the effects of vitronectin on signalling and cell migration induced by this serpin. We found that the interaction between vitronectin and the plasminogen activator inhibitor-1 suppressed signalling and cell migration. In fact, a purified vitronectin(1-97)/plasminogen activator inhibitor-1 complex was not chemotactic. Vitronectin interaction with the plasminogen activator inhibitor-1 blocks the binding of this serpin to its motogenic receptor, the low-density lipoprotein receptor-related protein. Consequently, vitronectin inhibits the activation of the Janus kinase/signal transducer and activator of transcription signalling pathway by the plasminogen activator inhibitor-1 and subsequent cell migration. In conclusion, we have unveiled a new inhibitory role of vitronectin, which turns off the intracellular signalling and migration-promoting activity of the plasminogen activator inhibitor-1. Thus, the motogenic (cleaved, latent or active) and non-motogenic (in complex with vitronectin) forms of the plasminogen activator inhibitor-1 have different properties that may explain the rather contrasting physiological and pathological roles of this serpin." 8949;"The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein.";"J. Neels";"Equipe 09, Team 09";10446132;"The Journal of biological chemistry";"Lenting PJ, Neels JG, van den Berg BM, Clijsters PP, Meijerman DW, Pannekoek H, van Mourik JA, Mertens K, van Zonneveld AJ";;"Aug 1999";934588800;;"In the present study, the interaction between the endocytic receptor low density lipoprotein receptor-related protein (LRP) and coagulation factor VIII (FVIII) was investigated. Using purified components, FVIII was found to bind to LRP in a reversible and dose-dependent manner (K(d) approximately 60 nM). The interaction appeared to be specific because the LRP antagonist receptor-associated protein readily inhibited binding of FVIII to LRP (IC(50) approximately 1 nM). In addition, a 12-fold molar excess of the physiological carrier of FVIII, i.e. von Willebrand factor (vWF), reduced the binding of FVIII to LRP by over 90%. Cellular degradation of (125)I-labeled FVIII by LRP-expressing cells ( approximately 8 fmol/10(5) cells after a 4.5-h incubation) was reduced by approximately 70% in the presence of receptor-associated protein. LRP-directed antibodies inhibited degradation to a similar extent, indicating that LRP indeed contributes to binding and transport of FVIII to the intracellular degradation pathway. Degradation of FVIII was completely inhibited by vWF. Because vWF binding by FVIII involves its light chain, LRP binding to this subunit was studied. In ligand blotting experiments, binding of FVIII light chain to LRP could be visualized. More detailed analysis revealed that FVIII light chain interacts with LRP with moderate affinity (k(on) approximately 5 x 10(4) M(-1) s(-1); k(off) approximately 2.5 x 10(-3) s(-1); K(d) approximately 50 nM). Furthermore, experiments using recombinant FVIII C2 domain showed that this domain contributes to the interaction with LRP. In contrast, no association of FVIII heavy chain to LRP could be detected under the same experimental conditions. Collectively, our data demonstrate that in vitro LRP is able to bind FVIII at the cell surface and to mediate its transport to the intracellular degradation pathway. FVIII-LRP interaction involves the FVIII light chain, and FVIII-vWF complex formation plays a regulatory role in LRP binding. Our findings may explain the beneficial effect of vWF on the in vivo survival of FVIII." 8943;"The second and fourth cluster of class A cysteine-rich repeats of the low density lipoprotein receptor-related protein share ligand-binding properties.";"J. Neels";"Equipe 09, Team 09";10531329;"The Journal of biological chemistry";"Neels JG, van Den Berg BM, Lookene A, Olivecrona G, Pannekoek H, van Zonneveld AJ";;"Oct 1999";940896000;;"The low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytic cell-surface receptor that binds and internalizes a diverse array of ligands. The receptor contains four putative ligand-binding domains, generally referred to as clusters I, II, III, and IV. In this study, soluble recombinant receptor fragments, representing each of the four individual clusters, were used to map the binding sites of a set of structurally and functionally distinct ligands. Using surface plasmon resonance, we studied the binding of these fragments to methylamine-activated alpha(2)-macroglobulin, pro-urokinase-type plasminogen activator, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1, t-PA.plasminogen activator inhibitor-1 complexes, lipoprotein lipase, apolipoprotein E, tissue factor pathway inhibitor, lactoferrin, the light chain of blood coagulation factor VIII, and the intracellular chaperone receptor-associated protein (RAP). No binding of the cluster I fragment to any of the tested ligands was observed. The cluster III fragment only bound to the anti-LRP monoclonal antibody alpha(2)MRalpha3 and weakly to RAP. Except for t-PA, we found that each of the ligands tested binds both to cluster II and to cluster IV. The affinity rate constants of ligand binding to clusters II and IV and to LRP were measured, showing that clusters II and IV display only minor differences in ligand-binding kinetics. Furthermore, we demonstrate that the subdomains C3-C7 of cluster II are essential for binding of ligands and that this segment partially overlaps with a RAP-binding site on cluster II. Finally, we show that one RAP molecule can bind to different clusters simultaneously, supporting a model in which RAP binding to LRP induces a conformational change in the receptor that is incompatible with ligand binding." 8944;"Selective screening of a large phage display library of plasminogen activator inhibitor 1 mutants to localize interaction sites with either thrombin or the variable region 1 of tissue-type plasminogen activator.";"J. Neels";"Equipe 09, Team 09";8631768;"The Journal of biological chemistry";"van Meijer M, Roelofs Y, Neels J, Horrevoets AJ, van Zonneveld AJ, Pannekoek H";;"Mar 1996";828057600;;"Phage display technology has been exploited to study in detail the interaction between plasminogen activator inhibitor 1 (PAI-1) and either thrombin or an essential positively charged ""loop"" of tissue-type plasminogen activator (t-PA), denoted variable region 1 (VR1). For this purpose, a PAI-1 mutant phage library was used that served as a reservoir of PAI-1 proteins potentially deficient in the interaction with either VR1 or thrombin. A stringent two-step selection procedure was developed. (i) A negative selection was performed by incubating the pComb3/PAI-1 mutant library with an excess of a thrombin mutant with its VR1 domain substituted with that of t-PA (thrombin-VR1). (ii) The remaining phages were complexed with t-PA (positive selection) and selected by panning with an immobilized anti-t-PA monoclonal antibody. Four consecutive panning rounds yielded an enrichment of pComb3/PAI-1 mutant phages of approximately 50-fold. Sequence analysis of 16 different cDNAs, encoding PAI-1 mutants that are hampered in the binding to thrombin-VR1, revealed the following mutations. Four independent variants share a mutation of the P4' residue (Glu350 --> Lys). Nine independent PAI-1 variants share a substitution of P1' (Met347 --> Lys), whereas three others share a P2 substitution (Ala345 --> Asp). Kinetic analysis of representative PAI-1 mutants provides evidence that the P4' residue is essential for the interaction with the VR1 domain, consistent with the data of Madison et al. (Madison, E.L., Goldsmith, E.J., Gething, M.J., Sambrook, J.F., and Gerard, R.D. (1990) J. Biol. Chem. 265, 21423-21426), whereas the P1' and P2 residues confer thrombin specificity. Concordant with the design of the selection procedure, mutants were obtained that inhibit thrombin-VR1 at least 100-fold slower than wild-type PAI-1, identifying residues that are central to the interaction with either thrombin or VR1. This study demonstrates that phage technology can be used to analyze large numbers of mutants defective in their interaction with other (domains of) proteins, provided an adequate selection scheme is devised." 8945;"Activation of factor IX zymogen results in exposure of a binding site for low-density lipoprotein receptor-related protein.";"J. Neels";"Equipe 09, Team 09";11071642;Blood;"Neels JG, van Den Berg BM, Mertens K, ter Maat H, Pannekoek H, van Zonneveld AJ, Lenting PJ";;"Nov 2000";973728000;;"The interaction between the endocytic receptor low density lipoprotein receptor-related protein (LRP) and either coagulation factor IX or its active derivative factor IXa was studied. Purified factor IX was unable to associate with LRP when analyzed by surface plasmon resonance. By contrast, factor XIa-mediated conversion of factor IX into factor IXa resulted in reversible dose- and calcium-dependent binding to LRP. Active-site blocking of factor IXa did not affect binding to LRP, whereas LRP binding was efficiently inhibited in the presence of heparin or antibodies against factor IX or LRP. The factor IXa-LRP interaction could be described by a 2-site binding model with equilibrium dissociation constants of 27 nmol/L and 69 nmol/L. Consistent with this model, it was observed that factor IXa binds to 2 different recombinant receptor fragments of LRP (denoted cluster II and cluster IV) with equilibrium dissociation constants of 227 nmol/L and 53 nmol/L, respectively. The amount of factor IXa degraded by LRP-deficient cells was 35% lower than by LRP-expressing cells, demonstrating that LRP contributes to the transport of factor IXa to the intracellular degradation pathway. Because ligand binding to LRP is often preceded by binding to proteoglycans, the contribution of proteoglycans to the catabolism of factor IXa was addressed by employing proteoglycan-deficient cells. Degradation of factor IXa by proteoglycan-deficient cells proceeded at a 83% lower rate than wild-type cells. In conclusion, the data presented here indicate that both LRP and proteoglycans have the potential to contribute to the catabolism of factor IXa." 8941;"Investigation of Plasma Inflammatory Profile in Diabetic Patients With Abdominal Aortic Aneurysm: A Pilot Study.";"E. Jean-Baptiste, F. Lareyre, G. Chinetti, J. Neels, J. Raffort, R. Hassen-Khodja";"Equipe 09, Team 09";29940819;"Vascular and endovascular surgery";"Lareyre F, Moratal C, Chikande J, Jean-Baptiste E, Hassen-Khodja R, Neels J, Chinetti G, Raffort J";;"Nov 2018";1541030400;;"Clinical studies have unraveled a negative association between diabetes and abdominal aortic aneurysm (AAA), but the mechanisms involved are still poorly understood. The aim of this study was to determine whether diabetic patients with AAA had a distinct plasma inflammatory profile compared to nondiabetic patients." 8933;"Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice.";"J. Neels";"Equipe 09, Team 09";21103061;"PloS one";"Chapman J, Miles PD, Ofrecio JM, Neels JG, Yu JG, Resnik JL, Wilkes J, Talukdar S, Thapar D, Johnson K, Sears DD";;"Nov 2010";1290643200;;"Insulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined." 8934;"Alpha-lipoic acid supplementation increases the efficacy of exercise- and diet-induced obesity treatment and induces immunometabolic changes in female mice and women.";"G. Chinetti, J. Neels, J. Murdaca";"Equipe 09, Team 09";33742689;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Le Garf S, Sibille B, Mothe-Satney I, Eininger C, Fauque P, Murdaca J, Chinetti G, Neels JG, Rousseau AS";;"Mar 2021";1616198400;;"The decrease in the regulatory T cells (Tregs) population is highly involved in adipose tissue inflammation and insulin resistance in obesity. Tregs depend on fatty acids via β-oxidation for immunosuppressive function adapting their antioxidant systems to allow survival to oxidative stress. In this study, we have hypothesized that a dietary supplementation with alpha-lipoic acid (ALA), a powerful antioxidant, would improve immunometabolism when added to the classical strategy of obesity treatment. First, we showed by in vitro experiments that ALA favors the polarization of mice CD4 + T cells toward Tregs. Next, we have carried out a translational study where female obese mice and women were supplemented with ALA or vehicle/placebo (mice: 2.5 g /kg ; 6 weeks women: 600 mg /day, 8 weeks) while following a protocol including regular exercise and a change in diet. Fatty acid oxidation potential and activity of nuclear erythroid-related factor 2 (NRF2) of mouse secondary lymphoid tissues were improved by ALA supplementation. ALA reduced visceral adipose tissue (VAT) mass and preserved Tregs in VAT in mice. In women, ALA supplementation induced significant metabolic changes of circulating CD4 + T cells including increased oxidative capacity and fatty acid oxidation, ameliorated their redox status, and improved the reduction of visceral fat mass. While appropriate biological markers are still required to be used in clinics to judge the effectiveness of long-term obesity treatment, further studies in female mice and women are needed to determine whether these immunometabolic changes would reduce VAT mass-associated risk for secondary health issues arising from obesity." 8935;"Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals.";"J. Neels";"Equipe 09, Team 09";18840360;"Cell metabolism";"Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG";;"Oct 2008";1223510400;;"Obese adipose tissue is characterized by infiltration of macrophages. We and others recently showed that a specific subset of macrophages is recruited to obese adipose and muscle tissue. This subset expresses CD11c and produces high levels of proinflammatory cytokines that are linked to the development of obesity-associated insulin resistance. Here, we used a conditional cell ablation system, based on transgenic expression of the diphtheria toxin receptor under the control of the CD11c promoter, to study the effects of depletion of CD11c+ cells in obese mouse models. Our results show that CD11c+ cell depletion results in rapid normalization of insulin sensitivity. Furthermore, CD11c+ cell ablation leads to a marked decrease in inflammatory markers, both locally and systemically, as reflected by gene expression and protein levels. Together, these results indicate that these CD11c+ cells are a potential therapeutic target for treatment of obesity-related insulin resistance and type II diabetes." 8929;"Adipocytes secrete leukotrienes: contribution to obesity-associated inflammation and insulin resistance in mice.";"J. Neels";"Equipe 09, Team 09";22688342;Diabetes;"Mothe-Satney I, Filloux C, Amghar H, Pons C, Bourlier V, Galitzky J, Grimaldi PA, Féral CC, Bouloumié A, Van Obberghen E, Neels JG";;"Jun 2012";1339545600;;"Leukotrienes (LTs) are potent proinflammatory mediators, and many important aspects of innate and adaptive immune responses are regulated by LTs. Key members of the LT synthesis pathway are overexpressed in adipose tissue (AT) during obesity, resulting in increased LT levels in this tissue. We observed that several mouse adipocyte cell lines and primary adipocytes from mice and humans both can secrete large amounts of LTs. Furthermore, this production increases with a high-fat diet (HFD) and positively correlates with adipocyte size. LTs produced by adipocytes play an important role in attracting macrophages and T cells in in vitro chemotaxis assays. Mice that are deficient for the enzyme 5-lipoxygenase (5-LO), and therefore lack LTs, exhibit a decrease in HFD-induced AT macrophage and T-cell infiltration and are partially protected from HFD-induced insulin resistance. Similarly, treatment of HFD-fed wild-type mice with the 5-LO inhibitor Zileuton also results in a reduction of AT macrophages and T cells, accompanied by a decrease in insulin resistance. Together, these findings suggest that LTs represent a novel target in the prevention or treatment of obesity-associated inflammation and insulin resistance." 8930;"Regulation of Immune Cell Function by PPARs and the Connection with Metabolic and Neurodegenerative Diseases.";"J. Neels";"Equipe 09, Team 09";29799467;"International journal of molecular sciences";"Le Menn G, Neels JG";;"May 2018";1525132800;;"Increasing evidence points towards the existence of a bidirectional interconnection between metabolic disease and neurodegenerative disorders, in which inflammation is linking both together. Activation of members of the peroxisome proliferator-activated receptor (PPAR) family has been shown to have beneficial effects in these interlinked pathologies, and these improvements are often attributed to anti-inflammatory effects of PPAR activation. In this review, we summarize the role of PPARs in immune cell function, with a focus on macrophages and T cells, and how this was shown to contribute to obesity-associated inflammation and insulin resistance, atherosclerosis, and neurodegenerative disorders. We address gender differences as a potential explanation in observed contradictory results, and we highlight PPAR-induced metabolic changes as a potential mechanism of regulation of immune cell function through these nuclear receptors. Together, immune cell-specific activation of PPARs present a promising therapeutic approach to treat both metabolic and neurodegenerative diseases." 8927;"α-Lipoic acid up-regulates expression of peroxisome proliferator-activated receptor β in skeletal muscle: involvement of the JNK signaling pathway.";"J. Neels, J. Murdaca";"Equipe 09, Team 09";26655383;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Rousseau AS, Sibille B, Murdaca J, Mothe-Satney I, Grimaldi PA, Neels JG";;"Dec 2015";1450137600;;"We hypothesized that α-lipoic acid (α-LA) might interact with the transcriptional control of peroxisome proliferator-activated receptor (PPAR)β in skeletal muscle. Molecular mechanisms were investigated using differentiated C2C12 myotubes treated with α-LA and/or PPARβ agonist GW0742. In vivo studies with 3-mo-old C57Bl6 mice were realized: voluntary wheel running (VWR) training (7 wk), and a 6 wk diet containing (or not) α-LA (0.25% wt/wt). This last condition was combined with (or not) 1 bout of treadmill exercise (18 m/min for 1 h). Using a reporter assay, we demonstrate that α-LA is not an agonist of PPARβ but regulates PPARβ target gene expression through an active PPARβ pathway. GW0742-induced pyruvate dehydrogenase kinase 4 mRNA is potentiated by α-LA. In C2C12, α-LA lowers the activation of the JNK signaling pathway and increases PPARβ mRNA and protein levels (2-fold) to the same extent as with the JNK inhibitor SP600125. Similarly to VWR training effect, PPARβ expression increases (2-fold) in vastus lateralis of animals fed an α-LA-enriched diet. However, α-LA treatment does not further stimulate the adaptive up-regulation of PPARβ observed in response to 1 bout of exercise. We have identified a novel mechanism of regulation of PPARβ expression/action in skeletal muscle with potential physiologic application through the action of α-LA, involving the JNK pathway." 8921;"Roles of Nuclear Receptors in Vascular Calcification.";"G. Chinetti, J. Neels";"Equipe 09, Team 09";34204304;"International journal of molecular sciences";"Chinetti G, Neels JG";;"Jul 2021";1625184000;;"Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification." 8922;"Alpha-lipoic acid supplementation increases the efficacy of exercise- and diet-induced obesity treatment and induces immunometabolic changes in female mice and women.";"G. Chinetti, J. Neels, J. Murdaca";"Equipe 09, Team 09";33742689;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Le Garf S, Sibille B, Mothe-Satney I, Eininger C, Fauque P, Murdaca J, Chinetti G, Neels JG, Rousseau AS";;"Mar 2021";1616198400;;"The decrease in the regulatory T cells (Tregs) population is highly involved in adipose tissue inflammation and insulin resistance in obesity. Tregs depend on fatty acids via β-oxidation for immunosuppressive function adapting their antioxidant systems to allow survival to oxidative stress. In this study, we have hypothesized that a dietary supplementation with alpha-lipoic acid (ALA), a powerful antioxidant, would improve immunometabolism when added to the classical strategy of obesity treatment. First, we showed by in vitro experiments that ALA favors the polarization of mice CD4 + T cells toward Tregs. Next, we have carried out a translational study where female obese mice and women were supplemented with ALA or vehicle/placebo (mice: 2.5 g /kg ; 6 weeks women: 600 mg /day, 8 weeks) while following a protocol including regular exercise and a change in diet. Fatty acid oxidation potential and activity of nuclear erythroid-related factor 2 (NRF2) of mouse secondary lymphoid tissues were improved by ALA supplementation. ALA reduced visceral adipose tissue (VAT) mass and preserved Tregs in VAT in mice. In women, ALA supplementation induced significant metabolic changes of circulating CD4 + T cells including increased oxidative capacity and fatty acid oxidation, ameliorated their redox status, and improved the reduction of visceral fat mass. While appropriate biological markers are still required to be used in clinics to judge the effectiveness of long-term obesity treatment, further studies in female mice and women are needed to determine whether these immunometabolic changes would reduce VAT mass-associated risk for secondary health issues arising from obesity." 8923;"Peroxisome Proliferator Activated Receptor Beta (PPARβ) activity increases the immune response and shortens the early phases of skeletal muscle regeneration.";"J. Neels, J. Murdaca";"Equipe 09, Team 09";27939528;Biochimie;"Mothe-Satney I, Piquet J, Murdaca J, Sibille B, Grimaldi PA, Neels JG, Rousseau AS";;"May 2017";1493596800;;"Peroxisome Proliferator-Activated Receptor Beta (PPARβ) is a transcription factor playing an important role in both muscle myogenesis and remodeling, and in inflammation. However, its role in the coordination of the transient muscle inflammation and reparation process following muscle injury has not yet been fully determined. We postulated that activation of the PPARβ pathway alters the early phase of the muscle regeneration process, i.e. when immune cells infiltrate in injured muscle. Tibialis anteriors of C57BL6/J mice treated or not with the PPARβ agonist GW0742 were injected with cardiotoxin (or with physiological serum for the contralateral muscle). Muscle regeneration was monitored on days 4, 7, and 14 post-injury. We found that treatment of mice with GW0742 increased, at day 4 post-damage, the recruitment of immune cells (M1 and M2 macrophages) and upregulated the expression of the anti-inflammatory cytokine IL-10 and TGF-β mRNA. Those effects were accompanied by a significant increase at day 4 of myogenic regulatory factors (Pax7, MyoD, Myf5, Myogenin) mRNA in GW0742-treated mice. However, we showed an earlier return (7 days vs 14 days) of Myf5 and Myogenin to basal levels in GW0742- compared to DMSO-treated mice. Differential effects of GW0742 observed during the regeneration were associated with variations of PPARβ pathway activity. Collectively, our findings indicate that PPARβ pathway activity shortens the early phases of skeletal muscle regeneration by increasing the immune response." 8919;"Angiogenesis in an in vivo model of adipose tissue development.";"J. Neels";"Equipe 09, Team 09";15084517;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Neels JG, Thinnes T, Loskutoff DJ";;"Jun 2004";1086048000;;"Obesity is associated with an increased risk for cardiovascular disease and cancer. Angiogenesis is a critical component of these pathological processes, and expanding adipose tissue represents one of the few sites of active angiogenesis in the adult. Despite the potential importance of angiogenesis in obesity, little is known about underlying mechanisms. This problem is magnified by the absence of useful quantitative model systems. In this report, we examine the angiogenic process using the 3T3-F442A model of adipose tissue development. In this model, 3T3-F442A preadipocytes are implanted subcutaneously into athymic Balb/c nude mice. We show that these cells develop into highly vascularized fat pads over the next 14-21 days, and that these fat pads are morphologically similar to normal subcutaneous adipose tissue. Histological studies demonstrate that a new microvasculature is evident as early as 5 days after cell implantation, and real-time quantitative RT-PCR analyses show that the expression of endothelial cell markers and adipogenesis markers increase in parallel during fat pad development. Finally, these preliminary studies suggest that the neovasculature originates by sprouting from larger, host-derived blood vessels that run parallel to peripheral nerves and that endothelial progenitor cells play little, if any, role in this process." 8914;"Inflamed fat: what starts the fire?";"J. Neels";"Equipe 09, Team 09";16395402;"The Journal of clinical investigation";"Neels JG, Olefsky JM";;"Jan 2006";1136505600;;"Obesity is associated with increased macrophage infiltration of adipose tissue, and these macrophages may be an important component of the chronic inflammatory response playing a crucial role in the development of insulin resistance. This prompts the question as to how macrophages infiltrate obese adipose tissue. In this issue of the JCI, Weisberg et al. show the importance of C-C motif chemokine receptor 2 (CCR2) in macrophage recruitment to adipose tissue and the development of obesity and its complications." 8915;"Autoamplification of tumor necrosis factor-alpha: a potential mechanism for the maintenance of elevated tumor necrosis factor-alpha in male but not female obese mice.";"J. Neels";"Equipe 09, Team 09";16436658;"The American journal of pathology";"Neels JG, Pandey M, Hotamisligil GS, Samad F";;"Jan 2006";1138320000;;"Although tumor necrosis factor-alpha (TNF-alpha) is elevated in adipose tissue in obesity and may contribute to the cardiovascular and metabolic risks associated with this condition, the mechanisms leading to elevated TNF-alpha remain elusive. We hypothesized that autoamplification of TNF-alpha contributes to the maintenance of elevated TNF-alpha in obesity. Treatment of 3T3-L1 adipocytes with TNF-alpha, or injection of TNF-alpha into C57BL/6J mice, up-regulated TNF-alpha mRNA in adipocytes and in adipose tissues, respectively. Ob/ob male but not female mice lacking TNF-alpha receptors showed significantly lower levels of adipose TNF-alpha mRNA when compared with TNF-alpha receptor-expressing ob/ob mice. Thus, the lack of endogenous TNF-alpha signaling reduced adipose TNF-alpha mRNA in ob/ob male mice. Additionally, hyperinsulinemia potentiated this TNF-alpha-mediated autoamplification response in adipose tissues and in adipocytes in a synergistic and dose-dependent manner. Studies in which TNF-alpha was injected into lean mice lacking individual TNF-alpha receptors indicated that TNF-alpha autoamplification in adipose tissues was mediated primarily via the p55 TNF-alpha receptor whereas the p75 TNF-alpha receptor appeared to augment this response. Finally, TNF-alpha autoamplification in adipocytes occurred via the protein kinase C signaling pathway and the transcription factor nuclear factor-kappaB. Thus, TNF-alpha can positively autoregulate its own biosynthesis in adipose tissue, contributing to the maintenance of elevated TNF-alpha in obesity." 8911;"Cell signaling. A new way to burn fat.";"J. Neels";"Equipe 09, Team 09";16794069;"Science (New York, N.Y.)";"Neels JG, Olefsky JM";;"Jun 2006";1151107200;; 8912;"A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.";"J. Neels";"Equipe 09, Team 09";17916553;"The Journal of biological chemistry";"Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM";;"Nov 2007";1193875200;;"Obesity and type 2 diabetes are characterized by decreased insulin sensitivity, elevated concentrations of free fatty acids (FFAs), and increased macrophage infiltration in adipose tissue (AT). Here, we show that FFAs can cause activation of RAW264.7 cells primarily via the JNK signaling cascade and that TLR2 and TLR4 are upstream of JNK and help transduce FFA proinflammatory signals. We also demonstrate that F4/80(+)CD11b(+)CD11c(+) bone marrow-derived dendritic cells (BMDCs) have heightened proinflammatory activity compared with F4/80(+)CD11b(+)CD11c(-) bone marrow-derived macrophages and that the proinflammatory activity and JNK phosphorylation of BMDCs, but not bone marrow-derived macrophages, was further increased by FFA treatment. F4/80(+)CD11b(+)CD11c(+) cells were found in AT, and the proportion and number of these cells in AT is increased in ob/ob mice and by feeding wild type mice a high fat diet for 1 and 12 weeks. AT F4/80(+)CD11b(+)CD11c(+) cells express increased inflammatory markers compared with F4/80(+)CD11b(+)CD11c(-) cells, and FFA treatment increased inflammatory responses in these cells. In addition, we found that CD11c expression is increased in skeletal muscle of high fat diet-fed mice and that conditioned medium from FFA-treated wild type BMDCs, but not TLR2/4 DKO BMDCs, can induce insulin resistance in L6 myotubes. Together our results show that FFAs can activate CD11c(+) myeloid proinflammatory cells via TLR2/4 and JNK signaling pathways, thereby promoting inflammation and subsequent cellular insulin resistance." 8908;"Blockade of alpha4 integrin signaling ameliorates the metabolic consequences of high-fat diet-induced obesity.";"J. Neels";"Equipe 09, Team 09";18426864;Diabetes;"Féral CC, Neels JG, Kummer C, Slepak M, Olefsky JM, Ginsberg MH";;"Apr 2008";1208908800;;"Many prevalent diseases of advanced societies, such as obesity-induced type 2 diabetes, are linked to indolent mononuclear cell-dependent inflammation. We previously proposed that blockade of alpha4 integrin signaling can inhibit inflammation while limiting mechanism-based toxicities of loss of alpha4 function. Thus, we hypothesized that mice bearing an alpha4(Y991A) mutation, which blocks signaling, would be protected from development of high-fat diet-induced insulin resistance." 8907;"JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity.";"J. Neels";"Equipe 09, Team 09";17983584;"Cell metabolism";"Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M";;"Nov 2007";1194393600;;"Obesity-induced insulin resistance is a major factor in the etiology of type 2 diabetes, and Jun kinases (JNKs) are key negative regulators of insulin sensitivity in the obese state. Activation of JNKs (mainly JNK1) in insulin target cells results in phosphorylation of insulin receptor substrates (IRSs) at serine and threonine residues that inhibit insulin signaling. JNK1 activation is also required for accumulation of visceral fat. Here we used reciprocal adoptive transfer experiments to determine whether JNK1 in myeloid cells, such as macrophages, also contributes to insulin resistance and central adiposity. Our results show that deletion of Jnk1 in the nonhematopoietic compartment protects mice from high-fat diet (HFD)-induced insulin resistance, in part through decreased adiposity. By contrast, Jnk1 removal from hematopoietic cells has no effect on adiposity but confers protection against HFD-induced insulin resistance by decreasing obesity-induced inflammation." 8905;"Keratinocyte-derived chemokine in obesity: expression, regulation, and role in adipose macrophage infiltration and glucose homeostasis.";"J. Neels";"Equipe 09, Team 09";19494115;"The Journal of biological chemistry";"Neels JG, Badeanlou L, Hester KD, Samad F";;"Jun 2009";1244160000;;"Obese adipose tissue (AT) is associated with chronic inflammation, and we hypothesized that the keratinocyte-derived chemokine (KC), the mouse ortholog of human interleukin-8, plays a role in obesity-mediated AT inflammation and the subsequent manifestation of insulin resistance. KC expression is increased in the AT and plasma of genetically (ob/ob) and high fat diet-induced obese mouse models, and this increase may be mediated by the elevated leptin and tumor necrosis factor-alpha levels associated with obesity. Obesity-induced KC expression occurs primarily in stromal vascular cells and not in adipocytes, and it is high in preadipocytes and decreases during adipogenesis. Although KC has no effect on adipogenesis, it induces adipocyte expression of inflammatory factors and the insulin resistance mediator, suppressor of cytokine signaling 3. Using chimeric mice deficient in the KC receptor CXCR2 in their bone marrow, we show that the lack of CXCR2 in hematopoietic cells is sufficient to protect from adipose and skeletal muscle macrophage recruitment and development of insulin resistance in diet-induced obese mice. These studies suggest that KC and its receptor CXCR2 are potential targets for the development of new therapeutic approaches for treatment of obesity-related insulin resistance, type II diabetes, and related cardiovascular diseases." 8901;"Physiological functions of peroxisome proliferator-activated receptor β.";"J. Neels";"Equipe 09, Team 09";24987006;"Physiological reviews";"Neels JG, Grimaldi PA";;"Jul 2014";1404345600;;"The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty acids and fatty acid metabolites. PPARs regulate the transcription of a large variety of genes implicated in metabolism, inflammation, proliferation, and differentiation in different cell types. These transcriptional regulations involve both direct transactivation and interaction with other transcriptional regulatory pathways. The functions of PPARα and PPARγ have been extensively documented mainly because these isoforms are activated by molecules clinically used as hypolipidemic and antidiabetic compounds. The physiological functions of PPARβ remained for a while less investigated, but the finding that specific synthetic agonists exert beneficial actions in obese subjects uplifted the studies aimed to elucidate the roles of this PPAR isoform. Intensive work based on pharmacological and genetic approaches and on the use of both in vitro and in vivo models has considerably improved our knowledge on the physiological roles of PPARβ in various cell types. This review will summarize the accumulated evidence for the implication of PPARβ in the regulation of development, metabolism, and inflammation in several tissues, including skeletal muscle, heart, skin, and intestine. Some of these findings indicate that pharmacological activation of PPARβ could be envisioned as a therapeutic option for the correction of metabolic disorders and a variety of inflammatory conditions. However, other experimental data suggesting that activation of PPARβ could result in serious adverse effects, such as carcinogenesis and psoriasis, raise concerns about the clinical use of potent PPARβ agonists. " 8902;"Glucocorticoids and thiazolidinediones interfere with adipocyte-mediated macrophage chemotaxis and recruitment.";"J. Neels";"Equipe 09, Team 09";19740750;"The Journal of biological chemistry";"Patsouris D, Neels JG, Fan W, Li PP, Nguyen MT, Olefsky JM";;"Nov 2009";1257033600;;"The link between intra-abdominal adiposity and type II diabetes has been known for decades, and adipose tissue macrophage (ATM)-associated inflammation has recently been linked to insulin resistance. However, the mechanisms associated with ATM recruitment remain ill defined. Herein, we describe in vitro chemotaxis studies, in which adipocyte conditioned medium was used to stimulate macrophage migration. We demonstrate that tumor necrosis factor alpha and free fatty acids, key inflammatory stimuli involved in obesity-associated autocrine/paracrine inflammatory signaling, stimulate adipocyte expression and secretion of macrophage chemoattractants. Pharmacological studies showed that peroxisome proliferator-activated receptor gamma agonists and glucocorticoids potently inhibit adipocyte- induced recruitment of macrophages. This latter effect was mediated by the glucocorticoid receptor, which led to decreased chemokine secretion and expression. In vivo results were quite comparable; treatment of high fat diet-fed mice with dexamethasone prevented ATM accumulation in epididymal fat. This decrease in ATM was most pronounced for the proinflammatory F4/80(+), CD11b(+), CD11c(+) M-1-like ATM subset. Overall, our results elucidate a beneficial function of peroxisome proliferator-activated receptor gamma activation and glucocorticoid receptor/glucocorticoids in adipose tissue and indicate that pharmacologic prevention of ATM accumulation could be beneficial." 8897;"A role for 5-lipoxygenase products in obesity-associated inflammation and insulin resistance.";"J. Neels";"Equipe 09, Team 09";24052903;Adipocyte;"Neels JG";;"Sep 2013";1379721600;;"There is a growing amount of evidence that obesity-induced low-grade inflammation is an important causative link between obesity and many of its associated pathologies such as type 2 diabetes and atherosclerosis. In the quest to identify the triggers of obesity-associated inflammation of adipose tissue, our laboratory recently demonstrated that adipocytes can secrete leukotrienes, and that these pro-inflammatory lipid mediators contribute to obesity-associated inflammation and insulin resistance in mice. Together with other recent studies, our recent findings identify an important role for the enzyme 5-lipoxygenase and its products in the induction and resolution of adipose tissue inflammation. Therefore, pharmaceutical approaches that target this enzyme or its products should be considered as novel treatments aimed at preventing or resolving obesity-induced inflammation and its associated pathologies. " 8898;"Adipocytes secrete leukotrienes: contribution to obesity-associated inflammation and insulin resistance in mice.";"J. Neels";"Equipe 09, Team 09";22688342;Diabetes;"Mothe-Satney I, Filloux C, Amghar H, Pons C, Bourlier V, Galitzky J, Grimaldi PA, Féral CC, Bouloumié A, Van Obberghen E, Neels JG";;"Jun 2012";1339545600;;"Leukotrienes (LTs) are potent proinflammatory mediators, and many important aspects of innate and adaptive immune responses are regulated by LTs. Key members of the LT synthesis pathway are overexpressed in adipose tissue (AT) during obesity, resulting in increased LT levels in this tissue. We observed that several mouse adipocyte cell lines and primary adipocytes from mice and humans both can secrete large amounts of LTs. Furthermore, this production increases with a high-fat diet (HFD) and positively correlates with adipocyte size. LTs produced by adipocytes play an important role in attracting macrophages and T cells in in vitro chemotaxis assays. Mice that are deficient for the enzyme 5-lipoxygenase (5-LO), and therefore lack LTs, exhibit a decrease in HFD-induced AT macrophage and T-cell infiltration and are partially protected from HFD-induced insulin resistance. Similarly, treatment of HFD-fed wild-type mice with the 5-LO inhibitor Zileuton also results in a reduction of AT macrophages and T cells, accompanied by a decrease in insulin resistance. Together, these findings suggest that LTs represent a novel target in the prevention or treatment of obesity-associated inflammation and insulin resistance." 8891;"Complementary Immunometabolic Effects of Exercise and PPARβ/δ Agonist in the Context of Diet-Induced Weight Loss in Obese Female Mice.";"G. Chinetti, J. Neels, J. Murdaca";"Equipe 09, Team 09";31635041;"International journal of molecular sciences";"Le Garf S, Murdaca J, Mothe-Satney I, Sibille B, Le Menn G, Chinetti G, Neels JG, Rousseau AS";;"Oct 2019";1569888000;;"Regular aerobic exercise, independently of weight loss, improves metabolic and anti-inflammatory states, and can be regarded as beneficial in counteracting obesity-induced low-grade inflammation. However, it is still unknown how exercise alters immunometabolism in a context of dietary changes. Agonists of the Peroxisome Proliferator Activated-Receptor beta/delta (PPARβ/δ) have been studied this last decade as ""exercise-mimetics"", which are potential therapies for metabolic diseases. In this study, we address the question of whether PPARβ/δ agonist treatment would improve the immunometabolic changes induced by exercise in diet-induced obese female mice, having switched from a high fat diet to a normal diet. 24 mice were assigned to groups according to an 8-week exercise training program and/or an 8-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist. Our results show metabolic changes of peripheral lymphoid tissues with PPARβ/δ agonist (increase in fatty acid oxidation gene expression) or exercise (increase in AMPK activity) and a potentiating effect of the combination of both on the percentage of anti-inflammatory Foxp3+ T cells. Those effects are associated with a decreased visceral adipose tissue mass and skeletal muscle inflammation (TNF-α, Il-6, Il-1β mRNA level), an increase in skeletal muscle oxidative capacities (citrate synthase activity, endurance capacity), and insulin sensitivity. We conclude that a therapeutic approach targeting the PPARβ/δ pathway would improve obesity treatment." 8892;"Peroxisome Proliferator Activated Receptor Beta (PPARβ) activity increases the immune response and shortens the early phases of skeletal muscle regeneration.";"J. Neels, J. Murdaca";"Equipe 09, Team 09";27939528;Biochimie;"Mothe-Satney I, Piquet J, Murdaca J, Sibille B, Grimaldi PA, Neels JG, Rousseau AS";;"Dec 2016";1481587200;;"Peroxisome Proliferator-Activated Receptor Beta (PPARβ) is a transcription factor playing an important role in both muscle myogenesis and remodeling, and in inflammation. However, its role in the coordination of the transient muscle inflammation and reparation process following muscle injury has not yet been fully determined. We postulated that activation of the PPARβ pathway alters the early phase of the muscle regeneration process, i.e. when immune cells infiltrate in injured muscle. Tibialis anteriors of C57BL6/J mice treated or not with the PPARβ agonist GW0742 were injected with cardiotoxin (or with physiological serum for the contralateral muscle). Muscle regeneration was monitored on days 4, 7, and 14 post-injury. We found that treatment of mice with GW0742 increased, at day 4 post-damage, the recruitment of immune cells (M1 and M2 macrophages) and upregulated the expression of the anti-inflammatory cytokine IL-10 and TGF-β mRNA. Those effects were accompanied by a significant increase at day 4 of myogenic regulatory factors (Pax7, MyoD, Myf5, Myogenin) mRNA in GW0742-treated mice. However, we showed an earlier return (7 days vs 14 days) of Myf5 and Myogenin to basal levels in GW0742- compared to DMSO-treated mice. Differential effects of GW0742 observed during the regeneration were associated with variations of PPARβ pathway activity. Collectively, our findings indicate that PPARβ pathway activity shortens the early phases of skeletal muscle regeneration by increasing the immune response." 8893;"Regulation of Immune Cell Function by PPARs and the Connection with Metabolic and Neurodegenerative Diseases.";"J. Neels";"Equipe 09, Team 09";29799467;"International journal of molecular sciences";"Le Menn G, Neels JG";;"May 2018";1527292800;;"Increasing evidence points towards the existence of a bidirectional interconnection between metabolic disease and neurodegenerative disorders, in which inflammation is linking both together. Activation of members of the peroxisome proliferator-activated receptor (PPAR) family has been shown to have beneficial effects in these interlinked pathologies, and these improvements are often attributed to anti-inflammatory effects of PPAR activation. In this review, we summarize the role of PPARs in immune cell function, with a focus on macrophages and T cells, and how this was shown to contribute to obesity-associated inflammation and insulin resistance, atherosclerosis, and neurodegenerative disorders. We address gender differences as a potential explanation in observed contradictory results, and we highlight PPAR-induced metabolic changes as a potential mechanism of regulation of immune cell function through these nuclear receptors. Together, immune cell-specific activation of PPARs present a promising therapeutic approach to treat both metabolic and neurodegenerative diseases." 8889;"Invalidation of the Transcriptional Modulator of Lipid Metabolism PPARβ/δ in T Cells Prevents Age-Related Alteration of Body Composition and Loss of Endurance Capacity.";"G. Chinetti, J. Neels, J. Murdaca";"Equipe 09, Team 09";33815130;"Frontiers in physiology";"Rousseau AS, Murdaca J, Le Menn G, Sibille B, Wahli W, Le Garf S, Chinetti G, Neels JG, Mothe-Satney I";;"Jan 2021";1609459200;;"Anti-inflammatory regulatory T cells (Tregs) are the most metabolically flexible CD4 T cells by using both glycolysis and fatty acid oxidation (FAO) which allow them to migrate in tissues. With aging, Tregs accumulate in secondary lymphoid organs and are involved in impairment of skeletal muscle (SKM) regeneration and mass maintenance. In this study, we showed that a deletion of a FAO modulator, peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), specifically in T cells (KO-T PPARβ/δ), increased the number of CD4 T cells at day 2 following a cardiotoxin-induced SKM regeneration. Older KO-T PPARβ/δ mice maintained a Tregs prevalence in lymph nodes similar to young mice. Surprisingly, KO-T PPARβ/δ mice were protected from the effects of age on lean and fat mass and endurance capacity. Our results lead us to propose an original potential role of T cell metabolism in the effects of aging on the maintenance of body composition and endurance capacity." 8885;"Nuclear receptors in abdominal aortic aneurysms.";"G. Chinetti, J. Neels, R. Hassen-Khodja";"Equipe 09, Team 09";32105947;Atherosclerosis;"Neels JG, Hassen-Khodja R, Chinetti G";;"03 2020";1583020800;;"Abdominal aortic aneurysms (AAA) pose a considerable health burden and at present are only managed surgically since there is no proven pharmacotherapy that will retard their expansion or reduce the incidence of fatal rupture. This pathology shares several pathophysiological mechanisms with atherosclerosis, such as macrophage infiltration, inflammation, and degradation of extracellular matrix. Therefore, therapeutic targets proven effective in the treatment of atherosclerosis could also be considered for treatment of AAA. Different members of the nuclear receptor (NR) superfamily have been extensively studied as potential targets in the treatment of cardiovascular disease (CVD) and therefore might also be suited for AAA treatment. In this context, this review summarizes the role of different NRs in CVD, mostly atherosclerosis, and discusses in detail the current knowledge of their implications in AAA. From this overview it becomes apparent that NRs that were attributed a beneficial or adverse role in CVD have similar roles in AAA. Together, this overview provides compelling evidence to consider several NRs as attractive targets for future treatment of AAA." 8886;"Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples.";"G. Chinetti, J. Neels, J. Murdaca";"Equipe 09, Team 09";34768927;"International journal of molecular sciences";"Sibille B, Mothe-Satney I, Le Menn G, Lepouse D, Le Garf S, Baudoin E, Murdaca J, Moratal C, Lamghari N, Chinetti G, Neels JG, Rousseau AS";;"Nov 2021";1636761600;;"Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method to detect the use of PPARβ/δ agonists. We analyzed in primary human T cells the in vitro effect of PPARβ/δ activation on fatty acid oxidation (FAO) and on their differentiation into regulatory T cells (Tregs). Furthermore, we conducted studies in mice assigned to groups according to an 8-week exercise training program and/or a 6-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist, in order to (1) determine the immune impact of the treatment on secondary lymphoid organs and to (2) validate a blood signature. Our results show that PPARβ/δ activation increases FAO potential in human and mouse T cells and mouse secondary lymphoid organs. This was accompanied by increased Treg polarization of human primary T cells. Moreover, Treg prevalence in mouse lymph nodes was increased when PPARβ/δ activation was combined with exercise training. Lastly, PPARβ/δ activation increased FAO potential in mouse blood T cells. Unfortunately, this signature was masked by training in mice. In conclusion, beyond the fact that it is unlikely that this signature could be used as a doping-control strategy, our results suggest that the use of PPARβ/δ agonists could have potential detrimental immune effects that may not be detectable in blood samples." 8739;"[Anorexia nervosa during pregnancy: an unusual association].";"N. Chevalier";"Equipe 05, Team 05";18952483;"Gynecologie, obstetrique & fertilite";"Chevalier N, Delotte J, Trastour C, Bongain A";;"Nov 2008";1225497600;;"We report the case of a pregnancy associated with severe restricting anorexia nervosa in a 33-year-old patient who weighed 41kg for 1.61m at conception. She continued to lose weight during pregnancy and she gave birth to an eutrophic child by cesarean section at 34 weeks of amenorrhea. Because of complications induced by the chronic food restriction, anorectic pregnant women should be viewed as being at high risk and also monitored closely both during and after pregnancy to optimize maternal and fetal outcomes." 8737;"[Oocyte donation in patients with Turner syndrome: A high-risk pregnancy].";"N. Chevalier";"Equipe 05, Team 05";19200942;"Annales d'endocrinologie";"Chevalier N, Bständig B, Galand-Portier M-, Isnard V, Bongain A, Fénichel P";;"Sep 2009";1251763200;;"Turner's syndrome is characterized by an ovarian failure, which occurs in most cases before puberty and leads to infertility. In vitro fertilization with oocyte donation has dramatically transformed the prognosis of infertility of these women. However, in the same time, it has become obvious that pregnancies in Turner's syndrome are at very high risk of possible sudden death because of a specific risk for cardiovascular complications involving aortic root dissection. We report the case of a serious cardiac failure occurred during a twin pregnancy obtained by oocyte donation in a 39-year-old patient with Turner's syndrome. Pregnancy outcome was hopefully favourable thanks to a foetal extraction at 27 weeks of amenorrhoea. If the most reported cases of maternal deaths in patients with Turner's syndrome are associated with an aortic root dissection, our observation is characterized by a full normal cardiologic assessment before the pregnancy and by the absence of aortic root dilatation during pregnancy. This case also illustrates the very high risk of pregnancy in women with Turner's syndrome and the importance of a multidisciplinary care by professionals informed and been used to this obstetric practice." 8735;"[Screening for gestational diabetes mellitus in 2009: Which approach for which patient?].";"N. Chevalier";"Equipe 05, Team 05";19410493;"Gynecologie, obstetrique & fertilite";"Chevalier N, Hiéronimus S, Bongain A, Fénichel P";;"May 2009";1241136000;; 8733;"[Iodine status and thyroid function of 330 pregnant women from Nice area assessed during the second part of pregnancy].";"N. Chevalier";"Equipe 05, Team 05";19481731;"Annales d'endocrinologie";"Hiéronimus S, Bec-Roche M, Ferrari P, Chevalier N, Fénichel P, Brucker-Davis F";;"Sep 2009";1251763200;;"Iodine deficiency (ID) is still common in Western Europe and its prevention remains a challenge, particularly during pregnancy." 8731;"[Oncofertility: a new focus in women health-care...].";"N. Chevalier";"Equipe 05, Team 05";19878767;"Annales d'endocrinologie";"Chevalier N, Dewailly D, Fenichel P";;"Sep 2009";1251763200;;"Although treatment and survival are the primary focus of health-care patients, with cancer survivors living longer it is now appropriate to consider their quality of life after treatment, including the possibility of becoming parents. There are several options for fertility preservation in cancer patients. Even though most of them are still experimental and their efficacy and reliability have not been determined, especially in women. The most successful alternative for female survivors is embryo cryopreservation, an approach not suitable for many single or virgin women or even possible for prepubertal girls. Reports of live birth after transplantation of human ovarian tissue have reinforced the clinical potential of ovarian tissue banking for fertility preservation. Many exciting studies are underway to improve the efficacy and solve the problems with current fertility preservation strategies, especially for in vitro culture of cryopreserved tissue or follicles. Continuous efforts to improve current strategies and to develop new strategies will benefit many women and children who are facing premature ovarian failure and sterility." 8729;"Adrenocortical incidentaloma with uncertain prognosis associated with an inadequately treated congenital adrenal hyperplasia.";"N. Chevalier";"Equipe 05, Team 05";19942208;"Annales d'endocrinologie";"Chevalier N, Carrier P, Piche M, Chevallier A, Wagner K, Tardy V, Benchimol D, Fénichel P";;"Feb 2010";1264982400;;"Large adrenal tumors are rarely associated with adrenal enzymatic deficiency, except in 11-ss-hydroxylase insufficiency. These tumors are exceptionally malignant. We report here the case of a patient with a congenital 21-hydroxylase deficiency (compound heterozygote for two severe mutations in the CYP21A2 gene) untreated for 20 years. His evaluation at 36 years of age showed a four-centimeter mass in the left adrenal gland, with most characteristics suggestive of malignancy (CT and positron emission tomography [PET] scan). We performed a surgical resection that established the diagnosis of adrenocortical tumor of uncertain prognosis (Weiss's score: 3). Even though malignant tumors are unusual in adrenal deficiency, our observation shows the need for a replacement therapy during adulthood, with a regular CT scan follow up in order to diagnose early isolated adrenal adenoma and remove it in case of malignancy suspicion." 8727;"Lethal acute demyelinization with encephalo-myelitis as a complication of cured Cushing's disease.";"N. Chevalier";"Equipe 05, Team 05";20850107;"Annales d'endocrinologie";"Chevalier N, Hieronimus S, Vandenbos F, Delmont E, Cua E, Cherick F, Paquis P, Michiels JF, Fenichel P, Brucker-Davis F";;"Dec 2010";1291161600;;"Cushing's disease is usually associated with higher mortality rate, especially from cardiovascular causes. Development or exacerbation of autoimmune or inflammatory diseases is known to occur in patients with hypercortisolism after cure. We report for the first time a 34-year old woman with a psychiatric background, who developed four months after the surgical cure of Cushing's disease an acute disseminated encephalomyelitis (ADEM) presenting initially as a psychiatric illness. We hypothesize that the recent correction of hypercortisolism triggered ADEM and that the atypical presentation, responsible for diagnosis delay, led to the death of this patient." 8725;"Materno-fetal cardiovascular complications in Turner syndrome after oocyte donation: insufficient prepregnancy screening and pregnancy follow-up are associated with poor outcome.";"PS. ROHRLICH, N. Chevalier";"Equipe 04, Team 04, Equipe 05, Team 05";21147890;"The Journal of clinical endocrinology and metabolism";"Chevalier N, Letur H, Lelannou D, Ohl J, Cornet D, Chalas-Boissonnas C, Frydman R, Catteau-Jonard S, Greck-Chassain T, Papaxanthos-Roche A, Dulucq MC, Couet ML, Cédrin-Durnerin I, Pouly JL, Fénichel P, ";;"Feb 2011";1296518400;;"Recombinant human GH treatment and oocyte donation (OD) have improved the quality of life in women with Turner syndrome (TS). However, life expectancy is reduced, mainly due to cardiovascular complications. Pregnancy may itself increase that risk and be associated with hazardous materno-fetal outcome." 8723;"[Is there any medical treatment to preserve fertility during chemotherapy in women?].";"N. Chevalier";"Equipe 05, Team 05";21195008;"Gynecologie, obstetrique & fertilite";"Fénichel P, Chevalier N";;"Jan 2011";1293840000;;"Intensive use of radio-chemotherapy has greatly improved the prognosis associated with cancer in young girl or women patients. However, improvement of the vital prognosis is frequently associated with impairment of fertility and premature ovarian failure. In vitro fertilization (IVF) followed by embryo cryopreservation is an available method, which needs a partner and a pretreatment stimulation. Ovarian and oocyte cryopreservation are techniques showing great promise. However, the nec plus ultra would be to be able to protect ovaries during chemotherapy. Since more than 10 years Gonadotropin releasing hormone (GnRH) analogues have been investigated as possible means to preserve fertility in young women. However, even recent prospective, randomized studies do not demonstrate clearly their effectiveness. To prevent primordial follicle apoptosis, an inhibitor of tysosine kinase, imatinib, has recently been proposed and positively evaluated in mice. It could represent an interesting hope to preserve female fertility during chemotherapy." 8721;"Bisphenol A promotes testicular seminoma cell proliferation through GPER/GPR30.";"N. Chevalier";"Equipe 05, Team 05";21312194;"International journal of cancer";"Chevalier N, Bouskine A, Fenichel P";;"Jan 2012";1325376000;; 8719;"Universal two-step screening strategy for gestational diabetes has weak relevance in French Mediterranean women: should we simplify the screening strategy for gestational diabetes in France?";"N. Chevalier";"Equipe 05, Team 05";21489844;"Diabetes & metabolism";"Chevalier N, Fénichel P, Giaume V, Loizeau S, Bongain A, Daideri G, Brucker-Davis F, Hiéronimus S";;"Nov 2011";1320105600;;"Currently, there is no international consensus for gestational diabetes mellitus (GDM) diagnosis. This is a report of our experience of GDM screening according to the 1996 French guidelines." 8717;"Role of GPER/GPR30 in tumoral testicular germ cells proliferation.";"N. Chevalier";"Equipe 05, Team 05";21508670;"Cancer biology & therapy";"Chevalier N, Bouskine A, Fenichel P";;"Jul 2011";1309478400;;"In a recent issue of Cancer Biology & Therapy, Vitale et al. introduced the paper of Franco et al. reporting the expression of GPER (a seven-transmembrane-spanning receptor also known as GPR30) on testicular germ cell tumors (TGCTs). The paper commented on the possible pathophysiological role of this G-protein-coupled receptor (GPCR) during testicular germ cell carcinogenesis. They also proposed the potential use of selective antagonists of GPER as new-targeted therapy in these tumors. We agree with this hypothesis and would like to highlight here some published results supporting this hypothesis and give some details concerning the role of estrogens and xeno-estrogens in testicular carcinogenesis and the effects of GPER antagonist in human seminoma cells. We are sure that this information we obtained by working for several years on a human seminoma cell line will be appreciated by the readers of Cancer Biology & Therapy." 8715;"GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation.";"N. Chevalier";"Equipe 05, Team 05";22496838;"PloS one";"Chevalier N, Vega A, Bouskine A, Siddeek B, Michiels JF, Chevallier D, Fénichel P";;"Jan 2012";1325376000;;"Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation." 8713;"Molecular diagnosis of 5α-reductase deficiency in 4 elite young female athletes through hormonal screening for hyperandrogenism.";"N. Chevalier";"Equipe 05, Team 05";23633205;"The Journal of clinical endocrinology and metabolism";"Fénichel P, Paris F, Philibert P, Hiéronimus S, Gaspari L, Kurzenne JY, Chevallier P, Bermon S, Chevalier N, Sultan C";;"Jun 2013";1370044800;;"Although a rare occurrence, previously undiagnosed disorders of sex development (DSD) with hyperandrogenism are sometimes detected by hormonal screening during the international sports competitions. Identifying the cause of XY,DSD raises medical and ethical concerns, especially with regard to issues of the eligibility to compete." 8711;"Bisphenol A: an endocrine and metabolic disruptor.";"N. Chevalier";"Equipe 05, Team 05";23796010;"Annales d'endocrinologie";"Fenichel P, Chevalier N, Brucker-Davis F";;"Jul 2013";1372636800;;"Bisphenol A (BPA), initially designed, like diethylstilbestrol, as a synthetic estrogen, has been rapidly and widely used for its cross-linking properties in the manufacture of polycarbonate plastics and epoxy resins. Because of incomplete polymerization and degradation of the polymers by exposure to higher than usual temperatures, BPA leaches out from food and beverage containers, as well as from dental sealants. In humans, free active unconjugated BPA is metabolized by rapid glucurono- or sulfo-conjugation and eliminated via renal clearance. However, exposure to environmental nanomolar concentrations of BPA is ubiquitous and continuous via different routes: oral, air, skin. In rodents, fetal and perinatal exposure to such environmentally relevant doses of BPA has been shown to affect the brain, liver, gut, adipose tissue, endocrine pancreas, mammary gland and reproductive tract and function. Similar concentrations are also able in vitro to impact human malignant breast, prostate, male germ or adipocyte cell lines (with a promoting effect and by interfering with chemotherapy drugs), or to stimulate pancreatic β cell insulin secretion. High levels of BPA have recently been correlated with obesity, diabetes, cardiovascular diseases, polycystic ovarian disease or low sperm count. However, before the real impact of BPA on human health can be clearly assessed, prospective longitudinal epidemiological studies are needed as well as characterization of selective biomarkers to verify long-term exposure and selective imprinting. " 8709;"Genetic variants of GPER/GPR30, a novel estrogen-related G protein receptor, are associated with human seminoma.";"N. Chevalier, R. Paul-Bellon";"Equipe 05, Team 05, Team 03, Equipe 03";24451139;"International journal of molecular sciences";"Chevalier N, Paul-Bellon R, Camparo P, Michiels JF, Chevallier D, Fénichel P";;"Jan 2014";1388534400;;"Testicular germ cell tumors (TGCTs) are the most common solid cancers in young men, with an increasing incidence over several years. However, their pathogenesis remains a matter of debate. Some epidemiological data suggest the involvement of both environmental and genetic factors. We reported two distinct effects of estrogens and/or xeno-estrogens on in vitro human seminoma-derived cells proliferation: (1) an antiproliferative effect via a classical estrogen receptor beta-dependent pathway, and (2) a promotive effect via a non-classical membrane G-protein-coupled receptor, GPR30/GPER, which is only overexpressed in seminomas, the most common TGCT. In order to explain this overexpression, we investigated the possible association of polymorphisms in the GPER gene by using allele-specific tetra-primer polymerase chain reaction performed on tissue samples from 150 paraffin-embedded TGCT specimens (131 seminomas, 19 non seminomas). Compared to control population, loss of homozygous ancestral genotype GG in two polymorphisms located in the promoter region of GPER (rs3808350 and rs3808351) was more frequent in seminomas but not in non-seminomas (respectively, OR = 1.960 (1.172-3.277) and 7.000 (2.747-17.840); p < 0.01). These polymorphisms may explain GPER overexpression and represent a genetic factor of susceptibility supporting the contribution of environmental GPER ligands in testicular carcinogenesis. " 8707;"Endocrine disruptors: new players in the pathophysiology of type 2 diabetes?";"N. Chevalier";"Equipe 05, Team 05";25454091;"Diabetes & metabolism";"Chevalier N, Fénichel P";;"Apr 2015";1427846400;;"The prevalence of type 2 diabetes (T2D) has dramatically increased worldwide during the last few decades. While lifestyle factors, such as decreased physical activity and energy-dense diets, together with genetic predisposition, are well-known actors in the pathophysiology of T2D, there is accumulating evidence suggesting that the increased presence of endocrine-disrupting chemicals (EDCs) in the environment, such as bisphenol A, phthalates and persistent organic pollutants, may also explain an important part in the incidence of metabolic diseases (the metabolic syndrome, obesity and T2D). EDCs are found in everyday products (including plastic bottles, metal cans, toys, cosmetics and pesticides) and used in the manufacture of food. They interfere with the synthesis, secretion, transport, activity and elimination of natural hormones. Such interferences can block or mimic hormone actions and thus induce a wide range of adverse effects (developmental, reproductive, neurological, cardiovascular, metabolic and immune). In this review, both in vivo and in vitro experimental data and epidemiological evidence to support an association between EDC exposure and the induction of insulin resistance and/or disruption of pancreatic β-cell function are summarized, while the epidemiological links with disorders of glucose homoeostasis are also discussed." 8705;"A negative correlation between insulin-like peptide 3 and bisphenol A in human cord blood suggests an effect of endocrine disruptors on testicular descent during fetal development.";"N. Chevalier";"Equipe 05, Team 05";25527819;"Human reproduction (Oxford, England)";"Chevalier N, Brucker-Davis F, Lahlou N, Coquillard P, Pugeat M, Pacini P, Panaïa-Ferrari P, Wagner-Mahler K, Fénichel P";;"Feb 2015";1422748800;;"Does a relationship exist between insulin-like peptide 3 (INSL3) and selected environmental endocrine disruptors (EEDs) in human cord blood (cb)?" 8703;"A commentary on ""Involvement of activating ERK1/2 trough G protein coupled receptor 30 and estrogen receptor α/β in low doses of bisphenol A promoting growth of Sertoli TM4 cells"".";"N. Chevalier, R. Paul-Bellon";"Equipe 05, Team 05, Team 03, Equipe 03";25758025;"Toxicology letters";"Chevalier N, Paul-Bellon R, Fénichel P";;"Sep 2015";1441065600;; 8701;"The history of Distilbène® (Diethylstilbestrol) told to grandchildren--the transgenerational effect.";"N. Chevalier";"Equipe 05, Team 05";25934356;"Annales d'endocrinologie";"Fénichel P, Brucker-Davis F, Chevalier N";;"Jul 2015";1435708800;;"The Distilbène® story is a dramatic episode which belongs to the history of medicine. It provided several useful lessons such as the importance of evidence-based medicine and the hazard to develop treatments during pregnancy without careful animal verifications. However, this experience has also provided unexpected progress by suggesting new pathophysiological concepts: fetal programming of adult diseases and/or transgenerational transmission of environmental effects through epigenetic modifications." 8699;"Postpubertal Persistent Hyperestrogenemia in McCune-Albright Syndrome: Unilateral Oophorectomy Improved Fertility but Detected an Unexpected Borderline Epithelial Ovarian Tumor.";"N. Chevalier";"Equipe 05, Team 05";26321108;"Journal of pediatric and adolescent gynecology";"Chevalier N, Paris F, Fontana S, Delotte J, Gaspari L, Ferrari P, Sultan C, Fénichel P";;"Dec 2015";1448928000;;"McCune-Albright syndrome (MAS), due to a somatic mutation of the GNAS1 gene, begins usually in girls with peripheral precocious puberty. Ovarian autonomy may persist in adulthood with acyclic hyperestrogenemia, infertility, and a potential risk of estrogen-dependent cancer." 8697;"[Endocrine disruptors, reproduction and hormone-dependent cancers].";"N. Chevalier";"Equipe 05, Team 05";26655259;"Presse medicale (Paris, France : 1983)";"Fenichel P, Brucker-Davis F, Chevalier N";;"Jan 2016";1451606400;;"Endocrine disruptors are natural or synthetic chemical compounds which are present in the environment and which are able to interfere with hormonal regulation pathways and to induce human health deleterious effects. While their precise implication in human health and diseases is still matter of debates, it becomes likely that they have to be considered as risk factors in numerous chronic diseases: developmental and reproductive defects and hormone dependent cancers (present review), metabolic diseases (obesity and type 2 diabetes), neurodevelopmental or neurodegenerative diseases. Low doses exposure during critical windows of exposure such as foetal, perinatal and peri-pubertal periods, or chronic exposure with bioaccumulation in the adipose tissue, and possible synergic effects of several compounds (""cocktail effect"") may participate to the genetic/environment interface suspected to participate to the pathophysiology of many diseases." 8695;"[Endocrine disruptors: A missing link in the pandemy of type 2 diabetes and obesity?].";"N. Chevalier";"Equipe 05, Team 05";26655260;"Presse medicale (Paris, France : 1983)";"Chevalier N, Fénichel P";;"Jan 2016";1451606400;;"The prevalence of metabolic syndrome, obesity and type 2 diabetes has dramatically increased worldwide during the last few decades and exceeds World Health Organisation's predictions. Lifestyle factors such as decreased physical activity and energy dense diet, together with a genetic predisposition, are well-known actors in the pathophysiology of these metabolic diseases. However, there is accumulating evidence suggesting that the increased presence of endocrine disrupting chemicals (EDCs) in the environment, may also explain an important part in the incidence of metabolic syndrome, obesity and type 2 diabetes. EDCs are found in everyday products (including food, plastic bottles, metal cans, toys, cosmetics, pesticides…) and used in the manufacture of food. They interfere with the synthesis, secretion, transport, activity and/or elimination of natural hormones. Those interferences can block or mimic hormone actions and thus induce a wide range of adverse effects (especially reproductive effects and hormone-dependent cancers). In rodents, acute exposure to bisphenol A is responsible for modifications of insulin synthesis and secretion in pancreatic beta cells but also for modifications of insulin signalling in liver, skeletal muscle and adipose tissue, which both lead to insulin-resistance, a major condition in pathophysiology of metabolic syndrome, obesity and type 2 diabetes. In humans, some epidemiologic reports suggested a strong link between exposure to some persistant EDCs (as organochlorine pesticides, dioxins and polychlorinated biphenyl ethers) and type 2 diabetes and obesity, especially after acute and accidental releases of EDCs (Seveso plant explosion, Vietnam war veterans). Other cross-sectional studies among the world reported suggestive to strong association between diabetes and obesity and EDCs exposure, especially for persistant organic pollutants, which should now be considered as insulin-resistance risk factors." 8693;"Bisphenol A: Targeting metabolic tissues.";"N. Chevalier";"Equipe 05, Team 05";26820262;"Reviews in endocrine & metabolic disorders";"Chevalier N, Fénichel P";;"Dec 2015";1448928000;;"The prevalence of obesity, metabolic syndrome and type 2 diabetes has dramatically increased worldwide over the last few decades. Although genetic predisposition and lifestyle factors like decreased physical activity and energy-dense diet are well-known factors in the pathophysiology of these conditions, accumulating evidence suggests that the increase in endocrine disrupting chemicals (EDCs) in the environment also explains a substantial part of the incidence of these metabolic diseases. Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide. Most people are exposed to it daily by consuming food and beverages into which BPA has leached from polycarbonate containers, including reusable bottles and baby bottles. Although initially considered to be a weak environmental estrogen, BPA may be similar in potency to 17β-estradiol in stimulating cellular responses, especially at low but environmentally relevant doses (nM), as more recent studies have demonstrated. In this review, we summarize both epidemiological evidence and in vivo experimental data that point to an association between BPA exposure and the induction of insulin resistance and/or disruption of pancreatic beta cell function and/or obesity. We then discuss the in vitro data and explain the potential mechanisms involved in the metabolic disorders observed after BPA exposure. " 8691;"Comment on ""Effects of Atrazine on Estrogen Receptor α- and G Protein-Coupled Receptor 30-Mediated Signaling and Proliferation in Cancer Cells and Cancer-Associated Fibroblasts"".";"N. Chevalier, R. Paul-Bellon";"Equipe 05, Team 05, Team 03, Equipe 03";27035794;"Environmental health perspectives";"Chevalier N, Paul-Bellon R, Fénichel P";;"Apr 2016";1459468800;; 8689;"Which origin for polycystic ovaries syndrome: Genetic, environmental or both?";"N. Chevalier";"Equipe 05, Team 05";28606381;"Annales d'endocrinologie";"Fenichel P, Rougier C, Hieronimus S, Chevalier N";;"Jul 2017";1498867200;;"Polycystic ovaries syndrome (PCOS), the most common female endocrine disorder, affects 7-10% of women of childbearing age. It includes ovarian hyperandrogenism, impaired follicular maturation, anovulation and subfertility. Insulin resistance, although present in most cases, is not necessary for diagnosis. It increases hyperandrogenism and long-term metabolic, cardiovascular and oncological risks. The origin of hyperandrogenism and hyperinsulinemia has a genetic component, as demonstrated by familial aggregation studies and recent identification of associated genomic variants, conferring a particular susceptibility to the syndrome. However, experimental and epidemiological evidences also support a developmental origin via a deleterious foetal environment, concerning the endocrine status (foetal hyperandrogenism), the nutritional level (intrauterine growth retardation), or the toxicological exposure (endocrine disruptors). Epigenetic changes recently reported in the literature as associated with PCOS, enhance this hypothesis of foetal reprogramming of the future adult ovarian function by environmental factors. Better characterisation of these genetic, epigenetic, or environmental factors, could lead to earlier prevention and more efficient treatments." 8687;"Environmental endocrine disruptors: New diabetogens?";"N. Chevalier";"Equipe 05, Team 05";28826789;"Comptes rendus biologies";"Fénichel P, Chevalier N";;"Oct Sep 2017";1505001600;;"The prevalence of type-2 diabetes has dramatically increased worldwide during the last few decades. While lifestyle factors (sedentariness, noxious food), together with genetic susceptibility, are well-known actors, there is accumulating evidence suggesting that endocrine disrupting chemicals (EDCs) may also play a pathophysiological role in the occurrence of metabolic diseases. Both experimental and epidemiological evidence support a role for early and chronic exposure to low doses of chemical pollutants with endocrine and metabolic disrupting effects. Most are present in the food chain and accumulate in the fat mass after absorption. In rodents, bisphenol A stimulates synthesis and secretion of pancreatic β cells and disturbs insulin signaling in liver, muscle and adipose tissue through epigenetic changes leading to insulin resistance and β cell impairment. In humans, epidemiological reports show statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, dioxins or aromatic polycyclic hydrocarbides or heavy metals and DT2 after acute accidental releases or early in life and/or chronic, low doses exposure. More prospective, longitudinal studies are needed to determine the importance of such environmental risk factors." 8685;"Endocrine Disrupting Chemicals Interfere With Leydig Cell Hormone Pathways During Testicular Descent in Idiopathic Cryptorchidism.";"N. Chevalier";"Equipe 05, Team 05";30687232;"Frontiers in endocrinology";"Fénichel P, Chevalier N, Lahlou N, Coquillard P, Wagner-Mahler K, Pugeat M, Panaïa-Ferrari P, Brucker-Davis F";;"Jan 2018";1514764800;;"Cryptorchidism, a frequent genital malformation in male newborn, remains in most cases idiopathic. On the basis of experimental, epidemiological, and clinical data, it has been included in the testicular dysgenesis syndrome and believed to be influenced, together with genetic and anatomic factors, by maternal exposure to endocrine disrupting chemicals (EDCs). Here, we analyze how EDCs may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3)." 8683;"Variation of carbohydrate intake in diabetic children on carbohydrate counting.";"A. TRAN, N. Chevalier";"Equipe 08, Team 08, Equipe 05, Team 05";30872065;"Diabetes research and clinical practice";"Robart E, Giovannini-Chami L, Savoldelli C, Baechler-Sadoul E, Gastaud F, Tran A, Chevalier N, Hoflack M";;"Apr 2019";1554076800;;"Carbohydrate counting (CC) is a technique for managing diabetes particularly based on the counting of carbohydrates. It allows diabetic patients to vary their amount of carbohydrates from one meal to another by adjusting their insulin dose. The primary objective was to determine the variation of carbohydrate intake (CI) in children on CC." 8681;"Is Testicular Germ Cell Cancer Estrogen Dependent? The Role of Endocrine Disrupting Chemicals.";"N. Chevalier";"Equipe 05, Team 05";31617897;Endocrinology;"Fénichel P, Chevalier N";;"12 2019";1575158400;;"Testicular germ cell cancer (TGCC) is the most frequent cancer of the young male, with an increasing incidence worldwide. The pathogenesis and reasons for this increase remain unknown. However, epidemiological and experimental data have suggested that, similar to genital malformations and sperm impairment, it could result from the interaction of genetic and environmental factors including fetal exposure to endocrine-disrupting chemicals (EDCs) with estrogenic effects. In this review, we analyze the expression of classic and nonclassic estrogen receptors by TGCC cells, the way they may influence germ cell proliferation induced by EDCs, and discuss how this estrogen dependency supports the developmental and environmental hypothesis." 8679;"Clinical phenotype of mitochondrial diabetes due to rare mitochondrial DNA mutations.";"N. Chevalier";"Equipe 05, Team 05";32409007;"Annales d'endocrinologie";"Decoux-Poullot AG, Bannwarth S, Procaccio V, Lebre AS, Jardel C, Vialettes B, Paquis-Flucklinger V, Chevalier N";;"Jun 2020";1590969600;;"While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations." 8675;"Pre-term birth in women exposed to Cushing's disease: the baby-cush study.";"N. Chevalier";"Equipe 05, Team 05";33486470;"European journal of endocrinology";"Hochman C, Cristante J, Geslot A, Salenave S, Sonnet E, Briet C, Bachelot A, Chevalier N, Gilly O, Brue T, Hadjadj S, Kerlan V, Chanson P, Vezzosi D, Chabre O, Drui D, Castinetti F";;"Mar 2021";1614556800;;"Hypercortisolism during pregnancy is a risk factor for prematurity. Long-term exposure to hypercortisolism may lead to permanent comorbidities, such as hypertension or diabetes, even after remission. Our aim was to determine whether women with a history of Cushing's disease (and being eu-, hypo- or hypercortisolic at the time of pregnancy) had the same risks of comorbidities, and especially prematurity, during pregnancy." 8673;"Human Health and Ocean Pollution.";"N. Chevalier";"Equipe 05, Team 05";33354517;"Annals of global health";"Landrigan PJ, Stegeman JJ, Fleming LE, Allemand D, Anderson DM, Backer LC, Brucker-Davis F, Chevalier N, Corra L, Czerucka D, Bottein MD, Demeneix B, Depledge M, Deheyn DD, Dorman CJ, Fénichel P, Fisher S, Gaill F, Galgani F, Gaze WH, Giuliano L, Grandjean P, Hahn ME, Hamdoun A, Hess P, Judson B, Laborde A, McGlade J, Mu J, Mustapha A, Neira M, Noble RT, Pedrotti ML, Reddy C, Rocklöv J, Scharler UM, Shanmugam H, Taghian G, van de Water JAJM, Vezzulli L, Weihe P, Zeka A, Raps H, Rampal P";;"12 2020";1606780800;;"Pollution - unwanted waste released to air, water, and land by human activity - is the largest environmental cause of disease in the world today. It is responsible for an estimated nine million premature deaths per year, enormous economic losses, erosion of human capital, and degradation of ecosystems. Ocean pollution is an important, but insufficiently recognized and inadequately controlled component of global pollution. It poses serious threats to human health and well-being. The nature and magnitude of these impacts are only beginning to be understood." 8671;"Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.";"N. Chevalier";"Equipe 05, Team 05";33528920;"Diabetes, obesity & metabolism";"Roussel R, Darmon P, Pichelin M, Goronflot T, Abouleka Y, Ait Bachir L, Allix I, Ancelle D, Barraud S, Bordier L, Carlier A, Chevalier N, Coffin-Boutreux C, Cosson E, Dorange A, Dupuy O, Fontaine P, Fremy B, Galtier F, Germain N, Guedj AM, Larger E, Laugier-Robiolle S, Laviolle B, Ludwig L, Monier A, Montanier N, Moulin P, Moura I, Prevost G, Reznik Y, Sabbah N, Saulnier PJ, Serusclat P, Vatier C, Wargny M, Hadjadj S, Gourdy P, Cariou B, ";;"05 2021";1619827200;;"To investigate the association between routine use of dipeptidyl peptidase-4 (DPP-4) inhibitors and the severity of coronavirus disease 2019 (COVID-19) infection in patient with type 2 diabetes in a large multicentric study." 8669;"Sustained bloodstream release of persistent organic pollutants induced by extensive weight loss after bariatric surgery: Implications for women of childbearing age.";"A. IANNELLI, N. Chevalier";"Team 08, Equipe 08, Equipe 05, Team 05";33611106;"Environment international";"Fénichel P, Coquillard P, Brucker-Davis F, Marchand P, Cano-Sancho G, Boda M, Antignac JP, Iannelli A, Gugenheim J, Le Bizec B, Chevalier N";;"06 2021";1622505600;;"Lipophilic persistent organic pollutants (POPs) are stored in adipose tissues and released in case of weight loss." 8667;"Sex disparities in COVID-19 outcomes of inpatients with diabetes: insights from the CORONADO study.";"N. Chevalier";"Equipe 05, Team 05";34085949;"European journal of endocrinology";"Tramunt B, Smati S, Coudol S, Wargny M, Pichelin M, Guyomarch B, Al-Salameh A, Amadou C, Barraud S, Bigot E, Bordier L, Borot S, Bourgeon M, Bourron O, Charrière S, Chevalier N, Cosson E, Fève B, Flaus-Furmaniuk A, Fontaine P, Galioot A, Gonfroy-Leymarie C, Guerci B, Lablanche S, Lalau JD, Larger E, Lasbleiz A, Laviolle B, Marre M, Munch M, Potier L, Prevost G, Renard E, Reznik Y, Seret-Bégué D, Sibilia P, Thuillier P, Vergès B, Gautier JF, Hadjadj S, Cariou B, Mauvais-Jarvis F, Gourdy P";;"Jul 2021";1625097600;;"Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19." 8660;"Human inter-alpha-trypsin inhibitor: full-length cDNA sequence of the heavy chain H1.";"F. BOST";"Equipe 05, Team 05";1380832;"Biochimica et biophysica acta";"Diarra-Mehrpour M, Bourguignon J, Bost F, Sesboüé R, Muschio F, Sarafan N, Martin JP";;"Aug 1992";712627200;;"Inter-alpha-trypsin inhibitor (ITI), called inter-alpha-inhibitor, is a 220 kDa serine proteinase inhibitor found in human serum. It is composed of at least three distinct polypeptide chains. These chains, named H1, H2 and L, are an independently synthesized and proteolytically processed precursor protein. Only the complete structure of H2 and L has been established so far. We used a PCR-based cloning approach and a cDNA screening library to isolate the full-length cDNA H1. The amino acid sequences of the two heavy chains deduced from the cDNA are highly similar (40% identity). Nevertheless, the structure of the signal peptide and propeptide in the N-terminal region is different in these two chains. A complex posttranslational cleavage at both ends of H1 and H2 may be proposed prior to assembly of the ITI chains." 8658;"Effect of maternal hyperglycemia on NaK ATPase activity in fetal rat kidney.";"F. BOST";"Equipe 05, Team 05";8297940;"Biology of the neonate";"Freund N, Bost F, Prieur B, Bismuth J, Geloso JP, Delaval E";;"Jan 1993";725846400;;"The effect of moderate hyperglycemia on renal ATP production and ATPase activity of rat fetus was investigated using the experimental procedure of maternal continuous infusion of glucose during the last 5 days of gestation. Glucose-infused mothers and their fetuses showed a high level of glycemia (8.8 and 5.5 mM, respectively) and a high level of insulinemia (3 times higher than in controls). No change in either ATP or ADP concentration was detectable but an increase in NaK ATPase activity occurred without any change in Mg ATPase activity. These modifications should be the result of an enhanced Na/glucose cotransport leading to an enhanced extrusion of Na at the basolateral membrane. These results indicate that immature kidney is able to increase NaK ATPase activity to maintain Na homeostasis." 8656;"Human pre-alpha-trypsin inhibitor-precursor heavy chain. cDNA and deduced amino-acid sequence.";"F. BOST";"Equipe 05, Team 05";7681778;"European journal of biochemistry";"Bourguignon J, Diarra-Mehrpour M, Thiberville L, Bost F, Sesboüé R, Martin JP";;"Mar 1993";730944000;;"Pre-alpha-trypsin inhibitor (P alpha I) is a serine-proteinase inhibitor of M(r) 130,000 found in human serum. This protein belongs to the family of proteins called inter-alpha-trypsin inhibitor (ITI). P alpha I is composed of a heavy chain (HC3) and of a light chain (bikunin), synthesized by two separate mRNA. Bikunin is identical to the ITI light chain, the structure of which has already been established. The HC3 is obtained from a precursor called H3. The bikunin is covalently linked to HC3 by a chondroitin-4-sulfate glycosaminoglycan. We report here the H3 full-length cDNA sequence and the deduced amino-acid sequence of the heavy-chain H3 precursor. The high degree of similarity between the nucleotide and amino-acid sequences of ITI heavy-chain families H1, H2, H3 is examined with respect to their probable structure and assembly with bikunin in the final proteins, P alpha I and ITI." 8654;"Isolation and characterization of the human inter-alpha-trypsin inhibitor heavy-chain H1 gene.";"F. BOST";"Equipe 05, Team 05";7505744;"European journal of biochemistry";"Bost F, Bourguignon J, Martin JP, Sesboüé R, Thiberville L, Diarra-Mehrpour M";;"Dec 1993";754704000;;"The human inter-alpha-trypsin inhibitor heavy chain H1 (ITI heavy chain H1) gene was isolated from two overlapping clones. It spans 14 kbp and is composed of 22 exons from 15 bp to 281 bp in size and has consensus splice sites. Intron sizes range from 80 bp to 2000 bp. It codes for the precursor of HC1 that is part of the serum ITI form of 220 kDa. Two major transcriptional initiation sites were identified in the 5'-flanking region, which contained putative promoter elements, but no typical TATA and CAAT boxes. mRNA for the ITI heavy chain H1 was found only in liver. The tissue-specific transcription of the gene might be due to the presence of binding sites for the hepatocyte nuclear factor HNF-5 and to the octameric motifs. A previous overlapping of cDNA clones indicated the absence of 29 bp in one of these clones. The present study shows that the 29 bp is located within the gene at the end of exon 21. A reverse-transcriptase polymerase chain reaction mapping analysis of liver mRNA identified the two types of the mRNA for ITI heavy chain H1. Accordingly, the data demonstrate that there is alternative splicing of at least one exon of the ITI heavy chain H1 gene." 8652;"Tandem orientation of the inter-alpha-trypsin inhibitor heavy chain H1 and H3 genes.";"F. BOST";"Equipe 05, Team 05";7522574;"Biochimica et biophysica acta";"Diarra-Mehrpour M, Bourguignon J, Sarafan N, Bost F, Sesboüé R, Muschio-Bonnet F, Martin JP";;"Oct 1994";780969600;;"The inter-alpha-trypsin inhibitor H1 (ITIH1) and inter-alpha-trypsin inhibitor H3 (ITIH3) genes have both previously been mapped to chromosomes 3 and 14 in the human and mouse, respectively. We now present evidence that these genes are physically linked. By using cDNA probes, a recombinant DNA phage has been isolated from a bacteriophage DNA library, which contains sequences flanking the 5' end of the ITIH3 gene and the 3' end of the ITIH1 gene. Restriction endonuclease mapping, PCR analysis and DNA sequence determination of the recombinant phage and comparison to genomic DNA revealed that the genes are in tandem, 2721 base pairs apart, with the ITIH1 gene to the 5' side of the ITIH3 gene. Their respective transcriptional units are thus on the same strand of DNA and most probably arose in evolution as the consequence of a duplication of a common ancestral gene." 8650;"Frequency and prognostic evaluation of 3p21-22 allelic losses in non-small-cell lung cancer.";"F. BOST";"Equipe 05, Team 05";8550237;"International journal of cancer";"Thiberville L, Bourguignon J, Metayer J, Bost F, Diarra-Mehrpour M, Bignon J, Lam S, Martin JP, Nouvet G";;"Dec 1995";817776000;;"Previous loss of heterozygosity (LOH) studies of chromosome 3p loci have displayed a 60% deletion frequency in non-small-cell lung cancers (NSCLC), as opposed to small-cell lung cancers, in which the 3p deletion is consistently found. However, the high stromal-cell admixture found in NSCLC and the use of the Southern-blot method lead to under-evaluation of this frequency. In this study, we used a very precise microdissection technique followed by PCR amplification of 6 3p21-22 polymorphic genomic sequences to analyze LOH in 86 NSCLC and in normal adjacent tissue. We found the sensitivity of the microdissection-PCR-based LOH technique higher than the sensitivity of the Southern-blot technique: 87% of the squamous-cell carcinomas and 84% of the large-cell undifferentiated carcinomas showed a clear LOH for a 3p21-22 locus. All doubly informative cases but 4 showed concordant deletion at all 3p21-22 loci. The analysis of 3p microsatellite sequences displayed only 2 cases of genomic instability, one of them also displaying features of tumoral heterogeneity as regards the instability genotype. Four carcinomas in situ adjacent to these NSCLC showed the same allelic profile as the invasive tumors. The only prognostic factors in this study were the disease stage and histology. The 3p21-22 deletion was not related to the stage of the disease and did not appear to be a significant prognostic factor of survival. 3p21 loss appears, so far, to be the most frequent and the earliest genetic alteration described in NSCLC, but does not seem to carry significant prognostic information in invasive tumors." 8646;"Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines.";"F. BOST";"Equipe 05, Team 05";9671482;"Molecular and cellular biology";"Li Y, Lin B, Agadir A, Liu R, Dawson MI, Reed JC, Fontana JA, Bost F, Hobbs PD, Zheng Y, Chen GQ, Shroot B, Mercola D, Zhang XK";;"Aug 1998";901929600;;"6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN or CD437), originally identified as a retinoic acid receptor gamma-selective retinoid, was previously shown to induce growth inhibition and apoptosis in human breast cancer cells. In this study, we investigated the role of AHPN/CD437 and its mechanism of action in human lung cancer cell lines. Our results demonstrated that AHPN/CD437 effectively inhibited lung cancer cell growth by inducing G0/G1 arrest and apoptosis, a process that is accompanied by rapid induction of c-Jun, nur77, and p21(WAF1/CIP1). In addition, we found that expression of p53 and Bcl-2 was differentially regulated by AHPN/CD437 in different lung cancer cell lines and may play a role in regulating AHPN/CD437-induced apoptotic process. On constitutive expression of the c-JunAla(63,73) protein, a dominant-negative inhibitor of c-Jun, in A549 cells, nur77 expression and apoptosis induction by AHPN/CD437 were impaired, whereas p21(WAF1/CIP1) induction and G0/G1 arrest were not affected. Furthermore, overexpression of antisense nur77 RNA in A549 and H460 lung cancer cell lines largely inhibited AHPN/CD437-induced apoptosis. Thus, expression of c-Jun and nur77 plays a critical role in AHPN/CD437-induced apoptosis. Together, our results reveal a novel pathway for retinoid-induced apoptosis and suggest that AHPN/CD437 or analogs may have a better therapeutic efficacy against lung cancer." 8644;"Human inter-alpha-trypsin inhibitor heavy chain H3 gene. Genomic organization, promoter analysis, and gene linkage.";"F. BOST";"Equipe 05, Team 05";9756925;"The Journal of biological chemistry";"Diarra-Mehrpour M, Sarafan N, Bourguignon J, Bonnet F, Bost F, Martin JP";;"Oct 1998";907200000;;"To understand more about the human inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) expression and the relationship between this gene and the family of other ITI heavy chain genes, an analysis of the structure of the ITIH3 gene and its promoter region was performed. This gene is a single copy gene, 14 kilobase pair in length and consists of 22 exons. ITIH3 shares highly conserved exon size and intron-exon borders with other ITI heavy chain genes. We determined that the human ITIH1, ITIH3, and ITIH4 genes are closely linked within a 45-kilobase pair. They are arranged in the order of H1-H3-H4, with the ITIH4 gene transcribed in the opposite direction. A model for the evolution of the ITI heavy chain gene family is presented that involves multiple rounds of gene duplication plus inversion events. The minimum promoter region (-135 to +75) is identified in HepG2 cells. The transient transfection study in various cell lines indicates that the activity of the ITIH3 promoter is not liver-specific. DNase I footprinting, mobility shift assays, and cotransfection experiments reveal a functional CCAAT/enhancer-binding protein site (C/EBP, -1344 to -1305) which interacts with C/EBPalpha and C/EBPbeta factors. The latter factors control the transcription of the ITIH3 gene positively." 8642;"The Jun kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung carcinoma cells.";"F. BOST";"Equipe 05, Team 05";10022881;"Molecular and cellular biology";"Bost F, McKay R, Bost M, Potapova O, Dean NM, Mercola D";;"Mar 1999";920246400;;"We have previously found that epidermal growth factor (EGF) mediates growth through the Jun N-terminal kinase/stress-activated kinase (JNK/SAPK) pathway in A549 human lung carcinoma cells. As observed here, EGF treatment also greatly enhances the tumorigenicity of A549 cells, suggesting an important role for JNK in cancer cell growth (F. Bost, R. McKay, N. Dean, and D. Mercola, J. Biol. Chem. 272:33422-33429, 1997). Several isoforms families of JNK, JNK1, JNK2, and JNK3, have been isolated; they arise from alternative splicing of three different genes and have distinct substrate binding properties. Here we have used specific phosphorothioate oligonucleotides targeted against the two major isoforms, JNK1 and JNK2, to discriminate their roles in EGF-induced transformation. Multiple antisense sequences have been screened, and two high-affinity and specific candidates have been identified. Antisense JNK1 eliminated steady-state mRNA and JNK1 protein expression with a 50% effective concentration (EC50) of <0.1 microM but did not alter JNK2 mRNA or protein levels. Conversely, antisense JNK2 specifically eliminated JNK2 steady-state mRNA and protein expression with an EC50 of 0.1 microM. Antisense JNK1 and antisense JNK2 inhibited by 40 and 70%, respectively, EGF-induced total JNK activity, whereas sense and scrambled-sequence control oligonucleotides had no effect. The elimination of mRNA, protein, and JNK activities lasted 48 and 72 h following a single Lipofectin treatment with antisense JNK1 and JNK2, respectively, indicating sufficient duration for examining the impact of specific elimination on the phenotype. Direct proliferation assays demonstrated that antisense JNK2 inhibited EGF-induced doubling of growth as well as the combination of active antisense oligonucleotides did. EGF treatment also induced colony formation in soft agar. This effect was completely inhibited by antisense JNK2 and combined-antisense treatment but not altered by antisense JNK1 alone. These results show that EGF doubles the proliferation (growth in soft agar as well as tumorigenicity in athymic mice) of A549 lung carcinoma cells and that the JNK2 isoform but not JNK1 is utilized for mediating the effects of EGF. This study represents the first demonstration of a cellular phenotype regulated by a JNK isoform family, JNK2." 8640;"Differential effect of retinoic acid on growth regulation by phorbol ester in human cancer cell lines.";"F. BOST";"Equipe 05, Team 05";10514454;"The Journal of biological chemistry";"Agadir A, Chen Gq, Bost F, Li Y, Mercola D, Zhang X";;"Oct 1999";938736000;;"Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and all-trans-retinoic acid (trans-RA) are potent regulators of growth of cancer cells. In this study, we investigated the effect of TPA and trans-RA alone or their combination on proliferation of human breast cancer ZR75-1 and T47D and lung cancer H460 and H292 cell lines. trans-RA caused various degrees of growth inhibition of these cell lines. However, TPA showed inhibition of proliferation of H460 and H292 cells and induction of ZR75-1 cell growth. Although trans-RA did not significantly regulate the growth inhibitory effect of TPA, it completely prevented its growth stimulating function. The divergent effects of TPA were associated with specific disruption of cell cycle events, an induction of G(0)/G(1) arrest in H460 and H292 cells and inhibition of G(0)/G(1) arrest with increase of S phase in ZR75-1 cells. Induction of G(0)/G(1) arrest was accompanied by induction of p21(WAF1) and ERK activity, whereas inhibition of G(0)/G(1) arrest was associated with enhanced activity of JNK and AP-1 but not ERK. trans-RA did not affect TPA-induced p21(WAF1) expression. However, it inhibited TPA-induced AP-1 activity in ZR75-1 cells and the constitutive AP-1 activity in H460 and H292 cells. Thus, trans-RA modulates TPA activity through its interaction through TPA-induced JNK/AP-1 pathway but not TPA-induced ERK/p21(WAF1) pathway." 8638;"Antisense methods for discrimination of phenotypic properties of closely related gene products: Jun kinase family.";"F. BOST";"Equipe 05, Team 05";10565024;"Methods in enzymology";"Bost F, McKay R, Dean NM, Potapova O, Mercola D";;"Jan 2000";946684800;;"Methods for the selection and characterization of antisense oligonucleotides for specifically eliminating closely related gene family members are available. High-throughput semiautomated methods using 96-well plate formats and array technology and improved assays are under active development that will streamline many steps and will likely merge. Second-generation 20-mer antisense phosphorothioate oligonucleotides containing 2'-methoxyethyl groups at the first and last 6 nucleotides with improved nuclease resistance and RNA affinity are becoming available." 8636;"c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells.";"F. BOST";"Equipe 05, Team 05";10825181;"The Journal of biological chemistry";"Potapova O, Gorospe M, Bost F, Dean NM, Gaarde WA, Mercola D, Holbrook NJ";;"Aug 2000";965088000;;"The c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway is activated by numerous cellular stresses. Although it has been implicated in mediating apoptosis and growth factor signaling, its role in regulating cell growth is not yet clear. Here, the influence of JNK on basal (unstimulated) growth of human tumor glioblastoma T98G cells was investigated using highly specific JNK antisense oligonucleotides to inhibit JNK expression. Transient depletion of either JNK1 or JNK2 suppressed cell growth associated with an inhibition of DNA synthesis and cell cycle arrest in S phase. The growth-inhibitory potency of JNK2 antisense ((JNK)2 IC(50) = 0.14 micrometer) was greater than that of JNK1 antisense ((JNK)1 IC(50) = 0.37 micrometer), suggesting that JNK2 plays a dominant role in regulating growth of T98G cells. Indeed, JNK2 antisense-treated populations exhibited greater inhibition of DNA synthesis and accumulation of S-phase cells than did the JNK1 antisense-treated cultures, with a significant proportion of these cells detaching from the tissue culture plate. JNK2 (but not JNK1) antisense-treated cultures exhibited marked elevation in the expression of the cyclin-dependent kinase inhibitor p21(cip1/waf1) accompanied by inhibition of Cdk2/Cdc2 kinase activities. Taken together, these results indicate that JNK is required for growth of T98G cells in nonstress conditions and that p21(cip1/waf1) may contribute to the sustained growth arrest of JNK2-depleted T98G cultures." 8631;"A tamoxifen-inducible chimeric Cre recombinase specifically effective in the fetal and adult mouse liver.";;;11981757;"Hepatology (Baltimore, Md.)";"Tannour-Louet M, Porteu A, Vaulont S, Kahn A, Vasseur-Cognet M";;"May 2002";1020211200;;"The spatiotemporal control of somatic mutagenesis in mice is considered a promising step to determine the function of a given gene product in a defined population of cells at any given time during animal life and also to generate better mouse models of human diseases. To introduce defined mutations in a temporally controlled manner in the liver, we established transgenic mice expressing a tamoxifen-inducible Cre recombinase under the control of the transthyretin promoter (TTR-Cre ind). The recombinase activity was examined on 2 different floxed alleles by crossing TTR-Cre ind mice with either the reporter strain ROSA 26 or with homozygous mice carrying floxed catalytic alpha2 subunit of the adenosine monophosphate (AMP)-activated protein kinase gene. By placing 2 mutated hormone-binding domains of murine estrogen receptor (Mer) at both termini of the Cre, we show that the fusion protein is active only on administration of the synthetic estrogen antagonist 4-hydroxytamoxifen (4-OHT) without any background in the absence of the inducing agent. The recombination is specific of the fetal and adult liver, and we show that the efficiency of recombination reached 80% to 100% after treatment with 4-OHT. In conclusion, TTR-Cre ind transgenic mice represent a valuable tool for temporally controlling the desired gene modifications in vivo in the fetal and adult liver. This would certainly help to understand the physiologic functions of genes in the liver, to create various mouse models mimicking human diseases, and to contribute to liver cancer-specific suicide gene therapy studies." 8629;"INSL3/RXFP2 signaling in testicular descent.";;;19416188;"Annals of the New York Academy of Sciences";"Feng S, Ferlin A, Truong A, Bathgate R, Wade JD, Corbett S, Han S, Tannour-Louet M, Lamb DJ, Foresta C, Agoulnik AI";;"Apr 2009";1238544000;;"Mutations of the insulin-like peptide 3 (INSL3) hormone or its receptor, RXFP2, cause intraabdominal cryptorchidism in male mice. Specific RXFP2 expression in mouse gubernacula was detected at embryonic day 14.5 and markedly increased after birth in the developing cremaster muscle, as well as in the epididymis and testicular Leydig and germ cells. INSL3 treatment stimulated cell proliferation of embryonic gubernacular and Leydig cells, implicating active INSL3-mediated signaling. The transcription factor SOX9, a known male sex determination factor, upregulated the activity of the RXFP2 promoter. INSL3 is sufficient to direct the first transabdominal phase of testicular descent in the absence of hypothalamic-pituitary-gonadal axis signaling or Hoxa10, although these factors are important for inguinoscrotal testicular descent. Similarly, conditional ablation of the androgen receptor gene in gubernacular cells resulted in disruption of inguinoscrotal descent. We performed mutation screening of INSL3 and RXFP2 in human patients with cryptorchidism and control subjects from different populations in Europe and the USA. Several missense mutations were described in both the INSL3 and RXFP2 genes. A novel V39G INSL3 mutation in a patient with cryptorchidism was identified; however, the functional analysis of the mutant peptide did not reveal compromised function. In more than 2000 patients and controls analyzed to date, the T222P RXFP2 mutation is the only one strongly associated with the mutant phenotype. The T222P mutant receptor, when transfected into 293T cells, had severely decreased cell membrane expression, providing the basis for the functional deficiency of this mutation." 8627;"In vivo exploration of the functional activity of the non-coding 8q24 prostate cancer risk locus.";;;20818410;"Asian journal of andrology";"Lamb DJ, Tannour-Louet M";;"Nov 2010";1288569600;; 8625;"Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y-chromosome microdeletions.";;;21252244;"The Journal of clinical endocrinology and metabolism";"Jorgez CJ, Weedin JW, Sahin A, Tannour-Louet M, Han S, Bournat JC, Mielnik A, Cheung SW, Nangia AK, Schlegel PN, Lipshultz LI, Lamb DJ";;"Apr 2011";1301616000;;"The pseudoautosomal regions (PARs) of the Y-chromosome undergo meiotic recombination with the X-chromosome. PAR mutations are associated with infertility and mental and stature disorders." 8623;"Y-chromosome microdeletions are not associated with SHOX haploinsufficiency.";;;24634249;"Human reproduction (Oxford, England)";"Jorgez CJ, Weedin JW, Sahin A, Tannour-Louet M, Han S, Bournat JC, Mielnik A, Cheung SW, Nangia A, Schlegel PN, Lipshultz LI, Lamb DJ";;"May 2014";1398902400;; 8620;"The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin.";"F. BOST";"Equipe 05, Team 05";9162025;"The Journal of biological chemistry";"Potapova O, Haghighi A, Bost F, Liu C, Birrer MJ, Gjerset R, Mercola D";;"May 1997";862444800;;"We have studied the role of Jun/stress-activated protein kinase (JNK/SAPK) pathway in DNA repair and cisplatin resistance in T98G glioblastoma cells. JUN/SAPK is activated by DNA damage and phosphorylates serines 63 and 73 in the N-terminal domain of c-Jun, which is known to increase its transactivation properties. We show that treatment of T98G glioblastoma cells with cisplatin but not the transplatin isomer activates JNK/SAPK about 10-fold. T98G cells, which are highly resistent to cisplatin (IC50 = 140 +/- 13 microM), modified to express a nonphosphorylatable dominant negative c-Jun (termed dnJun) exhibit decreased viability following treatment with cisplatin, but not transplatin, in proportion (rPearson = 0.98) to the level of dnJun expressed leading to a 7-fold decreased IC50. Similar effects are observed in U87 cells, PC-3 cells, and MCF-7 cells, as well as in T98G cells modified to express TAM-67, a known inhibitor of c-Jun function. In contrast, no sensitization effect was observed in cells modified to express wild-type c-Jun. Furthermore, through quantitative polymerase chain reaction-stop assays, we show that dnJun expressing cells were inhibited in repair of cisplatin adducts (p = 0.55), whereas repair is readily detectable (p = 0.003) in parental cells. These observations indicate that the JNK/SAPK pathway is activated by cisplatin-induced DNA damage and that this response is required for DNA repair and viability following cisplatin treatment. Regulation of DNA repair following genotoxic stress may be a normal physiological role of the JNK/SAPK pathway." 8618;"The JUN kinase/stress-activated protein kinase pathway is required for epidermal growth factor stimulation of growth of human A549 lung carcinoma cells.";"F. BOST";"Equipe 05, Team 05";9407138;"The Journal of biological chemistry";"Bost F, McKay R, Dean N, Mercola D";;"Dec 1997";880934400;;"Epidermal growth factor (EGF) plays a major role in non-small cell lung cancer cell autocrine growth and has been reported to activate the JUN kinase/stress-activated protein kinase (JNK/SAPK) pathway in model cells. Activation of JNK/SAPK leads to the phosphorylation of c-JUN protooncogene on serines 63 and 73. This mechanism is required for and cooperates in the transformation of rat embryo fibroblasts by Ha-RAS. However, the function of JNK/SAPK in human tumor growth is unknown. We have tested several lung carcinoma cell lines. All exhibited UV-C-inducible JNK/SAPK activity; two exhibited constitutive activity in low serum, and two (M103 and A549) exhibited EGF-inducible JNK/SAPK activity. In A549 cells, EGF induced a rapid and prolonged (up to 24 h) activation of the JNK/SAPK pathway that correlated with a 150-190% growth stimulation. Stably transfected clones of A549 cells expressing c-JUN(S63A,S73A), a transdominant inhibitor of c-JUN, completely blocked the EGF-stimulated proliferation effect but did not alter the basal proliferation rate. Consistent with these results JNK antisense oligonucleotides targeted to JNK1 and JNK2 entirely eliminated the EGF-stimulated JNK/SAPK activity and blocked EGF-stimulated growth but not basal growth. In contrast, specific inhibition of the RAF/ERK pathway by PD98059 (MEK1 inhibitor) completely blocked ERK activation by EGF and basal cell growth but not EGF-stimulated growth, thereby dissociating the growth-promoting roles of each pathway. Our observations indicate, for the first time, that JNK/SAPK may be a preferential effector pathway for the growth properties of EGF in A549 cells." 8615;"Inter-alpha-trypsin inhibitor proteoglycan family--a group of proteins binding and stabilizing the extracellular matrix.";"F. BOST";"Equipe 05, Team 05";9546647;"European journal of biochemistry";"Bost F, Diarra-Mehrpour M, Martin JP";;"Mar 1998";888710400;;"Extracellular matrix (ECM) is composed of several macromolecules associated in a complex network. This structure allows cells to adhere, migrate and interact. Hyaluronic acid (HA) is a glycosaminoglycan (GAG) and a major representative of ECM. HA-binding proteins such as CD44, aggrecan, and versican, have been implicated in structuring the ECM by stabilizing large macromolecular aggregates. They also play an important role in tumor metastasis and cell motility. Recently, further HA-binding proteins were identified: the inter-alpha-trypsin inhibitor(ITI)-related proteins. ITI is a glycoprotein composed of three polypeptides: two heavy chains (HC1 and HC2) and one light chain (bikunin). Bikunin confers the protease-inhibitor function. The heavy chains' function was unknown. Recent studies have shown that HC1 and HC2 are linked in vivo and in vitro to hyaluronic acid. This linkage greatly improves extracellular matrix stability. It also demonstrates that ITI-related proteins might be considered as HA-binding proteins (HABP). The ITI related proteins are composed of four polypeptides (HC1, HC2, HC3 and the bikunin) encoded by four genes H1, H2, H3 and L. Unlike the majority of plasma protein a non-disulfide covalent linkage exists between heavy chains and bikunin. This review presents the recent progress concerning the interactions between ITI and ECM showing that ITI-related proteins are HABP members. We will focus on the heavy chain linkage with HA, which represents the demonstration of covalent binding between proteins and HA." 8606;"The defective transforming phenotype of c-Jun Ala(63/73) is rescued by mutation of the C-terminal phosphorylation site.";"F. BOST";"Equipe 05, Team 05";11704873;Oncogene;"Bost F, Caron L, Vial E, Montreau N, Marchetti I, Dejong V, Defize L, Castellazzi M, Binétruy B";;"Nov 2001";1004572800;;"Cotransfection of primary rat embryo fibroblasts (REF) with c-Jun and activated Ras leads to oncogenic transformation and this process requires the phosphorylation of the N-terminal domain of c-Jun. Ras augments this phosphorylation and, consequently activates the c-Jun transactivation property of TRE (TPA Responsive Element)-dependent promoters. To analyse the role of the c-Jun C-terminal phosphorylation site in oncogenic cooperation we tested the activities of N-terminal c-Jun Ala(63/73) (named Nt), C-terminal c-Jun Ala(234/242/246/252) (named Ct) and (Nt+Ct)-with both mutations-non-phosphorylatable c-Jun mutants. In cooperation with Ras, the Ct mutant and wt c-Jun display similar oncogenic properties whereas the Nt form was defective in transforming REF cells. Unexpectedly, the Nt+Ct mutant exhibited identical oncogenic properties to wt c-Jun, demonstrating that the Ct mutation rescues in cis the Nt mutation. The transcriptional activity and the capacity to bind the c-Jun coactivator CREB Binding Protein (CBP) were enhanced by Ras for the wt and Ct proteins but not for the Nt mutant. Interestingly, the Nt+Ct mutant presents identical transactivation and CBP binding activities to wt c-Jun. Therefore the rescue in cis of the defective Nt mutation by the Ct mutation seems to be due to the recovery of CBP binding. Our results revealed that the process of oncogenic cooperation can occur between Ras and the Nt+Ct non-phosphorylatable c-Jun protein." 8602;"The role of MAPKs in adipocyte differentiation and obesity.";"F. BOST";"Equipe 05, Team 05";15733737;Biochimie;"Bost F, Aouadi M, Caron L, Binétruy B";;"Jan 2005";1104537600;;"The ERK, p38 and JNK mitogen activated protein kinases (MAPKs) are intracellular signalling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. MAPKs are activated by a large variety of stimuli and one of their major functions is to connect cell surface receptors to transcription factors in the nucleus, which consequently triggers long-term cellular responses. This review focuses on their in vitro and in vivo roles in adipocyte differentiation and obesity. Hyperplasia of adipose tissue is a critical event for the development of obesity. Several studies have analysed the role of MAPKs in vitro in adipocyte differentiation of preadipocyte established cell lines. In the case of ERK, although the first data appeared contradictory, a consensus scenario arises: ERK would be necessary to initiate the preadipocyte into the differentiation process and, thereafter, this signal transduction pathway needs to be shut-off to proceed with adipocyte maturation. The limitation of these cellular models is that only terminal adipocyte differentiation can be analysed, eluding the early proliferative steps of adipogenesis. New insights are now emerging by investigations conducted either in vitro with the use of embryonic stem (ES) cells or in vivo with mice where these genes are invalidated. These studies not only confirm and/or precise the various functions of MAPKs in adipogenesis but, importantly, reveal unsuspected roles, for example JNK in obesity or ERK in adipogenesis of ES cells, and, for a given pathway, assign specific functions to each isoform. It appears now that a fine tuning of the MAPKs regulates both normal and pathological adipogenesis. The precise understanding of the cascade of these molecular events and the way to regulate them will be certainly crucial in order to efficiently fight obesity." 8600;"The Lac repressor provides a reversible gene expression system in undifferentiated and differentiated embryonic stem cell.";"F. BOST";"Equipe 05, Team 05";15968459;"Cellular and molecular life sciences : CMLS";"Caron L, Prot M, Rouleau M, Rolando M, Bost F, Binétruy B";;"Jul 2005";1120176000;;"Control of mammalian gene promoters by the bacterial LacI repressor provides reversible regulation and dose-response levels of derepressed expression by the lactose analog isopropyl thiogalactose (IPTG). Here, we show that insertion of LacI-binding sites in the ubiquitous beta-actin promoter confers a strong and dose-dependent IPTG-regulatable expression of transiently transfected reporter genes in mouse embryonic stem (ES) cells expressing LacI. We established ES cell lines stably expressing reporter genes under inducible control and found a five- to tenfold IPTG induction of transgene expression. The kinetics of induction is rapid and stable, and can be rapidly reversed after IPTG removal. Importantly, this regulatable expression was maintained throughout the differentiation process of ES cells, and observed in individual differentiated cardiomyocyte-like cells and neuronal-like cells. This reversible system is the first to function from undifferentiated to individual well-differentiated ES cells, providing a very useful tool to understand molecular mechanisms underlying ES cell self-renewal, commitment and differentiation." 8598;"Role of MAPKs in development and differentiation: lessons from knockout mice.";"F. BOST";"Equipe 05, Team 05";16854512;Biochimie;"Aouadi M, Binetruy B, Caron L, Le Marchand-Brustel Y, Bost F";;"Sep 2006";1157068800;;"The ERK, p38MAPK, JNK mitogen-activated protein kinases (MAPKs) are intracellular signaling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. These cascades are activated by a large variety of stimuli and display a high degree of homology. So far, seven MAPK isoforms have been invalidated in mice leading to the discovery of their important functions in development and differentiation. As we could expect because of their multiple and specific properties in vitro, knockout (KO) of MAPK pathways leads to distinct phenotypes in mice. Surprisingly, into a given cascade, KOs of the various isoforms assign specific non-redundant biological functions to each isoform, without compensation by the others. These results emphasize the notion that, although initiated by the same external stimuli, these intracellular cascades activate kinase isoforms each with its own specific role." 8595;"In rat hepatocytes glucagon increases mammalian target of rapamycin phosphorylation on serine 2448 but antagonizes the phosphorylation of its downstream targets induced by insulin and amino acids.";"C. Hinault";"Equipe 05, Team 05";15292249;"The Journal of biological chemistry";"Mothe-Satney I, Gautier N, Hinault C, Lawrence JC, Van Obberghen E";;"Oct 2004";1096588800;;"The major function of mammalian target of rapamycin (mTOR) is the control of cell growth. Insulin and amino acids regulate the mTOR pathway, and both are needed to promote its maximal activation. To further understand mTOR regulation by insulin and amino acids, we have studied the enzyme in primary cultures of hepatocytes. We show that insulin increases mTOR phosphorylation on Ser2448, a consensus phosphorylation site for protein kinase B (PKB). Ser2448 phosphorylation is also increased by amino acids, although they do not activate PKB. Furthermore, insulin and amino acids have an additive effect, indicating that they act through distinct pathways. We also show that phosphorylation of Ser2448 does not seem to modulate in vitro phosphorylation of eukaryotic initiation factor 4E-binding protein 1 by mTOR. However, stimulation of hepatocytes with insulin and amino acids leads to an increase in mTOR kinase activity. Rapamycin has no effect on insulin-, glucagon-, and 8-(4-chlorophenylthio)adenosine-cAMP-induced amino acid transport. Surprisingly, glucagon and 8-(4-chlorophenylthio)adenosine-cAMP, which do not activate PKB, stimulate the phosphorylation on Ser2448 of mTOR. However, glucagon inhibits amino acid- and insulin-induced activation of ribosomal S6 protein kinase 1 and phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1. Our results demonstrate that glucagon, which is not able to activate but rather inhibits the mTOR pathways, stimulates the phosphorylation of mTOR on Ser2448. This finding suggests that phosphorylation of this site might not be sufficient for mTOR kinase activity but is likely to be involved in other functions." 8593;"Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice.";"C. Hinault";"Equipe 05, Team 05";15479767;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Hinault C, Mothe-Satney I, Gautier N, Lawrence JC, Van Obberghen E";;"Oct 2004";1097712000;;"Amino acids are nutrients responsible for mammalian target of rapamycin (mTOR) regulation in mammalian cells. The mTOR protein is mainly known for its role in regulating cell growth, notably via protein synthesis. In addition to amino acids, mTOR is regulated by insulin via a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. mTOR mediates crosstalk between amino acids and insulin signaling. We show that in freshly isolated rat adipocytes, insulin stimulates the phosphorylation of mTOR on serine 2448, a protein kinase B (PKB) consensus phosphorylation site. This site is also phosphorylated by amino acids, which in contrast to insulin do not activate PKB. Moreover, insulin and amino acids have an additive effect on mTOR phosphorylation, indicating that they act via two independent pathways. Importantly, amino acids, notably leucine, permit insulin to stimulate PKB when PI 3-kinase is inhibited. They also rescue glucose transport and the mTOR pathway. Further, leucine alone can improve insulin activation of PKB in db/db mice. Our results define the importance of amino acids in insulin signaling and reveal leucine as a key amino acid in disease situations associated with insulin-resistance in adipocytes." 8591;"Amino acids require glucose to enhance, through phosphoinositide-dependent protein kinase 1, the insulin-activated protein kinase B cascade in insulin-resistant rat adipocytes.";"C. Hinault";"Equipe 05, Team 05";16550357;Diabetologia;"Hinault C, Mothe-Satney I, Gautier N, Van Obberghen E";;"May 2006";1146441600;;"Amino acids are well known to activate the mammalian target of the rapamycin (mTOR) pathway in synergy with insulin to regulate cell functions. Despite recent important advances, the mTOR signalling pathway is poorly understood. Our previous results revealed a new pathway in which amino acids permit insulin-induced activation of the protein kinase B (PKB)/mTOR pathway in freshly isolated adipocytes when phosphatidylinositol 3-kinase (PI3K) is inhibited. The aim of this study was to further investigate this pathway at the molecular level." 8589;"Role of amino acids in insulin signaling in adipocytes and their potential to decrease insulin resistance of adipose tissue.";"C. Hinault";"Equipe 05, Team 05";16644198;"The Journal of nutritional biochemistry";"Hinault C, Van Obberghen E, Mothe-Satney I";;"Jun 2006";1149120000;;"Recently, our knowledge concerning the role of amino acids in signal transduction in mammals has greatly improved. This significant advance is mainly due to the remarkable discovery that the mammalian target of rapamycin (mTOR) protein kinase, known to be activated in response to a large number of hormones, growth factors and cytokines, is also under the tight control of branched-chain amino acids. Actually, both inputs are necessary to fully activate the mTOR pathway, the main function of which is to increase cell size, via the regulation of translational processes. However, amino acids are able to modulate other biological effects and appear to have unexpected actions, as evidenced by our recent work in rat adipocytes. The aim of this review is to summarize novel findings on the role of mTOR and amino acids in insulin signaling in adipocytes. A possible beneficial impact of the use of amino acids in the treatment of insulin resistance is discussed, and hypotheses about the molecular mechanisms underlying their effect are proposed." 8587;"Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance.";"C. Hinault";"Equipe 05, Team 05";17416680;"Proceedings of the National Academy of Sciences of the United States of America";"Okada T, Liew CW, Hu J, Hinault C, Michael MD, Krtzfeldt J, Yin C, Holzenberger M, Stoffel M, Kulkarni RN";;"May 2007";1177977600;;"Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory beta-cell growth, we examined two models of insulin resistance. In the first model, we used liver-specific insulin receptor knockout (LIRKO) mice, which exhibit hyperinsulinemia without developing diabetes due to a compensatory increase in beta-cell mass. LIRKO mice, also lacking functional insulin receptors in beta-cells (beta IRKO/LIRKO), exhibited severe glucose intolerance but failed to develop compensatory islet hyperplasia, together leading to early death. In the second model, we examined the relative significance of insulin versus IGF1 receptors in islet growth by feeding high-fat diets to beta IRKO and beta-cell-specific IGF1 receptor knockout (beta IGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, beta IRKO, but not beta IGFRKO, mice exhibited poor islet growth consistent with insulin-stimulated phosphorylation, nuclear exclusion of FoxO1, and reduced expression of Pdx-1. Together these data provide direct genetic evidence that insulin/FoxO1/Pdx-1 signaling is one pathway that is crucial for islet compensatory growth response to insulin resistance." 8585;"Characterization of the mouse pancreatic islet proteome and comparative analysis with other mouse tissues.";"C. Hinault";"Equipe 05, Team 05";18570455;"Journal of proteome research";"Petyuk VA, Qian WJ, Hinault C, Gritsenko MA, Singhal M, Monroe ME, Camp DG, Kulkarni RN, Smith RD";;"Aug 2008";1217548800;;"The pancreatic islets of Langerhans, and especially the insulin-producing beta cells, play a central role in the maintenance of glucose homeostasis. Alterations in the expression of multiple proteins in the islets that contribute to the maintenance of islet function are likely to underlie the pathogenesis of types 1 and 2 diabetes. To identify proteins that constitute the islet proteome, we provide the first comprehensive proteomic characterization of pancreatic islets for mouse, the most commonly used animal model in diabetes research. Using strong cation exchange fractionation coupled with reversed phase LC-MS/MS we report the confident identification of 17,350 different tryptic peptides covering 2612 proteins having at least two unique peptides per protein. The data set also identified approximately 60 post-translationally modified peptides including oxidative modifications and phosphorylation. While many of the identified phosphorylation sites corroborate those previously known, the oxidative modifications observed on cysteinyl residues reveal potentially novel information suggesting a role for oxidative stress in islet function. Comparative analysis with 15 available proteomic data sets from other mouse tissues and cells revealed a set of 133 proteins predominantly expressed in pancreatic islets. This unique set of proteins, in addition to those with known functions such as peptide hormones secreted from the islets, contains several proteins with as yet unknown functions. The mouse islet protein and peptide database accessible at (http://ncrr.pnl.gov), provides an important reference resource for the research community to facilitate research in the diabetes and metabolism fields." 8583;"Growth factor control of pancreatic islet regeneration and function.";"C. Hinault";"Equipe 05, Team 05";18828795;"Pediatric diabetes";"Assmann A, Hinault C, Kulkarni RN";;"Feb 2009";1233446400;; 8581;"Differential expression of cell cycle proteins during ageing of pancreatic islet cells.";"C. Hinault";"Equipe 05, Team 05";18834441;"Diabetes, obesity & metabolism";"Hinault C, Hu J, Maier BF, Mirmira RG, Kulkarni RN";;"Nov 2008";1225497600;;"One of the major challenges for developmental biologists and investigators in the field of diabetes over the last few decades has been to dissect the origin of pancreatic endocrine cells and to accurately understand the mechanisms that regulate islet cell regeneration. While significant advances have been made recently, there continues to be a paucity of knowledge regarding the growth factor signalling pathways that directly regulate the proteins involved in islet cell cycle control. We will discuss recent work in these areas and provide insights from our studies into age-dependent alterations in the expression of growth factor signalling proteins and cell cycle proteins in islet cells." 8579;"miR-139 impacts FoxO1 action by decreasing FoxO1 protein in mouse hepatocytes.";"C. Hinault, R. Paul-Bellon";"Equipe 05, Team 05, Team 03, Equipe 03";19883627;"Biochemical and biophysical research communications";"Hasseine LK, Hinault C, Lebrun P, Gautier N, Paul-Bellon R, Van Obberghen E";;"Dec 2009";1259625600;;"FoxO1 is a master regulator of signaling pathways used by growth factors and hormones, including insulin. Its activity is regulated by changes in subcellular localization coupled to post-translational modifications such as phosphorylation, ubiquitination, and acetylation. As microRNAs have emerged as a newly identified means by which cells fine-tune gene expression, we hypothesized that they could regulate FoxO1. Since FoxO1 plays a key role in the liver, we used immortalized neonatal mouse hepatocytes to analyze the effects of potential microRNAs targeting FoxO1. We found that miR-139 targets FoxO1 mRNA directly and reduces the level of the protein without affecting transcript levels. This decrease in FoxO1 protein results in a decrease of its target genes, such as AdQR1, AdQR2 and Mttp. Our findings suggest a novel mode of FoxO1 regulation by which miR-139 could maintain the protein level of FoxO1 to preserve homeostatic regulation of its transcriptional activity in response to environmental stimuli." 8577;"Cyclin D2 is essential for the compensatory beta-cell hyperplastic response to insulin resistance in rodents.";"C. Hinault";"Equipe 05, Team 05";20103709;Diabetes;"Georgia S, Hinault C, Kawamori D, Hu J, Meyer J, Kanji M, Bhushan A, Kulkarni RN";;"Apr 2010";1270080000;;"A major determinant of the progression from insulin resistance to the development of overt type 2 diabetes is a failure to mount an appropriate compensatory beta-cell hyperplastic response to maintain normoglycemia. We undertook the present study to directly explore the significance of the cell cycle protein cyclin D2 in the expansion of beta-cell mass in two different models of insulin resistance." 8575;"Δ40 Isoform of p53 controls β-cell proliferation and glucose homeostasis in mice.";"C. Hinault";"Equipe 05, Team 05";21357466;Diabetes;"Hinault C, Kawamori D, Liew CW, Maier B, Hu J, Keller SR, Mirmira RG, Scrable H, Kulkarni RN";;"Apr 2011";1301616000;;"Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that β-cell proliferation and glucose homeostasis were controlled by Δ40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice." 8573;"Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway.";"C. Hinault";"Equipe 05, Team 05";22018470;Immunity;"Boyer L, Magoc L, Dejardin S, Cappillino M, Paquette N, Hinault C, Charriere GM, Ip WK, Fracchia S, Hennessy E, Erturk-Hasdemir D, Reichhart JM, Silverman N, Lacy-Hulbert A, Stuart LM";;"Oct 2011";1317427200;;"Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential." 8571;"MicroRNAs and metabolism crosstalk in energy homeostasis.";"C. Hinault";"Equipe 05, Team 05";23850315;"Cell metabolism";"Dumortier O, Hinault C, Van Obberghen E";;"Sep 2013";1377993600;;"In record time, microRNAs (miRNAs) have acquired the respected stature of important natural regulators of global gene expression. Multiple studies have demonstrated that a large number of miRNAs are under the control of various metabolic stimuli, including nutrients, hormones, and cytokines. Conversely, it is now well recognized that miRNAs control metabolism, thereby generating a bidirectional functional link, which perturbs energy homeostasis in case of disconnection in the miRNA-metabolism interplay. A challenging road lies ahead for defining the role of miRNAs in the pathogenesis of diseases such as diabetes and for establishing their usefulness as new medications and clinically reliable biomarkers." 8569;"[microRNA and diabetes: tiny things causing huge effects].";"C. Hinault";"Equipe 05, Team 05";24005635;"Medecine sciences : M/S";"Hinault C, Dumortier O, Van Obberghen E";;"Sep Aug 2013";1376006400;;"Soon after their discovery microRNA (miRNA) emerged as central natural regulators of gene expression. Although the complex mechanisms of action and impact of miRNA on development, physiology and disease are still elusive, significant progress has been made in deciphering the roles of some miRNA in insulin secretion and action. Here we examine the close relationship existing between miRNA and glucose metabolism as well as their putative role in the pathogenesis of diabetes and their possible utility as biomarkers of this disease." 8567;"Fast urinary screening of oligosaccharidoses by MALDI-TOF/TOF mass spectrometry.";"C. Hinault";"Equipe 05, Team 05";24502792;"Orphanet journal of rare diseases";"Bonesso L, Piraud M, Caruba C, Van Obberghen E, Mengual R, Hinault C";;"Feb 2014";1391212800;;"Oligosaccharidoses, which belong to the lysosomal storage diseases, are inherited metabolic disorders due to the absence or the loss of function of one of the enzymes involved in the catabolic pathway of glycoproteins and indirectly of glycosphingolipids. This enzymatic deficiency typically results in the abnormal accumulation of uncompletely degraded oligosaccharides in the urine. Since the clinical features of many of these disorders are not specific for a single enzyme deficiency, unambiguous screening is critical to limit the number of costly enzyme assays which otherwise must be performed." 8565;"Maternal protein restriction leads to pancreatic failure in offspring: role of misexpressed microRNA-375.";"C. Hinault, S. PATOURAUX";"Equipe 05, Team 05, Equipe 08, Team 08";24834976;Diabetes;"Dumortier O, Hinault C, Gautier N, Patouraux S, Casamento V, Van Obberghen E";;"Oct 2014";1412121600;;"The intrauterine environment of the fetus is a preeminent actor in long-term health. Indeed, mounting evidence shows that maternal malnutrition increases the risk of type 2 diabetes (T2D) in progeny. Although the consequences of a disturbed prenatal environment on the development of the pancreas are known, the underlying mechanisms are poorly defined. In rats, restriction of protein during gestation alters the development of the endocrine pancreas and favors the occurrence of T2D later in life. Here we evaluate the potential role of perturbed microRNA (miRNA) expression in the decreased β-cell mass and insulin secretion characterizing progeny of pregnant dams fed a low-protein (LP) diet. miRNA profiling shows increased expression of several miRNAs, including miR-375, in the pancreas of fetuses of mothers fed an LP diet. The expression of miR-375 remains augmented in neoformed islets derived from fetuses and in islets from adult (3-month-old) progeny of mothers fed an LP diet. miR-375 regulates the proliferation and insulin secretion of dissociated islet cells, contributing to the reduced β-cell mass and function of progeny of mothers fed an LP diet. Remarkably, miR-375 normalization in LP-derived islet cells restores β-cell proliferation and insulin secretion. Our findings suggest the existence of a developmental memory in islets that registers intrauterine protein restriction. Hence, pancreatic failure after in utero malnutrition could result from transgenerational transmission of miRNA misexpression in β-cells." 8563;"Circulating microRNAs and diabetes: potential applications in medical practice.";"C. Hinault";"Equipe 05, Team 05";26155747;Diabetologia;"Raffort J, Hinault C, Dumortier O, Van Obberghen E";;"Sep 2015";1441065600;;"The explosive increase in the worldwide prevalence of diabetes over recent years has transformed the disease into a major public health concern. While diabetes can be screened for and diagnosed by reliable biological tests based on blood glucose levels, by and large there are no means of detecting at-risk patients or of following diabetic complications. The recent discovery that microRNAs are not only chief intracellular players in many biological processes, including insulin secretion and action, but are also circulating, has put them in the limelight as possible biological markers. Here we discuss the potential role of circulating microRNAs as biomarkers in the context of diabetes and its associated complications." 8561;"Visfatin expression analysis in association with recruitment and activation of human and rodent brown and brite adipocytes.";"C. Hinault";"Equipe 05, Team 05";27386154;Adipocyte;"Pisani DF, Dumortier O, Beranger GE, Casamento V, Ghandour RA, Giroud M, Gautier N, Balaguer T, Chambard JC, Virtanen KA, Nuutila P, Niemi T, Taittonen M, Van Obberghen E, Hinault C, Amri EZ";;"Jun Apr 2016";1459900800;;"Human brown adipocytes are able to burn fat and glucose and are now considered as a potential strategy to treat obesity, type 2 diabetes and metabolic disorders. Besides their thermogenic function, brown adipocytes are able to secrete adipokines. One of these is visfatin, a nicotinamide phosphoribosyltransferase involved in nicotinamide dinucleotide synthesis, which is known to participate in the synthesis of insulin by pancreatic β cells. In a therapeutic context, it is of interest to establish whether a potential correlation exists between brown adipocyte activation and/or brite adipocyte recruitment, and adipokine expression. We analyzed visfatin expression, as a pre-requisite to its secretion, in rodent and human biopsies and cell models of brown/brite adipocytes. We found that visfatin was preferentially expressed in mature adipocytes and that this expression was higher in brown adipose tissue of rodents compared to other fat depots. However, using various rodent models we were unable to find any correlation between visfatin expression and brown or brite adipocyte activation or recruitment. Interestingly, the situation is different in humans where visfatin expression was found to be equivalent between white and brown or brite adipocytes in vivo and in vitro. In conclusion, visfatin can be considered only as a rodent brown adipocyte biomarker, independently of tissue activation." 8559;"Age-Dependent Control of Energy Homeostasis by Brown Adipose Tissue in Progeny Subjected to Maternal Diet-Induced Fetal Programming.";"C. Hinault";"Equipe 05, Team 05";27927722;Diabetes;"Dumortier O, Roger E, Pisani DF, Casamento V, Gautier N, Lebrun P, Johnston H, Lopez P, Amri EZ, Jousse C, Fafournoux P, Prentki M, Hinault C, Van Obberghen E";;"03 2017";1488326400;;"Epidemiological and animal studies show that deleterious maternal environments predispose aging offspring to metabolic disorders and type 2 diabetes. Young progenies in a rat model of maternal low-protein (LP) diet are normoglycemic despite collapsed insulin secretion. However, without further worsening of the insulin secretion defect, glucose homeostasis deteriorates in aging LP descendants. Here we report that normoglycemic and insulinopenic 3-month-old LP progeny shows increased body temperature and energy dissipation in association with enhanced brown adipose tissue (BAT) activity. In addition, it is protected against a cold challenge and high-fat diet (HFD)-induced obesity with associated insulin resistance and hyperglycemia. Surgical BAT ablation in 3-month-old LP offspring normalizes body temperature and causes postprandial hyperglycemia. At 10 months, BAT activity declines in LP progeny with the appearance of reduced protection to HFD-induced obesity; at 18 months, LP progeny displays a BAT activity comparable to control offspring and insulin resistance and hyperglycemia occur. Together our findings identify BAT as a decisive physiological determinant of the onset of metabolic dysregulation in offspring predisposed to altered β-cell function and hyperglycemia and place it as a critical regulator of fetal programming of adult metabolic disease." 8557;"Argonaute-2 is associated to brown adipose tissue activation.";"C. Hinault";"Equipe 05, Team 05";31152866;"Biochimica et biophysica acta. Molecular basis of disease";"Roger E, Dumortier O, Pisani DF, Gautier N, Van Obberghen E, Hinault C";;"09 2019";1567296000;;"MicroRNAs (miRNAs) are important modulators of thermogenic brown adipose tissue (BAT). They have been involved in its differentiation and hence its functioning. While different regulators of the miRNA machinery have been shown to be essential for BAT differentiation, little is known about their implication in BAT activation. The aim of this work was to evaluate the role of AGO2, the chief miRNA mediator, in BAT activation. We took advantage of two non-genetic models of BAT activation to analyze the miRNA machinery and miRNA expression in BAT. We used principal component analysis (PCA) to obtain an overview of miRNA expression according to the BAT activation state. In vitro, we examined AGO2 expression during brown adipocyte differentiation and activation. Finally, we downregulated AGO2 to reveal its potential role in the thermogenic function of brown adipocytes. PCA analysis allowed to cluster animals on their miRNA signature in active BAT. Moreover, hierarchical clustering showed a positive correlation between global upregulation of miRNA expression and active BAT. Consistently, the miRNA machinery, particularly AGO2, was upregulated in vivo in active BAT and in vitro in mature brown adipocytes. Finally, the partial loss-of-function of AGO2 in mature brown adipocytes is sufficient to lead to a diminished expression of UCP1 associated to a decreased uncoupled respiration. Therefore, our study shows the potential contribution of AGO2 in BAT activation. Since BAT is a calorie-burning tissue these data have a translational potential in terms of therapeutic target in the field of altered fuel homeostasis associated to obesity and diabetes." 8555;"microRNA-375 regulates glucose metabolism-related signaling for insulin secretion.";"C. Hinault";"Equipe 05, Team 05";31697642;"The Journal of endocrinology";"Dumortier O, Fabris G, Pisani DF, Casamento V, Gautier N, Hinault C, Lebrun P, Duranton C, Tauc M, Dalle S, Kerr-Conte J, Pattou F, Prentki M, Van Obberghen E";;"01 2020";1577836800;;"Enhanced beta cell glycolytic and oxidative metabolism are necessary for glucose-induced insulin secretion. While several microRNAs modulate beta cell homeostasis, miR-375 stands out as it is highly expressed in beta cells where it regulates beta cell function, proliferation and differentiation. As glucose metabolism is central in all aspects of beta cell functioning, we investigated the role of miR-375 in this process using human and rat islets; the latter being an appropriate model for in-depth investigation. We used forced expression and repression of mR-375 in rat and human primary islet cells followed by analysis of insulin secretion and metabolism. Additionally, miR-375 expression and glucose-induced insulin secretion were compared in islets from rats at different developmental ages. We found that overexpressing of miR-375 in rat and human islet cells blunted insulin secretion in response to glucose but not to α-ketoisocaproate or KCl. Further, miR-375 reduced O2 consumption related to glycolysis and pyruvate metabolism, but not in response to α-ketoisocaproate. Concomitantly, lactate production was augmented suggesting that glucose-derived pyruvate is shifted away from mitochondria. Forced miR-375 expression in rat or human islets increased mRNA levels of pyruvate dehydrogenase kinase-4, but decreased those of pyruvate carboxylase and malate dehydrogenase1. Finally, reduced miR-375 expression was associated with maturation of fetal rat beta cells and acquisition of glucose-induced insulin secretion function. Altogether our findings identify miR-375 as an efficacious regulator of beta cell glucose metabolism and of insulin secretion, and could be determinant to functional beta cell developmental maturation." 8543;"Mutations away from splice site recognition sequences might cis-modulate alternative splicing of goat alpha s1-casein transcripts. Structural organization of the relevant gene.";"N. Mazure";"Equipe 05, Team 05";1372900;"The Journal of biological chemistry";"Leroux C, Mazure N, Martin P";;"Mar 1992";699408000;;"alpha s1-Casein variants F and D, synthesized in goat milk at lower levels than variant A, essentially differ from it by internal deletions of 37 and 11 amino acid residues, respectively. Northern blot analysis of mRNAs encoding alpha s1-casein F and A and sequencing of the relevant cloned cDNAs, as well as sequencing of in vitro amplified genomic fragments, revealed multiple alternatively processed transcripts, from the F allele. Although correctly spliced messengers were identified, most of the FmRNAs lacked three exons. These exons, further identified as exons 9, 10, and 11, together encode the 37 amino acid residues present in alpha s1-casein variant A but missing in variant F. Exon 9 codes for the sequence present in variant A but deleted in variant D. A single nucleotide deletion in exon 9 and two insertions, 11 and 3 base pairs in length, in the downstream intron, were identified as mutations potentially responsible for the alternative skipping of these 3 exons. From a computer-predicted secondary structure it appeared that the 11-base pair insertion might be involved in base-pairing interactions with the intron 5' splice site which might consequently be less accessible to U1 snRNA. We also report here the complete structural organization of the goat alpha s1-casein transcription unit, deduced from polymerase chain reaction experiments. It contains 19 exons scattered within a nucleotide stretch nearly 17-kilobase pairs long." 8541;"Degradation of morpholine by Mycobacterium aurum MO1.";"N. Mazure";"Equipe 05, Team 05";7954109;"Canadian journal of microbiology";"Mazure N, Truffaut N";;"Sep 1994";778377600;;"When Mycobacterium aurum MO1 was grown with morpholine, the release of ammonia into the supernatant was proportional to the disappearance of morpholine, showing that this compound was mineralized. MO1 was able to grow in high concentrations of morpholine but accumulation of ammonia inhibited growth and degradation of morpholine. Immobilization of bacterial cells in carrageenan gel beads showed that morpholine degradation in these conditions began earlier and was faster than in free culture. One of the two branches of the lower pathway of morpholine biodegradation was induced while the other branch was inhibited in the presence of morpholine. Strain MO1 grew on heterocyclic compounds similar to morpholine, demonstrating that MO1 is able to degrade heterocyclic compounds containing nitrogen atoms (piperidine and pyrrolidine). Compounds containing sulphur or oxygen atoms or compounds with double bonds were not degraded." 8539;"Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression.";"N. Mazure";"Equipe 05, Team 05";8758908;"Cancer research";"Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ";;"Aug 1996";838857600;;"Hypoxia can select for cells that have lost their apoptotic potential, thereby making them resistant to adverse conditions. However, long-term survival of transformed cells which have diminished apoptotic sensitivity when exposed to low oxygen conditions would require the activation of their angiogenic program to compensate for an insufficient oxygen supply. In this report, we show that the activity (of oncogenic Ha-ras, either constitutively or transiently, enhances the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF), by hypoxia. Analysis of the 5' flanking region of the VEGF promoter indicates that a HIF-1-like sequence is to promote a 15-fold increase in reporter gene activity in Ha-ras-transformed cells when exposed to hypoxia, whereas mutations in the same site totally inhibited VEGF induction. Under low oxygen conditions, VEGF induction is inhibited in cells expressing a mutant inhibitory allele of Ha-ras (RasN17), indicating a direct role for Ras in modulating VEGF activity. We propose that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through VEGF induction." 8537;"Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element.";"N. Mazure";"Equipe 05, Team 05";9345014;Blood;"Mazure NM, Chen EY, Laderoute KR, Giaccia AJ";;"Nov 1997";878342400;;"Tumor angiogenesis, the development of new blood vessels, is a highly regulated process that is controlled genetically by alterations in oncogene and tumor suppressor gene expression and physiologically by the tumor microenvironment. Previous studies indicate that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF). In this report, we show Ras-transformed cells do not use the downstream effectors c-Raf-1 or mitogen activated protein kinases (MAPK) in signaling VEGF induction by hypoxia as overexpression of kinase-defective alleles of these genes does not inhibit VEGF induction under low oxygen conditions. In contrast to the c-Raf-1/MAP kinase pathway, hypoxia increases phosphatidylinositol 3-kinase (PI 3-kinase) activity in a Ras-dependent manner, and inhibition of PI 3-kinase activity genetically and pharmacologically results in inhibition of VEGF induction. We propose that hypoxia modulates VEGF induction in Ras-transformed cells through the activation of a stress inducible PI 3-kinase/Akt pathway and the hypoxia inducible factor-1 (HIF-1) transcriptional response element." 8535;"Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: a possible model for IGFBP-1 expression in fetal hypoxia.";"N. Mazure";"Equipe 05, Team 05";9707622;"Proceedings of the National Academy of Sciences of the United States of America";"Tazuke SI, Mazure NM, Sugawara J, Carland G, Faessen GH, Suen LF, Irwin JC, Powell DR, Giaccia AJ, Giudice LC";;"Aug 1998";901929600;;"IGFBP-1 is elevated in fetuses with long-term, chronic hypoxia and intrauterine growth restriction. We investigated the hypothesis that hypoxia regulates IGFBP-1 in the human fetus in vivo and IGFBP-1 gene expression and protein in vitro. Umbilical artery IGFBP-1 levels (mean +/- SEM) from term babies with respiratory acidosis (acute hypoxia), normal babies, and those with mixed respiratory/metabolic acidosis (more profound and prolonged hypoxia) were measured using an immunoradiometric assay. IGFBP-1 levels were similar in normal (n = 12) and acutely hypoxic (n = 6) babies (189.1 +/- 71.8 vs. 175.8 +/- 45.9 ng /ml, respectively, P = 0.789). However, with more profound and prolonged hypoxia (n = 19), IGFBP-1 levels were markedly elevated (470.6 +/- 80.0 ng /ml, P = 0.044). To investigate IGFBP-1 regulation by hypoxia in vitro, HepG2 cells were incubated under hypoxia (pO2 = 2%) and normoxia (pO2 = 20%). IGFBP-1 protein and mRNA increased 8- and 12-fold, respectively, under hypoxic conditions. Hypoxia did not affect protein or mRNA levels of IGFBP-2 or -4. IGFBP-5 and -6 mRNAs, undetectable in control cells, were not induced by hypoxia, whereas minimally expressed IGFBP-3 mRNA increased twofold. Investigation into IGFBP-1 gene structure revealed three potential consensus sequences for the hypoxia response element (HRE) in the first intron. To investigate functionality, a 372-bp fragment of IGFBP-1 intron 1, containing putative HREs, was placed 5' to a heterologous hsp70 promoter in a plasmid using luciferase as a reporter gene. Under hypoxia, reporter gene activity increased up to 30-fold. Mutations in the middle HRE abolished reporter activity in response to hypoxia, suggesting that this HRE is functional in the IGFBP-1 hypoxia response. Cotransfection of HRE reporter genes with a constitutively expressing hypoxia-inducible factor 1 plasmid in HepG2 cells resulted in a fourfold induction of reporter activity, suggesting a role for hypoxia-inducible factor 1 in hypoxia induction of IGFBP-1 gene expression. These data support the hypothesis that hypoxia regulation of IGFBP-1 may be a mechanism operating in the human fetus to restrict insulin-like growth factor-mediated growth in utero under conditions of chronic hypoxia and limited substrate availability." 8533;"Modulation of the far-upstream enhancer of the rat alpha-fetoprotein gene by members of the ROR alpha, Rev-erb alpha, and Rev-erb beta groups of monomeric orphan nuclear receptors.";"N. Mazure";"Equipe 05, Team 05";11058961;"DNA and cell biology";"Bois-Joyeux B, Chauvet C, Nacer-Chérif H, Bergeret W, Mazure N, Giguère V, Laudet V, Danan JL";;"Oct 2000";970358400;;"Expression of the oncodevelopmental alpha-fetoprotein (AFP) gene is tightly regulated and occurs in the yolk sac, fetal liver and intestine, and cancerous liver cells. Transcription of the AFP gene is under the control of three enhancers that are very tissue specific. We have shown that the most upstream of these enhancers, located at -6 kb, works through the combined action of liver-enriched factors and nuclear receptors that bind to three regions of this DNA regulatory element. This study showed that orphan nuclear receptors of the ROR alpha, Re-verb alpha, and Rev-erb beta groups can bind as monomers with high affinity and specificity to an evolutionarily conserved AGGTCA motif in the functionally important region 1 of this AFP enhancer. Transient transfection experiments performed with human HepG2 hepatoma cells showed that overproduction of ROR alpha 4 stimulated the activity of the AFP enhancer in a dose-dependent manner, while that of Rev-erb alpha and Rev-erb beta had the opposite effect. These effects were highly specific and required the integrity of the AGGTCA motif. The action of these nuclear receptors also occurred in the context of the entire 7-kb regulatory region of the rat AFP gene. These results suggest that altering the amounts or activities of these orphan receptors in cells of hepatic or endodermal origin could modulate AFP gene expression in response to a variety of developmental or carcinogenic stimuli." 8531;"Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation.";"N. Mazure";"Equipe 05, Team 05";11289110;"Cancer research";"Chen EY, Mazure NM, Cooper JA, Giaccia AJ";;"Mar 2001";983404800;;"Hypoxia initiates numerous intracellular signaling pathways important in regulating cell proliferation, differentiation, and death. In this study, we investigated the pathway that hypoxia uses to activate Akt and inactivate glycogen synthase kinase-3 (GSK-3), two proteins the functions of which are important in cell survival and energy metabolism. Severe hypoxia (0.01% oxygen) initiated a signaling cascade by inducing the tyrosine phosphorylation of the platelet-derived growth factor (PDGF) receptor within 1 h of treatment and increasing receptor association with the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K). Hypoxia-induced signaling also resulted in PI 3-K-dependent phosphorylation of Akt on Ser-473, a modification of Akt that is important for its activation. This activation of Akt by hypoxia was substantially diminished in cells that possessed mutations in their PDGF receptor-PI 3-K interaction domain. In addition, Akt activation by hypoxia was resistant to treatment with the growth factor receptor poison suramin but was sensitive to treatment with the PI 3-K inhibitor wortmannin. Activation of Akt by hypoxia resulted in the phosphorylation of GSK-3alpha and GSK-3beta at Ser-9 and Ser-21, two well-documented Akt phosphorylation sites, respectively, that are inactivating modifications of each GSK-3 isoform. In support of the phosphorylation data, GSK-3 activity was significantly reduced under hypoxia. In conclusion, we propose that hypoxia activates a growth factor receptor/PI 3-K/Akt cascade that leads to GSK-3 inactivation, a pathway that can impact cell survival, proliferation, and metabolism." 8529;"Severe hypoxia specifically downregulates hepatocyte nuclear factor-4 gene expression in HepG2 human hepatoma cells.";"N. Mazure";"Equipe 05, Team 05";11553861;"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine";"Mazure NM, Nguyen TL, Danan JL";;"Oct Sep 2001";1000080000;;"The liver is one of the organs in which hypoxia helps to regulate gene expression under normal physiological conditions and in diseases such as cirrhosis and cancer. We postulated that the expression/activity of some of the 'liver-enriched' transcription factors, which control liver-specific genes, was sensitive to hypoxia. We tested hepatocyte nuclear factor-1 (HNF-1), HNF-3 and HNF-4, which play key roles in differentiation, development and hepatic gene expression, using HepG2 human hepatoma cells cultured under hypoxic conditions. Severe hypoxia/anoxia downregulated HNF-4 DNA-binding activity while DNA-binding activity of HNF-1 and HNF-3 remained unaffected. These hypoxic conditions also strongly and specifically decreased cell contents of HNF-4 protein, indicating that the decrease in HNF-4 DNA-binding activity was due to the lower amount of protein and not to decreased DNA-binding affinity. Northern analysis indicated that the expression of the hnf-4 gene was also downregulated in HepG2 cells cultured under hypoxic conditions. These results provide evidence that hypoxic stress triggers a cascade of events that inhibits the transactivation potential of HNF-4 in HepG2 cells. This step may be crucial in modulating the expression of a subset of liver genes that are targets for this nuclear receptor. This relationship provides a new route for the investigation of the effects of hypoxia on the liver cell." 8527;"Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis.";"N. Mazure";"Equipe 05, Team 05";12570801;"Current pharmaceutical design";"Mazure NM, Brahimi-Horn MC, Pouysségur J";;"Jan 2003";1041379200;;"In the last few decades it has become clear that detailed understanding of the mechanisms of angiogenesis, a process leading to growth of new blood vessels, should lead to improved treatment of diseases such as ischemic disorders and cancer where neovascularization is impaired or activated, respectively. In this review, we will outline some of our recent findings concerning the regulation of the vascular endothelial growth factor (VEGF), a key player in angiogenesis and one of its transcription factors, the hypoxia-inducible factor-1 (HIF-1) a master gene product driving adaptation to hypoxia. We will discuss the observation that growth factors and oncogenic transformation via the mitogen-activated protein kinases p42/p44 MAPKs not only activate the VEGF promoter through the Sp1/AP-2 transcriptional factor complex but also phosphorylate HIF-1alpha leading in turn to enhance HIF-1 dependent transcriptional activation of VEGF. The stress-activated protein kinases (SAPK) also contribute to angiogenesis by stabilizing VEGF mRNA. Finally, we will present recent advances into oxygen-sensing, in particular the HIF-hydroxylases that govern HIF-1alpha instability (PHD2) or inactivation (FIH-1). The revelation of these oxygen sensors has provided pharmacologists with new molecular targets for the development of novel therapies to control angiogenesis either positively or negatively." 8515;"Regulation of Monocytes/Macrophages by the Renin-Angiotensin System in Diabetic Nephropathy: State of the Art and Results of a Pilot Study.";"G. Chinetti, J. Neels, N. Chevalier";"Equipe 09, Team 09, Equipe 05, Team 05";34199409;"International journal of molecular sciences";"Moratal C, Laurain A, Naïmi M, Florin T, Esnault V, Neels JG, Chevalier N, Chinetti G, Favre G";;"Jun 2021";1622505600;;"Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin-angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2." 8513;"Erratum: ""Sub-10 nm spatial resolution for electrical properties measurements using bimodal excitation in electric force microscopy"" [Rev. Sci. Instrum. 92, 023703 (2021)].";"N. Chevalier";"Equipe 05, Team 05";34243477;"The Review of scientific instruments";"Kaja K, Mariolle D, Chevalier N, Naja A, Jouiad M";;"Apr 2021";1617235200;; 8511;"Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network.";"N. Chevalier";"Equipe 05, Team 05";34291731;"European journal of endocrinology";"Deflorenne E, Peuchmaur M, Vezzosi D, Ajzenberg C, Brunaud L, Chevalier N, Christin-Maitre S, Decoudier B, Driessens N, Drui DD, Gilly O, Goudet P, Illouz F, Jublanc C, Lefebvre H, Lopez AG, Lussey C, Morini A, Raffin-Sanson ML, Raingeard I, Renoult-Pierre P, Storey C, Tabarin A, Vantyghem MC, Vidal-Petiot E, Baudin E, Bertherat J, Amar L";;"Aug 2021";1627776000;;"Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management." 8509;"Effects of technology-based physical activity interventions for women after bariatric surgery: study protocol for a three-arm randomised controlled trial.";"A. IANNELLI, N. Chevalier";"Team 08, Equipe 08, Equipe 05, Team 05";34330855;"BMJ open";"Hayotte M, Iannelli A, Nègre V, Pradier C, Thérouanne P, Fuch A, Diagana O, Garbarino JM, Vuillemin A, Colson SS, Chevalier N, d'Arripe-Longueville F";;"07 2021";1625097600;;"A recent meta-analysis provided proof of efficacy for mobile technology to increase physical activity or weight loss in the short term. Videoconferencing may also be effective, especially as it reduces the barriers related to face-to-face physical activity interventions. Both technologies seem particularly interesting for bariatric surgery management, but their long-term effects on physical activity maintenance are unknown. Moreover, the mechanisms underlying their effectiveness, such as technology acceptability and motivational processes, have not been examined.The objectives of this study are to determine the effects of two technology-based (mobile technology and videoconferencing) physical activity programmes after bariatric surgery compared with standard care and to assess the contribution of acceptability and motivational mechanisms in explaining these effects on physical activity, physiological measures and health indicators." 8507;"Understanding and Supporting Inhibitory Control: Unique Contributions From Proactive Monitoring and Motoric Stopping to Children's Improvements With Practice.";"N. Chevalier";"Equipe 05, Team 05";34339051;"Child development";"Traut HJ, Chevalier N, Guild RM, Munakata Y";;"11 2021";1635724800;;"Children struggle to stop inappropriate behaviors. What interventions improve inhibitory control, for whom, and why? Prior work suggested that practice proactively monitoring for relevant signals improved children's inhibitory control more than practice with motoric stopping. However, these processes were not clearly dissociated. This study tested 162 seven- to nine-year-old children (89 female, 72 male, 1 unreported; 82% White) on the stop-signal task, following monitoring or stopping-focused practice. Both methods improved inhibitory control, supported generalization, and interacted (  = .20-.73). Practice approaches differentially impacted variability (  = .01-.09). Only monitoring benefits showed signs of depending upon proactive control (  = .02). These findings highlight unique contributions of attentional and stopping processes to inhibitory control, suggesting possibilities for tailored interventions." 8505;"Position statement on the diagnosis and management of premature/primary ovarian insufficiency (except Turner Syndrome).";"N. Chevalier";"Equipe 05, Team 05";34508691;"Annales d'endocrinologie";"Christin-Maitre S, Givony M, Albarel F, Bachelot A, Bidet M, Blanc JV, Bouvattier C, Brac de la Perrière A, Catteau-Jonard S, Chevalier N, Carel JC, Coutant R, Donadille B, Duranteau L, El-Khattabi L, Hugon-Rodin J, Houang M, Grynberg M, Kerlan V, Leger J, Misrahi M, Pienkowski C, Plu-Bureau G, Polak M, Reynaud R, Siffroi JP, Sonigo C, Touraine P, Zenaty D";;"Dec 2021";1638316800;;"Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the ""France Génomique"" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed." 8503;"Regulatory and academic studies to derive reference values for human health: The case of bisphenol S.";"N. Chevalier";"Equipe 05, Team 05";34688643;"Environmental research";"Beausoleil C, Le Magueresse-Battistoni B, Viguié C, Babajko S, Canivenc-Lavier MC, Chevalier N, Emond C, Habert R, Picard-Hagen N, Mhaouty-Kodja S";;"Mar 2022";1646092800;;"The close structural analogy of bisphenol (BP) S with BPA, a recognized endocrine-disrupting chemical and a substance of very high concern in the European Union, highlights the need to assess the extent of similarities between the two compounds and carefully scrutinize BPS potential toxicity for human health. This analysis aimed to investigate human health toxicity data regarding BPS, to find a point of departure for the derivation of human guidance values. A systematic and transparent methodology was applied to determine whether European or international reference values have been established for BPS. In the absence of such values, the scientific literature on human health effects was evaluated by focusing on human epidemiological and animal experimental studies. The results were analyzed by target organ/system: male and female reproduction, mammary gland, neurobehavior, and metabolism/obesity. Academic experimental studies were analyzed and compared to regulatory data including subchronic studies and an extended one-generation and reproduction study. In contrast to the regulatory studies, which were performed at dose levels in the mg/kg bw/day range, the academic dataset on specific target organs or systems showed adverse effects for BPS at much lower doses (0.5-10 μg/kg bw/day). A large disparity between the lowest-observed-adverse-effect levels (LOAELs) derived from regulatory and academic studies was observed for BPS, as for BPA. Toxicokinetic data on BPS from animal and human studies were also analyzed and showed a 100-fold higher oral bioavailability compared to BPA in a pig model. The similarities and differences between the two bisphenols, in particular the higher bioavailability of BPS in its active (non-conjugated) form and its potential impact on human health, are discussed. Based on the available experimental data, and for a better human protection, we propose to derive human reference values for exposure to BPS from the N(L)OAELs determined in academic studies." 8501;"Midfrontal theta oscillations and conflict monitoring in children and adults.";"N. Chevalier";"Equipe 05, Team 05";34813101;"Developmental psychobiology";"Chevalier N, Hadley LV, Balthrop K";;"Dec 2021";1638316800;;"Conflict monitoring is central in cognitive control, as detection of conflict serves as a signal for the need to engage control. This study examined whether (1) midfrontal theta oscillations similarly support conflict monitoring in children and adults, and (2) performance monitoring difficulty influences conflict monitoring and resolution. Children (n = 25) and adults (n = 24) completed a flanker task with fair or rigged response feedback. Relative to adults, children showed a smaller congruency effect on midfrontal theta power, overall lower midfrontal theta power and coherence, and (unlike adults) no correlation between midfrontal theta power and N2 amplitude, suggesting that reduced neural communication efficiency contributes to less efficient conflict monitoring in children than adults. In both age groups, response feedback fairness affected response times and the P3, but neither midfrontal theta oscillations nor the N2, indicating that performance monitoring difficulty influenced conflict resolution but not conflict monitoring." 8499;"Conversations and Reactions Around Severe Hypoglycemia (CRASH) global survey of people with type-1 diabetes or insulin-treated type-2 diabetes and caregivers: findings from the French cohort.";"N. Chevalier";"Equipe 05, Team 05";34871601;"Annales d'endocrinologie";"Chevalier N, Penfornis A, Riveline JP, Chartier F, Mitchell B, Osumili B, Spaepen E, Snoek F, Peyrot M, Benabbad I";;"Dec 2021";1638316800;;"The objective of the CRASH (Conversations and Reactions Around Severe Hypoglycemia) survey was to further our understanding of the characteristics, experience, behavior and conversations with healthcare professionals (HCPs) of persons with diabetes (PWD) receiving insulin, and of their caregivers (CGs), concerning hypoglycemia requiring external assistance (severe hypoglycemic events [SHEs])." 8497;"Understanding autonomous behaviour development: Exploring the developmental contributions of context-tracking and task selection to self-directed cognitive control.";"N. Chevalier";"Equipe 05, Team 05";34954860;"Developmental science";"Frick A, Brandimonte MA, Chevalier N";;"Dec 2021";1638316800;;"Gaining autonomy is a key aspect of growing up and cognitive control development across childhood. However, little is known about how children engage cognitive control in an autonomous (or self-directed) fashion. Here, we propose that in order to successfully engage self-directed control, children identify, and achieve goals by tracking contextual information and using this information to select relevant tasks. To disentangle the respective contributions of these processes, we manipulated the difficulty of context-tracking via altering the presence or absence of contextual support (Study 1) and the difficulty of task selection by varying task difficulty (a)symmetry (Study 2) in 5-6 and 9-10-year-olds, and adults. Results suggested that, although both processes contribute to successful self-directed engagement of cognitive control, age-related progress mostly relates to context-tracking." 8494;"Effect of endurance training and/or fish oil supplemented diet on cytoplasmic fatty acid binding protein in rat skeletal muscles and heart.";;;12111278;"European journal of applied physiology";"Clavel S, Farout L, Briand M, Briand Y, Jouanel P";;"Jul 2002";1025481600;;"Endurance training and/or a fish oil supplemented diet affect cytoplasmic fatty acid binding protein (FABP(c)) content in rat skeletal muscles and heart. After 8 weeks of swimming, trained rats exhibited higher FABP(c) content in the extensor digitorum longus (EDL) and in the gastrocnemius than did control rats (30%). The FABP(c) increase was associated with an increase of citrate synthase activity (85% and 93%, respectively, in the two muscles), whereas lactate dehydrogenase activity decreased significantly. In contrast, in the soleus and in the heart we did not observe any effect of exercise either on FABP(c) or on the metabolic profile. Therefore, increasing oxidative capacities of muscle by exercise resulted in a concomitant increase of the FABP(c) content. Giving a polyunsaturated fatty acid (omega-3) supplemented diet for eight weeks induced a large rise of the FABP(c) in EDL (300%), gastrocnemius (250%), soleus (50%) and heart (15%) without a concurrent accumulation of intramuscular triglycerides or modification of the citrate synthase activity, suggesting that polyunsaturated fatty acids may increase FABP(c) content by up-regulating fatty acid metabolism genes via peroxisome proliferator-activated receptor alpha activation. Endurance trained rats fed with an omega-3 diet had similar FABP(c) content in the gastrocnemius muscle when compared to sedentary omega-3 fed rats, whereas an additive effect of exercise and diet was observed in the EDL. The FABP(c) in the soleus and in the heart of rats fed with omega-3 supplements remained constant whether rats performed exercise or not. As a result, both exercise and omega-3-enriched diet influenced FABP(c) content in muscle. These two physiological treatments presumably acted on FABP(c) content by increasing fatty acid flux within the cell." 8492;"Differential expression of ubiquitin and proteasome-dependent pathway components in rat tissues.";;;12568808;"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology";"Farout L, Lamare M, Clavel S, Briand M, Briand Y";;"Feb 2003";1044057600;;"The ATP-ubiquitin-dependent pathway in eukaryotes is a complex system, which plays an essential role in selective protein degradation. The functional diversity of this system must be matched to the specific protein metabolism related to the physiology of each cell types. The aim of our work was to study the expression of different components of the proteasome-dependent pathway in various rat tissues. Therefore we quantified the 20S proteasome and the 19S and 11S regulators by Western blot, and measured the expression of the mRNAs of certain subunits, which are markers of these components. We compared the peptidase activities of the purified 20S proteasomes, and also mapped its components by 2D electrophoresis. Our results show that the components of the ATP-ubiquitin-dependent pathway vary considerably both in abundance and activity from one tissue to another. This diversity allows the cells to respond appropriately to tissue-specific protein metabolism in the rat." 8490;"Increased muscle proteasome activities in rats fed a polyunsaturated fatty acid supplemented diet.";;;12672466;"The international journal of biochemistry & cell biology";"Vigouroux S, Farout L, Clavel S, Briand Y, Briand M";;"May 2003";1051747200;;"Changes in the proteasome system, a dominant actor in protein degradation in eukaryotic cells, have been documented in a large number of physiological and pathological conditions. We investigated the influence of monounsaturated or polyunsaturated fatty acids (PUFAs) supplemented diets on the proteasome system, in rat skeletal muscles. Thirty rats were randomly assigned to three groups. The control group received only a standard diet. The monounsaturated fatty acid (MUFA) enriched diet group was fed with 3% sunflower oil in addition to standard food, and the polyunsaturated fatty acid supplemented diet group received 9% Maxepa) in addition to the standard diet. We analyzed muscle proteasome activities and content. Monounsaturated or PUFAs supplemented diets given for 8 weeks induced a significant increase in proteasome activities. With the polyunsaturated fatty acid enriched diet, the chymotrypsin-like and peptidylglutamylpeptide hydrolase activities increased by 45% in soleus and extensor digitorum longus (EDL), and by 90% in the gastrocnemius medialis (GM) muscle. Trypsin-like activity of the proteasome increased by 250% in soleus, EDL and GM. This increase in proteasome activities was associated with a concomitant enhancement in the muscle content of proteasome. Proteasome activities and level were less stimulated with a monounsaturated fatty acid supplemented diet. This study provides evidence that a monounsaturated or polyunsaturated fatty acid supplemented diet may regulate muscle proteasomes. Unsaturated fatty acids are particularly prone to free radical attack. Thus, we suggest that alterations in muscle proteasome may result from monounsaturated and polyunsaturated fatty acid-induced peroxidation, in order to eliminate damaged proteins." 8488;"Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle.";;;16949134;"Mechanisms of ageing and development";"Clavel S, Coldefy AS, Kurkdjian E, Salles J, Margaritis I, Derijard B";;"Oct 2006";1159660800;;"A phenotypic feature of aging is skeletal muscle wasting. It is characterized by a loss of muscle mass and strength. Age-related loss of muscle mass occurs through a reduction in the rate of protein synthesis, an increase in protein degradation or a combination of both. However, the underlying mechanism is still poorly understood. To test the hypothesis that the ubiquitin-proteasome pathway contributes to this phenomenon, we studied MuRF1 and atrogin-1 expression in Tibialis Anterior muscle of aged rats. These two E3 ligases are considered as sensitive markers of muscle protein degradation by the ubiquitin-proteasome system. Our results revealed that, in skeletal muscle of aged rats, the decline in muscle mass is accompanied by an increase in the level of oxidized proteins and ubiquitin conjugates (90%) whereas the functionality of the proteasome remains constant compared to young rats. Furthermore, the level of both MuRF1 and atrogin-1 mRNA is markedly up-regulated in aged muscle (respectively x2 and x2.5). Taken together these data argue for the involvement of the ubiquitin-proteasome pathway in sarcopenia of fast-twitch muscle, in particular through increased expression of MuRF1 and atrogin-1. Moreover, we observed a decrease in the IGF-1/Akt signalling pathways and elevated level of TNFalpha mRNA in aged rat muscle. Therefore, IGF-1/Akt and TNFalpha represent potential mediators implicated in the regulation of MuRF1 and atrogin-1 genes during aging." 8486;"Regulation of the intracellular localization of Foxo3a by stress-activated protein kinase signaling pathways in skeletal muscle cells.";;;19917721;"Molecular and cellular biology";"Clavel S, Siffroi-Fernandez S, Coldefy AS, Boulukos K, Pisani DF, Dérijard B";;"Jan 2010";1262304000;;"Muscle atrophy is a debilitating process associated with many chronic wasting diseases, like cancer, diabetes, sepsis, and renal failure. Rapid loss of muscle mass occurs mainly through the activation of protein breakdown by the ubiquitin proteasome pathway. Foxo3a transcription factor is critical for muscle atrophy, since it activates the expression of ubiquitin ligase Atrogin-1. In several models of atrophy, inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway induces nuclear import of Foxo3a through an Akt-dependent process. This study aimed to identify signaling pathways involved in the control of Foxo3a nuclear translocation in muscle cells. We observed that after nuclear import of Foxo3a by PI3K/Akt pathway inhibition, activation of stress-activated protein kinase (SAPK) pathways induced nuclear export of Foxo3a through CRM1. This mechanism involved the c-Jun NH(2)-terminal kinase (JNK) signaling pathway and was independent of Akt. Likewise, we showed that inhibition of p38 induced a massive nuclear relocalization of Foxo3a. Our results thus suggest that SAPKs are involved in the control of Foxo3a nucleocytoplasmic translocation in C2C12 cells. Moreover, activation of SAPKs decreases the expression of Atrogin-1, and stable C2C12 myotubes, in which the p38 pathway is constitutively activated, present partial protection against atrophy." 8484;"The UbL protein UBTD1 stably interacts with the UBE2D family of E2 ubiquitin conjugating enzymes.";;;24211586;"Biochemical and biophysical research communications";"Uhler JP, Spåhr H, Farge G, Clavel S, Larsson NG, Falkenberg M, Samuelsson T, Gustafsson CM";;"Jan 2014";1388534400;;"UBTD1 is a previously uncharacterized ubiquitin-like (UbL) domain containing protein with high homology to the mitochondrial Dc-UbP/UBTD2 protein. Here we show that UBTD1 and UBTD2 belong to a family of proteins that is conserved through evolution and found in metazoa, funghi, and plants. To gain further insight into the function of UBTD1, we screened for interacting proteins. In a yeast-2-hybrid (Y2H) screen, we identified several proteins involved in the ubiquitylation pathway, including the UBE2D family of E2 ubiquitin conjugating enzymes. An affinity capture screen for UBTD1 interacting proteins in whole cell extracts also identified members of the UBE2D family. Biochemical characterization of recombinant UBTD1 and UBE2D demonstrated that the two proteins form a stable, stoichiometric complex that can be purified to near homogeneity. We discuss the implications of these findings in light of the ubiquitin proteasome system (UPS)." 8482;"GPER and Testicular Germ Cell Cancer.";"C. Hinault, N. Chevalier, R. Paul-Bellon";"Equipe 05, Team 05, Team 03, Equipe 03";33574796;"Frontiers in endocrinology";"Chevalier N, Hinault C, Clavel S, Paul-Bellon R, Fenichel P";;"Jan 2020";1577836800;;"The G protein-coupled estrogen receptor (GPER), also known as GPR30, is a widely conserved 7-transmembrane-domain protein which has been identified as a novel 17β-estradiol-binding protein that is structurally distinct from the classic oestrogen receptors (ERα and ERβ). There are still conflicting data regarding the exact role and the natural ligand of GPER/GPR30 in reproductive tracts as both male and female knock-out mice are fertile and have no abnormalities of reproductive organs. Testicular germ cell cancers (TGCCs) are the most common malignancy in young males and the most frequent cause of death from solid tumors in this age group. Clinical and experimental studies suggested that estrogens participate in the physiological and pathological control of male germ cell proliferation. In human seminoma cell line, while 17β-estradiol (E2) inhibits cell proliferation through an ERβ-dependent mechanism, an impermeable E2 conjugate (E2 coupled to BSA), cell proliferation is stimulated by activating ERK1/2 and protein kinase A through a membrane GPCR that we further identified as GPER/GPR30. The same effect was observed with low but environmentally relevant doses of BPA, an estrogenic endocrine disrupting compound. Furthermore, GPER/GPR30 is specifically overexpressed in seminomas but not in non-seminomas and this overexpression is correlated with an ERβ-downregulation. This GPER/GPR30 overexpression could be linked to some genetic variations, as single nucleotide polymorphisms, which was also reported in other hormone-dependent cancers. We will review here the implication of GPER/GPR30 in TGCCs pathophysiology and the arguments to consider GPER/GPR30 as a potential therapeutic target in humans." 8440;"Repression of alpha-fetoprotein gene expression under hypoxic conditions in human hepatoma cells: characterization of a negative hypoxia response element that mediates opposite effects of hypoxia inducible factor-1 and c-Myc.";"N. Mazure";"Equipe 05, Team 05";11861398;"Cancer research";"Mazure NM, Chauvet C, Bois-Joyeux B, Bernard MA, Nacer-Chérif H, Danan JL";;"Feb 2002";1012521600;;"Hypoxia is an important component of many pathological processes including cancerogenesis and cirrhosis. We have attempted to identify additional hepatic genes sensitive to hypoxia by postulating that genes with possible binding sites for hypoxia inducible factor-1 (HIF-1) are regulated by hypoxia. A computer analysis identified the oncodevelopmental alpha-fetoprotein gene (afp) as one of them. The amounts of both alpha-fetoprotein mRNA and protein were decreased under hypoxic conditions in HepG2 hepatoma cells. Stability of afp mRNA was not altered, and de novo synthesis of proteins was required. Transfection experiments in HepG2 cells showed that both hypoxia and overproduction of HIF-1alpha specifically repressed the transcriptional activity of the rat afp regulatory region through the sequence 5'-CACGTGGG-3' located at -3625 to -3619. Mutation in this sequence strongly impaired these repressions. Interestingly, this sequence was a functional stimulatory target for c-Myc, suggesting that c-Myc regulates afp gene expression. Lastly, the amounts of c-myc mRNA and protein were reduced when these cells were grown under hypoxic conditions. Taken together, these results suggest the existence of a possible competition between HIF-1 and c-Myc that could modulate the transcriptional activity of the afp gene in response to hypoxia." 8436;"Signalling via the hypoxia-inducible factor-1alpha requires multiple posttranslational modifications.";"N. Mazure";"Equipe 05, Team 05";15451019;"Cellular signalling";"Brahimi-Horn C, Mazure N, Pouysségur J";;"Jan 2005";1104537600;;"Cellular hypoxia, a local decrease in the oxygen concentration below normal (21%) atmospheric concentrations, occurs in both physiological and pathological situations. The transcriptional complex Hypoxia-Inducible Factor-1 (HIF-1) is the key player in the signalling pathway that controls the hypoxic response of mammalian cells. Tight regulation of this response involves posttranslational modification of the alpha subunit of HIF-1. Hydroxylation, ubiquitination, acetylation, S-nitrosation and phosphorylation have been shown to determine its half-life and/or transcriptional activity. The precise spatio-temporal occurrence of these multiple modifications is still not fully understood but is dependent on the microenvironment and determines the driving force of variable cellular responses." 8434;"Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1alpha and is not induced by hypoxia or HIF.";"N. Mazure";"Equipe 05, Team 05";15994306;"The Journal of biological chemistry";"Bilton R, Mazure N, Trottier E, Hattab M, Déry MA, Richard DE, Pouysségur J, Brahimi-Horn MC";;"Sep 2005";1125532800;;"The hypoxia-inducible factor (HIF) is a key player in a transcriptional pathway that controls the hypoxic response of mammalian cells. Post-translational modification of the alpha subunit of HIF determines its half-life and activity. Among the multiple reported modifications, acetylation, by an acetyltransferase termed arrest-defective-1 protein (ARD1), has been reported to decrease HIF-1alpha stability and therefore impact on hypoxic gene expression. In contrast, we report that both overexpression and silencing of ARD1 had no impact on the stability of HIF-1alpha or -2alpha and that cells silenced for ARD1 maintained hypoxic nuclear localization of HIF-1alpha. In addition, we show that the ARD1 mRNA and protein levels are not regulated by hypoxia in several human tumor cell lines, including cervical adenocarcinoma HeLa cells, fibrosarcoma HT1080 cells, adenovirus-transformed human kidney HEK293 cells, and human breast cancer MCF-7 cells. Using two model systems ((a) wild-type and HIF-1alpha-null mouse embryo fibroblasts and (b) HeLa cells silenced for HIF-1alpha or -2alpha by RNA interference), we demonstrate that the level of expression of the ARD1 protein is independent of HIF-1alpha and -2alpha. We also demonstrate that ARD1 is a stable, predominantly cytoplasmic protein expressed in a broad range of tissues, tumor cell lines, and endothelial cells. Taken together, our findings demonstrate that ARD1 has limited, if any, impact on the HIF signaling pathway." 8432;"The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha.";"N. Mazure";"Equipe 05, Team 05";16585195;"Cancer research";"Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM";;"Apr 2006";1143849600;;"The function of the hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in cellular adaptation to hypoxia, is restricted to low oxygen tension (pO(2)). As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1alpha subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1alpha possesses two transcriptional activation domains [TAD; NH(2)-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1alpha that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygen-sensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO(2)." 8429;"Hypoxia signalling in cancer and approaches to enforce tumour regression.";"N. Mazure";"Equipe 05, Team 05";16724055;Nature;"Pouysségur J, Dayan F, Mazure NM";;"May 2006";1146441600;;"Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems." 8428;"SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity.";"N. Mazure";"Equipe 05, Team 05";17610843;"Biochemical and biophysical research communications";"Berta MA, Mazure N, Hattab M, Pouysségur J, Brahimi-Horn MC";;"Aug 2007";1185926400;;"The hypoxic response of mammalian cells is controlled through a transcriptional pathway that is mediated by the hypoxia-inducible factor (HIF). Here, we show that HIF-1alpha undergoes post-translational modification by the three isoforms of the small ubiquitin-related modifier (SUMO-1, -2 and -3) in vitro in proximity to and within the oxygen-dependent degradation domain (ODDD). SUMO conjugation is promoted in vitro by the E3 SUMO ligase RanBP2/Nup538 and SUMO modification in vivo does not change HIF-1alpha turnover rate. Using cotransfection of siRNA targeted to endogenous HIF-1alpha together with HIF-1alpha siRNA-resistant expression vectors carrying mutations for SUMO modification we demonstrate increased hypoxia-response element-dependent transcriptional activity for SUMO-deficient HIF-1alpha. These results indicate that when HIF-1alpha is conjugated to SUMO its transcriptional activity is decreased and that this is not mediated by a change in the protein's half-life." 8426;"Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH.";"J. Chiche, N. Mazure";"Team 03, Equipe 03, Equipe 05, Team 05";19118021;"Cancer research";"Chiche J, Ilc K, Laferrière J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouysségur J";;"Jan 2009";1230768000;;"Acidosis of the tumor microenvironment is typical of a malignant phenotype, particularly in hypoxic tumors. All cells express multiple isoforms of carbonic anhydrase (CA), enzymes catalyzing the reversible hydration of carbon dioxide into bicarbonate and protons. Tumor cells express membrane-bound CAIX and CAXII that are controlled via the hypoxia-inducible factor (HIF). Despite the recognition that tumor expression of HIF-1alpha and CAIX correlates with poor patient survival, the role of CAIX and CAXII in tumor growth is not fully resolved. To understand the advantage that tumor cells derive from expression of both CAIX and CAXII, we set up experiments to either force or invalidate the expression of these enzymes. In hypoxic LS174Tr tumor cells expressing either one or both CA isoforms, we show that (a) in response to a ""CO(2) load,"" both CAs contribute to extracellular acidification and (b) both contribute to maintain a more alkaline resting intracellular pH (pH(i)), an action that preserves ATP levels and cell survival in a range of acidic outside pH (6.0-6.8) and low bicarbonate medium. In vivo experiments show that ca9 silencing alone leads to a 40% reduction in xenograft tumor volume with up-regulation of ca12 mRNA levels, whereas invalidation of both CAIX and CAXII gives an impressive 85% reduction. Thus, hypoxia-induced CAIX and CAXII are major tumor prosurvival pH(i)-regulating enzymes, and their combined targeting shows that they hold potential as anticancer targets." 8424;"Hypoxia down-regulates CCAAT/enhancer binding protein-alpha expression in breast cancer cells.";"N. Mazure";"Equipe 05, Team 05";18381421;"Cancer research";"Seifeddine R, Dreiem A, Blanc E, Fulchignoni-Lataud MC, Le Frère Belda MA, Lecuru F, Mayi TH, Mazure N, Favaudon V, Massaad C, Barouki R, Massaad-Massade L";;"Apr 2008";1207180800;;"The transcription factor CCAAT/enhancer binding protein-alpha (C/EBP alpha) is involved in the control of cell differentiation and proliferation, and has been suggested to act as a tumor suppressor in several cancers. By using microarray analysis, we have previously shown that hypoxia and estrogen down-regulate C/EBP alpha mRNA in T-47D breast cancer cells. Here, we have examined the mechanism by which the down-regulation by hypoxia takes place. Using the specific RNA polymerase II inhibitor 5,6-dichlorobenzimidazole-1-beta-D-ribofuranoside, the mRNA stability was analyzed under normoxia or hypoxia by quantitative reverse transcription-PCR. Hypoxia reduced the half-life of C/EBP alpha mRNA by approximately 30%. C/EBP alpha gene promoter studies indicated that hypoxia also repressed the transcription of the gene and identified a hypoxia-responsive element (-522; -527 bp), which binds to hypoxia-inducible factor (HIF)-1 alpha, as essential for down-regulation of C/EBP alpha transcription in hypoxia. Immunocytochemical analysis showed that C/EBP alpha was localized in the nucleus at 21% O(2), but was mostly cytoplasmic under 1% O(2). Knockdown of HIF-1 alpha by RNAi restored C/EBP alpha to normal levels under hypoxic conditions. Immunohistochemical studies of 10 tumor samples did not show any colocalization of C/EBP alpha and glucose transporter 1 (used as a marker for hypoxia). Taken together, these results show that hypoxia down-regulates C/EBP alpha expression in breast cancer cells by several mechanisms, including transcriptional and posttranscriptional effects. The down-regulation of C/EBP alpha in hypoxia is mediated by HIF-1." 8422;"Activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway.";"N. Mazure";"Equipe 05, Team 05";18781596;"Journal of cellular physiology";"Dayan F, Bilton RL, Laferrière J, Trottier E, Roux D, Pouyssegur J, Mazure NM";;"Jan 2009";1230768000;;"Accumulation of HIF-1alpha during normoxic conditions at high cell density has previously been shown to occur and can be used to stabilize HIF-1alpha protein in the absence of a specific anaerobic chamber. However, the impact and origin of this pool of HIF-1alpha, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1alpha stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1alpha stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1alpha accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70(S6K) phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O(2) levels, only slightly impacts upon the mTOR pathway under low cell density conditions. Thus, activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway whereas HIF-1alpha activation obtained in high confluency is totally dependent on mTOR pathway as rapamycin totally impaired (i) HIF-1alpha stabilization and (ii) mRNA levels of CA9 and BNIP3, two HIF-target genes." 8420;"The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis.";"N. Mazure";"Equipe 05, Team 05";19265129;"Journal of immunology (Baltimore, Md. : 1950)";"Noman MZ, Buart S, Van Pelt J, Richon C, Hasmim M, Leleu N, Suchorska WM, Jalil A, Lecluse Y, El Hage F, Giuliani M, Pichon C, Azzarone B, Mazure N, Romero P, Mami-Chouaib F, Chouaib S";;"Mar 2009";1235865600;;"Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO(2)) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1alpha (HIF-1alpha) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1alpha and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1alpha inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1alpha resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phospho-STAT3 and HIF-1alpha are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1alpha in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention." 8418;"Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.";"J. Chiche, N. Mazure";"Team 03, Equipe 03, Equipe 05, Team 05";19273585;"Molecular and cellular biology";"Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM";;"May 2009";1241136000;;"While hypoxia-inducible factor (HIF) is a major actor in the cell survival response to hypoxia, HIF also is associated with cell death. Several studies implicate the HIF-induced putative BH3-only proapoptotic genes bnip3 and bnip3l in hypoxia-mediated cell death. We, like others, do not support this assertion. Here, we clearly demonstrate that the hypoxic microenvironment contributes to survival rather than cell death by inducing autophagy. The ablation of Beclin1, a major actor of autophagy, enhances cell death under hypoxic conditions. In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. First, while the small interfering RNA-mediated ablation of either BNIP3 or BNIP3L has little effect on autophagy, the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy. Second, the ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy. Third, 20-mer BH3 peptides of BNIP3 or BNIP3L are sufficient in initiating autophagy in normoxia. Herein, we propose a model in which the atypical BH3 domains of hypoxia-induced BNIP3/BNIP3L have been designed to induce autophagy by disrupting the Bcl-2-Beclin1 complex without inducing cell death. Hypoxia-induced autophagy via BNIP3 and BNIP3L is clearly a survival mechanism that promotes tumor progression." 8416;"Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli.";"J. Chiche, N. Mazure";"Team 03, Equipe 03, Equipe 05, Team 05";19957303;"Journal of cellular physiology";"Chiche J, Rouleau M, Gounon P, Brahimi-Horn MC, Pouysségur J, Mazure NM";;"Mar 2010";1267401600;;"It is well established that cells exposed to the limiting oxygen microenvironment (hypoxia) of tumors acquire resistance to chemotherapy, through mechanisms not fully understood. We noted that a large number of cell lines showed protection from apoptotic stimuli, staurosporine, or etoposide, when exposed to long-term hypoxia (72 h). In addition, these cells had unusual enlarged mitochondria that were induced in a HIF-1-dependent manner. Enlarged mitochondria were functional as they conserved their transmembrane potential and ATP production. Here we reveal that mitochondria of hypoxia-induced chemotherapy-resistant cells undergo a HIF-1-dependent and mitofusin-1-mediated change in morphology from a tubular network to an enlarged phenotype. An imbalance in mitochondrial fusion/fission occurs since silencing of not only the mitochondrial fusion protein mitofusin 1 but also BNIP3 and BNIP3L, two mitochondrial HIF-targeted genes, reestablished a tubular morphology. Hypoxic cells were insensitive to staurosporine- and etoposide-induced cell death, but the silencing of mitofusin, BNIP3, and BNIP3L restored sensitivity. Our results demonstrate that some cancer cells have developed yet another way to evade apoptosis in hypoxia, by inducing mitochondrial fusion and targeting BNIP3 and BNIP3L to mitochondrial membranes, thereby giving these cells a selective growth advantage." 8406;"Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli.";"J. Chiche, N. Mazure";"Team 03, Equipe 03, Equipe 05, Team 05";19957303;"Journal of cellular physiology";"Chiche J, Rouleau M, Gounon P, Brahimi-Horn MC, Pouysségur J, Mazure NM";;"Dec 2009";1259884800;;"It is well established that cells exposed to the limiting oxygen microenvironment (hypoxia) of tumors acquire resistance to chemotherapy, through mechanisms not fully understood. We noted that a large number of cell lines showed protection from apoptotic stimuli, staurosporine, or etoposide, when exposed to long-term hypoxia (72 h). In addition, these cells had unusual enlarged mitochondria that were induced in a HIF-1-dependent manner. Enlarged mitochondria were functional as they conserved their transmembrane potential and ATP production. Here we reveal that mitochondria of hypoxia-induced chemotherapy-resistant cells undergo a HIF-1-dependent and mitofusin-1-mediated change in morphology from a tubular network to an enlarged phenotype. An imbalance in mitochondrial fusion/fission occurs since silencing of not only the mitochondrial fusion protein mitofusin 1 but also BNIP3 and BNIP3L, two mitochondrial HIF-targeted genes, reestablished a tubular morphology. Hypoxic cells were insensitive to staurosporine- and etoposide-induced cell death, but the silencing of mitofusin, BNIP3, and BNIP3L restored sensitivity. Our results demonstrate that some cancer cells have developed yet another way to evade apoptosis in hypoxia, by inducing mitochondrial fusion and targeting BNIP3 and BNIP3L to mitochondrial membranes, thereby giving these cells a selective growth advantage." 8408;"Oxygen tension regulates pancreatic beta-cell differentiation through hypoxia-inducible factor 1alpha.";"N. Mazure";"Equipe 05, Team 05";20009089;Diabetes;"Heinis M, Simon MT, Ilc K, Mazure NM, Pouysségur J, Scharfmann R, Duvillié B";;"Dec 2009";1261008000;;"Recent evidence indicates that low oxygen tension (pO2) or hypoxia controls the differentiation of several cell types during development. Variations of pO2 are mediated through the hypoxia-inducible factor (HIF), a crucial mediator of the adaptative response of cells to hypoxia. The aim of this study was to investigate the role of pO2 in beta-cell differentiation." 8410;"A dialogue between the hypoxia-inducible factor and the tumor microenvironment.";"N. Mazure";"Equipe 05, Team 05";19308685;"Cancer microenvironment : official journal of the International Cancer Microenvironment Society";"Dayan F, Mazure NM, Brahimi-Horn MC, Pouysségur J";;"Mar 2009";1237939200;;"The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel ""anti-microenvironment"" directed therapies." 8404;"Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia.";"N. Mazure";"Equipe 05, Team 05";19587545;Autophagy;"Mazure NM, Pouysségur J";;"Aug 2009";1249084800;;"Normal and tumor cells subjected to a hypoxic microenvironment show evidence of autophagy. We hypothesize that cells will sense hypoxia as a warning signal to upcoming drastic microenvironmental conditions and that autophagy, acting as a survival mechanism, will provide time for cells to adapt. This work demonstrates for the first time that the atypical BH3-domain of BNIP3 and BNIP3L, two HIF-target genes, can compete with Beclin 1-Bcl-2 and Beclin 1-Bcl-X(L) complexes, releasing Beclin 1 from the complex and then enhancing autophagy. We thus revealed a new role for BH3-only proteins in the cellular response to hypoxia." 8403;"Hypoxia-induced autophagy: cell death or cell survival?";"N. Mazure";"Equipe 05, Team 05";20022734;"Current opinion in cell biology";"Mazure NM, Pouysségur J";;"Apr 2010";1270080000;;"Hypoxia (approximately 3-0.1% oxygen) is capable of rapidly inducing, via the hypoxia-inducible factor (HIF-1), a cell survival response engaging autophagy. This process is mediated by the atypical BH3-only proteins the Bcl-2/E1B 19kDa-interacting protein 3 (BNIP3/BNIP3L (NIX)) that are induced by HIF-1. These mitochondrial associated BNIP proteins also mediate mitophagy, a metabolic adaptation for survival that is able to control reactive oxygen species (ROS) production and DNA damage. In contrast, severe hypoxic conditions or anoxia (<0.1% oxygen), where the latter is often confused with physiological hypoxia, are capable of inducing a HIF-independent autophagic response, generated via an extreme nutritional stress response implicating the AMPK-mTOR and unfolded protein response (UPR) pathways. The autophagic cell death that is often observed in these extreme stress conditions should be seen as the outcome of failed adaptation." 8401;"High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer.";"N. Mazure";"Equipe 05, Team 05";20461082;"British journal of cancer";"Ilie M, Mazure NM, Hofman V, Ammadi RE, Ortholan C, Bonnetaud C, Havet K, Venissac N, Mograbi B, Mouroux J, Pouysségur J, Hofman P";;"May 2010";1273708800;;"Carbonic anhydrase IX (CAIX) is an enzyme upregulated by hypoxia during tumour development and progression. This study was conducted to assess if the expression of CAIX in tumour tissue and/or plasma can be a prognostic factor in patients with non-small cell lung cancer (NSCLC)." 8399;"Overexpression of carbonic anhydrase XII in tissues from resectable non-small cell lung cancers is a biomarker of good prognosis.";"N. Mazure";"Equipe 05, Team 05";20521252;"International journal of cancer";"Ilie MI, Hofman V, Ortholan C, Ammadi RE, Bonnetaud C, Havet K, Venissac N, Mouroux J, Mazure NM, Pouysségur J, Hofman P";;"Apr 2011";1301616000;;"The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase XII (CAXII) is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation and enhanced expression is often present in several types of tumors. The aim of our study was to assess the prognostic significance of CAXII tumor tissues expression in patients with NSCLC. Five hundred fifty-five tumors were immunostained for CAXII on tissue microarrays (TMA) and the results were correlated with clinicopathological parameters and outcome of patients. CAXII overexpression was present in 105/555 (19%) cases and was associated with tumors of lower grade (p = 0.015) and histological type (p < 0.001), being significantly higher in squamous cell carcinoma. High CAXII expression correlated with better overall and disease-specific survival of patients with resectable NSCLC in univariate (p < 0.001) and multivariate survival analyses (p < 0.001). In conclusion, this is the first study demonstrating that a high CAXII tumor tissue expression evaluated on TMAs is related to a better outcome in a large series of patients with resectable NSCLC." 8397;"Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells.";"N. Mazure";"Equipe 05, Team 05";21593445;"American journal of physiology. Cell physiology";"Bourcier C, Griseri P, Grépin R, Bertolotto C, Mazure N, Pagès G";;"Sep 2011";1314835200;;"Most melanoma cells are characterized by the V600E mutation in B-Raf kinase. This mutation leads to increased expression of interleukin (CXCL8), which plays a key role in cell growth and angiogenesis. Thus CXCL8 appears to be an interesting therapeutic target. Hence, we performed vaccination of mice with GST-CXCL8, which results in a reduced incidence of syngenic B16 melanoma cell xenograft tumors. We next addressed the molecular mechanisms responsible for aberrant CXCL8 expression in melanoma. The CXCL8 mRNA contains multiples AU-rich sequences (AREs) that modulate mRNA stability through the binding of tristetraprolin (TTP). Melanoma cell lines express very low TTP levels. We therefore hypothesized that the very low endogenous levels of TTP present in different melanoma cell lines might be responsible for the relative stability of CXCL8 mRNAs. We show that TTP is actively degraded by the proteasome and that extracellular-regulated kinase inhibition results in TTP accumulation. Conditional expression of TTP in A375 melanoma cells leads to CXCL8 mRNA destabilization via its 3' untranslated regions (3'-UTR), and TTP overexpression reduces its production. In contrast, downregulation of TTP by short hairpin RNA results in upregulation of CXCL8 mRNA. Maintaining high TTP levels in melanoma cells decreases cell proliferation and autophagy and induces apoptosis. Sorafenib, a therapeutic agent targeting Raf kinases, decreases CXCL8 expression in melanoma cells through reexpression of TTP. We conclude that loss of TTP represents a key event in the establishment of melanomas through constitutive expression of CXCL8, which constitutes a potent therapeutic target." 8395;"Hypoxic mitochondria: accomplices in resistance.";"N. Mazure";"Equipe 05, Team 05";21609892;"Bulletin du cancer";"Mazure NM, Brahimi-Horn MC, Pouysségur J";;"May 2011";1304208000;;"Mitochondria originated from a distant ancestor: the α-proteobacteria. They evolved over millions of years in a symbiotic relationship in eukaryotic cells by favoring consumption of oxygen by the electron transport chain with production of ATP. Contemporary mitochondria still play a crucial role in providing energy but also in apoptosis. Because of this symbiotic relationship and their pivotal function, mitochondria undoubtedly participate in tumorigenesis. Genetic defects in mitochondrial DNA, blockade of oxidative phosphorylation and mitophagy in tumor cells modify the production of damaging reactive oxygen species and restrain apoptosis. As the environment of tumor cells becomes more and more hypoxic, the hypoxia-inducible factor (HIF) is stabilized and participates in the reprogramming of cell metabolism. Recently, we became interested in asking whether HIF and hypoxia affect mitochondrial function. In this review, we show that hypoxia induces enlargement of mitochondria, due to abnormal fusion, which results in resistance to apoptosis and thus in survival. The role of hypoxia-induced BNIP3 and BNIP3L, proteins recently described as pro-survival proteins, in survival is also discussed." 8393;"Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia.";"N. Mazure";"Equipe 05, Team 05";21933857;Haematologica;"Ladroue C, Hoogewijs D, Gad S, Carcenac R, Storti F, Barrois M, Gimenez-Roqueplo AP, Leporrier M, Casadevall N, Hermine O, Kiladjian JJ, Baruchel A, Fakhoury F, Bressac-de Paillerets B, Feunteun J, Mazure N, Pouysségur J, Wenger RH, Richard S, Gardie B";;"Jan 2012";1325376000;;"Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma." 8391;"The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53-p21 axis.";"N. Mazure";"Equipe 05, Team 05";22002313;Oncogene;"Pelletier J, Dayan F, Durivault J, Ilc K, Pécou E, Pouysségur J, Mazure NM";;"Jun 2012";1338508800;;"We showed previously that factor-inhibiting hypoxia-inducible factor HIF (FIH) monitors the expression of a spectrum of genes that are dictated by the cell's partial oxygen pressure. This action is mediated by the C-TAD, one of two transactivation domains (TADs) of the hypoxia-inducible factor. Here, we questioned: (1) the function of FIH as a HIF-1 modulator of gene expression in the context of a physiological oxygen gradient occurring in three-dimensional cultures and in tumors and (2) the role of FIH as a modulator of the growth of human tumor cells. We first showed that the expression pattern of HIF target genes that depend on the C-TAD, such as carbonic anhydrase IX, was spacially displaced to more oxygenated areas when FIH was silenced, whereas overexpression of FIH restricted this pattern to more hypoxic areas. Second, we showed that silencing fih severely reduced in vitro cell proliferation and in vivo tumor growth of LS174 colon adenocarcinoma and A375 melanoma cells. Finally, silencing of fih significantly increased both the total and phosphorylated forms of the tumor suppressor p53, leading to an increase in its direct target, the cell cycle inhibitor p21. Moreover, p53-deficient or mutant cells were totally insensitive to FIH expression. Thus, FIH activity is essential for tumor growth through the suppression of the p53-p21 axis, the major barrier that prevents cancer progression." 8389;"Expression of a truncated active form of VDAC1 in lung cancer associates with hypoxic cell survival and correlates with progression to chemotherapy resistance.";"N. Mazure";"Equipe 05, Team 05";22389449;"Cancer research";"Brahimi-Horn MC, Ben-Hail D, Ilie M, Gounon P, Rouleau M, Hofman V, Doyen J, Mari B, Shoshan-Barmatz V, Hofman P, Pouysségur J, Mazure NM";;"Apr 2012";1333238400;;"Resistance to chemotherapy-induced apoptosis of tumor cells represents a major hurdle to efficient cancer therapy. Although resistance is a characteristic of tumor cells that evolve in a low oxygen environment (hypoxia), the mechanisms involved remain elusive. We observed that mitochondria of certain hypoxic cells take on an enlarged appearance with reorganized cristae. In these cells, we found that a major mitochondrial protein regulating metabolism and apoptosis, the voltage-dependent anion channel 1 (VDAC1), was linked to chemoresistance when in a truncated (VDAC1-ΔC) but active form. The formation of truncated VDAC1, which had a similar channel activity and voltage dependency as full-length, was hypoxia-inducible factor-1 (HIF-1)-dependent and could be inhibited in the presence of the tetracycline antibiotics doxycycline and minocycline, known inhibitors of metalloproteases. Its formation was also reversible upon cell reoxygenation and associated with cell survival through binding to the antiapoptotic protein hexokinase. Hypoxic cells containing VDAC1-ΔC were less sensitive to staurosporine- and etoposide-induced cell death, and silencing of VDAC1-ΔC or treatment with the tetracycline antibiotics restored sensitivity. Clinically, VDAC1-ΔC was detected in tumor tissues of patients with lung adenocarcinomas and was found more frequently in large and late-stage tumors. Together, our findings show that via induction of VDAC1-ΔC, HIF-1 confers selective protection from apoptosis that allows maintenance of ATP and cell survival in hypoxia. VDAC1-ΔC may also hold promise as a biomarker for tumor progression in chemotherapy-resistant patients." 8387;"Positron emission tomography/computed tomography imaging of residual skull base chordoma before radiotherapy using fluoromisonidazole and fluorodeoxyglucose: potential consequences for dose painting.";"N. Mazure";"Equipe 05, Team 05";22391104;"International journal of radiation oncology, biology, physics";"Mammar H, Kerrou K, Nataf V, Pontvert D, Clemenceau S, Lot G, George B, Polivka M, Mokhtari K, Ferrand R, Feuvret L, Habrand JL, Pouysségur J, Mazure N, Talbot JN";;"Nov 2012";1351728000;;"To detect the presence of hypoxic tissue, which is known to increase the radioresistant phenotype, by its uptake of fluoromisonidazole (18F) (FMISO) using hybrid positron emission tomography/computed tomography (PET/CT) imaging, and to compare it with the glucose-avid tumor tissue imaged with fluorodeoxyglucose (18F) (FDG), in residual postsurgical skull base chordoma scheduled for radiotherapy." 8385;"Glycogen Synthesis is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival.";"N. Mazure";"Equipe 05, Team 05";22649778;"Frontiers in oncology";"Pelletier J, Bellot G, Gounon P, Lacas-Gervais S, Pouysségur J, Mazure NM";;"Jan 2012";1325376000;;"The hypoxia-inducible factor 1 (HIF-1), in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumor cells. This transcription factor not only favors cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. In this study we showed that glycogen synthesis is enhanced in non-cancer and cancer cells when exposed to hypoxia, resulting in a large increase in glycogen stores. Furthermore, we demonstrated that the mRNA and protein levels of the first enzyme of glycogenesis, phosphoglucomutase1 (PGM1), were increased in hypoxia. We showed that induction of glycogen storage as well as PGM1 expression were dependent on HIF-1 and HIF-2. We established that hypoxia-induced glycogen stores are rapidly mobilized in cells that are starved of glucose. Glycogenolysis allows these ""hypoxia-preconditioned"" cells to confront and survive glucose deprivation. In contrast normoxic control cells exhibit a high rate of cell death following glucose removal. These findings point to the important role of hypoxia and HIF in inducing mechanisms of rapid adaptation and survival in response to a decrease in oxygen tension. We propose that a decrease in pO(2) acts as an ""alarm"" that prepares the cells to face subsequent nutrient depletion and to survive." 8383;"""Seed-Milarity"" confers to hsa-miR-210 and hsa-miR-147b similar functional activity.";"N. Mazure";"Equipe 05, Team 05";23028679;"PloS one";"Bertero T, Grosso S, Robbe-Sermesant K, Lebrigand K, Hénaoui IS, Puisségur MP, Fourre S, Zaragosi LE, Mazure NM, Ponzio G, Cardinaud B, Barbry P, Rezzonico R, Mari B";;"Jan 2012";1325376000;;"Specificity of interaction between a microRNA (miRNA) and its targets crucially depends on the seed region located in its 5'-end. It is often implicitly considered that two miRNAs sharing the same biological activity should display similarity beyond the strict six nucleotide region that forms the seed, in order to form specific complexes with the same mRNA targets. We have found that expression of hsa-miR-147b and hsa-miR-210, though triggered by different stimuli (i.e. lipopolysaccharides and hypoxia, respectively), induce very similar cellular effects in term of proliferation, migration and apoptosis. Hsa-miR-147b only shares a ""minimal"" 6-nucleotides seed sequence with hsa-miR-210, but is identical with hsa-miR-147a over 20 nucleotides, except for one base located in the seed region. Phenotypic changes induced after heterologous expression of miR-147a strikingly differ from those induced by miR-147b or miR-210. In particular, miR-147a behaves as a potent inhibitor of cell proliferation and migration. These data fit well with the gene expression profiles observed for miR-147b and miR-210, which are very similar, and the gene expression profile of miR-147a, which is distinct from the two others. Bioinformatics analysis of all human miRNA sequences indicates multiple cases of miRNAs from distinct families exhibiting the same kind of similarity that would need to be further characterized in terms of putative functional redundancy. Besides, it implies that functional impact of some miRNAs can be masked by robust expression of miRNAs belonging to distinct families." 8379;"MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines.";"N. Mazure";"Equipe 05, Team 05";23492775;"Cell death & disease";"Grosso S, Doyen J, Parks SK, Bertero T, Paye A, Cardinaud B, Gounon P, Lacas-Gervais S, Noël A, Pouysségur J, Barbry P, Mazure NM, Mari B";;"Mar 2013";1363392000;;"The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Recently, an additional mode of hypoxia-inducible factor (HIF)-dependent transcriptional regulation, involving modulation of a specific set of micro RNAs (miRNAs), including miR-210, has emerged. We have recently shown that HIF-1 induction of miR-210 also stabilizes HIF-1 through a positive regulatory loop. Therefore, we hypothesized that by stabilizing HIF-1 in normoxia, miR-210 may protect cancer cells from radiation. We developed a non-small cell lung carcinoma (NSCLC)-derived cell line (A549) stably expressing miR-210 (pmiR-210) or a control miRNA (pmiR-Ctl). The miR-210-expressing cells showed a significant stabilization of HIF-1 associated with mitochondrial defects and a glycolytic phenotype. Cells were subjected to radiation levels ranging from 0 to 10 Gy in normoxia and hypoxia. Cells expressing miR-210 in normoxia had the same level of radioresistance as control cells in hypoxia. Under hypoxia, pmiR-210 cells showed a low mortality rate owing to a decrease in apoptosis, with an ability to grow even at 10 Gy. This miR-210 phenotype was reproduced in another NSCLC cell line (H1975) and in HeLa cells. We have established that radioresistance was independent of p53 and cell cycle status. In addition, we have shown that genomic double-strand breaks (DSBs) foci disappear faster in pmiR-210 than in pmiR-Ctl cells, suggesting that miR-210 expression promotes a more efficient DSB repair. Finally, HIF-1 invalidation in pmiR-210 cells removed the radioresistant phenotype, showing that this mechanism is dependent on HIF-1. In conclusion, miR-210 appears to be a component of the radioresistance of hypoxic cancer cells. Given the high stability of most miRNAs, this advantage could be used by tumor cells in conditions where reoxygenation has occurred and suggests that strategies targeting miR-210 could enhance tumor radiosensitization." 8381;"Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels.";"N. Mazure";"Equipe 05, Team 05";23459996;"Journal of cellular physiology";"Parks SK, Mazure NM, Counillon L, Pouysségur J";;"Sep 2013";1377993600;;"The efficacy of targeting pH disruption to induce cell death in the acidic and hypoxic tumor microenvironment continues to be assessed. Here we analyzed the impact of varying levels of hypoxia in acidic conditions on fibroblast and tumor cell survival. Across all cell lines tested, hypoxia (1% O(2)) provided protection against acidosis induced cell death compared to normoxia. Meanwhile severe hypoxia (0.1% O(2)) removed this protection and in some cases exacerbated acidosis-induced cell death. Differential survival between cell types during external acidosis correlated with their respective intracellular pH regulating capabilities. Cellular ATP measurements were conducted to determine their contribution to cell survival under these combined stresses. In general, hypoxia (1% O(2)) maintained elevated ATP levels in acidic conditions while severe hypoxia did not. To further explore this interaction we combined acidosis with ATP depletion using 2-deoxyglucose and observed an enhanced rate of cell mortality. Striking results were also observed with hypoxia providing protection against cell death in spite of a severe metabolic stress induced by a combination of acidosis and oligomycin. Finally, we demonstrated that both HIF1α and HIF2α expression were drastically reduced in hypoxic and acidic conditions indicating a sensitivity of this protein to cellular pH conditions. This knockdown of HIF expression by acidosis has implications for the development of therapies targeting the disruption of cellular pH regulation. Our results reinforce the proof of concept that acidosis and metabolic disruption affecting ATP levels could be exploited as a tumor cell killing strategy." 8377;"Response of CAIX and CAXII to in vitro re-oxygenation and clinical significance of the combined expression in NSCLC patients.";"J. Chiche, N. Mazure";"Team 03, Equipe 03, Equipe 05, Team 05";23910904;"Lung cancer (Amsterdam, Netherlands)";"Ilie M, Hofman V, Zangari J, Chiche J, Mouroux J, Mazure NM, Pouysségur J, Brest P, Hofman P";;"Oct 2013";1380585600;;"The disorganized neo-vasculature in tumours causes fluctuations in the concentration of oxygen, which contributes to tumour development and metastatic potential. Although hypoxic regulation of the expression of the carbonic anhydrases CAIX and CAXII is well established, the effect of re-oxygenation on these proteins remains to be elucidated. A549 and H1975 human lung cancer cell lines were exposed to hypoxia for 24 h and then re-oxygenated. CAIX or CAXII expression and cell cycle progression at different time-points were monitored. A549-shCA9 cells were analyzed for cell cycle progression in the same conditions. We demonstrate for the first time an association between the stability of CAIX and restoration of the S/G2 phase of hypoxia-arrested cells subjected to re-oxygenation. In exchange, we have found that the loss of CA9 did not cause a decreased progression into S/G2 phase during re-oxygenation, but rather affected the hypoxic growth arrest. We previously demonstrated that CAIX expression is a poor prognostic factor and that CAXII expression is a good prognostic factor in non-small cell lung cancer (NSCLC) patients. We further detail the relevance of the combined expression of these proteins for predicting outcome in a large population of NSCLC patients after long-term follow-up. The high CAIX/low CAXII expression sub-group was associated with a high cumulative incidence of relapse and with poor overall survival of NSCLC patients (P < 0.0001). Our results demonstrate a critical role for re-oxygenation on CAIX and CAXII levels that may select for an aggressive lung cancer phenotype. These findings suggest that CAIX and CAXII play dual roles in tumour progression and emphasize their significant prognostic and potential therapeutic value." 8375;"MicroRNA target identification: lessons from hypoxamiRs.";"N. Mazure";"Equipe 05, Team 05";24111877;"Antioxidants & redox signaling";"Bertero T, Robbe-Sermesant K, Le Brigand K, Ponzio G, Pottier N, Rezzonico R, Mazure NM, Barbry P, Mari B";;"Sep 2014";1409529600;;"MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as key regulators of many physiological and pathological processes, including those relevant to hypoxia such as cancer, neurological dysfunctions, myocardial infarction, and lung diseases." 8373;"Hypoxic VDAC1: a potential mitochondrial marker for cancer therapy.";"N. Mazure";"Equipe 05, Team 05";24272356;"Advances in experimental medicine and biology";"Brahimi-Horn MC, Mazure NM";;"Jan 2014";1388534400;;"Finding new therapeutic targets to fight cancer is an ongoing quest. Because of insufficiencies in tumor vasculature, cells often are exposed to a hostile microenvironment that is low in oxygen (hypoxic) and nutrients. Thus, tumor cells face the challenge of finding new sources of energy and defying apoptosis, which allow them to survive, grow, and colonize other tissues. Eradicating specifically these hypoxic cells is one of the many goals of anticancer therapies. The mitochondrial voltage-dependent anion channel (VDAC) is a protein at the crossroads of metabolic and survival pathways. As its name suggests, VDAC is involved in ion transport as well as adenosine triphosphate and NAD(+) transport. We recently reported the presence in tumor cells of a novel hypoxia-induced form of VDAC. This form, a C-terminal truncated protein (VDAC1-ΔC), was associated in some cancer cell lines with a high output of adenosine triphosphate and a strong resistance to chemotherapy-induced apoptosis. Furthermore, VDAC1-ΔC was detected in tissues of 50 % of 46 patients with lung cancer. This review examines the significance of this new form of VDAC1 for anticancer therapy." 8369;"Why do some human viruses remain recalcitrant to cultivation?";"N. Mazure";"Equipe 05, Team 05";24336825;"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America";"Morinet F, Capron C, Mazure NM, Pillet S";;"Dec 2013";1387238400;; 8370;"Biochemical titration of glycogen in vitro.";"N. Mazure";"Equipe 05, Team 05";24300406;"Journal of visualized experiments : JoVE";"Pelletier J, Bellot G, Pouysségur J, Mazure NM";;"Nov 2013";1383264000;;"Glycogen is the main energetic polymer of glucose in vertebrate animals and plays a crucial role in whole body metabolism as well as in cellular metabolism. Many methods to detect glycogen already exist but only a few are quantitative. We describe here a method using the Abcam Glycogen assay kit, which is based on specific degradation of glycogen to glucose by glucoamylase. Glucose is then specifically oxidized to a product that reacts with the OxiRed probe to produce fluorescence. Titration is accurate, sensitive and can be achieved on cell extracts or tissue sections. However, in contrast to other techniques, it does not give information about the distribution of glycogen in the cell. As an example of this technique, we describe here the titration of glycogen in two cell lines, Chinese hamster lung fibroblast CCL39 and human colon carcinoma LS174, incubated in normoxia (21% O2) versus hypoxia (1% O2). We hypothesized that hypoxia is a signal that prepares cells to synthesize and store glycogen in order to survive(1)." 8367;"AmotL2 disrupts apical-basal cell polarity and promotes tumour invasion.";"N. Mazure";"Equipe 05, Team 05";25080976;"Nature communications";"Mojallal M, Zheng Y, Hultin S, Audebert S, van Harn T, Johnsson P, Lenander C, Fritz N, Mieth C, Corcoran M, Lembo F, Hallström M, Hartman J, Mazure NM, Weide T, Grandér D, Borg JP, Uhlén P, Holmgren L";;"Aug 2014";1406851200;;"The establishment and maintenance of apical-basal cell polarity is essential for the functionality of glandular epithelia. Cell polarity is often lost in advanced tumours correlating with acquisition of invasive and malignant properties. Despite extensive knowledge regarding the formation and maintenance of polarity, the mechanisms that deregulate polarity in metastasizing cells remain to be fully characterized. Here we show that AmotL2 expression correlates with loss of tissue architecture in tumours from human breast and colon cancer patients. We further show that hypoxic stress results in activation of c-Fos-dependent expression of AmotL2 leading to loss of polarity. c-Fos/hypoxia-induced p60 AmotL2 interacts with the Crb3 and Par3 polarity complexes retaining them in large vesicles and preventing them from reaching the apical membrane. The resulting loss of polarity potentiates the response to invasive cues in vitro and in vivo in mice. These data provide a molecular mechanism how hypoxic stress deregulates cell polarity during tumour progression." 8365;"Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium.";"J. Chiche, N. Mazure";"Team 03, Equipe 03, Equipe 05, Team 05";25347767;"Journal of enzyme inhibition and medicinal chemistry";"Pettersen EO, Ebbesen P, Gieling RG, Williams KJ, Dubois L, Lambin P, Ward C, Meehan J, Kunkler IH, Langdon SP, Ree AH, Flatmark K, Lyng H, Calzada MJ, Peso LD, Landazuri MO, Görlach A, Flamm H, Kieninger J, Urban G, Weltin A, Singleton DC, Haider S, Buffa FM, Harris AL, Scozzafava A, Supuran CT, Moser I, Jobst G, Busk M, Toustrup K, Overgaard J, Alsner J, Pouyssegur J, Chiche J, Mazure N, Marchiq I, Parks S, Ahmed A, Ashcroft M, Pastorekova S, Cao Y, Rouschop KM, Wouters BG, Koritzinsky M, Mujcic H, Cojocari D";;"Jan 2015";1420070400;;"The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as potential targets for hypoxia-specific treatment. Also the chemistry related to reactive oxygen radicals (ROS) and the biological handling of ROS are part of the problem complex. The problem is further complicated by the great variety in oxygen concentrations found in tissues. For tumour hypoxia to be used as a marker for individualisation of treatment there is a need for non-invasive methods to measure oxygen routinely in patient tumours. A large-scale collaborative EU-financed project 2009-2014 denoted METOXIA has studied all the mentioned aspects of hypoxia with the aim of selecting potential targets for new hypoxia-specific therapy and develop the first stage of tests for this therapy. A new non-invasive PET-imaging method based on the 2-nitroimidazole [(18)F]-HX4 was found to be promising in a clinical trial on NSCLC patients. New preclinical models for testing of the metastatic potential of cells were developed, both in vitro (2D as well as 3D models) and in mice (orthotopic grafting). Low density quantitative real-time polymerase chain reaction (qPCR)-based assays were developed measuring multiple hypoxia-responsive markers in parallel to identify tumour hypoxia-related patterns of gene expression. As possible targets for new therapy two main regulatory cascades were prioritised: The hypoxia-inducible-factor (HIF)-regulated cascades operating at moderate to weak hypoxia (<1% O(2)), and the unfolded protein response (UPR) activated by endoplasmatic reticulum (ER) stress and operating at more severe hypoxia (<0.2%). The prioritised targets were the HIF-regulated proteins carbonic anhydrase IX (CAIX), the lactate transporter MCT4 and the PERK/eIF2α/ATF4-arm of the UPR. The METOXIA project has developed patented compounds targeting CAIX with a preclinical documented effect. Since hypoxia-specific treatments alone are not curative they will have to be combined with traditional anti-cancer therapy to eradicate the aerobic cancer cell population as well." 8363;"Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis.";"N. Mazure";"Equipe 05, Team 05";25371412;"Cancer research";"Couvé S, Ladroue C, Laine E, Mahtouk K, Guégan J, Gad S, Le Jeune H, Le Gentil M, Nuel G, Kim WY, Lecomte B, Pagès JC, Collin C, Lasne F, Benusiglio PR, Bressac-de Paillerets B, Feunteun J, Lazar V, Gimenez-Roqueplo AP, Mazure NM, Dessen P, Tchertanov L, Mole DR, Kaelin W, Ratcliffe P, Richard S, Gardie B";;"Nov 2014";1414800000;;"The classic model of tumor suppression implies that malignant transformation requires full ""two-hit"" inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a ""continuum"" model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the ""continuum"" model of tumor suppression." 8361;"Local mitochondrial-endolysosomal microfusion cleaves voltage-dependent anion channel 1 to promote survival in hypoxia.";"N. Mazure";"Equipe 05, Team 05";25691661;"Molecular and cellular biology";"Brahimi-Horn MC, Lacas-Gervais S, Adaixo R, Ilc K, Rouleau M, Notte A, Dieu M, Michiels C, Voeltzel T, Maguer-Satta V, Pelletier J, Ilie M, Hofman P, Manoury B, Schmidt A, Hiller S, Pouysségur J, Mazure NM";;"May 2015";1430438400;;"The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53." 8359;"AMP-activated protein kinase is dispensable for maintaining ATP levels and for survival following inhibition of glycolysis, but promotes tumour engraftment of Ras-transformed fibroblasts.";"N. Mazure";"Equipe 05, Team 05";26059436;Oncotarget;"Pelletier J, Roux D, Viollet B, Mazure NM, Pouysségur J";;"May 2015";1430438400;;"Lactic acid generated by highly glycolytic tumours is exported by the MonoCarboxylate Transporters, MCT1 and MCT4, to maintain pHi and energy homeostasis. We report that MCT1 inhibition combined with Mct4 gene disruption severely reduced glycolysis and tumour growth without affecting ATP levels. Because of the key role of the 5'-AMP-activated protein kinase (AMPK) in energy homeostasis, we hypothesized that targeting glycolysis (MCT-blockade) in AMPK-null (Ampk(-/-)) cells should kill tumour cells from 'ATP crisis'. We show that Ampk(-/-)-Ras-transformed mouse embryonic fibroblasts (MEFs) maintained ATP levels and viability when glycolysis was inhibited. In MCT-inhibited MEFs treated with OXPHOS inhibitors the ATP level and viability collapsed in both Ampk(+/+) and Ampk(-/-) cells. We therefore propose that the intracellular acidification resulting from lactic acid sequestration mimicks AMPK by blocking mTORC1, a major component of an ATP consuming pathway, thereby preventing 'ATP crisis'. Finally we showed that genetic disruption of Mct4 and/or Ampk dramatically reduced tumourigenicity in a xenograft mouse model suggesting a crucialrolefor these two actors in establishment of tumours in a nutrient-deprived environment. These findings demonstrated that blockade of lactate transport is an efficient anti-cancer strategy that highlights the potential in targeting Mct4 in a context of impaired AMPK activity." 8356;"News about VDAC1 in Hypoxia.";"N. Mazure";"Equipe 05, Team 05";27625993;"Frontiers in oncology";"Mazure NM";;"Jan 2016";1451606400;;"The voltage-dependent anion channel (VDAC) is the main interface between the cytosol and mitochondria of cells. It plays a crucial role in both mitochondrial metabolism and cell death. The main basic function of this channel is to mediate and gate the flux of small ions, metabolites, and adenosine triphosphate. Changes in its structure, and thus conformation, are expected to affect its activity and modulate the ability of cancer cells to expand. In this review, we describe a novel mechanism by which mitochondria of cells in hypoxia, a low level of oxygen, protects from apoptosis. In hypoxia, some mitochondria become enlarged due to hyperfusion. These mitochondria possess a truncated form of VDAC1 (VDAC1-ΔC), which is linked to the higher metabolic capacity and the greater resistance to cell death of hypoxic cells. However, not all of the VDAC1 protein is truncated, but the amount of the full-length form is diminished compared to the amount in normoxic cells. First, we describe how such a decrease effects cell proliferation, respiration, glycolysis, and other processes. Second, we report on a novel mitochondrial-endolysosomal crosstalk that leads to VDAC1 truncation. By pharmacological targeting of VDAC1-ΔC, the production of energy could be turned off and the sensitivity to cell death restored. This could counteract the favorable microenvironment that gives cancer cells a growth advantage and thereby disrupts the balance between life and death, which is controlled by VDAC1." 8355;"VDAC in cancer.";"N. Mazure";"Equipe 05, Team 05";28283400;"Biochimica et biophysica acta. Bioenergetics";"Mazure NM";;"Aug 2017";1501545600;;"The voltage-dependent anion channel (VDAC) is a pore located at the outer membrane of the mitochondrion. It allows the entry and exit of numerous ions and metabolites between the cytosol and the mitochondrion. Flux through the pore occurs in an active way: first, it depends on the open or closed state and second, on the negative or positive charges of the different ion species passing through the pore. The flux of essential metabolites, such as ATP, determines the functioning of the mitochondria to a noxious stimulus. Moreover, VDAC acts as a platform for many proteins and in so doing supports glycolysis and prevents apoptosis by interacting with hexokinase, or members of the Bcl-2 family, respectively. VDAC is thus involved in the choice the cells make to survive or die, which is particularly relevant to cancer cells. For these reasons, VDAC has become a potential therapeutic target to fight cancer but also other diseases in which mitochondrial metabolism is modified. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux." 8353;"The Leukemic Stem Cell Niche: Adaptation to ""Hypoxia"" versus Oncogene Addiction.";"N. Mazure";"Equipe 05, Team 05";29118813;"Stem cells international";"Cheloni G, Poteti M, Bono S, Masala E, Mazure NM, Rovida E, Lulli M, Dello Sbarba P";;"Jan 2017";1483228800;;"Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern the maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC). The physiological oxygen concentration in tissues ranges between 0.1 and 5.0%. Stem cell niches (SCN) are placed in tissue areas at the lower end of this range (""hypoxic"" SCN), to which stem cells are metabolically adapted and where they are selectively hosted. The data reported here indicated that driver oncogenic proteins of several leukemias are suppressed following cell incubation at oxygen concentration compatible with SCN physiology. This suppression is likely to represent a key positive regulator of LSC survival and maintenance (self-renewal) within the SCN. On the other hand, LSC committed to differentiation, unable to stand suppression because of addiction to oncogenic signalling, would be unfit to home in SCN. The loss of oncogene addiction in SCN-adapted LSC has a consequence of crucial practical relevance: the refractoriness to inhibitors of the biological activity of oncogenic protein due to the lack of their molecular target. Thus, LSC hosted in SCN are suited to sustain the long-term maintenance of therapy-resistant minimal residual disease." 8351;"Disrupting glucose-6-phosphate isomerase fully suppresses the ""Warburg effect"" and activates OXPHOS with minimal impact on tumor growth except in hypoxia.";"N. Mazure";"Equipe 05, Team 05";29152106;Oncotarget;"de Padua MC, Delodi G, Vučetić M, Durivault J, Vial V, Bayer P, Noleto GR, Mazure NM, Ždralević M, Pouysségur J";;"Oct 2017";1506816000;;"As Otto Warburg first observed, cancer cells largely favor fermentative glycolysis for growth even under aerobic conditions. This energy paradox also extends to rapidly growing normal cells indicating that glycolysis is optimal for fast growth and biomass production. Here we further explored this concept by genetic ablation of fermentative glycolysis in two fast growing cancer cell lines: human colon adenocarcinoma LS174T and B16 mouse melanoma. We disrupted the upstream glycolytic enzyme, glucose-6-phosphate isomerase (), to allow cells to re-route glucose-6-phosphate flux into the pentose-phosphate branch. Indeed, -KO severely reduced glucose consumption and suppressed lactic acid secretion, which reprogrammed these cells to rely on oxidative phosphorylation and mitochondrial ATP production to maintain viability. In contrast to previous pharmacological inhibition of glycolysis that suppressed tumor growth, -KO surprisingly demonstrated only a moderate impact on normoxic cell growth. However, hypoxic (1% O) cell growth was severely restricted. Despite growth restriction under hypoxia, tumor growth rates were reduced less than 2-fold for both -KO cancer cell lines. Combined our results indicate that exclusive use of oxidative metabolism has the capacity to provide metabolic precursors for biomass synthesis and fast growth. This work and others clearly indicate that metabolic cancer cell plasticity poses a strong limitation to anticancer strategies." 8349;"Immunosuppressive Mesenchymal Stromal Cells Derived from Human-Induced Pluripotent Stem Cells Induce Human Regulatory T Cells and .";"N. Mazure";"Equipe 05, Team 05";29422893;"Frontiers in immunology";"Roux C, Saviane G, Pini J, Belaïd N, Dhib G, Voha C, Ibáñez L, Boutin A, Mazure NM, Wakkach A, Blin-Wakkach C, Rouleau M";;"Jan 2017";1483228800;;"Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited expansion, absence of a full phenotypic characterization, few insights on their fate). Standardized MSCs derived from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4 FoxP3 regulatory T (Treg) cells. Further tested in a model of human T-cell expansion in immune-deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3-Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells . They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance." 8347;"The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma.";"N. Mazure";"Equipe 05, Team 05";29481555;"PloS one";"Ambrosetti D, Dufies M, Dadone B, Durand M, Borchiellini D, Amiel J, Pouyssegur J, Rioux-Leclercq N, Pages G, Burel-Vandenbos F, Mazure NM";;"Jan 2018";1514764800;;"Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed." 8345;"Hypoxic-induced truncation of voltage-dependent anion channel 1 is mediated by both asparagine endopeptidase and calpain 1 activities.";"N. Mazure";"Equipe 05, Team 05";29560113;Oncotarget;"Pahima H, Reina S, Tadmor N, Dadon-Klein D, Shteinfer-Kuzmine A, Mazure NM, De Pinto V, Shoshan-Barmatz V";;"02 2018";1517443200;;"The voltage-dependent anion channel 1 (VDAC1), an outer mitochondria membrane (OMM) protein, serves as a mitochondrial gatekeeper, mediating the transport of nucleotides, Ca and other metabolites across the OMM. VDAC1 also plays a central role in mitochondria-mediated apoptosis by facilitating the release of apoptotic proteins and by association with both pro- and anti-apoptotic proteins. Tumor cells, which are constantly exposed to hypoxic conditions, affect the cell via the transcription factor hypoxia-inducible factor (HIF) that induces transcriptional activity. In cultured cells and in lung cancer patients, hypoxia induces VDAC1 truncation at the C-terminus (VDAC1-ΔC). However, the molecular mechanisms involved in VDAC1-ΔC formation are unknown. Here, we show that hypoxia-induced VDAC1-ΔC formation is inhibited by the Ca chelator BAPTA-AM, by calpain inhibitor-1, by inhibitor of the asparagine endopeptidase (AEP) and by si-RNA targeting HIF1-α or Ca-activated protease calpain-1 expression but not that of calpain-2. Finally, VDAC1-ΔC expressed in bacteria and reconstituted into a planar lipid bilayer exhibited decreased channel conductance relative to the full-length protein, yet retained voltage-dependent conductance. These findings suggest that hypoxia, acting via HIF-1α expression, leads to VDAC1 cleavage involving the activation of calpain 1 and AEP." 8343;"Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation.";"N. Mazure";"Equipe 05, Team 05";29596470;"PloS one";"Ferecatu I, Canal F, Fabbri L, Mazure NM, Bouton C, Golinelli-Cohen MP";;"Jan 2018";1514764800;;"Biogenesis of iron-sulfur clusters (ISC) is essential to almost all forms of life and involves complex protein machineries. This process is initiated within the mitochondrial matrix by the ISC assembly machinery. Cohort and case report studies have linked mutations in ISC assembly machinery to severe mitochondrial diseases. The voltage-dependent anion channel (VDAC) located within the mitochondrial outer membrane regulates both cell metabolism and apoptosis. Recently, the C-terminal truncation of the VDAC1 isoform, termed VDAC1-ΔC, has been observed in chemoresistant late-stage tumor cells grown under hypoxic conditions with activation of the hypoxia-response nuclear factor HIF-1α. These cells harbored atypical enlarged mitochondria. Here, we show for the first time that depletion of several proteins of the mitochondrial ISC machinery in normoxia leads to a similar enlarged mitochondria phenotype associated with accumulation of VDAC1-ΔC. This truncated form of VDAC1 accumulates in the absence of HIF-1α and HIF-2α activations and confers cell resistance to drug-induced apoptosis. Furthermore, we show that when hypoxia and siRNA knock-down of the ISC machinery core components are coupled, the cell phenotype is further accentuated, with greater accumulation of VDAC1-ΔC. Interestingly, we show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis. Finally, we have identified the mitochondria-associated membrane (MAM) localized Fe-S protein CISD2 as a link between ISC machinery downregulation and accumulation of anti-apoptotic VDAC1-ΔC. Our results are the first to associate dysfunction in Fe-S cluster biogenesis with cleavage of VDAC1, a form which has previously been shown to promote tumor resistance to chemotherapy, and raise new perspectives for targets in cancer therapy." 8341;"[The oyster Crassostrea gigas, a new model against cancer].";"N. Mazure";"Equipe 05, Team 05";31115329;"Medecine sciences : M/S";"Corporeau C, Huvet A, Pichereau V, Delisle L, Quéré C, Dubreuil C, Artigaud S, Brenner C, Meyenberg Cunha-De Padua M, Mazure N";;"May 2019";1556668800;;"The Warburg effect is one of the hallmarks of cancer cells in humans. It is a true metabolic reprogramming to aerobic glycolysis, allowing cancer cells to meet their particular energy needs for growth, proliferation, and resistance to apoptosis, depending on the microenvironment they encounter within the tumor. We have recently discovered that the Crassostrea gigas oyster can naturally reprogram its metabolism to the Warburg effect. Thus, the oyster becomes a new invertebrate model useful for cancer research. Due to its lifestyle, the oyster C. gigas has special abilities to adapt its metabolism to the extreme changes in the environment in which it is located. The oyster C. gigas is therefore a model of interest to study how the environment can control the Warburg effect under conditions that could not be explored in vertebrate model species." 8339;"Resveratrol and HIV-protease inhibitors control UCP1 expression through opposite effects on p38 MAPK phosphorylation in human adipocytes.";"N. Mazure";"Equipe 05, Team 05";31294462;"Journal of cellular physiology";"Ravaud C, Paré M, Yao X, Azoulay S, Mazure NM, Dani C, Ladoux A";;"02 2020";1580515200;;"Brown and brown-like adipocytes (BBAs) control thermogenesis and are detected in adult humans. They express UCP1, which transforms energy into heat. They appear as promising cells to fight obesity. Deciphering the molecular mechanisms leading to the browning of human white adipocytes or the whitening of BBAs represents a goal to properly and safely control the pathways involved in these processes. Here, we analyzed how drugs endowed with therapeutic potential affect the differentiation of human adipose progenitor-cells into BBAs and/or their phenotype. We showed that HIV-protease inhibitors (PI) reduced UCP1 expression in BBAs modifying their metabolic profile and the mitochondria functionality. Lopinavir (LPV) was more potent than darunavir (DRV), a last PI generation. PPARγ and PGC-1α were decreased in a PI or cell-specific manner, thus altering UCP1's constitutive expression. In addition, LPV altered p38 MAPK phosphorylation, blunting then the β-adrenergic responses. In contrast, low doses of resveratrol stimulated the activatable expression of UCP1 in a p38 MAPK-dependent manner and counteracted the LPV induced loss of UCP1. This effect was independent of the resveratrol-induced sirtuin-1 expression. Altogether our results uncover how drugs impact crucial components of the networks regulating the expression of the thermogenic signature. They provide important information to control the relevant pathways involved in energy expenditure." 8337;"Role of Hypoxia and Metabolism in the Development of Neointimal Hyperplasia in Arteriovenous Fistulas.";"J. Contenti, N. Mazure";"Equipe 05, Team 05";31671790;"International journal of molecular sciences";"Sadaghianloo N, Contenti J, Dardik A, Mazure NM";;"Oct 2019";1569888000;;"For patients with end-stage renal disease requiring hemodialysis, their vascular access is both their lifeline and their Achilles heel. Despite being recommended as primary vascular access, the arteriovenous fistula (AVF) shows sub-optimal results, with about 50% of patients needing a revision during the year following creation. After the AVF is created, the venous wall must adapt to new environment. While hemodynamic changes are responsible for the adaptation of the extracellular matrix and activation of the endothelium, surgical dissection and mobilization of the vein disrupt the , causing wall ischemia and oxidative stress. As a consequence, migration and proliferation of vascular cells participate in venous wall thickening by a mechanism of neointimal hyperplasia (NH). When aggressive, NH causes stenosis and AVF dysfunction. In this review we show how hypoxia, metabolism, and flow parameters are intricate mechanisms responsible for the development of NH and stenosis during AVF maturation." 8335;"[About the 2019 Nobel Prize in Medicine].";"N. Mazure";"Equipe 05, Team 05";31711571;"Bulletin du cancer";"Mazure N";;"Nov 2019";1572566400;; 8333;"Cyclin D1 targets hexokinase 2 to control aerobic glycolysis in myeloma cells.";"N. Mazure";"Equipe 05, Team 05";32709889;Oncogenesis;"Caillot M, Bourgeais J, Dakik H, Costé É, Mazure NM, Lelièvre É, Coqueret O, Hérault O, Mazurier F, Sola B";;"Jul 2020";1593561600;;"Cancer cells are characterized by the Warburg effect, a shift from mitochondrial respiration to oxidative glycolysis. We report here the crucial role of cyclin D1 in promoting this effect in a cyclin-dependent kinase (CDK)4/6-independent manner in multiple myeloma (MM) cells. We show that the cyclin D1 oncoprotein targets hexokinase 2 (HK2), a major glycolysis regulator, through two original molecular mechanisms in the cytoplasmic and nuclear compartments. In the cytoplasm, cyclin D1 binds HK2 at the outer mitochondrial membrane, and in the nucleus, it binds hypoxia-inducible factor-1α (HIF1α), which regulates HK2 gene transcription. We also show that high levels of HK2 expression are correlated with shorter event-free survival (EFS) and overall survival (OS) in MM patients. HK2 may therefore be considered as a possible target for antimyeloma therapy." 8331;"Artery to vein configuration of arteriovenous fistula improves hemodynamics to increase maturation and patency.";"N. Mazure";"Equipe 05, Team 05";32817365;"Science translational medicine";"Bai H, Sadaghianloo N, Gorecka J, Liu S, Ono S, Ramachandra AB, Bonnet S, Mazure NM, Declemy S, Humphrey JD, Dardik A";;"08 2020";1596240000;;"Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, but 60% of conventional [vein-to-artery (V-A)] AVF fail to mature, and only 50% remain patent at 1 year. We previously showed improved maturation and patency in a pilot study of the radial artery deviation and reimplantation (RADAR) technique that uses an artery-to-vein (A-V) configuration. Here, we show that RADAR exhibits higher rates of maturation, as well as increased primary and secondary long-term patencies. RADAR is also protective in female patients, where it is associated with decreased reintervention rates and improved secondary patency. RADAR and conventional geometries were compared further in a rat bilateral carotid artery-internal jugular vein fistula model. There was decreased cell proliferation and neointimal hyperplasia in the A-V configuration in male and female animals, but no difference in hypoxia between the A-V and V-A configurations. Similar trends were seen in uremic male rats. The A-V configuration also associated with increased peak systolic velocity and expression of Kruppel-like factor 2 and phosphorylated endothelial nitric oxide synthase, consistent with improved hemodynamics. Computed tomography and ultrasound-informed computational modeling showed different hemodynamics in the A-V and V-A configurations, and improving the hemodynamics in the V-A configuration was protective against neointimal hyperplasia. These findings collectively demonstrate that RADAR is a durable surgical option for patients requiring radial-cephalic AVF for hemodialysis access." 8329;"Glutamine Availability Controls BCR/Abl Protein Expression and Functional Phenotype of Chronic Myeloid Leukemia Cells Endowed with Stem/Progenitor Cell Potential.";"N. Mazure";"Equipe 05, Team 05";34503182;Cancers;"Poteti M, Menegazzi G, Peppicelli S, Tusa I, Cheloni G, Silvano A, Mancini C, Biagioni A, Tubita A, Mazure NM, Lulli M, Rovida E, Dello Sbarba P";;"Aug 2021";1627776000;;"This study was directed to characterize the role of glutamine in the modulation of the response of chronic myeloid leukemia (CML) cells to low oxygen, a main condition of hematopoietic stem cell niches of bone marrow. Cells were incubated in atmosphere at 0.2% oxygen in the absence or the presence of glutamine. The absence of glutamine markedly delayed glucose consumption, which had previously been shown to drive the suppression of BCR/Abl oncoprotein (but not of the fusion oncogene /) in low oxygen. Glutamine availability thus emerged as a key regulator of the balance between the pools of BCR/Abl protein-expressing and -negative CML cells endowed with stem/progenitor cell potential and capable to stand extremely low oxygen. These findings were confirmed by the effects of the inhibitors of glucose or glutamine metabolism. The BCR/Abl-negative cell phenotype is the best candidate to sustain the treatment-resistant minimal residual disease (MRD) of CML because these cells are devoid of the molecular target of the BCR/Abl-active tyrosine kinase inhibitors (TKi) used for CML therapy. Therefore, the treatments capable of interfering with glutamine action may result in the reduction in the BCR/Abl-negative cell subset sustaining MRD and in the concomitant rescue of the TKi sensitivity of CML stem cell potential. The data obtained with glutaminase inhibitors seem to confirm this perspective." 8311;"c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.";;;16847353;"Genes & development";"Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster JC";;"Aug 2006";1154390400;;"Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells." 8307;"Extrathymic hemopoietic progenitors committed to T cell differentiation in the adult mouse.";;;15699126;"Journal of immunology (Baltimore, Md. : 1950)";"Arcangeli ML, Lancrin C, Lambolez F, Cordier C, Schneider E, Rocha B, Ezine S";;"Feb 2005";1107907200;;"The role of the thymus in T cell commitment of hemopoietic precursor is yet controversial. We previously identified a major T cell progenitor activity in precursor cells isolated from bone marrow-derived spleen colonies. In this study, we characterize the properties of these pre-T cells. We demonstrate that they have unique phenotype and can be generated in a total absence of any thymic influence. Indeed, even when studied at the single-cell level, extrathymic T cell-committed precursors express T cell-specific genes. Moreover, these cells are not committed to a particular T cell differentiation pathway because they can generate both extrathymic CD8alphaalpha+ intraepithelial lymphocytes and thymus-derived conventional thymocytes. We also compared these pre-T cells with fully T cell-committed thymic progenitors. When tested in vitro or by direct intrathymic transfer, these cells have a low clonogenic activity. However, after i.v. transfer, thymus repopulation is efficient and these precursors generate very high numbers of peripheral T cells. These results suggest the existence of extra steps of pre-T cell maturation that improve thymus reconstitution capacity and that can be delivered even after full T cell commitment. Consequently, our studies identify a source of extrathymic progenitors that will be helpful in defining the role of the thymus in the earliest steps of T cell differentiation." 8309;"Major T cell progenitor activity in bone marrow-derived spleen colonies.";;;11927635;"The Journal of experimental medicine";"Lancrin C, Schneider E, Lambolez F, Arcangeli ML, Garcia-Cordier C, Rocha B, Ezine S";;"Apr 2002";1017619200;;"Common lymphoid progenitors (CLP) are generated in adult bone marrow (BM), but the intermediate steps leading to T cell commitment are unknown, and so is the site at which this commitment occurs. Here, we show that colonies arising in the spleen 12 days after BM injection harbor T cell precursors that are undetectable in BM. These precursors did not generate myeloid cells in vivo but repopulated the thymus and the peripheral T cell compartment much faster than did CLP. Two lineage negative (Lin(-)) subpopulations were distinguished, namely CD44(+) Thy1(-) cells still capable of natural killer generation and transient low-level B cell generation, and T cell-restricted CD44(-) Thy1(+) cells. At a molecular level, frequency of CD3epsilon and preTalpha mRNA was very different in each subset. Furthermore, only the CD44(-) Thy1(+) subset have initiated rearrangements in the T cell receptor beta locus. Thus, this study identifies extramedullary T cell progenitors and will allow easy approach to T cell commitment studies." 8305;"The thymus exports long-lived fully committed T cell precursors that can colonize primary lymphoid organs.";;;16341216;"Nature immunology";"Lambolez F, Arcangeli ML, Joret AM, Pasqualetto V, Cordier C, Di Santo JP, Rocha B, Ezine S";;"Jan 2006";1136073600;;"Thymic export of cells is believed to be restricted to mature T cells. Here we show that the thymus also exports fully committed T cell precursors that colonize primary lymphoid organs. These precursor cells exited the thymus before T cell receptor rearrangements and colonized lymphoid organs such as the thymus and the gut. Migration of the thymic T cell-committed precursors led to permanent colonization of the gut precursor compartment, improved the capacity of gut precursors to further differentiate into T cells and was sufficient for the generation of 'euthymic like' CD8alphaalpha(+) intraepithelial lymphocytes. These data demonstrate a new function for the thymus in peripheral seeding with T cell precursors that become long lived after thymus export." 8303;"Hierarchy of Notch-Delta interactions promoting T cell lineage commitment and maturation.";;;17261636;"The Journal of experimental medicine";"Besseyrias V, Fiorini E, Strobl LJ, Zimber-Strobl U, Dumortier A, Koch U, Arcangeli ML, Ezine S, Macdonald HR, Radtke F";;"Jan 2007";1170201600;;"Notch1 (N1) receptor signaling is essential and sufficient for T cell development, and recently developed in vitro culture systems point to members of the Delta family as being the physiological N1 ligands. We explored the ability of Delta1 (DL1) and DL4 to induce T cell lineage commitment and/or maturation in vitro and in vivo from bone marrow (BM) precursors conditionally gene targeted for N1 and/or N2. In vitro DL1 can trigger T cell lineage commitment via either N1 or N2. N1- or N2-mediated T cell lineage commitment can also occur in the spleen after short-term BM transplantation. However, N2-DL1-mediated signaling does not allow further T cell maturation beyond the CD25(+) stage due to a lack of T cell receptor beta expression. In contrast to DL1, DL4 induces and supports T cell commitment and maturation in vitro and in vivo exclusively via specific interaction with N1. Moreover, comparative binding studies show preferential interaction of DL4 with N1, whereas binding of DL1 to N1 is weak. Interestingly, preferential N1-DL4 binding reflects reduced dependence of this interaction on Lunatic fringe, a glycosyl transferase that generally enhances the avidity of Notch receptors for Delta ligands. Collectively, our results establish a hierarchy of Notch-Delta interactions in which N1-DL4 exhibits the greatest capacity to induce and support T cell development." 8301;"Identification of an IL-7-dependent pre-T committed population in the spleen.";;;17709507;"Journal of immunology (Baltimore, Md. : 1950)";"Gautreau L, Arcangeli ML, Pasqualetto V, Joret AM, Garcia-Cordier C, Mégret J, Schneider E, Ezine S";;"Sep 2007";1188604800;;"Several extrathymic T cell progenitors have been described but their various contributions to the T cell lineage puzzle are unclear. In this study, we provide evidence for a splenic Lin(-)Thy1.2(+) T cell-committed population, rare in B6 mice, abundant in TCRalpha(-/-), CD3epsilon(-/-), and nude mice, and absent in IL-7- and Rag-2-deficient mice. Neither B nor myeloid cells are generated in vivo and in vitro. The incidence of these pre-T cells is under the control of thymus and/or mature T cells, as revealed by graft experiments. Indeed, IL-7 consumption by mature T cells inhibits the growth of these pre-T cells. Moreover, the nude spleen contains an additional Lin(-)Thy1.2(+)CD25(+) subset which is detected in B6 mice only after thymectomy. We establish that the full pre-T cell potential and proliferation capacity are only present in the c-kit(low) fraction of progenitors. We also show that most CCR9(+) progenitors are retained in the spleen of nude mice, but present in the blood of B6 mice. Thus, our data describe a new T cell lineage restricted subset that accumulates in the spleen before migration to the thymus." 8299;"Cutting edge: JAM-C controls homeostatic chemokine secretion in lymph node fibroblastic reticular cells expressing thrombomodulin.";;;21685324;"Journal of immunology (Baltimore, Md. : 1950)";"Frontera V, Arcangeli ML, Zimmerli C, Bardin F, Obrados E, Audebert S, Bajenoff M, Borg JP, Aurrand-Lions M";;"Jun 2011";1308614400;;"The development and maintenance of secondary lymphoid organs, such as lymph nodes, occur in a highly coordinated manner involving lymphoid chemokine production by stromal cells. Although developmental pathways inducing lymphoid chemokine production during organogenesis are known, signals maintaining cytokine production in adults are still elusive. In this study, we show that thrombomodulin and platelet-derived growth factor receptor α identify a population of fibroblastic reticular cells in which chemokine secretion is controlled by JAM-C. We demonstrate that Jam-C-deficient mice and mice treated with Ab against JAM-C present significant decreases in stromal cell-derived factor 1α (CXCL12), CCL21, and CCL19 intranodal content. This effect is correlated with reduced naive T cell egress from lymph nodes of anti-JAM-C-treated mice." 8297;"JAM-B regulates maintenance of hematopoietic stem cells in the bone marrow.";;;21868569;Blood;"Arcangeli ML, Frontera V, Bardin F, Obrados E, Adams S, Chabannon C, Schiff C, Mancini SJ, Adams RH, Aurrand-Lions M";;"Oct 2011";1317427200;;"In adult mammals, hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and are maintained in a quiescent and undifferentiated state through adhesive interactions with specialized microenvironmental niches. Although junctional adhesion molecule-C (JAM-C) is expressed by HSCs, its function in adult hematopoiesis remains elusive. Here, we show that HSCs adhere to JAM-B expressed by BM stromal cells in a JAM-C dependent manner. The interaction regulates the interplay between HSCs and BM stromal cells as illustrated by the decreased pool of quiescent HSCs observed in jam-b deficient mice. We further show that this is probably because of alterations of BM stromal compartments and changes in SDF-1α BM content in jam-b(-/-) mice, suggesting that JAM-B is an active player in the maintenance of the BM stromal microenvironment." 8295;"The Junctional Adhesion Molecule-B regulates JAM-C-dependent melanoma cell metastasis.";;;23068611;"FEBS letters";"Arcangeli ML, Frontera V, Bardin F, Thomassin J, Chetaille B, Adams S, Adams RH, Aurrand-Lions M";;"Nov 2012";1351728000;;"Metastasis is a major clinical issue and results in poor prognosis for most cancers. The Junctional Adhesion Molecule-C (JAM-C) expressed by B16 melanoma and endothelial cells has been involved in metastasis of tumor cells through homophilic JAM-C/JAM-C trans-interactions. Here, we show that JAM-B expressed by endothelial cells contributes to murine B16 melanoma cells metastasis through its interaction with JAM-C on tumor cells. We further show that this adhesion molecular pair mediates melanoma cell adhesion to primary Lung Microvascular Endothelial Cells and that it is functional in vivo as demonstrated by the reduced metastasis of B16 cells in Jam-b deficient mice." 8293;"Function of junctional adhesion molecules (JAMs) in leukocyte migration and homeostasis.";;;22940878;"Archivum immunologiae et therapiae experimentalis";"Arcangeli ML, Frontera V, Aurrand-Lions M";;"Feb 2013";1359676800;;"Homeostasis is a word widely used in the scientific community to refer to the property of a system to maintain its uniformity and functionality. In living organisms, the word refers to the concept enunciated 150 years ago by C. Bernard by which external variations must be compensated for in order to maintain internal conditions compatible with life. This is especially true in the case of highly dynamic system such as the hematopoietic system that requires the coordinated control of cell proliferation and death within specialized microenvironments that are anatomically distinct. As a consequence, hematopoietic cell adhesion and migration must be tightly controlled in order for hematopoietic cells to reach and to be maintained in appropriate microenvironments. The junctional adhesion molecules (JAMs) are adhesion molecules that belong to the immunoglobulin superfamily (IgSf) and that have been initially identified as important players controlling vascular permeability and leukocyte transendothelial migration. This involves the regulated localization of the JAMs at lateral endothelial cell/cell borders and their interaction with leukocyte integrins. More recently, some of the JAM family members have also been found to be expressed by stromal cells and to regulate chemokine secretion within lymphoid organs, acting not only on leukocyte transendothelial migration, but also on hematopoietic cell retention within specialized microenvironments. This review summarizes recent progress in understanding the role of the JAMs in leukocyte adhesion and migration to tentatively draw an integrated view of the homeostatic function of the JAMs within the hematopoietic system." 8291;"KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570.";;;23416972;Oncogene;"Chaix A, Arcangeli ML, Lopez S, Voisset E, Yang Y, Vita M, Letard S, Audebert S, Finetti P, Birnbaum D, Bertucci F, Aurrand-Lions M, Dubreuil P, De Sepulveda P";;"Feb 2014";1391212800;;"Mutation of KIT receptor tyrosine kinase at residue D816 results in ligand-independent constitutive kinase activity. This mutation occurs in most patients with mastocytosis, a myeloproliferative neoplasm, and is detected at lower frequencies in acute myeloid leukemia and in germ cell tumors. Other KIT mutations occur in gastrointestinal stromal tumors (GIST) and mucosal melanoma. KIT is considered as a bona fide therapeutic target as c-kit mutations are driving oncogenes in these pathologies. However, several evidences suggest that KIT-D816V mutant is not as aggressive as other KIT mutants. Here, we show that an intracellular docking site in the juxtamembrane region of KIT maintains a negative regulation on KIT-D816V transforming potential. Sixteen signaling proteins were shown to interact with this motif. We further demonstrate that mutation of this site results in signaling modifications, altered gene expression profile and increased transforming activity of KIT-D816V mutant. This result was unexpected as mutations of the homologous sites on wild-type (WT) KIT, or on the related oncogenic FLT3-ITD receptor, impair their function. Our results support the hypothesis that, KIT-D816V mutation is a mild oncogenic event that is sufficient to confer partial transforming properties, but requires additional mutations to acquire its full transforming potential." 8289;"Identification of a new stromal cell type involved in the regulation of inflamed B cell follicles.";;;24130458;"PLoS biology";"Mionnet C, Mondor I, Jorquera A, Loosveld M, Maurizio J, Arcangeli ML, Ruddle NH, Nowak J, Aurrand-Lions M, Luche H, Bajénoff M";;"Oct 2013";1380585600;;"Lymph node (LN) stromal cells provide survival signals and adhesive substrata to lymphocytes. During an immune response, B cell follicles enlarge, questioning how LN stromal cells manage these cellular demands. Herein, we used a murine fate mapping system to describe a new stromal cell type that resides in the T cell zone of resting LNs. We demonstrated that upon inflammation, B cell follicles progressively trespassed into the adjacent T cell zone and surrounded and converted these stromal cells into CXCL13 secreting cells that in return delineated the new boundaries of the growing follicle. Acute B cell ablation in inflamed LNs abolished CXCL13 secretion in these cells, while LT-β deficiency in B cells drastically affected this conversion. Altogether, we reveal the existence of a dormant stromal cell subset that can be functionally awakened by B cells to delineate the transient boundaries of their expanding territories upon inflammation." 8287;"Function of Jam-B/Jam-C interaction in homing and mobilization of human and mouse hematopoietic stem and progenitor cells.";;;24357068;"Stem cells (Dayton, Ohio)";"Arcangeli ML, Bardin F, Frontera V, Bidaut G, Obrados E, Adams RH, Chabannon C, Aurrand-Lions M";;"Apr 2014";1396310400;;"The junctional adhesion molecules Jam-b and Jam-c interact together at interendothelial junctions and have been involved in the regulation of immune response, inflammation, and leukocyte migration. More recently, Jam-c has been found to be expressed by hematopoietic stem and progenitor cells (HSPC) in mouse. Conversely, we have reported that Jam-b is present on bone marrow stromal cells and that Jam-b-deficient mice have defects in the regulation of hematopoietic stem cell pool. In this study, we have addressed whether interaction between Jam-b and Jam-c participates to HSPC mobilization or hematopoietic reconstitution after irradiation. We show that a blocking monoclonal antibody directed against Jam-c inhibits hematopoietic reconstitution, progenitor homing to the bone marrow, and induces HSPC mobilization in a Jam-b dependent manner. In the latter setting, antibody treatment over a period of 3 days does not alter hematopoietic differentiation nor induce leukocytosis. Results are translated to human hematopoietic system in which a functional adhesive interaction between JAM-B and JAM-C is found between human HSPC and mesenchymal stem cells. Such an interaction does not occur between HSPC and human endothelial cells or osteoblasts. It is further shown that anti-JAM-C blocking antibody interferes with CD34(+) hematopoietic progenitor homing in mouse bone marrow suggesting that monoclonal antibodies inhibiting JAM-B/JAM-C interaction may represent valuable therapeutic tools to improve stem cell mobilization protocols." 8285;"The SCL/TAL1 Transcription Factor Represses the Stress Protein DDiT4/REDD1 in Human Hematopoietic Stem/Progenitor Cells.";;;25858676;"Stem cells (Dayton, Ohio)";"Benyoucef A, Calvo J, Renou L, Arcangeli ML, van den Heuvel A, Amsellem S, Mehrpour M, Larghero J, Soler E, Naguibneva I, Pflumio F";;"Apr 2015";1428710400;;"Hematopoietic stem/progenitor cells (HSPCs) are regulated through numerous molecular mechanisms that have not been interconnected. The transcription factor stem cell leukemia/T-cell acute leukemia 1 (TAL1) controls human HSPC but its mechanism of action is not clarified. In this study, we show that knockdown (KD) or short-term conditional over-expression (OE) of TAL1 in human HSPC ex vivo, respectively, blocks and maintains hematopoietic potentials, affecting proliferation of human HSPC. Comparative gene expression analyses of TAL1/KD and TAL1/OE human HSPC revealed modifications of cell cycle regulators as well as previously described TAL1 target genes. Interestingly an inverse correlation between TAL1 and DNA damage-induced transcript 4 (DDiT4/REDD1), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, is uncovered. Low phosphorylation levels of mTOR target proteins in TAL1/KD HSPC confirmed an interplay between mTOR pathway and TAL1 in correlation with TAL1-mediated effects of HSPC proliferation. Finally chromatin immunoprecipitation experiments performed in human HSPC showed that DDiT4 is a direct TAL1 target gene. Functional analyses showed that TAL1 represses DDiT4 expression in HSPCs. These results pinpoint DDiT4/REDD1 as a novel target gene regulated by TAL1 in human HSPC and establish for the first time a link between TAL1 and the mTOR pathway in human early hematopoietic cells. Stem Cells 2015;33:2268-2279." 8283;"Control of developmentally primed erythroid genes by combinatorial co-repressor actions.";;;26593974;"Nature communications";"Stadhouders R, Cico A, Stephen T, Thongjuea S, Kolovos P, Baymaz HI, Yu X, Demmers J, Bezstarosti K, Maas A, Barroca V, Kockx C, Ozgur Z, van Ijcken W, Arcangeli ML, Andrieu-Soler C, Lenhard B, Grosveld F, Soler E";;"Nov 2015";1446336000;;"How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2-IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation." 8281;"Dok1 and Dok2 Proteins Regulate Cell Cycle in Hematopoietic Stem and Progenitor Cells.";;;27183638;"Journal of immunology (Baltimore, Md. : 1950)";"Coppin E, De Grandis M, Pandolfi PP, Arcangeli ML, Aurrand-Lions M, Nunès JA";;"05 2016";1462060800;;"Dok1 and Dok2 proteins play a crucial role in myeloid cell proliferation as demonstrated by Dok1 and Dok2 gene inactivation, which induces a myeloproliferative disease in aging mice. In this study, we show that Dok1/Dok2 deficiency affects myeloproliferation even at a young age. An increase in the cellularity of multipotent progenitors is observed in young Dok1/Dok2-deficient mice. This is associated with an increase in the cells undergoing cell cycle, which is restricted to myeloid committed progenitors. Furthermore, cellular stress triggered by 5-fluorouracil (5-FU) treatment potentiates the effects of the loss of Dok proteins on multipotent progenitor cell cycle. In addition, Dok1/Dok2 deficiency induces resistance to 5-FU-induced hematopoietic stem cell exhaustion. Taken together, these results demonstrate that Dok1 and Dok2 proteins are involved in the control of hematopoietic stem cell cycle regulation." 8279;"Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools as a Result of Deregulated Proliferation and Migration.";;;27183644;"Journal of immunology (Baltimore, Md. : 1950)";"Lhoumeau AC, Arcangeli ML, De Grandis M, Giordano M, Orsoni JC, Lembo F, Bardin F, Marchetto S, Aurrand-Lions M, Borg JP";;"May 2016";1463443200;;"Hematopoietic stem cells (HSCs) located in adult bone marrow or fetal liver in mammals produce all cells from the blood system. At the top of the hierarchy are long-term HSCs endowed with lifelong self-renewal and differentiation properties. These features are controlled through key microenvironmental cues and regulatory pathways, such as Wnt signaling. We showed previously that PTK7, a tyrosine kinase receptor involved in planar cell polarity, plays a role in epithelial Wnt signaling; however, its function in hematopoiesis has remained unexplored. In this article, we show that PTK7 is expressed by hematopoietic stem and progenitor cells, with the highest level of protein expression found on HSCs. Taking advantage of a Ptk7-deficient mouse strain, we demonstrate that loss of Ptk7 leads to a diminished pool of HSCs but does not affect in vitro or in vivo hematopoietic cell differentiation. This is correlated with increased quiescence and reduced homing abilities of Ptk7-deficient hematopoietic stem and progenitor cells, unraveling novel and unexpected functions for planar cell polarity pathways in HSC fate." 8277;"Stem Cell Leukemia: how a TALented actor can go awry on the hematopoietic stage.";;;27443261;Leukemia;"Correia NC, Arcangeli ML, Pflumio F, Barata JT";;"10 2016";1475280000;;"TAL1/SCL/TCL5 is a critical transcription factor for hematopoietic stem cell maintenance and regulation of early hematopoiesis. However, aberrant expression of TAL1 in committed T-cell precursors is also directly implicated in the development of T-cell leukemia. Roughly 25 years ago TAL1 was identified in early hematopoietic cells and involved in leukemia. Here, we review the wealth of knowledge gained since then on its physiological roles and mechanisms by which TAL1 ectopic expression contributes to leukemogenesis. We emphasize recent findings that shed light into the intricacies of TAL1 (epi)genetic regulation and the transcription network orchestrated by this major T-cell oncogene. Importantly, an exciting time is coming when data using the mechanistic knowledge accumulated on TAL1 may be used to develop novel anti-leukemia targeted therapies." 8275;"Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes.";;;27856460;Blood;"Chesnais V, Arcangeli ML, Delette C, Rousseau A, Guermouche H, Lefevre C, Bondu S, Diop M, Cheok M, Chapuis N, Legros L, Raynaud S, Willems L, Bouscary D, Lauret E, Bernard OA, Kosmider O, Pflumio F, Fontenay M";;"01 2017";1483228800;;"Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non-del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34CD38 hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell compartment that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage. The pattern of mutations may differ between common myeloid progenitors (CMPs), granulomonocytic progenitors (GMPs), and megakaryocytic-erythroid progenitors (MEPs). Rare STAG2 mutations can amplify at the level of GMPs, from which it may drive the transformation to acute myeloid leukemia. We report that major truncating BCOR gene mutation affecting HSPC and CMP was beneath the threshold of detection in GMP or MEP. Consistently, BCOR knock-down (KD) in normal CD34 progenitors modifies their granulocytic and erythroid differentiation. Clonal architecture of the HSPC compartment and mutations selected during differentiation contribute to the phenotypic heterogeneity of MDS. Defining the hierarchy of driver mutations provides insights into the process of transformation and may guide the search for novel therapeutic strategies." 8273;"Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia.";;;29296822;"Blood advances";"Cahu X, Calvo J, Poglio S, Prade N, Colsch B, Arcangeli ML, Leblanc T, Petit A, Baleydier F, Baruchel A, Landman-Parker J, Junot C, Larghero J, Ballerini P, Delabesse E, Uzan B, Pflumio F";;"Sep 2017";1504224000;;"T-cell acute lymphoblastic leukemia (T-ALL) expands in various bone marrow (BM) sites of the body. We investigated whether different BM sites could differently modulate T-ALL propagation using in vivo animal models. We observed that mouse and human T-ALL develop slowly in the BM of tail vertebrae compared with the BM from thorax vertebrae. T-ALL recovered from tail BM displays lower cell-surface marker expression and decreased metabolism and cell-cycle progression, demonstrating a dormancy phenotype. Functionally, tail-derived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are noncell-autonomous because T-ALL from tail and thorax shares identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL displays higher intrinsic resistance to cell-cycle-related drugs (ie, vincristine sulfate and cytarabine). Of note, T-ALL recovered from gonadal adipose tissues or from cocultures with adipocytes shares metabolic, cell-cycle, and phenotypic or chemoresistance features, with tail-derived T-ALL suggesting adipocytes may participate in the tail BM imprints on T-ALL. Altogether these results demonstrate that BM sites differentially orchestrate T-ALL propagation stamping specific features to leukemic cells such as quiescence and decreased response to cell-cycle-dependent chemotherapy." 8271;"Frontline Science: Exhaustion and senescence marker profiles on human T cells in BRGSF-A2 humanized mice resemble those in human samples.";;;31378988;"Journal of leukocyte biology";"Labarthe L, Henriquez S, Lambotte O, Di Santo JP, Le Grand R, Pflumio F, Arcangeli ML, Legrand N, Bourgeois C";;"01 2020";1577836800;;"This work sought to confirm the human-like expression of exhaustion and senescence markers in a mouse model with a humanized immune system (HIS): the Balb/c Rag2 IL2rgc Sirpα Flk2 HLA-A2 (BRGSF-A2) mouse reconstituted with human CD34 cord blood cells. With regard to senescence markers, the percentage of CD57 T cells was higher in the bone marrow (BM) than in the spleen or blood. The same was true for KLRG1 hCD8 T cells. With regard to exhaustion markers, the percentage of programmed death 1 (PD-1 ) T cells was higher in the BM than in the spleen or blood; the same was true for TIGIT hCD4 cells. These tissue-specific differences were related to both higher proportions of memory T cells in BM and intrinsic differences in expression within the memory fraction. In blood samples from HIS mice and healthy human donors (HDs), we found that the percentage of KLRG1 cells among hCD8 T cells was lower in HIS compared to HDs. The opposite was true for CD4 T cells. Unexpectedly, a high frequency of KLRG1 cells was observed among naive T cells in HIS mice. CD57 expression on T cells was similar in blood samples from HIS mice and HDs. Likewise, PD-1 expression was similar in the two systems, although a relatively low proportion of HIS hCD4 T cells expressed TIGIT. The BRGSF-A2 HIS mouse's exhaustion and senescence profile was tissue specific and relatively human like; hence, this mouse might be a valuable tool for determining the preclinical efficacy of immunotherapies." 8269;"Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.";;;31662298;"Cancer discovery";"Lopez CK, Noguera E, Stavropoulou V, Robert E, Aid Z, Ballerini P, Bilhou-Nabera C, Lapillonne H, Boudia F, Thirant C, Fagnan A, Arcangeli ML, Kinston SJ, Diop M, Job B, Lecluse Y, Brunet E, Babin L, Villeval JL, Delabesse E, Peters AHFM, Vainchenker W, Gaudry M, Masetti R, Locatelli F, Malinge S, Nerlov C, Droin N, Lobry C, Godin I, Bernard OA, Göttgens B, Petit A, Pflumio F, Schwaller J, Mercher T";;"12 2019";1575158400;;"Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as , are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and -induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state..." 8267;"Hypoxia Regulates Lymphoid Development of Human Hematopoietic Progenitors.";;;31747603;"Cell reports";"Chabi S, Uzan B, Naguibneva I, Rucci J, Fahy L, Calvo J, Arcangeli ML, Mazurier F, Pflumio F, Haddad R";;"11 2019";1572566400;;"Hypoxia plays a major role in the physiology of hematopoietic and immune niches. Important clues from works in mouse have paved the way to investigate the role of low O levels in hematopoiesis. However, whether hypoxia impacts the initial steps of human lymphopoiesis remains unexplored. Here, we show that hypoxia regulates cellular and metabolic profiles of umbilical cord blood (UCB)-derived hematopoietic progenitor cells. Hypoxia more specifically enhances in vitro lymphoid differentiation potentials of lymphoid-primed multipotent progenitors (LMPPs) and pro-T/natural killer (NK) cells and in vivo B cell potential of LMPPs. In accordance, hypoxia exacerbates the lymphoid gene expression profile through hypoxia-inducible factor (HIF)-1α (for LMPPs) and HIF-2α (for pro-T/NK). Moreover, loss of HIF-1/2α expression seriously impedes NK and B cell production from LMPPs and pro-T/NK. Our study describes how hypoxia contributes to the lymphoid development of human progenitors and reveals the implication of the HIF pathway in LMPPs and pro-T/NK-cell lymphoid identities." 8265;"Human hematopoietic stem/progenitor cells display reactive oxygen species-dependent long-term hematopoietic defects after exposure to low doses of ionizing radiations.";;;31780635;Haematologica;"Henry E, Souissi-Sahraoui I, Deynoux M, Lefèvre A, Barroca V, Campalans A, Ménard V, Calvo J, Pflumio F, Arcangeli ML";;"08 2020";1596240000;;"Hematopoietic stem cells are responsible for life-long blood cell production and are highly sensitive to exogenous stresses. The effects of low doses of ionizing radiations on radiosensitive tissues such as the hematopoietic tissue are still unknown despite their increasing use in medical imaging. Here, we study the consequences of low doses of ionizing radiations on differentiation and self-renewal capacities of human primary hematopoietic stem/progenitor cells (HSPC). We found that a single 20 mGy dose impairs the hematopoietic reconstitution potential of human HSPC but not their differentiation properties. In contrast to high irradiation doses, low doses of irradiation do not induce DNA double strand breaks in HSPC but, similar to high doses, induce a rapid and transient increase of reactive oxygen species (ROS) that promotes activation of the p38MAPK pathway. HSPC treatment with ROS scavengers or p38MAPK inhibitor prior exposure to 20 mGy irradiation abolishes the 20 mGy-induced defects indicating that ROS and p38MAPK pathways are transducers of low doses of radiation effects. Taken together, these results show that a 20 mGy dose of ionizing radiation reduces the reconstitution potential of HSPC suggesting an effect on the self-renewal potential of human hematopoietic stem cells and pinpointing ROS or the p38MAPK as therapeutic targets. Inhibition of ROS or the p38MAPK pathway protects human primary HSPC from low-dose irradiation toxicity." 8263;"Combined G-CSF and Plerixafor enhance hematopoietic recovery of CD34 cells from poor mobilizer patients in NSG mice.";;;32450206;"Experimental hematology";"Arcangeli ML, Brault P, Bourhis JH, Kuhnowskie F, Henry E, Barroca V, Koscielny S, Pflumio F, Amsellem S";;"06 2020";1590969600;;"Transplantable CD34 hematopoietic stem/progenitor cells (HSPCs) are currently isolated mainly from peripheral blood after mobilization with granulocyte colony-stimulating factor (G-CSF). These mobilized CD34 cells have the potential to generate all blood cell types. For autologous transplantation, the minimal number of mobilized CD34 cells is 2 × 10 CD34 cells/kg body weight. However, up to 30% of patients fail to mobilize enough peripheral CD34 cells after G-CSF treatment. To overcome this limitation, a combination of G-CSF and Plerixafor, a CXCR4 chemokine receptor inhibitor, is proposed to enhance CD34 cell mobilization in poor mobilizer patients. However, only limited data are available on quantification of the functional quality of such patients' mobilized hematopoietic stem cells. Here, for six poor mobilizer patients, a head-to-head comparison of their CD34 cells mobilized without versus with Plerixafor was performed to assess their properties with respect to the reconstitution of human hematopoiesis in vivo in immune-deficient mice. Our results indicate that mobilized CD34 cells recovered after the G-CSF + Plerixafor mobilization protocol have an enhanced intrinsic hematopoietic reconstitution potential compared with CD34 cells mobilized with G-CSF alone." 8261;"How Hematopoietic Stem Cells Respond to Irradiation: Similarities and Differences between Low and High Doses of Ionizing Radiations.";;;33290858;"Experimental hematology";"Henry E, Arcangeli ML";;"02 2021";1612137600;;"In this review, we will specifically address the newest insights on the effect of low doses of ionizing radiations on the hematopoietic stem cells, which are prone to long-term deleterious effects. Impact of high doses of irradiation on hematopoietic cells has been widely studied over the years, in line with the risk of accidental or terrorist exposure to irradiation and with a particular attention to the sensitivity of the hematopoietic system. Recently, more studies have focused on lower doses of irradiation on different tissues, due to the increasing exposure caused by medical imaging, radiotherapy or plane travelling for instance. Hence, we will delineate similarities and discrepancies in HSC response to high and low doses of irradiation from these studies." 8258;"Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop.";;;33496749;"Blood advances";"Fahy L, Calvo J, Chabi S, Renou L, Le Maout C, Poglio S, Leblanc T, Petit A, Baruchel A, Ballerini P, Naguibneva I, Haddad R, Arcangeli ML, Mazurier F, Pflumio F, Uzan B";;"01 2021";1609459200;;"Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches." 8257;"JAM-C/ Expression Is Primarily Expressed in Mouse Hematopoietic Stem Cells.";;;34131634;HemaSphere;"Henry E, Barroca V, Lopez CK, Aurrand-Lions M, Lewandowski D, Mercher T, Arcangeli ML";;"Jul 2021";1625097600;; 8253;"Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage.";"F. BOST";"Equipe 05, Team 05";11802792;"The Biochemical journal";"Bost F, Caron L, Marchetti I, Dani C, Le Marchand-Brustel Y, Binétruy B";;"Feb 2002";1012521600;;"Mouse embryonic stem (ES) cells are pluripotent cells that differentiate into multiple cell lineages. The commitment of ES cells into the adipocyte lineage is dependent on an early 3-day treatment with all-trans retinoic acid (RA). To characterize the molecular mechanisms underlying this process, we examined the contribution of the extracellular-signal-regulated kinase (ERK) pathway. Treatment of ES cell-derived embryoid bodies with RA resulted in a prolonged activation of the ERK pathway, but not the c-Jun N-terminal kinase, p38 mitogen-activated protein kinase or phosphoinositide 3-kinase pathways. To investigate the role of ERK activation, co-treatment of RA with PD98059, a specific inhibitor of the ERK signalling pathway, prevented both adipocyte formation and expression of the adipogenic markers, adipocyte lipid-binding protein and peroxisome-proliferator-activated receptor gamma. Furthermore, we show that ERK activation is required only during RA treatment. PD98059 does not interfere with the commitment of ES cells into other lineages, such as neurogenesis, myogenesis and cardiomyogenesis. As opposed to the controversial role of the ERK pathway in terminal differentiation, our results clearly demonstrate that this pathway is specifically required at an early stage of adipogenesis, corresponding to the RA-dependent commitment of ES cells." 8251;"C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma.";"F. BOST";"Equipe 05, Team 05";12538493;"Clinical cancer research : an official journal of the American Association for Cancer Research";"Yang YM, Bost F, Charbono W, Dean N, McKay R, Rhim JS, Depatie C, Mercola D";;"Jan 2003";1041379200;;"C-Jun NH(2)-terminal kinase (JNK) has been implicated in numerous functions including stress responses, apoptosis,and transformation. The role in transformation is based largely on studies of isolated cell types with little indication of whether JNK plays a general role in a specific human tumor type or whether this occurs in vivo." 8249;"The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis.";"F. BOST";"Equipe 05, Team 05";15677498;Diabetes;"Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M, Dani C, Hofman P, Pagès G, Pouysségur J, Le Marchand-Brustel Y, Binétruy B";;"Feb 2005";1107216000;;"Hyperplasia of adipose tissue is critical for the development of obesity, but molecular mechanisms governing normal or pathological recruitment of new adipocytes remain unclear. The extracellular signal-regulated kinase (ERK) pathway plays a pivotal role in many essential cellular functions, such as proliferation and differentiation. Using ERK1(-/-) mice, we investigated the role of this isoform in adipose tissue development. Mice lacking ERK1 have decreased adiposity and fewer adipocytes than wild-type animals. Furthermore, ERK1(-/-) mice challenged with high-fat diet are resistant to obesity, are protected from insulin resistance, and have a higher postprandial metabolic rate. To get insights into cellular mechanisms implicated in reduced adiposity in ERK1(-/-) animals, we analyzed adipocyte differentiation in ERK1(-/-) cells. Compared with wild-type control cells, mouse embryo fibroblasts and cultures of adult preadipocytes isolated from ERK1(-/-) adult animals exhibit impaired adipogenesis. An inhibitor of the ERK pathway does not affect the residual adipogenesis of the ERK1(-/-) cells, suggesting that ERK2 is not implicated in adipocyte differentiation. Our results clearly link ERK1 to the regulation of adipocyte differentiation, adiposity, and high-fat diet-induced obesity. This suggests that a therapeutic approach of obesity targeting specifically the ERK1 isoform and not ERK2 would be of particular interest." 8247;"A new role for the oncogenic high-mobility group A2 transcription factor in myogenesis of embryonic stem cells.";"F. BOST";"Equipe 05, Team 05";16007198;Oncogene;"Caron L, Bost F, Prot M, Hofman P, Binétruy B";;"Sep 2005";1125532800;;"The high mobility group type A-2 (HMGA 2) transcription factor is involved in proliferation and differentiation, mainly during embryogenesis. Its activated form (HMGA 2/T) presents oncogenic activities both in vivo and in vitro. However, its precise role during embryogenesis is unknown. We investigated its role during the commitment of mouse embryonic stem (ES) cells by constructing cell lines expressing either wild type (wt) or HMGA 2/T forms of the gene. Following differentiation, control and wt HMGA 2 ES cells did not display myotubes; whereas HMGA 2/T ES cell lines massively formed contractile myotubes. Furthermore, as opposed to control cells, HMGA 2/T ES cells highly expressed the muscle myosin heavy chain (MHC) marker. Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA 2/T cells. By contrast, commitment into adipocyte, neuron, and cardiomyocyte lineages was not affected. Teratocarcinomas induced by HMGA 2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA 2 or control tumours. Finally, rapamycin, an inhibitor of the mTOR kinase, downregulated endogenous HMGA-2 expression and inhibited myogenesis. This effect was prevented by overexpression of exogenous HMGA-2. Our results reveal a novel function of HMGA-2 in skeletal muscle differentiation." 8245;"p38 mitogen-activated protein kinase activity commits embryonic stem cells to either neurogenesis or cardiomyogenesis.";"F. BOST";"Equipe 05, Team 05";16424397;"Stem cells (Dayton, Ohio)";"Aouadi M, Bost F, Caron L, Laurent K, Le Marchand Brustel Y, Binétruy B";;"May 2006";1146441600;;"Mouse embryonic stem (ES) cells can be differentiated, in vitro into a variety of cell types including cardiac cells and neurons. This process is strictly controlled by the potent morphogen retinoic acid (RA). At a concentration of 10(-7) M, RA induces ES cell differentiation into neurons and, conversely, inhibits cardiomyogenesis. We found that p38 mitogen-activated protein kinase (p38MAPK) activity peaked spontaneously, between day 3 and day 5, during ES cell differentiation and that RA completely inhibited this peak of activity. In contrast to wild-type cells, which required RA treatment, p38alpha(-/-) ES cells differentiated spontaneously into neurons and did not form cardiomyocytes. Moreover, inhibition of the peak of p38MAPK activity by a specific inhibitor, PD169316, committed ES cells into the neuronal lineage and blocked cardiomyogenesis. By genetic and biochemical approaches, we demonstrate that, in two different ES cell lines, the control of p38MAPK activity constitutes an early switch, committing ES cells into either neurogenesis (p38 off) or cardiomyogenesis (p38 on)." 8243;"Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages.";"F. BOST";"Equipe 05, Team 05";16443758;Diabetes;"Aouadi M, Laurent K, Prot M, Le Marchand-Brustel Y, Binétruy B, Bost F";;"Feb 2006";1138752000;;"Formation of new adipocytes from precursor cells contributes to adipose tissue expansion and obesity. In this study, we asked whether p38 mitogen-activated protein kinase (MAPK) pathway regulates normal and pathological adipogenesis. In both dietary and genetically (ob/ob) obese mice, adipose tissues displayed a marked decrease in p38MAPK activity compared with the same tissues from lean mice. Furthermore, p38MAPK activity was significantly higher in preadipocytes than in adipocytes, suggesting that p38MAPK activity decreases during adipocyte differentiation. In agreement with an inhibitory role of p38MAPK in this process, we found that in vitro inhibition of p38MAPK, with the specific inhibitor PD169316, increased the expression of adipocyte markers in several cellular models, from embryonic to adult stages. Importantly, the expression of adipocyte markers was higher in p38MAPKalpha knockout cells than in their wild-type counterparts. Phosphorylation of C/EBPbeta, which enhances its transcriptional activity, is increased after p38MAPK inhibition. Finally, either inhibition or disruption of p38MAPK increased peroxisome proliferator-activated receptor (PPAR)gamma expression and transactivation. Rescue of p38MAPK in knockout cells reduced PPARgamma activity to the low basal level of wild-type cells. We demonstrate here, by using multipronged approaches involving p38 chemical inhibitor and p38MAPKalpha knockout cells, that p38MAPK plays a negative role in adipogenesis via inhibition of C/EBPbeta and PPARgamma transcriptional activities." 8241;"Concise review: regulation of embryonic stem cell lineage commitment by mitogen-activated protein kinases.";"F. BOST";"Equipe 05, Team 05";17218395;"Stem cells (Dayton, Ohio)";"Binétruy B, Heasley L, Bost F, Caron L, Aouadi M";;"May 2007";1177977600;;"Embryonic stem (ES) cells can give rise, in vivo, to the ectodermal, endodermal, and mesodermal germ layers and, in vitro, can differentiate into multiple cell lineages, offering broad perspectives in regenerative medicine. Understanding the molecular mechanisms governing ES cell commitment is an essential challenge in this field. The mitogen-activated protein kinase (MAPK) pathways extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38MAPK are able to regulate ES commitment from early steps of the process to mature differentiated cells. Whereas the ERK pathway inhibits the self-renewal of ES cells, upon commitment this pathway is involved in the development of extraembryonic tissues, in early mesoderm differentiation, and in the formation of mature adipocytes; p38MAPK displays a large spectrum of action from neurons to adipocytes, and JNK is involved in both ectoderm and primitive endoderm differentiations. Furthermore, for a given pathway, several of these effects are isoform-dependent, revealing the complexity of the cellular response to activation of MAPK pathways. Regarding tissue regeneration, the potential outcome of systematic analysis of the function of different MAPKs in different ES cell differentiation programs is discussed. Disclosure of potential conflicts of interest is found at the end of this article." 8239;"""Double hit"" makes the difference.";"F. BOST";"Equipe 05, Team 05";22874594;"Cell cycle (Georgetown, Tex.)";"Bost F";;"Aug 2012";1343779200;; 8237;"Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation.";"F. BOST, N. Mazure";"Equipe 05, Team 05";26322231;"Cancer & metabolism";"Brahimi-Horn MC, Giuliano S, Saland E, Lacas-Gervais S, Sheiko T, Pelletier J, Bourget I, Bost F, Féral C, Boulter E, Tauc M, Ivan M, Garmy-Susini B, Popa A, Mari B, Sarry JE, Craigen WJ, Pouysségur J, Mazure NM";;"Jan 2015";1420070400;;"Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconnected networks with enhanced metabolic efficacy and resistance to apoptosis. Modifications to the appearance and metabolic capacity of mitochondria have been reported in cancer. However, the precise mechanisms regulating mitochondrial dynamics and metabolism in cancer are unknown. Since hypoxia plays a role in the generation of these abnormal mitochondria, we questioned if it modulates mitochondrial function. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) is at center stage in regulating metabolism and apoptosis. We demonstrated previously that VDAC1 was post-translationally C-terminal cleaved not only in various hypoxic cancer cells but also in tumor tissues of patients with lung adenocarcinomas. Cells with enlarged mitochondria and cleaved VDAC1 were also more resistant to chemotherapy-stimulated cell death than normoxic cancer cells." 8235;"Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells.";"F. BOST";"Equipe 05, Team 05";28239646;"JCI insight";"Wang YY, Attané C, Milhas D, Dirat B, Dauvillier S, Guerard A, Gilhodes J, Lazar I, Alet N, Laurent V, Le Gonidec S, Biard D, Hervé C, Bost F, Ren GS, Bono F, Escourrou G, Prentki M, Nieto L, Valet P, Muller C";;"02 2017";1485907200;;"In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase-dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid β-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression." 8233;"Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation.";"F. BOST";"Equipe 05, Team 05";28317937;"Scientific reports";"Andrio E, Lotte R, Hamaoui D, Cherfils J, Doye A, Daugaard M, Sorensen PH, Bost F, Ruimy R, Mettouchi A, Lemichez E";;"03 2017";1488326400;;"The E3 ubiquitin ligase HACE1 is a potent tumor suppressor that controls cell proliferation and ubiquitylates the small GTPase Rac1 to target it to proteasomal degradation. Whether and how the activity of HACE1 is regulated by the N-terminal ankyrin (ANK) and the middle (MID) domains is ill defined. Here, we identified in the version 64 of the Catalogue of Somatic Mutations in Cancer (COSMIC) 13 missense mutations of hace1 located outside the HECT domain, and found that all lead to defective control of cell proliferation. In addition, several mutations located in the ankyrin domain displayed a dramatic reduction in Rac1 ubiquitylation associated with a decrease of colony formation in soft agar. 3D structure modelling of the 7 ankyrin-repeats coupled to functional analysis identified a surface epitope centered on one of the mutated residue, Gly-175, which is critical for controlling Rac1 binding and ubiquitylation. We also identified a role for the MID domain in conferring the specificity of association of HACE1 to the active form of Rac1. Our study of the functional interplay between HACE1 and Rac1 in cancer thus sheds a new light on the molecular mechanism of Rac1 ubiquitylation by HACE1 and the impact of its cancer-associated mutations in cell proliferation." 8231;"Protein N-glycosylation alteration and glycolysis inhibition both contribute to the antiproliferative action of 2-deoxyglucose in breast cancer cells.";"F. BOST";"Equipe 05, Team 05";29971627;"Breast cancer research and treatment";"Berthe A, Zaffino M, Muller C, Foulquier F, Houdou M, Schulz C, Bost F, De Fay E, Mazerbourg S, Flament S";;"Oct 2018";1538352000;;"Cancer cells often elicit a higher glycolytic rate than normal cells, supporting the development of glycolysis inhibitors as therapeutic agents. 2-Deoxyglucose (2-DG) is used in this context due to its ability to compete with glucose. However, many studies do not take into account that 2-DG inhibits not only glycolysis but also N-glycosylation. Since there are limited publications on 2-DG mechanism of action in breast cancer, we studied its effects in breast cancer cell lines to determine the part played by glycolysis inhibition and N-linked glycosylation interference." 8229;"UBTD1 is a mechano-regulator controlling cancer aggressiveness.";"F. BOST";"Equipe 05, Team 05";30804013;"EMBO reports";"Torrino S, Roustan FR, Kaminski L, Bertero T, Pisano S, Ambrosetti D, Dufies M, Uhler JP, Lemichez E, Mettouchi A, Gesson M, Laurent K, Gaggioli C, Michiels JF, Lamaze C, Bost F, Clavel S";;"Feb 2019";1551225600;;"Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with β-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase β-TrCP Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression." 8225;"The metabolic modulator PGC-1α in cancer.";"F. BOST";"Equipe 05, Team 05";30906622;"American journal of cancer research";"Bost F, Kaminski L";;"Jan 2019";1546300800;;"The peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is a central modulator of cell metabolism. It regulates mitochondrial biogenesis and oxidative metabolism. Modifications and adaptations in cellular metabolism are hallmarks of cancer cells, thus, it is not surprising that PGC-1α plays a role in cancer. Several recent articles have shown that PGC-1α expression is altered in tumors and metastasis in relation to modifications in cellular metabolism. The potential uses of PGC-1α as a therapeutic target and a biomarker of the advanced form of cancer will be summarized in this review." 8223;"Hypoxia protects against the cell death triggered by oxovanadium-galactomannan complexes in HepG2 cells.";"F. BOST, N. Mazure";"Equipe 05, Team 05";30949212;"Cellular & molecular biology letters";"Meyenberg Cunha-de Padua M, Noleto GR, de Oliveira Petkowicz CL, Cadena SMSC, Bost F, Pouysségur J, Mazure NM";;"Jan 2019";1546300800;;"Polysaccharides from various sources have been used in traditional medicine for centuries. The beneficial pharmacological effects of plant-derived polysaccharides include anti-tumor activity." 8221;"Editorial: Metformin: Beyond Diabetes.";"F. BOST";"Equipe 05, Team 05";31866949;"Frontiers in endocrinology";"Bost F, Rena G, Viollet B";;"Jan 2019";1546300800;; 8219;"Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients.";"F. BOST, J. Contenti, N. Mazure";"Equipe 05, Team 05";32194829;Theranostics;"Fabbri L, Dufies M, Lacas-Gervais S, Gardie B, Gad-Lapiteau S, Parola J, Nottet N, Meyenberg Cunha de Padua M, Contenti J, Borchiellini D, Ferrero JM, Leclercq NR, Ambrosetti D, Mograbi B, Richard S, Viotti J, Chamorey E, Sadaghianloo N, Rouleau M, Craigen WJ, Mari B, Clavel S, Pagès G, Pouysségur J, Bost F, Mazure NM";;"Jan 2020";1577836800;;": Renal cell carcinoma (RCC) accounts for about 2% of all adult cancers, and clear cell RCC (ccRCC) is the most common RCC histologic subtype. A hallmark of ccRCC is the loss of the primary cilium, a cellular antenna that senses a wide variety of signals. Loss of this key organelle in ccRCC is associated with the loss of the von Hippel-Lindau protein (VHL). However, not all mechanisms of ciliopathy have been clearly elucidated. : By using RCC4 renal cancer cells and patient samples, we examined the regulation of ciliogenesis the presence or absence of the hypoxic form of the voltage-dependent anion channel (VDAC1-ΔC) and its impact on tumor aggressiveness. Three independent cohorts were analyzed. Cohort A was from PREDIR and included 12 patients with hereditary pVHL mutations and 22 sporadic patients presenting tumors with wild-type pVHL or mutated pVHL; Cohort B included tissue samples from 43 patients with non-metastatic ccRCC who had undergone surgery; and Cohort C was composed of 375 non-metastatic ccRCC tumor samples from The Cancer Genome Atlas (TCGA) and was used for validation. The presence of VDAC1-ΔC and legumain was determined by immunoblot. Transcriptional regulation of IFT20/GLI1 expression was evaluated by qPCR. Ciliogenesis was detected using both mouse anti-acetylated α-tubulin and rabbit polyclonal ARL13B antibodies for immunofluorescence. : Our study defines, for the first time, a group of ccRCC patients in which the hypoxia-cleaved form of VDAC1 (VDAC1-ΔC) induces resorption of the primary cilium in a Hypoxia-Inducible Factor-1 (HIF-1)-dependent manner. An additional novel group, in which the primary cilium is re-expressed or maintained, lacked VDAC1-ΔC yet maintained glycolysis, a signature of epithelial-mesenchymal transition (EMT) and more aggressive tumor progression, but was independent to VHL. Moreover, these patients were less sensitive to sunitinib, the first-line treatment for ccRCC, but were potentially suitable for immunotherapy, as indicated by the immunophenoscore and the presence of PDL1 expression. : This study provides a new way to classify ccRCC patients and proposes potential therapeutic targets linked to metabolism and immunotherapy." 8217;"Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites.";"F. BOST";"Equipe 05, Team 05";32792483;"Nature communications";"Bosc C, Broin N, Fanjul M, Saland E, Farge T, Courdy C, Batut A, Masoud R, Larrue C, Skuli S, Espagnolle N, Pagès JC, Carrier A, Bost F, Bertrand-Michel J, Tamburini J, Récher C, Bertoli S, Mansat-De Mas V, Manenti S, Sarry JE, Joffre C";;"08 2020";1596240000;;"Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia." 8215;"Evidences of a Direct Relationship between Cellular Fuel Supply and Ciliogenesis Regulated by Hypoxic VDAC1-ΔC.";"F. BOST, J. Contenti, M. IRONDELLE, N. Mazure";"Equipe 05, Team 05";33238609;Cancers;"Meyenberg Cunha-de Padua M, Fabbri L, Dufies M, Lacas-Gervais S, Contenti J, Voyton C, Fazio S, Irondelle M, Mograbi B, Rouleau M, Sadaghianloo N, Rovini A, Brenner C, Craigen WJ, Bourgeais J, Herault O, Bost F, Mazure NM";;"Nov 2020";1604188800;;"Metabolic flexibility is the ability of a cell to adapt its metabolism to changes in its surrounding environment. Such adaptability, combined with apoptosis resistance provides cancer cells with a survival advantage. Mitochondrial voltage-dependent anion channel 1 (VDAC1) has been defined as a metabolic checkpoint at the crossroad of these two processes. Here, we show that the hypoxia-induced cleaved form of VDAC1 (VDAC1-ΔC) is implicated in both the up-regulation of glycolysis and the mitochondrial respiration. We demonstrate that VDAC1-ΔC, due to the loss of the putative phosphorylation site at serine 215, concomitantly with the loss of interaction with tubulin and microtubules, reprograms the cell to utilize more metabolites, favoring cell growth in hypoxic microenvironment. We further found that VDAC1-ΔC represses ciliogenesis and thus participates in ciliopathy, a group of genetic disorders involving dysfunctional primary cilium. Cancer, although not representing a ciliopathy, is tightly linked to cilia. Moreover, we highlight, for the first time, a direct relationship between the cilium and cancer cell metabolism. Our study provides the first new comprehensive molecular-level model centered on VDAC1-ΔC integrating metabolic flexibility, ciliogenesis, and enhanced survival in a hypoxic microenvironment." 8213;"Hypoxia and hypoxia-inducible factors promote the development of neointimal hyperplasia in arteriovenous fistula.";"F. BOST, J. Contenti, N. Mazure";"Equipe 05, Team 05";33608879;"The Journal of physiology";"Sadaghianloo N, Contenti J, Declemy S, Ambrosetti D, Zdralevic M, Tannour-Louet M, Fabbri L, Pagès G, Bost F, Hassen-Khodja R, Pouysségur J, Jean-Baptiste E, Dardik A, Mazure NM";;"04 2021";1617235200;;"Patients with end-stage renal failure need arteriovenous fistulas (AVF) to undergo dialysis. However, AVFs present a high rate of failure as a result of excessive venous thickness. Excessive venous thickness may be a consequence of surgical dissection and change in oxygen concentration within the venous wall. We show that venous cells adapt their metabolism and growth depending on oxygen concentration, and drugs targeting the hypoxic response pathway modulate this response in vitro. We used the same drugs on a mouse model of AVF and show that direct or indirect inhibition of the hypoxia-inducible factors (HIFs) help decrease excessive venous thickness. Hypoxia and HIFs can be targets of therapeutic drugs to prevent excessive venous thickness in patients undergoing AVF surgical creation." 8211;"The Adipose Tissue at the Crosstalk Between EDCs and Cancer Development.";"C. Hinault, F. BOST, N. Chevalier";"Equipe 05, Team 05";34354670;"Frontiers in endocrinology";"Bokobza E, Hinault C, Tiroille V, Clavel S, Bost F, Chevalier N";;"Jan 2021";1609459200;;"Obesity is a major public health concern at the origin of many pathologies, including cancers. Among them, the incidence of gastro-intestinal tract cancers is significantly increased, as well as the one of hormone-dependent cancers. The metabolic changes caused by overweight mainly with the development of adipose tissue (AT), insulin resistance and chronic inflammation induce hormonal and/or growth factor imbalances, which impact cell proliferation and differentiation. AT is now considered as the main internal source of endocrine disrupting chemicals (EDCs) representing a low level systemic chronic exposure. Some EDCs are non-metabolizable and can accumulate in AT for a long time. We are chronically exposed to low doses of EDCs able to interfere with the endocrine metabolism of the body. Importantly, several EDCs have been involved in the genesis of obesity affecting profoundly the physiology of AT. In parallel, EDCs have been implicated in the development of cancers, in particular hormone-dependent cancers (prostate, testis, breast, endometrium, thyroid). While it is now well established that AT secretes adipocytokines that promote tumor progression, it is less clear whether they can initiate cancer. Therefore, it is important to better understand the effects of EDCs, and to investigate the buffering effect of AT in the context of progression but also initiation of cancer cells using adequate models recommended to uncover and validate these mechanisms for humans. We will review and argument here the potential role of AT as a crosstalk between EDCs and hormone-dependent cancer development, and how to assess it." 7758;"Physiological and physiopathological aspects of connexins and communicating gap junctions in spermatogenesis.";"J. GILLERON";"Equipe 07, Team 07";20403873;"Philosophical transactions of the Royal Society of London. Series B, Biological sciences";"Pointis G, Gilleron J, Carette D, Segretain D";;"May 2010";1272672000;;"Spermatogenesis is a highly regulated process of germ cell proliferation and differentiation, starting from spermatogonia to spermatocytes and giving rise to spermatids, the future spermatozoa. In addition to endocrine regulation, testicular cell-cell interactions are essential for spermatogenesis. This precise control is mediated through paracrine/autocrine pathways, direct intercellular contacts and through intercellular communication channels, consisting of gap junctions and their constitutive proteins, the connexins. Gap junctions are localized between adjacent Leydig cells, between Sertoli cells and between Sertoli cells and specific germ cells. This review focuses on the distribution of connexins within the seminiferous epithelium, their participation in gap junction channel formation, the control of their expression and the physiological relevance of these junctions in both the Sertoli-Sertoli cell functional synchronization and the Sertoli-germ cell dialogue. In this review, we also discuss the potential implication of disrupted connexin in testis cancer, since impaired expression of connexin has been described as a typical feature of tumoral proliferation." 7756;"Major involvement of connexin 43 in seminiferous epithelial junction dynamics and male fertility.";"J. GILLERON";"Equipe 07, Team 07";20655897;"Developmental biology";"Carette D, Weider K, Gilleron J, Giese S, Dompierre J, Bergmann M, Brehm R, Denizot JP, Segretain D, Pointis G";;"Oct 2010";1285891200;;"In different epithelia, cell membranes contacting one another form intercellular junctional complexes including tight, adherens and gap junctions, which could mutually influence the expression of each other. We have here investigated the role of Cx43 in the control of adherens and tight junction proteins (N-cadherin, beta-catenin, occludin and ZO-1) by using conditional Sertoli cell knockout Cx43 (SCCx43KO(-/-)) transgenic mice and specific anti-Cx43 siRNA. Gap junction coupling and Cx43 levels were reduced in SCCx43KO(-/-) as compared to Wild-type testes. Ultrastructural analysis revealed disappearance of gap junctions, the presence of tight and adherens junctions and persistent integrity of the blood-testis barrier in SCCx43KO(-/-) testis. Occludin, N-cadherin and beta-catenin levels were enhanced in SCCx43KO(-/-) mice as compared to Wild-type animals whereas ZO-1 levels were reduced. Cx43 siRNA blocked gap junction functionality in Sertoli cells and altered tight and adherens protein levels. The Cx43 control of tight and adherens junctions appeared channel-dependent since gap junction blockers (glycyrrhetinic acid and oleamide) led to similar results. These data suggest that the control of spermatogenesis by Cx43 may be mediated through Sertoli cell Cx43 channels, which are required, not only in cell/cell communication between Sertoli and germ cells, but also in the regulation of other junctional proteins essential for the blood-testis barrier." 7754;"The large GTPase dynamin2: a new player in connexin 43 gap junction endocytosis, recycling and degradation.";"J. GILLERON";"Equipe 07, Team 07";21554976;"The international journal of biochemistry & cell biology";"Gilleron J, Carette D, Fiorini C, Dompierre J, Macia E, Denizot JP, Segretain D, Pointis G";;"Aug 2011";1312156800;;"Connexins (Cx) are key regulators of cell proliferation, differentiation and apoptosis. Cx trafficking and endocytosis need interactions with a large number of signaling and scaffolding proteins. We demonstrate herein that Cx43-GFP gap junction plaque endocytosis was blocked in cells transfected by the dominant-negative form of dynamin2 (Dyn2K44A) and by dynasore, an inhibitor of dynamin GTPase activity, which reduced the association between dynamin2 and Cx43. Our data also reveal that recruitment of the GTPase at the plasma membrane and its activation by c-Src are key events for Cx43 internalization. In addition they show that dynamin2 participated in internalization and degradation of the gap junction plaque but also in recycling of Cx43 to the plasma membrane through respectively Rab5/Rab7 and Rab11 pathways. These results demonstrate for the first time that dynamin2 is a new Cx partner and report an innovating mechanistic model by which dynamin2 may control Cx43 gap junction plaque invagination, endocytosis, recycling and degradation. These processes are magnified in response to carcinogen exposure underlining their potential importance during carcinogenesis." 7752;"Chemical connexin impairment in the developing gonad associated with offspring infertility.";"J. GILLERON";"Equipe 07, Team 07";22050760;"Current medicinal chemistry";"Gilleron J, Malassiné A, Carette D, Segretain D, Pointis G";;"Jan 2011";1293840000;;"A dramatical decline in human male reproductive function has been reported for the past 20 years. Many recent epidemiological, clinical and experimental findings suggest that the reproductive dysfunction could result from prenatal and neonatal chemical compound exposure. Even if numerous studies argue for a relationship between male infertility and environmental and/or occupational exposure, the molecular mechanisms by which these anti-reproductive compounds act are still unclear. Recent findings showed that a family of transmembranous proteins, connexins, regulates numerous physiological functions involved in the development such as cell proliferation, differentiation, migration and apoptosis. In the testis and the ovary, connexins are known to be essential for the establishment and the maintenance of spermatogenesis in males and oogenesis and folliculogenesis in females. Moreover, mutation of connexin genes leads to several developmental human diseases (myelin-related diseases, hearing loss, congenital cataract, skin disorders or more complex syndromes such as the oculodendrodigital dysplasia....) and altered connexin expression, trafficking and degradation are often associated with the tumoral process. We propose, in the present work, to give an overview of connexin expression and intercellular gap junction coupling during development: in preimplantation, implantation and postimplantation embryos. Moreover, we underline the impact of maternal chemical exposure on connexin expression during fetal gonad development and we link this effect to future offspring fertility." 7750;"Testicular connexin 43, a precocious molecular target for the effect of environmental toxicants on male fertility.";"J. GILLERON";"Equipe 07, Team 07";22332114;Spermatogenesis;"Pointis G, Gilleron J, Carette D, Segretain D";;"Oct 2011";1317427200;;"Many recent epidemiological, clinical and experimental findings support the hypothesis that environmental toxicants are responsible for the increasing male reproductive disorders (congenital malformations, declining sperm counts and testicular cancer) over the past 20 years. It has also been reported that exposure to these toxicants, during critical periods of development (fetal and neonatal), represents a more considerable risk for animals and humans than exposure during adulthood. However, the molecular targets for these chemicals have not been clearly identified. Recent studies showed that a family of transmembranous proteins, named connexins, regulates numerous physiological processes involved in testicular development and function, such as Sertoli and germ cell proliferation, differentiation, germ cell migration and apoptosis. In the testis, knockout strategy revealed that connexin 43, the predominant connexin in this organ, is essential for spermatogenesis. In addition, there is evidence that many environmental toxicants could alter testicular connexin 43 by dysregulation of numerous mechanisms controlling its function. In the present work, we propose first to give an overview of connexin expression and intercellular gap junction coupling in the developing fetal and neonatal testes. Second, we underline the impact of maternally chemical exposure on connexin 43 expression in the perinatal developing testis. Lastly, we attempt to link this precocious effect to male offspring fertility." 7748;"Molecular connexin partner remodeling orchestrates connexin traffic: from physiology to pathophysiology.";"J. GILLERON";"Equipe 07, Team 07";22551357;"Critical reviews in biochemistry and molecular biology";"Gilleron J, Carette D, Chevallier D, Segretain D, Pointis G";;"Sep 2012";1346457600;;"Connexins, through gap junctional intercellular communication, are known to regulate many physiological functions involved in developmental processes such as cell proliferation, differentiation, migration and apoptosis. Strikingly, alterations of connexin expression and trafficking are often, if not always, associated with human developmental diseases and carcinogenesis. In this respect, disrupted trafficking dynamics and aberrant intracytoplasmic localization of connexins are considered as typical features of functionality failure leading to the pathological state. Recent findings demonstrate that interactions of connexins with numerous protein partners, which take place throughout connexin trafficking, are essential for gap junction formation, membranous stabilization and degradation. In the present study, we give an overview of the physiological molecular machinery and of the specific interactions between connexins and their partners, which are involved in connexin trafficking, and we highlight their changes in pathological situations." 7746;"Rab5 is necessary for the biogenesis of the endolysosomal system in vivo.";"J. GILLERON";"Equipe 07, Team 07";22622570;Nature;"Zeigerer A, Gilleron J, Bogorad RL, Marsico G, Nonaka H, Seifert S, Epstein-Barash H, Kuchimanchi S, Peng CG, Ruda VM, Del Conte-Zerial P, Hengstler JG, Kalaidzidis Y, Koteliansky V, Zerial M";;"May 2012";1335830400;;"An outstanding question is how cells control the number and size of membrane organelles. The small GTPase Rab5 has been proposed to be a master regulator of endosome biogenesis. Here, to test this hypothesis, we developed a mathematical model of endosome dependency on Rab5 and validated it by titrating down all three Rab5 isoforms in adult mouse liver using state-of-the-art RNA interference technology. Unexpectedly, the endocytic system was resilient to depletion of Rab5 and collapsed only when Rab5 decreased to a critical level. Loss of Rab5 below this threshold caused a marked reduction in the number of early endosomes, late endosomes and lysosomes, associated with a block of low-density lipoprotein endocytosis. Loss of endosomes caused failure to deliver apical proteins to the bile canaliculi, suggesting a requirement for polarized cargo sorting. Our results demonstrate for the first time, to our knowledge, the role of Rab5 as an endosome organizer in vivo and reveal the resilience mechanisms of the endocytic system." 7744;"Connexin 43 a check-point component of cell proliferation implicated in a wide range of human testis diseases.";"J. GILLERON";"Equipe 07, Team 07";22918484;"Cellular and molecular life sciences : CMLS";"Chevallier D, Carette D, Segretain D, Gilleron J, Pointis G";;"Apr 2013";1364774400;;"Gap junction channels link cytoplasms of adjacent cells. Connexins, their constitutive proteins, are essential in cell homeostasis and are implicated in numerous physiological processes. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival, and apoptosis, in which a connexin isotype, connexin 43, plays a crucial role as evidenced by genomic approaches based on gene deletion. The balance between cell proliferation/differentiation/apoptosis is a prerequisite for maintaining levels of spermatozoa essential for fertility and for limiting anarchic cell proliferation, a major risk of testis tumor. The present review highlights the emerging role of connexins in testis pathogenesis, focusing specifically on two intimately interconnected human testicular diseases (azoospermia with impaired spermatogenesis and testicular germ cell tumors), whose incidence increased during the last decades. This work proposes connexin 43 as a potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases." 7742;"SnapShot: Mammalian Rab proteins in endocytic trafficking.";"J. GILLERON";"Equipe 07, Team 07";23021225;Cell;"Galvez T, Gilleron J, Zerial M, O'Sullivan GA";;"Sep 2012";1346457600;; 7740;"[Key role of Rab5: from endosome biogenesis to liver metabolism].";"J. GILLERON";"Equipe 07, Team 07";23290397;"Medecine sciences : M/S";"Gilleron J, Zeigerer A, Marsico G, Galvez T, Zerial M";;"Dec 2012";1354320000;; 7738;"The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism.";"J. GILLERON";"Equipe 07, Team 07";23329179;"Apoptosis : an international journal on programmed cell death";"Mauro V, Carette D, Pontier-Bres R, Dompierre J, Czerucka D, Segretain D, Gilleron J, Pointis G";;"Apr 2013";1364774400;;"Griseofulvin, a widely used antifungal antimitotic drug has been proposed as an anti-tumoral treatment by way of in vitro experiments. Recently, in vivo demonstration of griseofulvin efficacy against multiple myeloma in mice argues for its potential as therapeutics for cancer. Nevertheless, the molecular mechanisms by which griseofulvin disrupts cancerous cell progression are far from being understood. In the present study, we found that griseofulvin inhibits human germ cell tumor cell growth through activation of mitochondrial caspase pathway (caspase 9 and 3) leading to the activation of apoptosis rather than an alteration of cell proliferation. Strikingly, we demonstrated that griseofulvin triggered the expression level of connexin 43 (mRNA and protein), a well described tumor-suppressor gene, known to participate in apoptosis regulation. Consistently, together with microtubule instability, a mechanism classically associated with cell death in response to griseofulvin, we observed a disruption of connexin 43/tubulin association concomitant of an enhanced translocation of connexin 43, or an immunoreactive fragment of the protein, from the cytoplasm to the nucleus. Finally, by using siRNA approaches we demonstrated the requirement of connexin 43 in the apoptotic induction of griseofulvin on our tumor cell model. Altogether, these results described a new molecular mechanism connexin 43-dependent targeted by griseofulvin leading to apoptosis of human germ cell tumor cells." 7736;"Hexavalent chromium at low concentration alters Sertoli cell barrier and connexin 43 gap junction but not claudin-11 and N-cadherin in the rat seminiferous tubule culture model.";"J. GILLERON";"Equipe 07, Team 07";23357549;"Toxicology and applied pharmacology";"Carette D, Perrard MH, Prisant N, Gilleron J, Pointis G, Segretain D, Durand P";;"Apr 2013";1364774400;;"Exposure to toxic metals, specifically those belonging to the nonessential group leads to human health defects and among them reprotoxic effects. The mechanisms by which these metals produce their negative effects on spermatogenesis have not been fully elucidated. By using the Durand's validated seminiferous tubule culture model, which mimics the in vivo situation, we recently reported that concentrations of hexavalent chromium, reported in the literature to be closed to that found in the blood circulation of men, increase the number of germ cell cytogenetic abnormalities. Since this metal is also known to affect cellular junctions, we investigated, in the present study, its potential influence on the Sertoli cell barrier and on junctional proteins present at this level such as connexin 43, claudin-11 and N-cadherin. Cultured seminiferous tubules in bicameral chambers expressed the three junctional proteins and ZO-1 for at least 12days. Exposure to low concentrations of chromium (10μg/l) increased the trans-epithelial resistance without major changes of claudin-11 and N-cadherin expressions but strongly delocalized the gap junction protein connexin 43 from the membrane to the cytoplasm of Sertoli cells. The possibility that the hexavalent chromium-induced alteration of connexin 43 indirectly mediates the effect of the toxic metal on the blood-testis barrier dynamic is postulated." 7734;"Integration of chemical and RNAi multiparametric profiles identifies triggers of intracellular mycobacterial killing.";"J. GILLERON";"Equipe 07, Team 07";23414754;"Cell host & microbe";"Sundaramurthy V, Barsacchi R, Samusik N, Marsico G, Gilleron J, Kalaidzidis I, Meyenhofer F, Bickle M, Kalaidzidis Y, Zerial M";;"Feb 2013";1359676800;;"Pharmacological modulators of host-microbial interactions can in principle be identified using high-content screens. However, a severe limitation of this approach is the lack of insights into the mode of action of compounds selected during the primary screen. To overcome this problem, we developed a combined experimental and computational approach. We designed a quantitative multiparametric image-based assay to measure intracellular mycobacteria in primary human macrophages, screened a chemical library containing FDA-approved drugs, and validated three compounds for intracellular killing of M. tuberculosis. By integrating the multiparametric profiles of the chemicals with those of siRNAs from a genome-wide survey on endocytosis, we predicted and experimentally verified that two compounds modulate autophagy, whereas the third accelerates endosomal progression. Our findings demonstrate the value of integrating small molecules and genetic screens for identifying cellular mechanisms modulated by chemicals. Furthermore, selective pharmacological modulation of host trafficking pathways can be applied to intracellular pathogens beyond mycobacteria." 7732;"Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape.";"J. GILLERON";"Equipe 07, Team 07";23792630;"Nature biotechnology";"Gilleron J, Querbes W, Zeigerer A, Borodovsky A, Marsico G, Schubert U, Manygoats K, Seifert S, Andree C, Stöter M, Epstein-Barash H, Zhang L, Koteliansky V, Fitzgerald K, Fava E, Bickle M, Kalaidzidis Y, Akinc A, Maier M, Zerial M";;"Jul 2013";1372636800;;"Delivery of short interfering RNAs (siRNAs) remains a key challenge in the development of RNA interference (RNAi) therapeutics. A better understanding of the mechanisms of siRNA cellular uptake, intracellular transport and endosomal release could critically contribute to the improvement of delivery methods. Here we monitored the uptake of lipid nanoparticles (LNPs) loaded with traceable siRNAs in different cell types in vitro and in mouse liver by quantitative fluorescence imaging and electron microscopy. We found that LNPs enter cells by both constitutive and inducible pathways in a cell type-specific manner using clathrin-mediated endocytosis as well as macropinocytosis. By directly detecting colloidal-gold particles conjugated to siRNAs, we estimated that escape of siRNAs from endosomes into the cytosol occurs at low efficiency (1-2%) and only during a limited window of time when the LNPs reside in a specific compartment sharing early and late endosomal characteristics. Our results provide insights into LNP-mediated siRNA delivery that can guide development of the next generation of delivery systems for RNAi therapeutics." 7730;"The emerging role of connexin 43 in testis pathogenesis.";"J. GILLERON";"Equipe 07, Team 07";23865425;"Current molecular medicine";"Chevallier D, Carette D, Gilleron J, Segretain D, Pointis G";;"Sep 2013";1377993600;;"Direct intercellular communication is mediated by gap junctions and their constitutive proteins, the connexins, which are organized in a hexameric arrangement forming a channel between adjacent cells. Connexins are essential for cell homeostasis and are also involved in many physiological processes such as cell growth, differentiation and death. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival and apoptosis, in which one connexin isoform, connexin 43, plays an essential role as evidenced by the targeted genetic deletion of Cx43 gene. A controlled balance of germ cell growth is a prerequisite to maintain either normal level of spermatozoa necessary for fertility and/or to limit an uncontrolled and anarchic germ cell proliferation, a major risk for germ cell tumor cell development. In the present review, we highlight the emerging role of connexins in testis pathogenesis, specifically in two intimately interconnected human testicular diseases: azoospermia with impaired spermatogenesis and testicular germ cell tumors, whose incidence increased during the last decades. This review proposes the gap junction protein connexin 43 as a new potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases. " 7728;"Connexin a check-point component of cell apoptosis in normal and physiopathological conditions.";"J. GILLERON";"Equipe 07, Team 07";24304817;Biochimie;"Carette D, Gilleron J, Chevallier D, Segretain D, Pointis G";;"Jun 2014";1401580800;;"Gap junction protein connexins (Cxs) play essential roles in cell homeostasis, growth, differentiation and death. Therefore, Cx dysfunction has been associated with many diseases and with tumor development. Cxs control cell apoptosis through different molecular mechanisms. First, gap junction channels classically facilitate the influx and flux of apoptotic signals between adjacent cells and hemichannels between the intracellular and extracellular environments. Second, recent studies demonstrate that Cx proteins, independently from their functional role through channels or hemichannels and in conjunction with their intracytoplasmic localization, may act as signaling effectors able to activate the canonical mitochondrial apoptotic pathway. In the present review, we dissected both functions of Cx in apoptosis, providing new avenues for apoptosis-mediated cancer therapy. " 7726;"New cellular mechanisms of gap junction degradation and recycling.";"J. GILLERON";"Equipe 07, Team 07";25818265;"Biology of the cell";"Carette D, Gilleron J, Denizot JP, Grant K, Pointis G, Segretain D";;"Jul 2015";1435708800;;"Connexins (Cxs), the constitutive proteins of gap junctions, are key actors of many physiological processes. Therefore, alterations of Cx expression and degradation lead to the development of physiopathological disorders. Because of the formation of a double membrane vesicle termed annular gap junction (AGJ), gap junction degradation is a unique physiological process for which many cellular aspects remain unclear." 7724;"Regulation of liver metabolism by the endosomal GTPase Rab5.";"J. GILLERON";"Equipe 07, Team 07";25937276;"Cell reports";"Zeigerer A, Bogorad RL, Sharma K, Gilleron J, Seifert S, Sales S, Berndt N, Bulik S, Marsico G, D'Souza RCJ, Lakshmanaperumal N, Meganathan K, Natarajan K, Sachinidis A, Dahl A, Holzhütter HG, Shevchenko A, Mann M, Koteliansky V, Zerial M";;"May 2015";1430438400;;"The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of the organism. Communication between hepatocytes and extracellular environment via endocytosis is key to such homeostasis. Here, we addressed the question of whether endosomes are required for gluconeogenic gene expression. We took advantage of the loss of endosomes in the mouse liver upon Rab5 silencing. Strikingly, we found hepatomegaly and severe metabolic defects such as hypoglycemia, hypercholesterolemia, hyperlipidemia, and glycogen accumulation that phenocopied those found in von Gierke's disease, a glucose-6-phosphatase (G6Pase) deficiency. G6Pase deficiency alone can account for the reduction in hepatic glucose output and glycogen accumulation as determined by mathematical modeling. Interestingly, we uncovered functional alterations in the transcription factors, which regulate G6Pase expression. Our data highlight a requirement of Rab5 and the endosomal system for the regulation of gluconeogenic gene expression that has important implications for metabolic diseases." 7722;"Physiological roles of connexins and pannexins in reproductive organs.";"J. GILLERON";"Equipe 07, Team 07";26100514;"Cellular and molecular life sciences : CMLS";"Kibschull M, Gellhaus A, Carette D, Segretain D, Pointis G, Gilleron J";;"Aug 2015";1438387200;;"Reproductive organs are complex and well-structured tissues essential to perpetuate the species. In mammals, the male and female reproductive organs vary on their organization, morphology and function. Connectivity between cells in such tissues plays pivotal roles in organogenesis and tissue functions through the regulation of cellular proliferation, migration, differentiation and apoptosis. Connexins and pannexins can be seen as major regulators of these physiological processes. In the present review, we assembled several lines of evidence demonstrating that these two families of proteins are essential for male and female reproduction. " 7720;"Identification of siRNA delivery enhancers by a chemical library screen.";"J. GILLERON";"Equipe 07, Team 07";26220182;"Nucleic acids research";"Gilleron J, Paramasivam P, Zeigerer A, Querbes W, Marsico G, Andree C, Seifert S, Amaya P, Stöter M, Koteliansky V, Waldmann H, Fitzgerald K, Kalaidzidis Y, Akinc A, Maier MA, Manoharan M, Bickle M, Zerial M";;"Sep 2015";1441065600;;"Most delivery systems for small interfering RNA therapeutics depend on endocytosis and release from endo-lysosomal compartments. One approach to improve delivery is to identify small molecules enhancing these steps. It is unclear to what extent such enhancers can be universally applied to different delivery systems and cell types. Here, we performed a compound library screen on two well-established siRNA delivery systems, lipid nanoparticles and cholesterol conjugated-siRNAs. We identified fifty-one enhancers improving gene silencing 2-5 fold. Strikingly, most enhancers displayed specificity for one delivery system only. By a combination of quantitative fluorescence and electron microscopy we found that the enhancers substantially differed in their mechanism of action, increasing either endocytic uptake or release of siRNAs from endosomes. Furthermore, they acted either on the delivery system itself or the cell, by modulating the endocytic system via distinct mechanisms. Interestingly, several compounds displayed activity on different cell types. As proof of principle, we showed that one compound enhanced siRNA delivery in primary endothelial cells in vitro and in the endocardium in the mouse heart. This study suggests that a pharmacological approach can improve the delivery of siRNAs in a system-specific fashion, by exploiting distinct mechanisms and acting upon multiple cell types." 7718;"Ultrastructural localization and distribution of Nardilysin in mammalian male germ cells.";"J. GILLERON";"Equipe 07, Team 07";27051521;"Basic and clinical andrology";"Segretain D, Gilleron J, Bacro JN, Di Marco M, Carette D, Pointis G";;"Jan 2016";1451606400;;"NRD convertase, also termed Nardilysin, is a Zn(++) metalloendopeptidase that specifically cleaves the N-terminus of arginine and lysine residues into dibasic moieties. Although this enzyme was found located within the testis, its function in male reproduction is largely unknown. In addition, the precise distribution of this enzyme within germ cells remains to be determined." 7716;"Effects of low doses of carbendazim or iprodione either separately or in mixture on the pubertal rat seminiferous epithelium: An ex vivo study.";"J. GILLERON";"Equipe 07, Team 07";28576679;"Toxicology in vitro : an international journal published in association with BIBRA";"Durand P, Martin G, Blondet A, Gilleron J, Carette D, Janczarski S, Christin E, Pointis G, Perrard MH";;"Dec 2017";1512086400;;"It has been shown that non-cytotoxic doses of Carbendazim (CBZ), a broad-spectrum benzimidazole fungicide, possess endocrine-disrupting (androgen-like) actions, ex vivo, on the pubertal rat seminiferous epithelium. Iprodione (IPR), a dicarboximide fungicide, is also known to be an endocrine-disrupter (anti-androgen). The effect of a mixture of these two pesticides was investigated in the validated rat seminiferous tubule culture model. Cultures were performed in the absence or presence of CBZ 50nM or IPR 50nM either alone or in mixture (Mix), over a 3-week period. Mix exerted a dramatic effect on two proteins (Connexin 43 and Claudin-11) of the blood-testis barrier and possessed similar effects to IPR on some germ cell populations. The presence of IPR together with CBZ (Mix) cancelled the effect of CBZ on the increase of the androgen-dependent TP1 and TP2 mRNAs and on the decrease of ERα, ERβ mRNAs. Nevertheless, CBZ alone or IPR alone or Mix induced toxicity on spermatogenesis resulting in a decrease of round spermatids (the precursors of spermatozoa). These results strongly suggest that, even at these low concentrations, the effects of IPR and of CBZ are not solely dependent on their respective anti-androgenic and androgen-like effects and should involve several mechanisms of action." 7714;"Multiple and complex influences of connexins and pannexins on cell death.";"J. GILLERON";"Equipe 07, Team 07";28625689;"Biochimica et biophysica acta. Biomembranes";"Gilleron J, Carette D, Segretain D, Pointis G";;"Jan 2018";1514764800;;"Cell death is a fundamental process for organogenesis, immunity and cell renewal. During the last decades a broad range of molecular tools were identified as important players for several different cell death pathways (apoptosis, pyroptosis, necrosis, autosis…). Aside from these direct regulators of cell death programs, several lines of evidence proposed connexins and pannexins as potent effectors of cell death. In the present review we discussed the potential roles played by connexins, pannexins and innexins in the different cell death programs at different scales from gap junction intercellular communication to protein-protein interactions. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve." 7712;"Essential and selective role of SNX12 in transport of endocytic and retrograde cargo.";"J. GILLERON";"Equipe 07, Team 07";28705836;"Journal of cell science";"Priya A, Sugatha J, Parveen S, Lacas-Gervais S, Raj P, Gilleron J, Datta S";;"Aug 2017";1501545600;;"The endosomal protein-sorting machineries play vital roles in diverse physiologically important cellular processes. Much of the core membrane-sorting apparatus is conserved in evolution, such as retromer, which is involved in the recycling of a diverse set of cargoes via the retrograde trafficking route. Here, in an RNAi-based loss-of-function study, we identified that suppression of SNX12 leads to a severe blockage in CIM6PR (also known as IGF2R) transport and alters the morphology of the endocytic compartments. We demonstrate that SNX12 is involved in the early phase of CIM6PR transport, and mediates receptor recycling upstream of the other well-established SNX components of retromer. Ultra-structural analysis revealed that SNX12 resides on tubulo-vesicular structures, despite it lacking a BAR domain. Furthermore, we illustrate that SNX12 plays a key role in intraluminal vesicle formation and in the maturation of a subpopulation of early endosomes into late endosomes, thereby regulating selective endocytic transport of cargo for degradation. This study therefore provides evidence for the existence of early endosomal subpopulations that have differential roles in the sorting of the cargoes along endocytic degradative pathways." 7710;"A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro.";"J. GILLERON";"Equipe 07, Team 07";29207017;"International journal of molecular medicine";"Bachelot A, Gilleron J, Meduri G, Guberto M, Dulon J, Boucherie S, Touraine P, Misrahi M";;"Feb 2018";1517443200;;"Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI." 7708;"Metabolic regulation through the endosomal system.";"J. GILLERON";"Equipe 07, Team 07";31177593;"Traffic (Copenhagen, Denmark)";"Gilleron J, Gerdes JM, Zeigerer A";;"08 2019";1564617600;;"The endosomal system plays an essential role in cell homeostasis by controlling cellular signaling, nutrient sensing, cell polarity and cell migration. However, its place in the regulation of tissue, organ and whole body physiology is less well understood. Recent studies have revealed an important role for the endosomal system in regulating glucose and lipid homeostasis, with implications for metabolic disorders such as type 2 diabetes, hypercholesterolemia and non-alcoholic fatty liver disease. By taking insights from in vitro studies of endocytosis and exploring their effects on metabolism, we can begin to connect the fields of endosomal transport and metabolic homeostasis. In this review, we explore current understanding of how the endosomal system influences the systemic regulation of glucose and lipid metabolism in mice and humans. We highlight exciting new insights that help translate findings from single cells to a wider physiological level and open up new directions for endosomal research." 7706;"Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity.";"J. GILLERON";"Equipe 07, Team 07";32694843;"Nature metabolism";"Seitz S, Kwon Y, Hartleben G, Jülg J, Sekar R, Krahmer N, Najafi B, Loft A, Gancheva S, Stemmer K, Feuchtinger A, Hrabe de Angelis M, Müller TD, Mann M, Blüher M, Roden M, Berriel Diaz M, Behrends C, Gilleron J, Herzig S, Zeigerer A";;"10 2019";1569888000;;"Non-alcoholic fatty liver disease (NAFLD) represents a key feature of obesity-related type 2 diabetes with increasing prevalence worldwide. To our knowledge, no treatment options are available to date, paving the way for more severe liver damage, including cirrhosis and hepatocellular carcinoma. Here, we show an unexpected function for an intracellular trafficking regulator, the small Rab GTPase Rab24, in mitochondrial fission and activation, which has an immediate impact on hepatic and systemic energy homeostasis. RAB24 is highly upregulated in the livers of obese patients with NAFLD and positively correlates with increased body fat in humans. Liver-selective inhibition of Rab24 increases autophagic flux and mitochondrial connectivity, leading to a strong improvement in hepatic steatosis and a reduction in serum glucose and cholesterol levels in obese mice. Our study highlights a potential therapeutic application of trafficking regulators, such as RAB24, for NAFLD and establishes a conceptual functional connection between intracellular transport and systemic metabolic dysfunction." 7704;"Lymphatic and Blood Network Analysis During Obesity.";"J. GILLERON";"Equipe 07, Team 07";33283786;"Journal of visualized experiments : JoVE";"Czepielewski RS, Gallerand A, Gilleron J, Khedher N, Randolph GJ, Ivanov S";;"11 2020";1604188800;;"Lymphatic collecting vessels and lymph nodes are inevitably embedded in adipose tissue. The physiological significance of this observation remains still not elucidated. However, obesity is characterized by impaired lymphatic function and increased vessel permeability. Inversely, lymphatic dysfunction induces obesity in mice, suggesting a significant interplay between lymphatic vessels and the adipose tissue. Therefore, understanding factors leading to lymphatic dysfunction might open new therapeutic windows to prevent obesity and associated comorbidities. The first step in this process requires a precise and detailed visualization of the lymphatic network in healthy and inflamed adipose tissue. Here, we describe a rapid, inexpensive, and efficient method that allows to label and analyze lymphatic and blood vessels. This approach takes advantage of the skin-draining brachial lymph node localization within the subcutaneous adipose tissue. The lymphatic arborization of this tissue can be revealed by injecting fluorochrome-conjugated lectins subcutaneously. Moreover, the in vivo labeling approach provides a way to evaluate lymphatic vessel density and functions. Coupled to blood vessel, adipocyte and immune cell staining, the protocol allows for high-resolution mapping of the subcutaneous adipose tissue by 3D imaging." 7702;"Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice.";"J. GILLERON";"Equipe 07, Team 07";33783350;eLife;"Raad G, Serra F, Martin L, Derieppe MA, Gilleron J, Costa VL, Pisani DF, Amri EZ, Trabucchi M, Grandjean V";;"03 2021";1614556800;;"Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal Western diet feeding for five consecutive generations in mice induces an enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational Western-diet-fed males develop a 'healthy' overweight phenotype characterized by normal glucose metabolism and without fatty liver that persists for four subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal Western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases." 7700;"IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";12618213;"Cellular signalling";"Ursø B, Ilondo MM, Holst PA, Christoffersen CT, Ouwens M, Giorgetti S, Van Obberghen E, Naor D, Tornqvist H, De Meyts P";;"Apr 2003";1049155200;;"Insulin and growth hormone (GH) induce mitogenic and metabolic signals in cells, GH either directly or indirectly via IGF-I production. We have studied a spontaneous murine T-cell lymphoma (LB cells) devoid of IGF-1 receptors in which proliferation is maintained by insulin [Int. J. Cancer 50 (1992) 80], and show that GH is more potent than insulin, with both GH and insulin dose-response curves for thymidine incorporation being bell-shaped. Binding showed somatogenic rather than lactogenic GH receptors. Insulin stimulated phosphorylation of the insulin receptor and of a 160-kDa protein, identified as the IRS-4 protein. This phosphorylated IRS-4 associated with PI3-kinase, which was activated along with the downstream p70(S6) kinase, whereas the Ras-MAPK pathway was not. Using selective inhibitors, the PI3-kinase, but not p70(S6) kinase or MEK, was found to be involved in insulin-stimulated DNA synthesis. GH induced tyrosine phosphorylation of IRS-4 and nuclear translocation of STAT5. The LB cells constitute a new model for studying GH and insulin signalling without interference of IGF-1 receptors." 7698;"Involvement of Src-homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";8033892;"European journal of biochemistry";"Giorgetti S, Pelicci PG, Pelicci G, Van Obberghen E";;"Jul 1994";773020800;;"Src homology/collagen (SHC) proteins are thought to participate in signaling through both receptor tyrosine kinases, such as the insulin receptor and the EGF (epidermal growth factor) receptor, and cytoplasmic tyrosine kinases, such as v-src and v-fps. Here we approached the insulin-induced and the insulin-like-growth-factor-I-induced (IGF-I-induced) phosphorylation of SHC proteins, and the possible role of these proteins in insulin and IGF-I signaling. First, we showed that SHC proteins are phosphorylated on tyrosine residues upon insulin and IGF-I treatment of fibroblasts transfected with a SHC cDNA construct. More important, ligand-activated insulin and IGF-I receptors phosphorylate SHC proteins in vitro, indicating that SHC proteins could be direct substrates for insulin and IGF-I receptors. Further, insulin or IGF-I treatment of SHC-transfected fibroblasts leads to immunoprecipitation of SHC proteins with insulin-receptor substrate 1 (IRS-1). We next looked at the possible effect of SHC proteins on biological responses in SHC-transfected fibroblasts. We found that the expression of exogenous SHC proteins results in an increased basal MEK (MAPK/ERK-activating kinase) activity. Further, neither the basal nor the insulin-induced or IGF-I-induced PtdIns-3-kinase activity were modified by expression of exogenous SHC proteins. These results illustrate that SHC proteins are implicated in the MAP (mitogen-activated protein)-kinase pathway, but not in that of PtdIns-3-kinase. Finally, we show that SHC-transfected cells, unlike control cells, are able to advance into the early phases of the cell cycle, and are more sensitive to the growth-promoting effect of insulin. In conclusion, SHC proteins are substrates for insulin and IGF-I receptors, and would appear to function as early post-receptor signaling components." 7696;"Antibodies to phosphotyrosine injected in Xenopus laevis oocytes modulate maturation induced by insulin/IGF-I.";"S. Giorgetti-Peraldi";"Team 07, Equipe 07";1711470;"Experimental cell research";"Hainaut P, Giorgetti S, Kowalski A, Ballotti R, Van Obberghen E";;"Jul 1991";678326400;;"Xenopus oocytes carry IGF-I receptors, and undergo meiotic maturation in response to binding of IGF-I or insulin to the IGF-I receptor. Maturation is initiated upon activation of the IGF-I receptor tyrosine kinase and requires tyrosine dephosphorylation of p34cdc2, the kinase component of maturation promoting factor (MPF). To further evaluate the role of tyrosine phosphorylation in the signalling pathway triggered by insulin/IGF-I, we have injected antibodies to phosphotyrosine into oocytes and examined their effects on oocyte maturation. Antibodies at a low concentration (40 ng/oocyte, corresponding to a concentration of 40 micrograms/ml), enhanced specifically insulin-, but not progesterone-induced maturation. In contrast, at 150 ng/oocyte, the same antibodies decreased maturation induced by insulin, progesterone, or microinjected MPF. In cell-free systems, antibodies to phosphotyrosine recognized the oocyte IGF-I receptor and modulated its ligand-induced tyrosine kinase activity in a biphasic manner, with a stimulation at 40 micrograms/ml and an inhibition at higher concentrations. Moreover, antibodies at 150 ng/oocyte neutralized the kinase activity of a crude MPF extract. This neutralization was not accompanied by a rephosphorylation of p34cdc2, but by a decrease in tyrosine phosphorylation of a 60-kDa protein, which was present in M phase extracts and undetectable in G2-arrested oocytes. Taken together, these results point to at least two levels of anti-phosphotyrosine antibody action: (i) the IGF-I receptor signalling system, and (ii) a regulatory step of MPF activation, which might be distinct of the well-documented inactivating phosphorylation of p34cdc2." 7694;"Insulin-like effects of vanadate on glucose uptake and on maturation in Xenopus laevis oocytes.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";2059660;"Cell regulation";"Hainaut P, Giorgetti S, Kowalski A, Van Obberghen E";;"Apr 1991";670464000;;"Vanadate, an inhibitor of phosphotyrosyl phosphatases that exerts insulin-like effects in intact cells, stimulated both maturation and glucose uptake in isolated Xenopus laevis oocytes. Vanadate enhanced the effects of insulin/IGF-I and progesterone on maturation in a dose-dependent manner, with an effective concentration of 750 microM and a maximum at 2 mM, whereas, in the absence of hormone, activation of maturation was seen at 10 mM vanadate. Further, vanadate at 2 mM increased glucose uptake, but this effect was not additive to that of the hormone. In cell-free systems, vanadate caused a 12-fold stimulation of autophosphorylation of the oocyte IGF-I receptor in the absence, but not in the presence, of IGF-I and inhibited largely, but not totally, receptor dephosphorylation induced by an extract of oocytes rich in phosphotyrosyl phosphatase activities. These effects were dose dependent, with effective concentrations of 50-100 microM and maxima at 2 mM. Moreover, using an acellular assay to study the effect of vanadate on the activation of maturation promoting factor (MPF), we found that vanadate at 2 mM stimulated the activation of the MPF H1 kinase. This suggests that vanadate did not prevent dephosphorylation of p34cdc2 on tyrosine residues. Vanadate thus exerted insulin-like effects in oocytes, including stimulation of maturation. These effects might result from a direct or indirect action of vanadate on the IGF-I receptor kinase and on MPF activity." 7692;"Effects of insulin, insulin-like growth factor-I (IGF-I) and progesterone on glucose and amino acid uptake in Xenopus laevis oocytes.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";2050272;"Molecular and cellular endocrinology";"Hainaut P, Kowalski A, Le Marchand-Brustel Y, Giorgetti S, Gautier N, Van Obberghen E";;"Feb 1991";665366400;;"In Xenopus oocytes, insulin or IGF-I activated glucose transport and maturation, but not amino acid transport, as measured by the uptake of alanine. Glucose transporter identical or closely related to the mammalian erythroid/brain transporter (Glut-1/EGT) were found in oocyte membranes. The EC50 for stimulation of glucose uptake and of maturation were similar (1-5 x 10(-8) M for insulin and 2-8 x 10(-10) M for IGF-I), confirming that these effects were mediated through IGF-I receptors. Other agents, such as phorbol 12-myristate 13-acetate (TPA) (0.5 microM) and vanadate (2 mM) evoked only part of the insulin effect on glucose uptake (50% and 65%, respectively), without being additive to insulin. In contrast, progesterone at 1 microM, a potent inducer of maturation, inhibited at least partially the insulin-induced glucose uptake. Uptake of alanine and glucose was decreased after prolonged incubations (3-6 h) with agents that trigger maturation, and was dramatically reduced in oocytes that have undergone maturation (unfertilized eggs). Maturation is thus accompanied by a reduction in glucose and amino acid transports. These result further document the validity of Xenopus oocytes as a model to study insulin and IGF-I signalling." 7690;"Insulin and insulin-like-growth-factor-I (IGF-I) receptors in Xenopus laevis oocytes. Comparison with insulin receptors from liver and muscle.";"S. Giorgetti-Peraldi";"Team 07, Equipe 07";1847619;"The Biochemical journal";"Hainaut P, Kowalski A, Giorgetti S, Baron V, Van Obberghen E";;"Feb 1991";665366400;;"Insulin and insulin-like-growth-factor-I (IGF-I) receptors were partially purified from full-grown (stages V-VI) Xenopus laevis oocytes by affinity chromatography on wheat-germ agglutinin-agarose. Competitive-binding assays revealed high-affinity binding sites for both insulin and IGF-I (Kd = 2.5 x 10(-10) M and 8 x 10(-10) M respectively). However, IGF-I receptors were about 15 times more abundant than insulin receptors (22.5 x 10(11) versus 1.5 x 10(11)/mg of protein). Moreover, comparison of intact and collagenase-treated oocytes showed that most of the insulin receptors were in the oocyte envelopes, whereas IGF-I receptors were essentially at the oocyte surface. Oocyte receptors were composed of alpha-subunits of approximately 130 kDa and a doublet of beta-subunits of 95 and 105 kDa, which both had ligand-induced phosphorylation patterns compatible with IGF-I receptor beta-subunits. Accordingly, the receptor tyrosine kinase was stimulated at low IGF-I concentrations [half-maximally effective concentration (EC50) approximately 0.5-1 nM], and at higher insulin concentrations (EC50 approximately 20-50 nM). Partially purified glycoproteins from Xenopus liver and muscle contained mainly receptors of the insulin-receptor type, with alpha-subunits of 140 kDa in liver and 125 kDa in muscle, and doublets of beta-subunits of 92-98 kDa in liver and 85-94 kDa in muscle. Immunoprecipitation of receptors from oocytes, liver and muscle by receptor-specific anti-peptide antibodies suggested that the beta-subunit heterogeneity resulted from the existence of two distinct IGF-I receptors in oocytes and of two distinct insulin receptors in both liver and muscle. In the different tissues, the two receptor subtypes differed at least by their beta-subunit C-terminal region." 7688;"Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function.";"J. Jager";"Equipe 07, Team 07";22474260;"Genes & development";"Bugge A, Feng D, Everett LJ, Briggs ER, Mullican SE, Wang F, Jager J, Lazar MA";;"Apr 2012";1333238400;;"The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology." 7686;"Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome.";"J. Jager";"Equipe 07, Team 07";22891325;"Proceedings of the National Academy of Sciences of the United States of America";"Yan Q, Carmody RJ, Qu Z, Ruan Q, Jager J, Mullican SE, Lazar MA, Chen YH";;"Aug 2012";1343779200;;"Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR-Hdac3-deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR-Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome." 7684;"Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erbα.";"J. Jager";"Equipe 07, Team 07";24552589;"Molecular endocrinology (Baltimore, Md.)";"Jager J, O'Brien WT, Manlove J, Krizman EN, Fang B, Gerhart-Hines Z, Robinson MB, Klein PS, Lazar MA";;"Apr 2014";1396310400;;"The regulation of behavior by the molecular components of the circadian clock is not well understood. Here we report that mice lacking the nuclear receptor Rev-erbα, a potent transcriptional repressor and core clock component, displayed marked hyperactivity and impaired response habituation in novel environments. In addition, Rev-erbα knockout (KO) mice were deficient in short-term, long-term, and contextual memories and also showed impairment in nest-building ability. Together, these results suggest that Rev-erbα KO mice manifest defective hippocampal function. Interestingly, the changes in novelty-induced locomotor activity of Rev-erbα KO mice were comparable at multiple times of day, potentially due to the muted amplitude of Rev-erbα oscillation in the hippocampus of wild-type mice. Hippocampal dopamine turnover was increased in Rev-erbα KO mice, due to up-regulation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine production, and pharmacologic inhibition of tyrosine hydroxylase activity partially rescued locomotor hyperactivity. These findings reveal a novel, nonredundant function for Rev-erbα that links a core component of the circadian gene-regulatory network to the control of dopaminergic and hippocampus-dependent behaviors." 7682;"Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo.";"J. Jager";"Equipe 07, Team 07";25416951;Cell;"Fang B, Everett LJ, Jager J, Briggs E, Armour SM, Feng D, Roy A, Gerhart-Hines Z, Sun Z, Lazar MA";;"Nov 2014";1414800000;;"Mammalian transcriptomes display complex circadian rhythms with multiple phases of gene expression that cannot be accounted for by current models of the molecular clock. We have determined the underlying mechanisms by measuring nascent RNA transcription around the clock in mouse liver. Unbiased examination of enhancer RNAs (eRNAs) that cluster in specific circadian phases identified functional enhancers driven by distinct transcription factors (TFs). We further identify on a global scale the components of the TF cistromes that function to orchestrate circadian gene expression. Integrated genomic analyses also revealed mechanisms by which a single circadian factor controls opposing transcriptional phases. These findings shed light on the diversity and specificity of TF function in the generation of multiple phases of circadian gene transcription in a mammalian organ." 7680;"GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock.";"J. Jager";"Equipe 07, Team 07";26044300;"Science (New York, N.Y.)";"Zhang Y, Fang B, Emmett MJ, Damle M, Sun Z, Feng D, Armour SM, Remsberg JR, Jager J, Soccio RE, Steger DJ, Lazar MA";;"Jun 2015";1433116800;;"Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbα modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbα to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbα regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erbα and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erbα uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue." 7678;"Liver innate immune cells and insulin resistance: the multiple facets of Kupffer cells.";"J. Jager";"Equipe 07, Team 07";26864622;"Journal of internal medicine";"Jager J, Aparicio-Vergara M, Aouadi M";;"08 2016";1470009600;;"Obesity, which affects 600 million adults worldwide, is a major risk factor for type 2 diabetes (T2D) and insulin resistance. Current therapies for these metabolic disorders include weight management by lifestyle intervention or bariatric surgery and pharmacological treatment with the aim of regulating blood glucose. Probably because of their short-term effectiveness, these therapies have not been able to stop the rapidly rising prevalence of T2D over the past decades, highlighting an urgent need to develop new therapeutic strategies. The role of immune cells, such as macrophages, in insulin resistance has been extensively studied. Major advances have been made to elucidate the role of adipose tissue macrophages in these pathogeneses. Recently, anti-inflammatory drugs have been suggested as an alternative treatment for T2D, and clinical trials of these agents are currently ongoing. In addition, results of previous clinical trials using antibodies against inflammatory cytokines, which showed modest effects, are now being rigorously re-evaluated. However, it is still unclear how liver macrophages [termed Kupffer cells (KCs)], which constitute the major source of macrophages in the body, contribute to the development of insulin resistance. In this review, we will discuss the present understanding of the role of liver immune cells in the development of insulin resistance. We will particularly focus on KCs, which could represent an attractive target for the treatment of metabolic diseases." 7676;"The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling.";"J. Jager";"Equipe 07, Team 07";27002153;"The Journal of biological chemistry";"Jager J, Wang F, Fang B, Lim HW, Peed LC, Steger DJ, Won KJ, Kharitonenkov A, Adams AC, Lazar MA";;"May 2016";1462060800;;"FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver. Rev-erbα ablation led to the robust elevated expression of βKlotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erbα. A major Rev-erbα-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) γ, which regulates its activity in the opposite direction. These findings establish Rev-erbα as a specific modulator of FGF21 signaling in adipose tissue." 7674;"Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion.";"J. Jager";"Equipe 07, Team 07";27991918;"Nature medicine";"Hong S, Zhou W, Fang B, Lu W, Loro E, Damle M, Ding G, Jager J, Zhang S, Zhang Y, Feng D, Chu Q, Dill BD, Molina H, Khurana TS, Rabinowitz JD, Lazar MA, Sun Z";;"Feb 2017";1485907200;;"Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance." 7672;"Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge.";"J. Jager";"Equipe 07, Team 07";28614293;Nature;"Emmett MJ, Lim HW, Jager J, Richter HJ, Adlanmerini M, Peed LC, Briggs ER, Steger DJ, Ma T, Sims CA, Baur JA, Pei L, Won KJ, Seale P, Gerhart-Hines Z, Lazar MA";;"06 2017";1496275200;;"Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature." 7670;"The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ.";"J. Jager";"Equipe 07, Team 07";28747429;"Genes & development";"Zhang Y, Papazyan R, Damle M, Fang B, Jager J, Feng D, Peed LC, Guan D, Sun Z, Lazar MA";;"06 2017";1496275200;;"Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors RORα and RORγ, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. RORα/γ controls circadian expression of , which keeps feeding-induced SREBP1c activation under check. Loss of RORα/γ causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders." 7668;"Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance.";"J. Jager";"Equipe 07, Team 07";32102936;"Science translational medicine";"Azzimato V, Jager J, Chen P, Morgantini C, Levi L, Barreby E, Sulen A, Oses C, Willerbrords J, Xu C, Li X, Shen JX, Akbar N, Haag L, Ellis E, Wålhen K, Näslund E, Thorell A, Choudhury RP, Lauschke VM, Rydén M, Craige SM, Aouadi M";;"02 2020";1580515200;;"Obesity and insulin resistance are risk factors for nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. Because no approved medication nor an accurate and noninvasive diagnosis is currently available for NAFLD, there is a clear need to better understand the link between obesity and NAFLD. Lipid accumulation during obesity is known to be associated with oxidative stress and inflammatory activation of liver macrophages (LMs). However, we show that although LMs do not become proinflammatory during obesity, they display signs of oxidative stress. In livers of both humans and mice, antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) was down-regulated with obesity and insulin resistance, yielding an impaired response to lipid accumulation. At the molecular level, a microRNA-targeting NRF2 protein, , was elevated in the livers of obese insulin-resistant humans and mice, and specific silencing of in murine and human LMs was sufficient to restore NRF2 protein expression and the antioxidant response. These results highlight the pathological role of LMs and their therapeutic potential to restore the impaired endogenous antioxidant response in obesity-associated NAFLD." 7666;"Author Correction: Liver macrophages regulate systemic metabolism through non-inflammatory factors.";"J. Jager";"Equipe 07, Team 07";33469210;"Nature metabolism";"Morgantini C, Jager J, Li X, Levi L, Azzimato V, Sulen A, Barreby E, Xu C, Tencerova M, Näslund E, Kumar C, Verdeguer F, Straniero S, Hultenby K, Björkström NK, Ellis E, Rydén M, Kutter C, Hurrell T, Lauschke VM, Boucher J, Tomčala A, Krejčová G, Bajgar A, Aouadi M";;"Feb 2021";1612137600;; 7664;"The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages.";"J. Jager";"Equipe 07, Team 07";33503407;"Molecular cell";"Huang Z, Liang N, Goñi S, Damdimopoulos A, Wang C, Ballaire R, Jager J, Niskanen H, Han H, Jakobsson T, Bracken AP, Aouadi M, Venteclef N, Kaikkonen MU, Fan R, Treuter E";;"03 2021";1614556800;;"While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates in vivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases." 7662;"The transcriptional repressor Rev-erbα regulates circadian expression of the astrocyte Fabp7 mRNA.";"J. Jager";"Equipe 07, Team 07";34056625;"Current research in neurobiology";"Vanderheyden WM, Fang B, Flores CC, Jager J, Gerstner JR";;"Jan 2021";1609459200;;"The astrocyte brain-type fatty-acid binding protein (Fabp7) circadian gene expression is synchronized in the same temporal phase throughout mammalian brain. Cellular and molecular mechanisms that contribute to this coordinated expression are not completely understood, but likely involve the nuclear receptor Rev-erbα (NR1D1), a transcriptional repressor. We performed ChIP-seq on ventral tegmental area (VTA) and identified gene targets of Rev-erbα, including . We confirmed that Rev-erbα binds to the promoter in multiple brain areas, including hippocampus, hypothalamus, and VTA, and showed that gene expression is upregulated in knock-out mice. Compared to mRNA levels, and mRNA were unaffected by depletion in hippocampus, suggesting that these effects are specific to . To determine whether these effects of depletion occur broadly throughout the brain, we also evaluated mRNA expression levels in multiple brain areas, including cerebellum, cortex, hypothalamus, striatum, and VTA in knock-out mice. While small but significant changes in mRNA expression exist in some of these areas, the magnitude of these effects are minimal to that of mRNA expression, which was over 6-fold across all brain regions. These studies suggest that Rev-erbα is a transcriptional repressor of gene expression throughout mammalian brain." 7581;"Identification of potentially anti-COVID-19 active drugs using the connectivity MAP.";"JF. PEYRON";"Equipe 04";35085325;"PloS one";"Bonnet R, Mariault L, Peyron JF";;"Jan 2022";1640995200;;"Drug repurposing can be an interesting strategy for an emergency response to the severe acute respiratory syndrome-coronavirus-2, (SARS-COV-2), the causing agent of the coronavirus disease-19 (COVID-19) pandemic. For this, we applied the Connectivity Map (CMap) bioinformatic resource to identify drugs that generate, in the CMap database, gene expression profiles (GEP) that negatively correlate with a SARS-COV-2 GEP, anticipating that these drugs could antagonize the deleterious effects of the virus at cell, tissue or organism levels. We identified several anti-cancer compounds that target MDM2 in the p53 pathway or signaling proteins: Ras, PKBβ, Nitric Oxide synthase, Rho kinase, all involved in the transmission of proliferative and growth signals. We hypothesized that these drugs could interfere with the high rate of biomass synthesis in infected cells, a feature shared with cancer cells. Other compounds including etomoxir, triacsin-c, PTB1-IN-3, are known to modulate lipid metabolism or to favor catabolic reactions by activating AMPK. Four different anti-inflammatory molecules, including dexamethasone, fluorometholone and cytosporone-b, targeting the glucocorticoid receptor, cyclooxygenase, or NUR77 also came out of the analysis. These results represent a first step in the characterization of potential repositioning strategies to treat SARS-COV-2." 7485;"Treatment of Chediak-Higashi syndrome by allogenic bone marrow transplantation: report of 10 cases.";"PS. ROHRLICH";"Equipe 04, Team 04";7756666;Blood;"Haddad E, Le Deist F, Blanche S, Benkerrou M, Rohrlich P, Vilmer E, Griscelli C, Fischer A";;"Jun 1995";801964800;;"Chediak-Higashi syndrome is a rare condition characterized by susceptibility to bacterial infections, defective natural killer activity, and episodes of macrophage activation known as accelerated phases. Chemotherapy can induce transient remission of the accelerated phase, but relapses become less and less sensitive to treatment and ultimately lead to death. Allogenic bone marrow transplantation (BMT) has been proposed as a curative treatment for Chediak-Higashi syndrome. We report the outcome of BMT in 10 such children. Seven received marrow from an HLA-identical related donor and three from an HLA-nonidentical related donor. Three patients died, two from a new accelerated phase after rejection of transplanted bone marrow and one from cytomegalovirus (CMV) pneumonia. Six of seven recipients of HLA-identical marrow and one of three recipients of HLA-nonidentical marrow are alive and well without treatment 1.5 to 13 years after transplantation (median, 6.5 years). No manifestations of accelerated phases have occurred in these seven patients, and significant natural killer activity is detectable. Interestingly, BMT prevented recurrence of accelerated phases in patients with limited numbers of donor-type leukocytes after transplantation. Ocular and cutaneous albinism were not corrected after transplantation. None of the patients developed serious toxic reactions to the BMT conditioning regimen or have long-term sequelae. These results show that HLA-identical BMT is an acceptable curative treatment for Chediak-Higashi syndrome, whereas HLA-nonidentical BMT remains an experimental approach." 7483;"Deletion mapping indicates that MTS1 is the target of frequent deletions at chromosome 9p21 in paediatric acute lymphoblastic leukaemias.";"PS. ROHRLICH";"Equipe 04, Team 04";8603008;"British journal of haematology";"Guidal-Giroux C, Gérard B, Cavé H, Duval M, Rohrlich P, Elion J, Vilmer E, Grandchamp B";;"Feb 1996";823132800;;"Recent reports have indicated a high frequency of deletions of MTS1 (CDKN2, p16ink4, CDKI4) in acute lymphoblastic leukaemias (ALLs). This gene is located at chromosome 9p21 and encodes an inhibitor of cyclin D-dependent kinases. In contrast with the observations in some other malignancies, no inactivation of MTS1 by intragenic mutation was demonstrated in leukaemias. A contribution of MTS1 alterations to leukaemogenesis therefore remains questionable. In order to test for the implication of MTS1 as a tumour suppressor gene in paediatric ALLs we have explored the 9p21 chromosomal region of 46 children with this disease. The copy number of the MTS1 gene in blasts from the patients was determined using a quantitative PCR assay enabling us to precisely detect mono- and bi-allelic deletions. Rearrangements of the gene were sought by Southern blot analysis. The extent of the deletions was studied using microsatellite markers spanning the 9p21 chromosomal region. Point mutations were sought in exon 1 and exon 2 of the MTS1 gene in patients with a mono-allelic deletion in addition, exon 2 of MTS1, which contains two-thirds of the coding region, was sequenced in all patients who had no deletion of the gene. Altogether, our data are consistent with the view that MTS1 is the target of 9p21 deletions. Either one or two alleles of the gene were deleted in 36% of non-selected children with B-lineage ALL and both alleles were deleted in all seven patients we studied with T-lineage ALL. The absence of any point mutation implies that the major mechanism of inactivation of MTS1 in ALLs is deletional." 7481;"Cutaneous involvement in children with acute lymphoblastic leukemia or lymphoblastic lymphoma. The Children's Leukemia Cooperative Group of the European Organization of Research and Treatment of Cancer (EORTC).";"PS. ROHRLICH";"Equipe 04, Team 04";9200360;Pediatrics;"Millot F, Robert A, Bertrand Y, Mechinaud F, Laureys G, Ferster A, Brock P, Rohrlich P, Mazingue F, Plantaz D, Plouvier E, Pacquement H, Behar C, Rialland X, Chantraine JM, Guilhot F, Otten J";;"Jul 1997";867715200;;"Skin involvement in children with acute monocytic leukemia or CD30-positive anaplastic large-cell lymphoma is well-known. In contrast, very little is known about the malignant cutaneous infiltrates in children with acute lymphoblatic leukemia (ALL) or lymphoblastic lymphoma (LBL). This study was designed to determine the frequency of these specific lesions in childhood ALL or LBL and the characteristics of such patients." 7479;"NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951.";"PS. ROHRLICH";"Equipe 04, Team 04";20861920;Leukemia;"Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, Kaltenbach S, Yakouben K, Mazingue F, Robert A, Boutard P, Plantaz D, Rohrlich P, van Vlierberghe P, Preudhomme C, Otten J, Speleman F, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cavé H, ";;"Dec 2010";1291161600;;"Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH+ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH+ patients showed a better early response to chemotherapy as compared with NOTCH- patients, according to the rate of poor pre-phase 'responders' (25% versus 44%; P=0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P=0.01) at completion of induction. However, the outcome of NOTCH+ patients was similar to that of NOTCH- patients, with a 5-year event-free survival (EFS) of 73% and 70% (P=0.82), and 5-year overall survival of 82% and 79% (P=0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH+) versus 42% (NOTCH-), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH+) versus 78% (NOTCH-). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1+ patients (8.3%), which could be related to a higher propensity of NOTCH+ leukemic blasts to target the CNS." 7477;"Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).";"PS. ROHRLICH";"Equipe 04, Team 04";21119115;Blood;"Pachlopnik Schmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, Kanegane H, Lopez-Granados E, Mejstrikova E, Pellier I, Galicier L, Galambrun C, Barlogis V, Bordigoni P, Fourmaintraux A, Hamidou M, Dabadie A, Le Deist F, Haerynck F, Ouachée-Chardin M, Rohrlich P, Stephan JL, Lenoir C, Rigaud S, Lambert N, Milili M, Schiff C, Chapel H, Picard C, de Saint Basile G, Blanche S, Fischer A, Latour S";;"Feb 2011";1296518400;;"X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions." 7475;"High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia.";"PS. ROHRLICH";"Equipe 04, Team 04";23223431;Blood;"Pasquet M, Bellanné-Chantelot C, Tavitian S, Prade N, Beaupain B, Larochelle O, Petit A, Rohrlich P, Ferrand C, Van Den Neste E, Poirel HA, Lamy T, Ouachée-Chardin M, Mansat-De Mas V, Corre J, Récher C, Plat G, Bachelerie F, Donadieu J, Delabesse E";;"Jan 2013";1356998400;;"Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome." 7473;"Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results.";"PS. ROHRLICH";"Equipe 04, Team 04";23321258;Blood;"Dastugue N, Suciu S, Plat G, Speleman F, Cavé H, Girard S, Bakkus M, Pagès MP, Yakouben K, Nelken B, Uyttebroeck A, Gervais C, Lutz P, Teixeira MR, Heimann P, Ferster A, Rohrlich P, Collonge MA, Munzer M, Luquet I, Boutard P, Sirvent N, Karrasch M, Bertrand Y, Benoit Y";;"Mar 2013";1362096000;;"The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy>50 chromosomes (HD>50), a group of B-cell precursor acute lymphoblastic leukemia with favorable outcome. The 541 HD>50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error [SE] = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P < .0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI < 1.16/≥1.16-<1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728." 7471;"Altered responses to homeostatic cytokines in patients with idiopathic CD4 lymphocytopenia.";"PS. ROHRLICH";"Equipe 04, Team 04";23383227;"PloS one";"Bugault F, Benati D, Mouthon L, Landires I, Rohrlich P, Pestre V, Thèze J, Lortholary O, Chakrabarti LA";;"Jan 2013";1356998400;;"Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4(+) T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4(+) T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4(+) T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4(+) T cells of some ICL patients, which correlated with a decreased expression of the IL-7Rα receptor chain (R = 0.74, p<0.005) and with lower CD4(+) T cell counts (R = 0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R = 0.75, p<0.005), pointing to combined defects that may significantly perturb CD4(+) T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R = -0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4(+) T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in γc cytokine responses." 7469;"A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee).";"PS. ROHRLICH";"Equipe 04, Team 04";26376115;"Pediatric blood & cancer";"Nelken B, Cave H, Leverger G, Galambrun C, Plat G, Schmitt C, Thomas C, Vérité C, Brethon B, Gandemer V, Bertrand Y, Baruchel A, Rohrlich P";;"Feb 2016";1454284800;;"Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine." 7467;"Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort.";"PS. ROHRLICH";"Equipe 04, Team 04";26484337;"Frontiers in pediatrics";"Aladjidi N, Fernandes H, Leblanc T, Vareliette A, Rieux-Laucat F, Bertrand Y, Chambost H, Pasquet M, Mazingue F, Guitton C, Pellier I, Roqueplan-Bellmann F, Armari-Alla C, Thomas C, Marie-Cardine A, Lejars O, Fouyssac F, Bayart S, Lutz P, Piguet C, Jeziorski E, Rohrlich P, Lemoine P, Bodet D, Paillard C, Couillault G, Millot F, Fischer A, Pérel Y, Leverger G";;"Jan 2015";1420070400;;"Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2-17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1-16.3). The follow-up period as from ES diagnosis was 6.5 years (0.1-28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7-28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies." 7465;"Results of successive EORTC-CLG 58 881 and 58 951 trials in paediatric T-cell acute lymphoblastic leukaemia (ALL).";"M. POIREE, PS. ROHRLICH";"Team 04, Equipe 04";31124581;"British journal of haematology";"Hofmans M, Suciu S, Ferster A, Van Vlierberghe P, Mazingue F, Sirvent N, Costa V, Yakouben K, Paillard C, Uyttebroeck A, Plantaz D, Plat G, Simon P, Millot F, Poirée M, van der Werff Ten Bosch J, Piette C, Minckes O, Rohrlich P, Girard S, Cavé H, Bertrand Y, De Moerloose B";;"09 2019";1567296000;;"Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m /day) versus prednisolone (60 mg/m /day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 10 /l and ""good responders"" to prephase. Medac E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P = 0·0015] and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 × 10 /l, representing approximately 50% of T-ALL patients." 7463;"Assessment of chimerism and immunomodulation to prevent post-transplantation relapse in childhood acute myeloblastic leukemia: is it the right approach?";"PS. ROHRLICH";"Equipe 04, Team 04";32028812;"Pediatric hematology and oncology";"Cousin E, Oger E, Dalle JH, Bertrand Y, Pertuisel S, Pochon C, Galambrun C, Simon P, Bruno B, Paillard C, Schneider P, Rohrlich P, de La Tour RP, Freycon C, Eliaou JF, Semana G, Jonveaux P, Drunat S, Bordigoni P, Gandemer V";;"Apr 2020";1585699200;;"Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission." 7461;"CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951.";"PS. ROHRLICH, M. POIREE";"Equipe 04, Team 04";34034929;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Sirvent N, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Paillard C, Costa V, Simon P, Pluchart C, Poirée M, Minckes O, Millot F, Freycon C, Maes P, Hoyoux C, Cavé H, Rohrlich P, Bertrand Y, Benoit Y, ";;"Jul 2021";1625097600;;"To evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial." 7459;"Fertility status among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: results of the 58 Late Adverse Effects study.";"PS. ROHRLICH";"Equipe 04, Team 04";34788455;"Human reproduction (Oxford, England)";"Rossi G, Kicinski M, Suciu S, Vandecruys E, Plat G, Uyttebroeck A, Paillard C, Barbati M, Dresse MF, Simon P, Minckes O, Pluchart C, Ferster A, Freycon C, Millot F, van der Werff Ten Bosch J, Chantrain C, Paulus R, de Rojas T, de Schaetzen G, Rohrlich P, Benoit Y, Piette C";;"Dec 2021";1638316800;;"What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors?" 7374;"Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control.";"M. Ohanna";"Equipe 11, Team 11";15723049;"Nature cell biology";"Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E, Sonenberg N, Kelly PA, Sotiropoulos A, Pende M";;"Mar 2005";1109635200;;"The mammalian target of rapamycin (mTOR) and Akt proteins regulate various steps of muscle development and growth, but the physiological relevance and the downstream effectors are under investigation. Here we show that S6 kinase 1 (S6K1), a protein kinase activated by nutrients and insulin-like growth factors (IGFs), is essential for the control of muscle cytoplasmic volume by Akt and mTOR. Deletion of S6K1 does not affect myoblast cell proliferation but reduces myoblast size to the same extent as that observed with mTOR inhibition by rapamycin. In the differentiated state, S6K1(-/-) myotubes have a normal number of nuclei but are smaller, and their hypertrophic response to IGF1, nutrients and membrane-targeted Akt is blunted. These growth defects reveal that mTOR requires distinct effectors for the control of muscle cell cycle and size, potentially opening new avenues of therapeutic intervention against neoplasia or muscle atrophy." 7372;"Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation.";"M. Ohanna";"Equipe 11, Team 11";16670201;"Proceedings of the National Academy of Sciences of the United States of America";"Sotiropoulos A, Ohanna M, Kedzia C, Menon RK, Kopchick JJ, Kelly PA, Pende M";;"May 2006";1146441600;;"Growth hormone (GH) participates in the postnatal regulation of skeletal muscle growth, although the mechanism of action is unclear. Here we show that the mass of skeletal muscles lacking GH receptors is reduced because of a decrease in myofiber size with normal myofiber number. GH signaling controls the size of the differentiated myotubes in a cell-autonomous manner while having no effect on size, proliferation, and differentiation of the myoblast precursor cells. The GH hypertrophic action leads to an increased myonuclear number, indicating that GH facilitates fusion of myoblasts with nascent myotubes. NFATc2, a transcription factor regulating this phase of fusion, is required for GH action because GH is unable to induce hypertrophy of NFATc2-/- myotubes. Finally, we provide three lines of evidence suggesting that GH facilitates cell fusion independent of insulin-like growth factor 1 (IGF-1) up-regulation. First, GH does not regulate IGF-1 expression in myotubes; second, GH action is not mediated by a secreted factor in conditioned medium; third, GH and IGF-1 hypertrophic effects are additive and rely on different signaling pathways. Taken together, these data unravel a specific function of GH in the control of cell fusion, an essential process for muscle growth." 7370;"S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover.";"M. Ohanna";"Equipe 11, Team 11";17494629;"American journal of physiology. Cell physiology";"Mieulet V, Roceri M, Espeillac C, Sotiropoulos A, Ohanna M, Oorschot V, Klumperman J, Sandri M, Pende M";;"Aug 2007";1185926400;;"A defect in protein turnover underlies multiple forms of cell atrophy. Since S6 kinase (S6K)-deficient cells are small and display a blunted response to nutrient and growth factor availability, we have hypothesized that mutant cell atrophy may be triggered by a change in global protein synthesis. By using mouse genetics and pharmacological inhibitors targeting the mammalian target of rapamycin (mTOR)/S6K pathway, here we evaluate the control of translational target phosphorylation and protein turnover by the mTOR/S6K pathway in skeletal muscle and liver tissues. The phosphorylation of ribosomal protein S6 (rpS6), eukaryotic initiation factor-4B (eIF4B), and eukaryotic elongation factor-2 (eEF2) is predominantly regulated by mTOR in muscle cells. Conversely, in liver, the MAPK and phosphatidylinositol 3-kinase pathways also play an important role, suggesting a tissue-specific control. S6K deletion in muscle mimics the effect of the mTOR inhibitor rapamycin on rpS6 and eIF4B phosphorylation without affecting eEF2 phosphorylation. To gain insight on the functional consequences of these modifications, methionine incorporation and polysomal distribution were assessed in muscle cells. Rates and rapamycin sensitivity of global translation initiation are not altered in S6K-deficient muscle cells. In addition, two major pathways of protein degradation, autophagy and expression of the muscle-specific atrophy-related E3 ubiquitin ligases, are not affected by S6K deletion. Our results do not support a role for global translational control in the growth defect due to S6K deletion, suggesting specific modes of growth control and translational target regulation downstream of mTOR." 7368;"Fifteen-year quest for microphthalmia-associated transcription factor target genes.";"M. Ohanna";"Equipe 11, Team 11";19995375;"Pigment cell & melanoma research";"Cheli Y, Ohanna M, Ballotti R, Bertolotto C";;"Feb 2010";1264982400;;"Microphthalmia-associated transcription factor (MITF) was initially shown to play a key role in melanocyte differentiation through the direct transcriptional control of TYROSINASE, TYRP1 and DCT genes, encoding the three enzymes involved in melanin synthesis or melanogenesis. Sixteen years after the first description of MITF, more than 40 direct MITF target genes have been described. They play a key role in melanocyte, osteoclast and mast cell specific functions. Furthermore, several MITF target genes, e.g. BCL2, CDK2, CDKN1A, CDKN2A, MET and HIF1A, link MITF to general cellular processes such as growth or survival. In this review, we provide an overview of the MITF-regulated genes. We pay special attention to the MITF target genes in melanocytes and raise questions about target specificity." 7366;"Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas.";"M. Ohanna";"Equipe 11, Team 11";20388797;"Cancer research";"Giuliano S, Cheli Y, Ohanna M, Bonet C, Beuret L, Bille K, Loubat A, Hofman V, Hofman P, Ponzio G, Bahadoran P, Ballotti R, Bertolotto C";;"May 2010";1272672000;;"Apoptosis and senescence are cellular failsafe programs that counteract excessive mitogenic signaling observed in cancer cells. Melanoma is known for its notorious resistance to apoptotic processes; therefore, senescence, which remains poorly understood in melanomas, can be viewed as a therapeutic alternative. Microphthalmia-associated transcription factor (MITF), in which its M transcript is specifically expressed in melanocyte cells, plays a critical role in melanoma proliferation, and its specific inhibition is associated with G(0)-G(1) growth arrest. Interestingly, decreased MITF expression has been described in senescent melanocytes, and we have observed an inhibition of MITF expression in melanoma cells exposed to chemotherapeutic drugs that induce their senescence. All these observations thereby question the role of MITF in controlling senescence in melanoma cells. Here, we report that long-term depletion of MITF in melanoma cells triggers a senescence program characterized by typical morphologic and biochemical changes associated with a sustained growth arrest. Further, we show that MITF-silenced cells engage a DNA damage response (DDR) signaling pathway, leading to p53 upregulation, which is critically required for senescence entry. This study uncovers the existence of a lineage-restricted DDR/p53 signaling pathway that is inhibited by MITF to prevent senescence and favor melanoma cell proliferation." 7364;"Fitting MITF regulation of PDE4D3 into the skin pigmentation puzzle.";"M. Ohanna";"Equipe 11, Team 11";21040501;"Pigment cell & melanoma research";"Ohanna M, Bertolotto C, Ballotti R";;"Feb 2011";1296518400;; 7362;"Advances in melanoma senescence and potential clinical application.";"M. Ohanna";"Equipe 11, Team 11";21143770;"Pigment cell & melanoma research";"Giuliano S, Ohanna M, Ballotti R, Bertolotto C";;"Apr 2011";1301616000;;"Normal cells possess a limited proliferative life span, after which they enter a state of irreversible growth arrest, called replicative senescence, which acts as a potent barrier against transformation. Transformed cells have escaped the process of replicative senescence and theoretically can not re-enter senescence. However, recent observations showed that transformed cells, and particularly the melanoma cells, can still undergo oncogene or stress-induced senescence. This senescence state is accompanied by many of the markers associated with replicative senescence, such as flattened shape, increased acidic β-galactosidase activity, characteristic changes in gene expression and growth arrest. Interestingly, in some cancers, senescence induction following chemotherapy has been correlated with a favorable patient outcome. In this review, we gathered recent results describing senescence-like phenotype induction in melanoma cells and discuss why senescence may also be exploited as a therapeutic strategy in melanoma." 7360;"BRCA1 is a new MITF target gene.";"M. Ohanna, T. Strub";"Equipe 11, Team 11, Equipe 01, Team 01";21501420;"Pigment cell & melanoma research";"Beuret L, Ohanna M, Strub T, Allegra M, Davidson I, Bertolotto C, Ballotti R";;"Aug 2011";1312156800;; 7354;"SIRT1 promotes proliferation and inhibits the senescence-like phenotype in human melanoma cells.";"M. Ohanna";"Equipe 11, Team 11";24742694;Oncotarget;"Ohanna M, Bonet C, Bille K, Allegra M, Davidson I, Bahadoran P, Lacour JP, Ballotti R, Bertolotto C";;"Apr 2014";1396310400;;"SIRT1 operates as both a tumor suppressor and oncogenic factor depending on the cell context. Whether SIRT1 plays a role in melanoma biology remained poorly elucidated. Here, we demonstrate that SIRT1 is a critical regulator of melanoma cell proliferation. SIRT1 suppression by genetic or pharmacological approaches induces cell cycle arrest and a senescence-like phenotype. Gain and loss of function experiments show that M-MITF regulates SIRT1 expression, thereby revealing a melanocyte-specific control of SIRT1. SIRT1 over-expression relieves the senescence-like phenotype and the proliferation arrest caused by MITF suppression, demonstrating that SIRT1 is an effector of MITF-induced proliferation in melanoma cells. Interestingly, SIRT1 level and activity are enhanced in the PLX4032-resistant BRAF(V600E)-mutated melanoma cells compared with their sensitive counterpart. SIRT1 inhibition decreases melanoma cell growth and rescues the sensibility to PLX4032 of PLX4032-resistant BRAF(V600E)-mutated melanoma cells. In conclusion, we provide the first evidence that inhibition of SIRT1 warrants consideration as an anti-melanoma therapeutic option." 7355;"Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype.";"M. Ohanna";"Equipe 11, Team 11";24344100;Oncotarget;"Ohanna M, Cheli Y, Bonet C, Bonazzi VF, Allegra M, Giuliano S, Bille K, Bahadoran P, Giacchero D, Lacour JP, Boyle GM, Hayward NF, Bertolotto C, Ballotti R";;"Dec 2013";1387324800;;"Here, we showed that the secretome of senescent melanoma cells drives basal melanoma cells towards a mesenchymal phenotype, with characteristic of stems illustrated by increased level of the prototype genes FN1, SNAIL, OCT4 and NANOG. This molecular reprogramming leads to an increase in the low-MITF and slow-growing cell population endowed with melanoma-initiating cell features. The secretome of senescent melanoma cells induces a panel of 52 genes, involved in cell movement and cell/cell interaction, among which AXL and ALDH1A3 have been implicated in melanoma development. We found that the secretome of senescent melanoma cells activates the STAT3 pathway and STAT3 inhibition prevents secretome effects, including the acquisition of tumorigenic properties. Collectively, the findings provide insights into how the secretome of melanoma cells entering senescence upon chemotherapy treatments increases the tumorigenicity of naïve melanoma cells by inducing, through STAT3 activation, a melanoma-initiating cell phenotype that could favor chemotherapy resistance and relapse. " 7352;"Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition.";"M. Ohanna";"Equipe 11, Team 11";27994032;"Nucleic acids research";"Zangari J, Ilie M, Rouaud F, Signetti L, Ohanna M, Didier R, Roméo B, Goldoni D, Nottet N, Staedel C, Gal J, Mari B, Mograbi B, Hofman P, Brest P";;"04 2017";1491004800;;"Extracellular vesicles (EVs) have been shown to play an important role in intercellular communication as carriers of DNA, RNA and proteins. While the intercellular transfer of miRNA through EVs has been extensively studied, the stability of extracellular miRNA (ex-miRNA) once engulfed by a recipient cell remains to be determined. Here, we identify the ex-miRNA-directed phenotype to be transient due to the rapid decay of ex-miRNA. We demonstrate that the ex-miR-223-3p transferred from polymorphonuclear leukocytes to cancer cells were functional, as demonstrated by the decreased expression of its target FOXO1 and the occurrence of epithelial-mesenchymal transition reprogramming. We showed that the engulfed ex-miRNA, unlike endogenous miRNA, was unstable, enabling dynamic regulation and a return to a non-invasive phenotype within 8 h. This transient phenotype could be modulated by targeting XRN1/PACMAN exonuclease. Indeed, its silencing was associated with slower decay of ex-miR-223-3p and subsequently prolonged the invasive properties. In conclusion, we showed that the 'steady step' level of engulfed miRNA and its subsequent activity was dependent on the presence of a donor cell in the surroundings to constantly fuel the recipient cell with ex-miRNAs and of XRN1 exonuclease, which is involved in the decay of these imported miRNA." 7348;"Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition.";"M. Ohanna";"Equipe 11, Team 11";29562367;"Nucleic acids research";"Zangari J, Ilie M, Rouaud F, Signetti L, Ohanna M, Didier R, Roméo B, Goldoni D, Nottet N, Staedel C, Gal J, Mari B, Mograbi B, Hofman P, Brest P";;"04 2018";1522540800;; 7346;"[Key role of nicotinamide phosphoribosyltransferase (NAMPT) and NAD metabolism in the transition of melanoma cells to an invasive and drug-resistant phenotype].";"M. Ohanna";"Equipe 11, Team 11";30623759;"Medecine sciences : M/S";"Bertolotto C, Ohanna M, Ballotti R";;"12 2018";1543622400;; 7344;"Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors.";"F. LARBRET";"Equipe 11, Team 11";12351405;Blood;"Giraudier S, Chagraoui H, Komura E, Barnache S, Blanchet B, LeCouedic JP, Smith DF, Larbret F, Taksin AL, Moreau-Gachelin F, Casadevall N, Tulliez M, Hulin A, Debili N, Vainchenker W";;"Oct 2002";1033430400;;"Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed, which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal megakaryocytes requiring cytokines to grow and IMF spontaneously proliferating megakaryocytes. Using a differential display technique, we found that the immunophilin FKBP51 was 2 to 8 times overexpressed in megakaryocytes derived from patients' CD34(+) cells in comparison to normal megakaryocytes. Overexpression was moderate and confirmed in 8 of 10 patients, both at the mRNA and protein levels. Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34(+) cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation. FKBP51 interacts with both calcineurin and heat shock protein (HSP)70/HSP90. However, a mutant FKBP51 deleted in the HSP70/HSP90 binding site kept the antiapoptotic effect, suggesting that the calcineurin pathway was responsible for the FKBP51 effect. Overexpression of FKBP51 in UT-7/Mpl cells induced a marked inhibition of calcineurin activity. Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51. The data support the conclusion that FKBP51 inhibits apoptosis through a calcineurin-dependent pathway. In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be, in part, responsible for the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program." 7342;"P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1.";"F. LARBRET";"Equipe 11, Team 11";18276842;Blood;"Gilles L, Guièze R, Bluteau D, Cordette-Lagarde V, Lacout C, Favier R, Larbret F, Debili N, Vainchenker W, Raslova H";;"Apr 2008";1207008000;;"The molecular mechanisms that regulate megakaryocyte (MK) ploidization are poorly understood. Using MK differentiation from primary human CD34(+) cells, we observed that p19(INK4D) expression was increased both at the mRNA and protein levels during ploidization. p19(INK4D) knockdown led to a moderate increase (31.7% +/- 5%) in the mean ploidy of MKs suggesting a role of p19(INK4D) in the endomitotic arrest. This increase in ploidy was associated with a decrease in the more mature MK population (CD41(high)CD42(high)) at day 9 of culture, which was related to a delay in differentiation. Inversely, p19(INK4D) overexpression in CD34(+) cells resulted in a decrease in mean ploidy level associated with an increase in CD41 and CD42 expression in each ploidy class. Confirming these in vitro results, bone marrow MKs from p19(INK4D) KO mice exhibited an increase in mean ploidy level from 18.7N (+/- 0.58N) to 52.7N (+/- 12.3N). Chromatin immunoprecipitation assays performed in human MKs revealed that AML-1 binds in vivo the p19(INK4D) promoter. Moreover, AML-1 inhibition led to the p19(INK4D) down-regulation in human MKs. These results may explain the molecular link at the transcriptional level between the arrest of endomitosis and the acceleration of MK differentiation." 7340;"Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.";"F. LARBRET";"Equipe 11, Team 11";20548097;Blood;"Lordier L, Chang Y, Jalil A, Aurade F, Garçon L, Lécluse Y, Larbret F, Kawashima T, Kitamura T, Larghero J, Debili N, Vainchenker W";;"Sep 2010";1283299200;;"Polyploidization of megakaryocytes (MKs), the platelet precursors, occurs by endomitosis, a mitotic process that fails at late stages of cytokinesis. Expression and function of Aurora B kinase during endomitosis remain controversial. Here, we report that Aurora B is normally expressed during the human MK endomitotic process. Aurora B localized normally in the midzone or midbody during anaphase and telophase in low ploidy megakaryocytes and in up to 16N rare endomitotic MKs was observed. Aurora B was also functional during cytokinesis as attested by phosphorylation of both its activation site and MgcRacGAP, its main substrate. However, despite its activation, Aurora B did not prevent furrow regression. Inhibition of Aurora B by AZD1152-HQPA decreased cell cycle entry both in 2N to 4N and polyploid MKs and induced apoptosis mainly in 2N to 4N cells. In both MK classes, AZD1152-HQPA induced p53 activation and retinoblastoma hypophosphorylation. Resistance of polyploid MKs to apoptosis correlated to a high BclxL level. Aurora B inhibition did not impair MK polyploidization but profoundly modified the endomitotic process by inducing a mis-segregation of chromosomes and a mitotic failure in anaphase. This indicates that Aurora B is dispensable for MK polyploidization but is necessary to achieve a normal endomitotic process." 7338;"Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression.";"F. LARBRET";"Equipe 11, Team 11";12842707;"Experimental hematology";"Komura E, Chagraoui H, Mansat de Mas V, Blanchet B, de Sepulveda P, Larbret F, Larghero J, Tulliez M, Debili N, Vainchenker W, Giraudier S";;"Jul 2003";1057017600;;"Spontaneous growth of megakaryocyte progenitors is one of the biologic hallmarks of idiopathic myelofibrosis (IMF). The molecular mechanisms underlying this hypersensitivity to cytokines are poorly understood. Using a differential display approach, we previously observed FK506 binding protein 51 (FKBP51) overexpression in pathologic megakaryocytes from IMF. Using an FKBP51-overexpressing cell line, we found sustained STAT5 activation associated with JAK2 phosphorylation. We subsequently tested whether this transcription factor was activated in patient samples. We detected a STAT5 nuclear translocation and activation in spontaneously grown megakaryocytes and in circulating CD34(+) cells from the majority of patients studied. The biologic role of this JAK/STAT pathway activation was demonstrated by inhibiting both the anti-apoptotic phenotype mediated by FKBP51 overexpression in UT7 cells and the spontaneous megakaryocytic growth by addition in culture of the JAK2 inhibitor AG490 or overexpression of a STAT5b dominant negative or SOCS-1. These results demonstrate that a constitutive STAT5 activation in IMF is indispensable for spontaneous growth of megakaryocytes. They also suggest that FKBP51 overexpression could be involved in STAT5 activation in IMF cells and in subsequent abnormal growth." 7336;"Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera.";"F. LARBRET";"Equipe 11, Team 11";15102479;"Experimental hematology";"Ugo V, Marzac C, Teyssandier I, Larbret F, Lécluse Y, Debili N, Vainchenker W, Casadevall N";;"Feb 2004";1075593600;;"Polycythemia vera (PV) is a myeloproliferative disorder arising in a multipotent hematopoietic stem cell. The pathogenesis of PV remains poorly understood; however, the biologic hallmark of this disease is the presence of erythropoietin (Epo)-independent colony formation (endogenous erythroid colony [EEC]) and cytokine hypersensitivity. We have developed a simple liquid culture from CD34+ cells to study PV erythroid differentiation. PV erythroid differentiation was characterized in this culture system by two types of abnormalities: 1) an increased proliferation of progenitors in response to cytokines, associated with strict cytokine dependency for preventing apoptosis; and 2) Epo-independent terminal erythroid differentiation in the presence of stem cell factor and interleukin-3 as evidenced by the acquisition of glycophorin A. The level of Epo-independent terminal differentiation correlates in PV patients with the number of EEC. Epo-independent terminal differentiation as well as normal Epo-induced differentiation were repressed by inhibitors of JAK2 (AG490), PI3K (LY294002), and the Src family kinases (PP2). In contrast, an inhibitor of the ERK/MAP kinase pathway (PD98059) had no effect on Epo-independent terminal differentiation. These signaling abnormalities were not mediated by a decreased expression or activity of the membrane tyrosine phosphatase CD45, which dephosphorylates JAK2 and Src family kinases. This study demonstrates that early steps of PV erythroid differentiation are strictly cytokine dependent. In contrast, late erythroid differentiation is an Epo-independent phenomenon that is mediated by signaling pathways identical to those in Epo-induced differentiation." 7332;"Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling.";"F. LARBRET";"Equipe 11, Team 11";18684864;Blood;"Lordier L, Jalil A, Aurade F, Larbret F, Larghero J, Debili N, Vainchenker W, Chang Y";;"Oct 2008";1222819200;;"Megakaryocyte (MK) is the naturally polyploid cell that gives rise to platelets. Polyploidization occurs by endomitosis, which was a process considered to be an incomplete mitosis aborted in anaphase. Here, we used time-lapse confocal video microscopy to visualize the endomitotic process of primary human megakaryocytes. Our results show that the switch from mitosis to endomitosis corresponds to a late failure of cytokinesis accompanied by a backward movement of the 2 daughter cells. No abnormality was observed in the central spindle of endomitotic MKs. A furrow formation was present, but the contractile ring was abnormal because accumulation of nonmuscle myosin IIA was lacking. In addition, a defect in cell elongation was observed in dipolar endomitotic MKs during telophase. RhoA and F-actin were partially concentrated at the site of furrowing. Inhibition of the Rho/Rock pathway caused the disappearance of F-actin at midzone and increased MK ploidy level. This inhibition was associated with a more pronounced defect in furrow formation as well as in spindle elongation. Our results suggest that the late failure of cytokinesis responsible for the endomitotic process is related to a partial defect in the Rho/Rock pathway activation." 7334;"A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell-derived primitive hematopoiesis.";"F. LARBRET";"Equipe 11, Team 11";19478046;Blood;"Klimchenko O, Mori M, Distefano A, Langlois T, Larbret F, Lecluse Y, Feraud O, Vainchenker W, Norol F, Debili N";;"Aug 2009";1249084800;;"The megakaryocytic (MK) and erythroid lineages are tightly associated during differentiation and are generated from a bipotent megakaryocyte-erythroid progenitor (MEP). In the mouse, a primitive MEP has been demonstrated in the yolk sac. In human, it is not known whether the primitive MK and erythroid lineages are generated from a common progenitor or independently. Using hematopoietic differentiation of human embryonic stem cells on the OP9 cell line, we identified a primitive MEP in a subset of cells coexpressing glycophorin A (GPA) and CD41 from day 9 to day 12 of coculturing. This MEP differentiates into primitive erythroid (GPA(+)CD41(-)) and MK (GPA(-)CD41(+)) lineages. In contrast to erythropoietin (EPO)-dependent definitive hematopoiesis, KIT was not detected during erythroid differentiation. A molecular signature for the commitment and differentiation toward both the erythroid and MK lineages was detected by assessing expression of transcription factors, thrombopoietin receptor (MPL) and erythropoietin receptor (EPOR). We showed an inverse correlation between FLI1 and both KLF1 and EPOR during primitive erythroid and MK differentiation, similar to definitive hematopoiesis. This novel MEP differentiation system may allow an in-depth exploration of the molecular bases of erythroid and MK commitment and differentiation." 7330;"FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia.";"F. LARBRET";"Equipe 11, Team 11";15232614;"The Journal of clinical investigation";"Raslova H, Komura E, Le Couédic JP, Larbret F, Debili N, Feunteun J, Danos O, Albagli O, Vainchenker W, Favier R";;"Jul 2004";1088640000;;"Paris-Trousseau syndrome (PTS; also known as Jacobsen syndrome) is characterized by several congenital anomalies including a dysmegakaryopoiesis with two morphologically distinct populations of megakaryocytes (MKs). PTS patients harbor deletions on the long arm of chromosome 11, including the FLI1 gene, which encodes a transcription factor essential for megakaryopoiesis. We show here that lentivirus-mediated overexpression of FLI1 in patient CD34(+) cells restores the megakaryopoiesis in vitro, indicating that FLI1 hemizygous deletion contributes to the PTS hematopoietic defects. FISH analysis on pre-mRNA and single-cell RT-PCR revealed that FLI1 expression is mainly monoallelic in CD41(+)CD42(-) progenitors, while it is predominantly biallelic in the other stages of megakaryopoiesis. In PTS cells, the hemizygous deletion of FLI1 generates a subpopulation of CD41(+)CD42(-) cells completely lacking FLI1 transcription. We propose that the absence of FLI1 expression in these CD41(+)CD42(-) cells might prevent their differentiation, which could explain the segregation of the PTS MKs into two subpopulations: one normal and one composed of small immature MKs undergoing a massive lysis, presumably originating from either FLI1(+) or FLI1(-) CD41(+)CD42(-) cells, respectively. Thus, we point to the role of transient monoallelic expression of a gene essential for differentiation in the genesis of human haploinsufficiency-associated disease and suggest that such a mechanism may be involved in the pathogenesis of other congenital or acquired genetic diseases." 7328;"Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach.";"F. LARBRET";"Equipe 11, Team 11";17170127;Blood;"Raslova H, Kauffmann A, Sekkaï D, Ripoche H, Larbret F, Robert T, Tronik Le Roux D, Kroemer G, Debili N, Dessen P, Lazar V, Vainchenker W";;"Apr 2007";1175385600;;"Polyploidization is a part of the normal developmental process leading to platelet production during megakaryocyte (MK) differentiation. Ploidization is mainly involved in cell enlargement, but it is not clear whether gene expression is modified during MK ploidization. In this study, human MKs were grown from CD34(+) cells in the presence of thrombopoietin and sorted according to their ploidy level. A pangenomic microarray technique was applied to compare gene expression in 2N-, 4N-, 8N-, and 16N-sorted MKs. Using hierarchical clustering, we demonstrated that 2N and 4N MKs or 8N and 16N MKs are 2 different close populations with 105 discriminating genes. In the second approach, we determined the profile of genes that were continuously down- and up-regulated during polyploidization. Among the 100 down-regulated genes, 24 corresponded to genes involved in DNA replication and repair. The great majority of up-regulated genes corresponded to genes directly involved in platelet functions, such as genes encoding specific platelet glycoproteins and alpha-granule proteins, actin and microtubule cytoskeleton, factors involved in signaling, and transport proteins. Together, these results suggest that MK polyploidization per se does not regulate gene expression but is intrinsically included in the differentiation process." 7326;"Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis.";"F. LARBRET";"Equipe 11, Team 11";17709604;Blood;"Chaligné R, James C, Tonetti C, Besancenot R, Le Couédic JP, Fava F, Mazurier F, Godin I, Maloum K, Larbret F, Lécluse Y, Vainchenker W, Giraudier S";;"Nov 2007";1193875200;;"The MPL (W515L and W515K) mutations have been detected in granulocytes of patients suffering from certain types of primitive myelofibrosis (PMF). It is still unknown whether this molecular event is also present in lymphoid cells and therefore potentially at the hematopoietic stem cell (HSC) level. Toward this goal, we conducted MPL genotyping of mature myeloid and lymphoid cells and of lymphoid/myeloid progenitors isolated from PMF patients carrying the W515 mutations. We detected both MPL mutations in granulocytes, monocytes, and platelets as well as natural killer (NK) cells but not in T cells. B/NK/myeloid and/or NK/myeloid CD34(+)CD38(-)-derived clones were found to carry the mutations. Long-term reconstitution of MPL W515 CD34(+) cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice was successful for as long as 12 weeks after transplantation, indicating that MPL W515 mutations were present in HSCs. Moreover, the 2 MPL mutations induced a spontaneous megakaryocytic growth in culture with an overall normal response to thrombopoietin (TPO). In contrast, erythroid progenitors remained EPO dependent. These results demonstrate that in PMF, the MPL W515L or K mutation induces a spontaneous megakaryocyte (MK) differentiation and occurs in a multipotent HSCs." 7324;"The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera.";"F. LARBRET";"Equipe 11, Team 11";17389763;Blood;"Dupont S, Massé A, James C, Teyssandier I, Lécluse Y, Larbret F, Ugo V, Saulnier P, Koscielny S, Le Couédic JP, Casadevall N, Vainchenker W, Delhommeau F";;"Mar 2007";1175126400;;"The JAK2 617V>F mutation is frequent in polycythemia vera (PV) and essential thrombocythemia (ET). Using quantitative polymerase chain reaction (PCR), we found that high levels of JAK2 617V>F in PV correlate with increased granulocytes and high levels of hemoglobin and endogenous erythroid colony formation. We detected normal progenitors and those that were heterozygous or homozygous for the mutation by genotyping ET and PV clonal immature and committed progenitors. In PV patients, we distinguished homozygous profiles with normal, heterozygous, and homozygous progenitors from heterozygous profiles with only heterozygous and normal progenitors. PV patients with a heterozygous profile had more mutated, committed progenitors than did other PV and ET patients, suggesting a selective amplification of mutated cells in the early phases of hematopoiesis. We demonstrated that mutated erythroid progenitors were more sensitive to erythropoietin than normal progenitors, and that most homozygous erythroid progenitors were erythropoietin independent. Moreover, we observed a greater in vitro erythroid amplification and a selective advantage in vivo for mutated cells in late stages of hematopoiesis. These results suggest that, for PV, erythrocytosis can occur through two mechanisms: terminal erythroid amplification triggered by JAK2 617V>F homozygosity, and a 2-step process including the upstream amplification of heterozygous cells that may involve additional molecular events." 7322;"Proplatelet formation is regulated by the Rho/ROCK pathway.";"F. LARBRET";"Equipe 11, Team 11";17244674;Blood;"Chang Y, Auradé F, Larbret F, Zhang Y, Le Couedic JP, Momeux L, Larghero J, Bertoglio J, Louache F, Cramer E, Vainchenker W, Debili N";;"May 2007";1177977600;;"Platelets are released by megakaryocytes (MKs) via cytoplasmic extensions called proplatelets, which require profound changes in the microtubule and actin organization. Here, we provide evidence that the Rho/ROCK pathway, a well-known regulator of actin cytoskeleton, acts as a negative regulator of proplatelet formation (PPF). Rho is expressed at a high level during the entire MK differentiation including human CD34(+) cells. Thrombopoietin stimulates its activity but at a higher extent in immature than in mature MKs. Overexpression of a dominant-negative or a spontaneously active RhoA leads to an increase or a decrease in PPF indicating that Rho activation inhibits PPF. This inhibitory effect is mediated through the main Rho effector, Rho kinase (ROCK), the inhibition of which also increases PPF. Furthermore, inhibition of Rho or ROCK in MKs leads to a decrease in myosin light chain 2 (MLC2) phosphorylation, which is required for myosin contractility. Interestingly, inhibition of the MLC kinase also decreases MLC2 phosphorylation while increasing PPF. Taken together, our results suggest that MLC2 phosphorylation is regulated by both ROCK and MLC kinase and plays an important role in platelet biogenesis by controlling PPF and fragmentation." 7317;"FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia.";"F. LARBRET";"Equipe 11, Team 11";15232614;"The Journal of clinical investigation";"Raslova H, Komura E, Le Couédic JP, Larbret F, Debili N, Feunteun J, Danos O, Albagli O, Vainchenker W, Favier R";;"Jul 2004";1088812800;;"Paris-Trousseau syndrome (PTS; also known as Jacobsen syndrome) is characterized by several congenital anomalies including a dysmegakaryopoiesis with two morphologically distinct populations of megakaryocytes (MKs). PTS patients harbor deletions on the long arm of chromosome 11, including the FLI1 gene, which encodes a transcription factor essential for megakaryopoiesis. We show here that lentivirus-mediated overexpression of FLI1 in patient CD34(+) cells restores the megakaryopoiesis in vitro, indicating that FLI1 hemizygous deletion contributes to the PTS hematopoietic defects. FISH analysis on pre-mRNA and single-cell RT-PCR revealed that FLI1 expression is mainly monoallelic in CD41(+)CD42(-) progenitors, while it is predominantly biallelic in the other stages of megakaryopoiesis. In PTS cells, the hemizygous deletion of FLI1 generates a subpopulation of CD41(+)CD42(-) cells completely lacking FLI1 transcription. We propose that the absence of FLI1 expression in these CD41(+)CD42(-) cells might prevent their differentiation, which could explain the segregation of the PTS MKs into two subpopulations: one normal and one composed of small immature MKs undergoing a massive lysis, presumably originating from either FLI1(+) or FLI1(-) CD41(+)CD42(-) cells, respectively. Thus, we point to the role of transient monoallelic expression of a gene essential for differentiation in the genesis of human haploinsufficiency-associated disease and suggest that such a mechanism may be involved in the pathogenesis of other congenital or acquired genetic diseases." 7320;"Transfer of differentiation signal by membrane microvesicles harboring hedgehog morphogens.";"F. LARBRET";"Equipe 11, Team 11";16778137;Blood;"Martínez MC, Larbret F, Zobairi F, Coulombe J, Debili N, Vainchenker W, Ruat M, Freyssinet JM";;"Jun 2006";1150502400;;"Hedgehog (Hh) proteins are considered diffusible morphogens that can be membrane anchored, playing an essential role during development. Here we show that Hh morphogens are associated with microvesicles (MVs) shed from the plasma membrane of apoptotic/stimulated T cells. Hh+ MVs induced differentiation of human K562 pluripotent erythroleukemic cells toward megakaryocytic lineage, as testified to by the expression of alpha(IIb)beta3 integrin and CD42b and changes in the cell cycle. Blocking Hh pathway with either cyclopamine, neutralizing antibodies, or inhibitors of the protein kinase A pathway resulted in the inhibition of these effects. Activation of Hh signaling by SAG, a synthetic agonist, mimicked effects of Hh+ MVs on K562 cells. Human Hh+ MVs, circulating in vivo or derived from apoptotic/stimulated lymphocytes from healthy and diabetic individuals, elicited K562 cell differentiation, also inhibited by cyclopamine. In addition, Hh+ MV-treated primary human CD34+ cells presented an increase of CD41+ CD42- and CD41+ CD42+ megakaryocytic populations with an increase of corresponding polyploidy, both being reduced by blockers of the Hh pathway. Because virtually all cell types undergo plasma membrane remodeling when stimulated, derived MVs can therefore be considered true vectors in the transfer of morphogen-borne biologic information to remote responsive cells, and thereby contribute to the maintenance of homeostasis." 7316;"Thrombopoietin responsiveness reflects the number of doublings undergone by megakaryocyte progenitors.";"F. LARBRET";"Equipe 11, Team 11";15172965;Blood;"Paulus JM, Debili N, Larbret F, Levin J, Vainchenker W";;"Oct 2004";1096588800;;"To assess the variation of thrombopoietin (TPO) responsiveness associated with megakaryocyte (MK) progenitor amplification, TPO dose-response curves were obtained for normal human, single-cell plated CD34(+)CD41(+) cells. The number of MKs per well was determined in situ and expressed as number of doublings (NbD). Dose-response curves of the mean frequency of clones of each size versus log TPO concentration showed highly significant differences in the TPO concentration needed for half-maximum generation of clones of different sizes (TPO(50)): 1.89 +/- 0.51 pg/mL for 1 MK clones; 7.75 +/- 0.81 pg/mL for 2 to 3 MK clones; 38.5 +/- 5.04 pg/mL for 4 to 7 MK clones, and 91.8 +/- 16.0 pg/mL for 8 to 15 MK clones. These results were consistent with a prediction of the generation-age model, because the number of previous doublings in vivo was inversely correlated with the number of residual doublings in vitro. TPO responsiveness decreased in vitro by a factor of 3.5 per doubling, reflecting the recruitment of progressively more ancestral progenitors. In support of this hypothesis, the more mature CD34(+)CD41(+)CD42(+) cell fraction had a lower TPO(50) (P < .001), underwent fewer NbD (P < .001), and expressed a 2.8-fold greater median Mpl receptor density (P < .001) than the CD34(+)CD41(+)CD42(-) fraction. Progenitors that have completed their proliferative program have maximum factor responsiveness and are preferentially induced to terminal differentiation." 7314;"CXCR7 receptors facilitate the progression of colon carcinoma within lung not within liver.";"F. LARBRET";"Equipe 11, Team 11";23169289;"British journal of cancer";"Guillemot E, Karimdjee-Soilihi B, Pradelli E, Benchetrit M, Goguet-Surmenian E, Millet MA, Larbret F, Michiels JF, Birnbaum D, Alemanno P, Schmid-Antomarchi H, Schmid-Alliana A";;"Dec 2012";1354320000;;"Liver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Chemokine-receptor pairs have a critical role in determining the metastatic progression of tumours. Our hypothesis was that disruption of CXCR7/CXCR7 ligands axis could lead to a decrease in CRC metastases." 7312;"CD99 isoforms regulate CD1a expression in human monocyte-derived DCs through ATF-2/CREB-1 phosphorylation.";"F. LARBRET";"Equipe 11, Team 11";27094031;"European journal of immunology";"Mahiddine K, Mallavialle A, Bziouech H, Larbret F, Bernard A, Bernard G";;"06 2016";1464739200;;"CD1a expression is considered one of the major characteristics qualifying in vitro human dendritic cells (DCs) during their generation process. Here, we report that CD1A transcription is regulated by a mechanism involving the long and short isoforms of CD99. Using a lentiviral construct encoding for a CD99 short hairpin RNA, we were able to inhibit CD99 expression in human primary DCs. In such cells, CD1a membrane expression increased and CD1A transcripts were much higher in abundance compared to cells expressing CD99 long form (CD99LF). We also show that CD1A transcription is accompanied by a switch in expression from CD99LF to expression at comparable levels of both CD99 isoforms during immature DCs generation in vitro. We demonstrate that CD99LF maintains a lower level of CD1A transcription by up-regulating the phosphorylated form of the ATF-2 transcription factor and that CD99 short form (SF) is required to counteract this regulatory mechanism. Elucidation of the molecular mechanisms related to CD99 alternative splicing will be very helpful to better understand the transcriptional regulatory mechanism of CD1a molecules during DCs differentiation and its involvement in the immune response." 7310;"A role for Peroxisome Proliferator-Activated Receptor Beta in T cell development.";"F. LARBRET, J. Neels";"Equipe 11, Team 11";27680392;"Scientific reports";"Mothe-Satney I, Murdaca J, Sibille B, Rousseau AS, Squillace R, Le Menn G, Rekima A, Larbret F, Pelé J, Verhasselt V, Grimaldi PA, Neels JG";;"Sep 2016";1472688000;;"Metabolism plays an important role in T cell biology and changes in metabolism drive T cell differentiation and fate. Most research on the role of metabolism in T lymphocytes focuses on mature T cells while only few studies have investigated the role of metabolism in T cell development. In this study, we report that activation or overexpression of the transcription factor Peroxisome Proliferator-Activated Receptor β (PPARβ) increases fatty acid oxidation in T cells. Furthermore, using both in vivo and in vitro models, we demonstrate that PPARβ activation/overexpression inhibits thymic T cell development by decreasing proliferation of CD4CD8 double-negative stage 4 (DN4) thymocytes. These results support a model where PPARβ activation/overexpression favours fatty acid- instead of glucose-oxidation in developing T cells, thereby hampering the proliferative burst normally occurring at the DN4 stage of T cell development. As a consequence, the αβ T cells that are derived from DN4 thymocytes are dramatically decreased in peripheral lymphoid tissues, while the γδ T cell population remains untouched. This is the first report of a direct role for a member of the PPAR family of nuclear receptors in the development of T cells." 7308;"Strain CNCM I-745 Modifies the Mononuclear Phagocytes Response in the Small Intestine of Mice Following Typhimurium Infection.";"F. LARBRET";"Equipe 11, Team 11";31001263;"Frontiers in immunology";"Ibáñez L, Pontier-Bres R, Larbret F, Rekima A, Verhasselt V, Blin-Wakkach C, Czerucka D";;"Jan 2019";1546300800;;"Intestinal mononuclear phagocytes (MPs) comprise dendritic cells (DCs) and macrophages (Mφs) that play different roles in response to infection. After phagocytosis, DCs expressing CD103 transport from the intestinal tract to the mesenteric lymph nodes (MLN) and induce adaptive immune responses whereas resident Mφs expressing CX3CR1 capture bacteria in the lumen and reside in the (LP) where they induce a local immune response. CX3CR1 Mφs are generated from Ly6C monocytes that enter the colonic mucosa and differentiate locally. We previously demonstrated that the probiotic yeast CNCM I-745 () prevents infection by serovar Typhimurium (ST), decreases ST translocation to the peripheral organs and modifies the pro-and anti-inflammatory cytokine profiles in the gut. In the present study, we investigated the effect of on the migratory CD103 DCs and the resident CX3CR1 Mφs. MPs were isolated from the LP of streptomycin-treated mice infected by ST with or without treatment before or during the infection. In -pretreated mice, we observed a decrease of the CD103 DCs in the LP that was associated with the drop of ST recovery from MLN. Interestingly, induced an infiltration of LP by classical Ly6C monocytes, and modified the monocyte-Mφ maturation process in ST-infected mice. Our results showed that treatment induced the expansion of Ly6C monocytes in the blood as well as in the bone marrow (BM) of mice, thus contributing to the Mφ replenishment in LP from blood monocytes. experiments conducted on BM cells confirmed that induced the expansion of CX3CR1 Mφs and concomitantly ST phagocytosis. Altogether, these data demonstrate that CNCM I-745 modulates the innate immune response. Although here, we cannot explicitly delineate direct effects on ST from innate immunity, -amplified innate immunity correlated with partial protection from ST infection. This study shows that can induce the expansion of classical monocytes that are precursors of resident Mφs in the LP." 7303;"Evidence for a differential interaction of SHC and the insulin receptor substrate-1 (IRS-1) with the insulin-like growth factor-I (IGF-I) receptor in the yeast two-hybrid system.";"S. Tartare-Deckert";"Equipe 11, Team 11";7559507;"The Journal of biological chemistry";"Tartare-Deckert S, Sawka-Verhelle D, Murdaca J, Van Obberghen E";;"Oct 1995";812937600;;"Using the yeast two-hybrid system, a genetic assay for studying protein-protein interactions, we have examined and compared the interaction of the insulin-like growth factor-I receptor (IGF-IR) and the insulin receptor (IR) with their two known substrates p52Shc and the insulin receptor substrate-1 (IRS-1). We also mapped the specific domains of the IGF-IR and p52Shc participating in these interactions. Our findings can be summarized as follows: (i) the tyrosine kinase activity of the IGF-IR is essential for the interaction with p52Shc and IRS-1, (ii) p52Shc and IRS-1 bind to the IGF-IR in the NPEY-juxtamembrane motif, (iii) contrary to p52Shc, IRS-1 binds also to the major autophosphorylation sites (Tyr-1131, -1135, and -1136) of the IGF-IR, and (iv) the amino-terminal domain of p52Shc is required for its association with the IR and the IGF-IR. We propose that (i) the IGF-IR and the IR share at least in part the same molecular mechanism underlying their interplay with their two substrates, p52Shc and IRS-1, and (ii) IRS-1 interacts with the IGF-IR in a fashion that is different from that used by p52Shc. Finally, our data highlight the crucial role of the juxtamembrane domain in signaling by both the IR and the IGF-IR." 7299;"Interaction of the molecular weight 85K regulatory subunit of the phosphatidylinositol 3-kinase with the insulin receptor and the insulin-like growth factor-1 (IGF- I) receptor: comparative study using the yeast two-hybrid system.";"S. Tartare-Deckert";"Equipe 11, Team 11";8603569;Endocrinology;"Tartare-Deckert S, Murdaca J, Sawka-Verhelle D, Holt KH, Pessin JE, Van Obberghen E";;"Mar 1996";825638400;;"Activation of the phosphatidyl inositol 3-kinase (PI 3-kinase) is one of the immediate events in signaling by the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-IR). The IR and IGF-IR are two closely related tyrosine kinases, which are activated on binding of their respective ligands. Previous studies have proposed that the two receptors interact directly with the SH2 domains of the Mr 85K regulatory subunit (p85) of PI 3- kinase via phosphorylated Y1322THM and Y1316AHM sequences located in the carboxyl-terminal domain of the IR and the IGF-IR, respectively. We In this study we have used the yeast two-hybrid system to compare the interaction of the cytoplasmic domains of the IR and the IGF-IR with p85. We found that the IR is more efficient in interacting with the p85 than is the IGF-IR. For both receptors, deletion of the region containing the Y1322THM sequence in the IR and the Y1316AHM-similar sequence in the IGF-IR decreases their ability to interact with p85. However, these mutated receptors still interacted with the full-length p85, suggesting that other regions in the receptors might be involved in the interaction. Furthermore, mutations of the three major autophosphorylation sites indicate that interactions with p85 are dependent on the receptor tyrosine kinase activity. Finally, we asked whether the two SH2 domains of p85 (n-SH2 and c-SH2) are involved in the same fashion in their association with the two receptors. Interestingly, we observed that the carboxyl- terminal domain of the IGF-IR associates only with the p85 c-SH2 domain, whereas the corresponding domain of the IR interacts with both the n-SH2 and the c-SH2 domains. In combination, both SH2 domains (n/c-SH2) contribute to the maximal interaction observed with the full-length p85. Although the precise impact on signaling resulting from these differences in the interaction of p85 with the IR vs. the IGF-IR remains to be determined, it is tempting to propose that they contribute, at least in part, to the specificity of the biological responses induced by insulin vs. IGF-1." 7297;"Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786.";"S. Tartare-Deckert";"Equipe 11, Team 11";8626379;"The Journal of biological chemistry";"Sawka-Verhelle D, Tartare-Deckert S, White MF, Van Obberghen E";;"Mar 1996";825638400;;"We compared the interaction between the insulin receptor (IR) and the IR substrate (IRS) proteins IRS-1 and IRS-2) using the yeast two-hybrid system. Both IRS proteins interact specifically with the cytoplasmic portion of the IR and the related insulin-like growth factor-I receptor, and these interactions require receptor tyrosine kinase activity. Alignment of IRS-1 and IRS-2 revealed two conserved domains at the NH2 terminus, called IH1PH and IH2PTB, which resemble a pleckstrin homology (PH) domain and a phosphotyrosine binding (PTB) domain, respectively. The IH2PTB binds to the phosphorylated NPXY motif (Tyr-960) in the activated insulin receptor, providing a specific mechanism for the interaction between the receptor and IRS-1. Although the IH2PTB of IRS-2 also interacts with the NPEY motif of the insulin receptor, it is not essential for the interaction between the insulin receptor and IRS-2 in the yeast two-hybrid system. IRS-2 contains another interaction domain between residues 591 and 786, which is absent in IRS-1. This IRS-2-specific domain is independent of the IH2PTB and does not require the NPEY motif; however, it requires a functional insulin receptor kinase and the presence of three tyrosine phosphorylation sites in the regulatory loop (Tyr-1146, Tyr-1150, and Tyr-1151). Importantly, this novel domain mediates the association between IRS-2 and insulin receptor lacking the NPXY motif and may provide a mechanism by which the stoichiometry of regulatory loop autophosphorylation enhances IRS-2 phosphorylation." 7293;"Evidence for a direct interaction between insulin receptor substrate-1 and Shc.";"S. Tartare-Deckert";"Equipe 11, Team 11";9202037;"The Journal of biological chemistry";"Kasus-Jacobi A, Perdereau D, Tartare-Deckert S, Van Obberghen E, Girard J, Burnol AF";;"Jul 1997";867715200;;"Insulin receptor substrate-1 (IRS-1) and Shc are two proteins implicated in intracellular signal transduction. They are activated by an increasing number of extracellular signals, mediated by receptor tyrosine kinases, cytokine receptors, and G protein-coupled receptors. In this study we demonstrate that Shc interacts directly with IRS-1, using the yeast two-hybrid system and an in vitro interaction assay. Deletion analysis of the proteins to map the domains implicated in this interaction shows that the phosphotyrosine binding domain of Shc binds to the region of IRS-1 comprising amino acids 583-661. An in vitro association assay, performed with or without activation of tyrosine kinases, gives evidence that tyrosine phosphorylation of IRS-1 and Shc drastically improves the interaction. Site-directed mutagenesis on IRS-1 583-693 shows that the asparagine, but not the tyrosine residue of the N625GDY628motif domain, is implicated in the IRS-1-Shc-phosphotyrosine binding interaction. Mutation of another tyrosine residue, Tyr608, also induced a 40% decrease in the interaction. This study, describing a phosphotyrosine-dependent interaction between IRS-1 and Shc, suggests that this association might be important in signal transduction." 7291;"Identification of Stat 5B as a substrate of the insulin receptor.";"S. Tartare-Deckert";"Equipe 11, Team 11";9428692;"European journal of biochemistry";"Sawka-Verhelle D, Filloux C, Tartare-Deckert S, Mothe I, Van Obberghen E";;"Jan 1998";884822400;;"We have screened a human placenta library using the yeast two-hybrid system to identify proteins that interact with the cytoplasmic domain of the insulin receptor. Doing so, we trapped a cDNA clone which encodes the Stat 5B region comprising amino acids 469 to 786. We show that interaction between Stat 5B and the receptor requires a functional insulin-receptor kinase, Tyr960 of insulin receptor is implicated in the interaction with Stat 5B, whereas asparagine and proline forming the NPEY960-motif are not, and Stat 5B mutated at Thr684, a potential phosphorylation site of mitogen-activated protein kinase, loses its ability to interact with the insulin receptor. Further, we found that insulin promotes rapid tyrosine phosphorylation of endogenous Stat 5B in 293 EBNA cells overexpressing insulin receptor and in NHIR cells. Taken together, our findings suggest that Stat 5B corresponds to a substrate for the insulin-receptor kinase, and this widens the repertoire of insulin-signaling pathways." 7287;"C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor.";"S. Tartare-Deckert";"Equipe 11, Team 11";10026153;"The Journal of biological chemistry";"Arbet-Engels C, Tartare-Deckert S, Eckhart W";;"Feb 1999";917827200;;"Increased expression of the insulin-like growth factor-I receptor (IGF-IR) protein-tyrosine kinase occurs in several kinds of cancer and induces neoplastic transformation in fibroblast cell lines. The transformed phenotype can be reversed by interfering with the function of the IGF-IR. The IGF-IR is required for transformation by a number of viral and cellular oncoproteins, including SV40 large T antigen, Ras, Raf, and Src. The IGF-IR is a substrate for Src in vitro and is phosphorylated in v-Src-transformed cells. We observed that the IGF-IR and IR associated with the C-terminal Src kinase (CSK) following ligand stimulation. We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR. We determined the tyrosine residues in the IGF-IR and in the IR responsible for this interaction. We also observed that fibroblasts stimulated with IGF-I or insulin showed a rapid and transient decrease in c-Src tyrosine kinase activity. The results suggest that c-Src and CSK are involved in IGF-IR and IR signaling and that the interaction of CSK with the IGF-IR may play a role in the decrease in c-Src activity following IGF-I stimulation." 7285;"Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effectors to a multifunctional docking site.";"S. Tartare-Deckert";"Equipe 11, Team 11";10484767;"Human molecular genetics";"Geneste O, Bidaud C, De Vita G, Hofstra RM, Tartare-Deckert S, Buys CH, Lenoir GM, Santoro M, Billaud M";;"Oct 1999";938736000;;"The RET gene codes for a transmembrane tyrosine kinase which is a subunit of a multimeric complex that acts as a receptor for four structurally related molecules: the glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin and persephin. Germline mutations of RET cause a dominantly inherited dysgenesis of the enteric nervous system known as Hirschsprung's disease (HSCR; aganglionosis megacolon). The majority of HSCR mutations results either in a reduction of dosage of the RET protein or in the loss of RET function. Two novel distinct mutations of RET that led either to the deletion of codon 1059 (denoted Delta1059) or to the substitution of a Pro for Leu1061 have been identified in five HSCR families. In one large pedigree, two children born from asymptomatic consanguineous parents presented a severe form of HSCR and were found to carry the mutation at codon 1061 in the homozygous state. A tyrosine residue at position 1062 is an intracytoplasmic docking site that enables RET to recruit several signalling molecules, including the Shc adaptor protein. We now report that both HSCR mutations impair the fixation of Shc to RET and consequently prevent its phosphorylation. In addition, quantitative analysis in PC12 cells reveals that mutation Delta1059 inactivates the ability of RET to transduce a downstream signal whereas mutation L1061P only partially inhibits the signalling of RET. Finally, we provide evidence that these effects are partly mediated via the disruption of the RET/Shc interaction. Collectively, these results demonstrate that HSCR can be ascribed to mutations of RET which interfere with the binding of transduction effectors, such as Shc, and further provide a biochemical explanation for the phenotype of patients carrying a homozygous mutation at codon 1061. Finally, these data indicate that Y1062 is a multifunctional docking site that confers to RET the capacity to engage downstream signalling pathways which exert a crucial role during enteric neurogenesis." 7283;"Stat 5B, activated by insulin in a Jak-independent fashion, plays a role in glucokinase gene transcription.";"S. Tartare-Deckert";"Equipe 11, Team 11";10830280;Endocrinology;"Sawka-Verhelle D, Tartare-Deckert S, Decaux JF, Girard J, Van Obberghen E";;"Jun 2000";959817600;;"Stat proteins are SH2 domain-containing transcription factors that are activated by various cytokines and growth factors. In a previous work, we have identified Stat 5B as a substrate of the insulin receptor based on yeast two-hybrid and mammalian cell transfection studies. In the present study, we have approached the biological relevance of the interaction between the insulin receptor and the transcription factor Stat 5B. Firstly, we show that both insulin and insulin-like growth factor I lead to tyrosine phosphorylation of Stat 5B, and this promotes binding of the transcription factor to the beta-casein promoter containing a Stat 5 binding site. Further, we demonstrate that insulin stimulates the transcriptional activity of Stat 5B. Activation of Stat 5B by insulin appears to be Jak2-independent, whereas Jak2 is required for GH-induced Stat 5B activation. Hence the pathway by which Stat 5B is activated by insulin is different from that used by GH. In addition, by using Jak1- and Tyk2-deficient cells we exclude the involvement of both Jak1 and Tyk2 in Stat 5B activation by insulin. Taken together, our results strengthen the notion that insulin receptor can directly activate Stat 5B. More importantly, we have identified a Stat 5 binding site in the human hepatic glucokinase promoter, and we show that insulin leads to a Stat 5B-dependent increase in transcription of a reporter gene carrying this promoter. These observations favor the idea that Stat 5B plays a role in mediating the expression of the glucokinase gene induced by insulin. As a whole, our results provide evidence for the occurrence of a newly identified circuit in insulin signaling in which the cell surface receptor is directly linked to nuclear events through a transcription factor. Further, we have revealed an insulin target gene whose expression is, at least in part, dependent on Stat 5B activation and/or binding." 7281;"PI3K mediates protection against TRAIL-induced apoptosis in primary human melanocytes.";"P. Auberger, S. Tartare-Deckert";"Equipe 02, Team 02, Equipe 11, Team 11";15243584;"Cell death and differentiation";"Larribere L, Khaled M, Tartare-Deckert S, Busca R, Luciano F, Bille K, Valony G, Eychene A, Auberger P, Ortonne JP, Ballotti R, Bertolotto C";;"Oct 2004";1096588800;;"Melanocytes are cells of the epidermis that synthesize melanin, which is responsible for skin pigmentation. Transformation of melanocytes leads to melanoma, a highly aggressive neoplasm, which displays resistance to apoptosis. In this report, we demonstrate that TNF-related apoptosis-inducing ligand (TRAIL), which was thought to kill only transformed cells, promotes very efficiently apoptosis of primary human melanocytes, leading to activation of caspases 8, 9 and 3, and the cleavage of vital proteins. Further, we show that stem cell factor (SCF), a physiologic melanocyte growth factor that activates both the phosphatidyl-inositol-3 kinase (PI3K) and the extracellular regulated kinase (ERK) pathways, strongly protects melanocytes from TRAIL and staurosporine killing. Interestingly, inhibition of PI3K or its downstream target AKT completely blocks the antiapoptotic effect of SCF, while inhibition of ERK has only a moderate effect. Our data indicate that protection evoked by SCF/PI3K/AKT cascade is not mediated by an increase in the intracellular level of FLIP. Further, only a sustained PI3K activity can protect melanocytes from apoptosis, thereby indicating that the PI3K/AKT pathway plays a pivotal role in melanocyte survival. The results gathered in this report bring new information on the molecular mechanisms involved in primary melanocyte apoptosis and survival that would help to better understand the process by which melanomas acquire their resistance to apoptosis." 7277;"Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells.";"S. Tartare-Deckert";"Equipe 11, Team 11";21996743;Oncogene;"Cheli Y, Giuliano S, Fenouille N, Allegra M, Hofman V, Hofman P, Bahadoran P, Lacour JP, Tartare-Deckert S, Bertolotto C, Ballotti R";;"May 2012";1335830400;;"Melanomas are very aggressive neoplasms with notorious resistance to therapeutics. It was recently proposed that the remarkable phenotypic plasticity of melanoma cells allows for the rapid development of both resistance to chemotherapeutic drugs and invasive properties. Indeed, the capacity of melanoma cells to form distant metastases is the main cause of mortality in melanoma patients. Therefore, the identification of the mechanism controlling melanoma phenotype is of paramount importance. In the present report, we show that deletion of microphthalmia-associated transcription factor (MITF), the master gene in melanocyte differentiation, is sufficient to increase the metastatic potential of mouse and human melanoma cells. MITF silencing also increases fibronectin and Snail, two mesenchymal markers that might explain the increased invasiveness in vitro and in vivo. Furthermore, ablation of this population by Forskolin-induced differentiation or MITF-forced expression significantly decreases tumour and metastasis formation, suggesting that eradication of low-MITF cells might improve melanoma treatment. Moreover, we demonstrate that a hypoxic microenvironment decreases MITF expression through an indirect, hypoxia-inducible factor 1 (HIF1)α-dependant transcriptional mechanism, and increases the tumourigenic and metastatic properties of melanoma cells. We identified Bhlhb2, a new factor in melanoma biology, as the mediator of hypoxia/HIF1α inhibitory effect on MITF expression. Our results reveal a hypoxia-HIF1α-BHLHB2-MITF cascade controlling the phenotypic plasticity in melanoma cells and favouring metastasis development. Targeting this pathway might be helpful in the design of new anti-melanoma therapies." 7275;"[The insulin receptor: mechanism of activation and message transmission].";"S. Tartare-Deckert";"Equipe 11, Team 11";1336594;Pathologie-biologie;"Ballotti R, Tartare S, Van Obberghen E";;"Oct 1992";717897600;;"The insulin receptor is a heterotetrameric glycoprotein composed of two 130 kD extracellular alpha subunits and two 95 kD membrane-spanning beta subunits. The insulin receptor functions as an allosteric enzyme which undergoes conformational changes when its alpha subunit binds insulin, resulting in activation and autophosphorylation of the tyrosine kinase contained in the beta subunit. This receptor activation is due to intermolecular reactions responsible for amplification of the hormone-induced response at the receptor level. Activation of the receptor tyrosine kinase initiates a cascade of phosphorylation/dephosphorylation reactions and enzyme activation/deactivation reactions. Insulin causes very rapid activation of the enzymes MAP kinase (Microtubule Associated Protein kinase) and phosphatidylinositol-3 kinase, which may act as key links between the insulin receptor and the cell effectors responsible for hormone-induced responses." 7273;"Functional analysis of two Kir6.2 (KCNJ11) mutations, K170T and E322K, causing neonatal diabetes.";"C. Girard";"Equipe 11, Team 11";17919178;"Diabetes, obesity & metabolism";"Tarasov AI, Girard CA, Larkin B, Tammaro P, Flanagan SE, Ellard S, Ashcroft FM";;"Nov 2007";1193875200;;"Heterozygous activating mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel, are a common cause of neonatal diabetes (ND). We assessed the functional effects of two Kir6.2 mutations associated with ND: K170T and E322K. K(ATP) channels were expressed in Xenopus oocytes, and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of sulphonylurea receptor (SUR)). Both mutations reduced the sensitivity of the K(ATP) channel to inhibition by MgATP and enhanced whole-cell K(ATP) currents. In pancreatic beta cells, such an increase in the K(ATP) current is expected to reduce insulin secretion and thereby cause diabetes. The E322K mutation was without effect when Kir6.2 was expressed in the absence of SUR1, suggesting that this residue impairs coupling to SUR1. This is consistent with its predicted location on the outer surface of the tetrameric Kir6.2 pore. The kinetics of K170T channel opening and closing were altered by the mutation, which may contribute to the lower ATP sensitivity. Neither mutation affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting that patients carrying these mutations may respond to these drugs." 7269;"The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression.";"M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";19581935;Oncogene;"Baudot AD, Jeandel PY, Mouska X, Maurer U, Tartare-Deckert S, Raynaud SD, Cassuto JP, Ticchioni M, Deckert M";;"Sep 2009";1251763200;;"B-cell chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of mature monoclonal CD5+ B cells. The disease results mainly from a failure of cells to undergo apoptosis, a process largely influenced by the existence of constitutively activated components of B-cell receptor signaling and the deregulated expression of anti-apoptotic molecules. Recent evidence pointing to a critical role of spleen tyrosine kinase (Syk) in ligand-independent BCR signaling prompted us to examine its role in primary B-CLL cell survival. We demonstrate that pharmacological inhibition of constitutive Syk activity and silencing by siRNA led to a dramatic decrease of cell viability in CLL samples (n=44), regardless of clinical and biological status and induced typical apoptotic cell death with mitochondrial failure followed by caspase 3-dependent cell death. We also provide functional and biochemical evidence that Syk regulated B-CLL cell survival through a novel pathway involving PKCdelta and a proteasome-dependent regulation of the anti-apoptotic protein Mcl-1. Together, our observations are consistent with a model wherein PKCdelta downstream of Syk stabilizes Mcl-1 through inhibitory phosphorylation of GSK3 by Akt. We conclude that Syk constitutes a key regulator of B-CLL cell survival, emphasizing the clinical utility of Syk inhibition in hematopoietic malignancies." 7263;"Hif-2alpha mediates UV-induced apoptosis through a novel ATF3-dependent death pathway.";"M. Deckert, N. Mazure";"Equipe 11, Team 11, Equipe 05, Team 05";18511933;"Cell death and differentiation";"Turchi L, Aberdam E, Mazure N, Pouysségur J, Deckert M, Kitajima S, Aberdam D, Virolle T";;"Sep 2008";1220227200;;"In this study, we describe a novel activating transcription factor 3 (ATF3)-dependent death pathway triggered by ultraviolet (UV) irradiation. We demonstrate that ATF3 contributes to UV-induced apoptosis through the regulation of hypoxia inducible factor (Hif)-2alpha expression, which in turn induces the expression of proapoptotic genes, such as Caspase7 or TRAIL (tumor necrosis factor (ligand) superfamily, member 10). Gain of function of Hif-2alpha as well as ATF3 is sufficient to trigger cell death, whereas loss of function of both proteins drastically inhibits UV-induced apoptosis. Repression of Hif-2alpha strongly impairs ATF3-mediated death, providing evidences that Hif-2alpha is the major death effector of ATF3. In addition, Hif-1alpha, already known as a proapoptotic gene, upon UV irradiation, is not able to compensate for the lack of Hif-2alpha expression, thereby confirming the major contribution of Hif-2alpha in UV-mediated cell death. We further demonstrate that this cascade of gene activation depends on p38 and c-Jun N-terminal kinase (JNK) activity. Impairment of such a pathway is likely to contribute to oncogenesis by promoting survival of cells that could accumulate severe chromosomal alterations." 7261;"Id3 is a novel regulator of p27kip1 mRNA in early G1 phase and is required for cell-cycle progression.";"M. Deckert";"Equipe 11, Team 11";17404577;Oncogene;"Chassot AA, Turchi L, Virolle T, Fitsialos G, Batoz M, Deckert M, Dulic V, Meneguzzi G, Buscà R, Ponzio G";;"Aug 2007";1185926400;;"P27kip is a key inhibitory protein of the cell-cycle progression, which is rapidly downregulated in early G1 phase by a post-translational mechanism involving the proteosomal degradation. In this study, using a wounding model that induces cell-cycle entry of human dermal fibroblasts, we demonstrate that p27mRNA is downregulated when cells progress into the G1 phase, and then it returns to its basal level when cells approach the S phase. By using a quantitative polymerase chain reaction screening we identified inhibitors of differentiation (Id3), a bHLH transcriptional repressor, as a candidate mediator accounting for p27 mRNA decrease. Id3 silencing, using an small interfering RNA approach, reversed the injury mediated p27 downregulation demonstrating that Id3 is involved in the transcriptional repression of p27. Reporter gene experiments and a chromatin immunoprecipitation assay showed that Id3 likely exerts its repressive action through ELK1 inhibition. By inhibiting early p27 downregulation, Id3 depletion blocked (i) the G1-phase progression as assessed by the inhibition of pRb phosphorylation and p130 degradation and (ii) the G1/S transition as observed by the inhibition of cyclin A induction, demonstrating that p27 mRNA decrease is required for cell proliferation. Apart from its effect on the early p27 diminution, Id3 appears also involved in the control of the steady-state level of p27 at the G1/S boundary. In conclusion, this study identifies a novel mechanism of p27 regulation which besides p27 protein degradation also implicates a transcriptional mechanism mediated by Id3." 7259;"Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a.";"M. Deckert";"Equipe 11, Team 11";17496928;Oncogene;"Ticchioni M, Essafi M, Jeandel PY, Davi F, Cassuto JP, Deckert M, Bernard A";;"Nov 2007";1193875200;;"B-chronic lymphocytic leukemia (B-CLL) cell is characterized by the accumulation of long-lived CD5+ B lymphocytes, whose survival in vivo is in part dependent on exogenous factors such as cytokines and/or extracellular matrix proteins. Homeostatic chemokines are critical mediators of lymphoid cell trafficking. However, how they function in cell signaling and survival remains ill-defined. In this study, we have investigated the role of the homeostatic chemokines, CXCL12, CCL21, CCL19 and CXCL13, in B-CLL cell survival. Using primary leukemic cells isolated from 26 patients, we observed that each chemokine enhances cell survival. Chemokines induced the phosphorylation of ERK1/2 and p90RSK, and of Akt and its effectors GSK3 and FOXO3a. Consistently, inhibitors against mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase inhibited chemokine-induced survival. Moreover, using a constitutively active mutated form of FOXO3a or siRNAs against FOXO3a in transfection experiments performed in primary B-CLL cells, we directly demonstrated the critical role of FOXO3a in both spontaneous and chemokine-induced B-CLL cell survival. Overall, our data support the notion that homeostatic chemokines contribute to B-CLL resistance to cell death through inactivation of the transcription factor FOXO3a, which may represent a novel therapeutic target in this hematopoietic malignancy." 7257;"The immunological synapse and Rho GTPases.";"M. Deckert";"Equipe 11, Team 11";15981460;"Current topics in microbiology and immunology";"Deckert M, Moon C, Le Bras S";;"Jan 2005";1104537600;;"Rho GTPases are molecular switches controlling a broad range of cellular processes including lymphocyte activation. Not surprisingly, Rho GTPases are now recognized as pivotal regulators of antigen-specific T cell activation by APCs and immunological synapse formation. This review summarizes recent advances in our understanding of how Rho GTPase-dependent pathways control T lymphocyte motility, polarization and activation." 7255;"A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis.";"A. Jacquel, M. Deckert, P. Auberger, S. Marchetti";"Equipe 02, Team 02, Equipe 11, Team 11, Team 03, Equipe 03";16186797;Oncogene;"Jacquel A, Herrant M, Defamie V, Belhacene N, Colosetti P, Marchetti S, Legros L, Deckert M, Mari B, Cassuto JP, Hofman P, Auberger P";;"Feb 2006";1138752000;;"The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA+SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMA-induced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation." 7253;"Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte.";"M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";11262396;"The Journal of biological chemistry";"Tartare-Deckert S, Monthouel MN, Charvet C, Foucault I, Van Obberghen E, Bernard A, Altman A, Deckert M";;"Jun 2001";991353600;;"Vav1 and Vav2 are members of the Dbl family of guanine nucleotide exchange factors for the Rho family of small GTPases. Although the role of Vav1 during lymphocyte development and activation is well characterized, the function of Vav2 is still unclear. In this study, we compared the signaling pathways regulated by Vav1 and Vav2 following engagement of the T cell receptor (TCR). We show that Vav2 is tyrosine-phosphorylated upon TCR stimulation and by co-expressed Src and Syk family kinases. Using glutathione S-transferase fusion proteins, we observed that the Src homology 2 domain of Vav2 binds tyrosine-phosphorylated proteins from TCR-stimulated Jurkat T cell lysates, including c-Cbl and SLP-76. Like Vav1, Vav2 cooperated with TCR stimulation to increase extracellular signal-regulated kinase activation and to promote c-fos serum response element transcriptional activity. Moreover, both proteins displayed a similar action in increasing the expression of the early activation marker CD69 in Jurkat T cells. However, in contrast to Vav1, Vav2 dramatically suppressed TCR signals leading to nuclear factor of activated T cells (NF-AT)-dependent transcription and induction of the interleukin-2 promoter. Vav2 appears to act upstream of the phosphatase calcineurin because a constitutively active form of calcineurin rescued the effect of Vav2 by restoring TCR-induced NF-AT activation. Interestingly, the Dbl homology and Src homology 2 domains of Vav2 were necessary for its inhibitory effect on NF-AT activation and for induction of serum response element transcriptional activity. Taken together, our results indicate that Vav1 and Vav2 exert overlapping but nonidentical functions in T cells. The negative regulatory pathway elicited by Vav2 might play an important role in regulating lymphocyte activation processes." 7251;"Vav-Rac1-mediated activation of the c-Jun N-terminal kinase/c-Jun/AP-1 pathway plays a major role in stimulation of the distal NFAT site in the interleukin-2 gene promoter.";"M. Deckert";"Equipe 11, Team 11";11287617;"Molecular and cellular biology";"Kaminuma O, Deckert M, Elly C, Liu YC, Altman A";;"May 2001";988675200;;"Vav, a hematopoiesis-specific signaling protein, plays an important role in T-cell development and activation. Vav upregulates the expression of the interleukin-2 (IL-2) gene, primarily via activation of the distal NFAT site in the IL-2 gene promoter (NFAT-IL-2). However, since this site cooperatively binds NFAT and AP-1, the relative contribution of Vav to NFAT versus AP-1 activation has not been determined. Here, we studied the respective roles of the AP-1 and NFAT pathways in the T-cell receptor (TCR)-mediated, Vav-dependent activation of NFAT-IL-2. Although Vav stimulated the transcriptional activity of an NFAT-IL-2 reporter gene, it failed to stimulate the transcriptional or DNA-binding activities of an AP-1-independent NFAT site derived from the human gamma interferon gene promoter. Vav also did not stimulate detectable Ca(2+) mobilization and nuclear translocation of NFATc or NFATp. On the other hand, Vav induced the activation of Rac1 or Cdc42 and c-Jun N-terminal kinase (JNK), enhanced the transcriptional and DNA-binding activities of AP-1, and induced increased phosphorylation of c-Jun. Dominant-negative Vav and/or Rac1 mutants blocked the TCR-mediated stimulation of these events, demonstrating the physiological relevance of these effects. Vav also associated with Rac1 or Cdc42 in T cells, and anti-CD3 antibody stimulation enhanced this association. These findings indicate that a Rac1-dependent JNK/c-Jun/AP-1 pathway, rather than the Ca(2+)/NFAT pathway, plays the predominant role in NFAT-IL-2 activation by Vav." 7249;"Differential requirements for ERK1/2 and P38 MAPK activation by thrombin in T cells. Role of P59Fyn and PKCepsilon.";"JE. Ricci, M. Deckert, P. Auberger";"Equipe 03, Team 03, Equipe 11, Team 11, Equipe 02, Team 02";11360180;Oncogene;"Maulon L, Mari B, Bertolotto C, Ricci JE, Luciano F, Belhacene N, Deckert M, Baier G, Auberger P";;"Apr 2001";986083200;;"Activation of the mitogen-activated protein kinase (MAPK) cascade is a well documented mechanism for the G-protein-coupled receptors. Here, we have analysed the requirements for ERKs and p38 MAPK activation by thrombin in Jurkat T cells. We show that thrombin-mediated ERKs activation requires both PTK and PKC activities, whereas p38 MAPK activation is dependent only on PTKs. Thrombin-induced ERK and p38 MAPK activation was more pronounced in p56Lck deficient cells indicating that this PTK exerts a negative control on MAPK activity. Accordingly, overexpression of p50 Csk a kinase that inactivates p56Lck induced constitutive activation of ERKs. Requirement for a Src kinase was evidenced by expression of a constitutively active form of p59Fyn in Jurkat cells. Besides its effect on tyrosine phosphorylation events, thrombin also triggered a rapid and robust redistribution of PKCepsilon and delta from the cytosol to the membrane. Expression of constitutively active and dominant negative PKCepsilon demonstrates the pivotal role of this PKC isoform in ERKs activation by thrombin. These data are consistent with a model where thrombin induces ERK activation via both PKC-dependent and independent pathways, whereas p38 MAPK activation requires only PTKs. The PKC-independent pathway requires Src kinases other than p56Lck more likely p59Fyn, while the PKC-dependent mechanism depends on PKCepsilon" 7247;"Vav modulation of the Ras/MEK/ERK signaling pathway plays a role in NFAT activation and CD69 up-regulation.";"M. Deckert";"Equipe 11, Team 11";10898494;"European journal of immunology";"Villalba M, Hernandez J, Deckert M, Tanaka Y, Altman A";;"Jun 2000";959817600;;"Vav is expressed exclusively in hematopoietic cells and becomes phosphorylated on tyrosine in response to antigen receptor ligation. Although Vav can act as a Rac-specific guanine nucleotide exchange factor in vitro and as a c-Jun N-terminal kinase (JNK) activator in ectopic expression systems, its physiological functions in lymphocytes remain unclear. Indirect evidence suggests that Vav interacts with the Ras/ERK pathway in T cells. Here, we analyzed the effects of Vav on three known downstream targets of Ras, i. e. activation of ERK and NFAT, and up-regulation of the activation antigen CD69. The MEK inhibitor PD90859 inhibited Vav-induced activation of ERK, and Vav- or anti-CD3-induced activation of NFAT, suggesting that MEK and ERK are involved in Vav-mediated NFAT activation. Similarly to Ras, Vav cooperated with constitutively active calcineurin and with ERK to activate NFAT, and was capable of up-regulating CD69 expression in T cells. Moreover, these Vav-mediated functions were all inhibited by a dominant negative Ras mutant. Conversely, however, dominant negative Vav did not inhibit NFAT and ERK activation or CD69 expression induced by an active Ras mutant. These findings indicate that Ras functions as an important downstream target of Vav in signaling pathways that lead to NFAT and ERK activation, and to CD69 expression. Moreover, the finding that Vav- (or Ras-) induced CD69 expression was not inhibited by a dominant negative Rac mutant indicates that Vav mediates some Ras-dependent, but Rac-independent, functions in T cells." 7245;"A novel functional interaction between Vav and PKCtheta is required for TCR-induced T cell activation.";"M. Deckert";"Equipe 11, Team 11";10714681;Immunity;"Villalba M, Coudronniere N, Deckert M, Teixeiro E, Mas P, Altman A";;"Feb 2000";949363200;;"Vav and PKCtheta play an early and important role in the TCR/CD28-induced stimulation of MAP kinases and activation of the IL-2 gene. Vav is also essential for actin cytoskeleton reorganization and TCR capping. Here, we report that PKCtheta function was selectively required in a Vav signaling pathway that mediates the TCR/CD28-induced activation of JNK and the IL-2 gene and the upregulation of CD69 expression. Vav also promoted PKCtheta translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCtheta to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production." 7243;"The function of small GTPases in signaling by immune recognition and other leukocyte receptors.";"M. Deckert";"Equipe 11, Team 11";10361572;"Advances in immunology";"Altman A, Deckert M";;"Jan 1999";915148800;; 7239;"Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases.";"M. Deckert";"Equipe 11, Team 11";9535867;"The Journal of biological chemistry";"Deckert M, Elly C, Altman A, Liu YC";;"Apr 1998";891388800;;"Cross-linking of the T cell antigen receptor (TCR)-CD3 complex induces rapid tyrosine phosphorylation and activation of Src (Lck and Fyn) and Syk (Syk and Zap-70) family protein tyrosine kinases (PTKs) which, in turn, phosphorylate multiple intracellular substrates. Cbl is a prominent PTK substrate suggesting a pivotal role for it in early signal transduction events. However, the regulation of Cbl function and tyrosine phosphorylation in T cells by upstream PTKs remains poorly understood. In the present study, we used genetic and biochemical approaches to demonstrate that Cbl directly interacts with Syk and Fyn via its N-terminal and C-terminal regions, respectively. Tyr-316 of Syk was required for the interaction with Cbl as well as for the maximal tyrosine phosphorylation of Cbl. However, both wild-type Syk and Y316F-mutated Syk phosphorylated equally well the C-terminal fragment of Cbl in vivo, suggesting the existence of an alternative, N terminus-independent mechanism for the Syk-induced tyrosine phosphorylation of Cbl. This mechanism appears to involve Fyn, since, in addition to its association with the C-terminal region of Cbl, Fyn also associated with Syk and enhanced the Syk-induced tyrosine phosphorylation of Cbl. These findings implicate Fyn as an adaptor protein that facilitates the interaction between Syk and Cbl, and suggest that Src and Syk family PTKs coordinately regulate the tyrosine phosphorylation of Cbl." 7240;"Adaptor function for the Syk kinases-interacting protein 3BP2 in IL-2 gene activation.";"M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";9846481;Immunity;"Deckert M, Tartare-Deckert S, Hernandez J, Rottapel R, Altman A";;"Dec 1998";913248000;;"Syk-family tyrosine kinases are essential for lymphocyte development and activation. Using a yeast two-hybrid screen to identify Syk kinases-interacting proteins (SKIPs), we isolated 3BP2, an Abl SH3-interacting protein of unknown function. 3BP2 was selectively expressed in hematopoietic/lymphoid tissues and bound via its SH2 domain activated Syk-family kinases in mammalian cells, including in antigen receptor-stimulated T cells. In addition to Zap-70, the 3BP2 SH2 domain associated in vitro with LAT, Grb2, PLCgamma1, and Cbl from activated T cell lysates. Transient 3BP2 overexpression induced transcriptional activation of the IL-2 promoter and its NFAT or AP-1 elements. This activity was dependent on the SH2 and pleckstrin-homology domains of 3BP2, and required functional Syk kinases, Ras, and calcineurin. Thus, 3BP2 is an important adaptor that may couple activated Zap-70/Syk to a LAT-containing signaling complex involved in TCR-mediated gene transcription." 7235;"Views on Vav.";"M. Deckert";"Equipe 11, Team 11";9153953;"Immunology today";"Collins TL, Deckert M, Altman A";;"May 1997";862444800;; 7233;"Reconstitution of T cell antigen receptor-induced Erk2 kinase activation in Lck-negative JCaM1 cells by Syk.";"M. Deckert";"Equipe 11, Team 11";9128727;"European journal of biochemistry";"Williams S, Couture C, Gilman J, Jascur T, Deckert M, Altman A, Mustelin T";;"Apr 1997";859852800;;"The two related protein-tyrosine kinases Syk and Zap are rapidly phosphorylated on tyrosine residues and enzymatically activated upon crosslinking of the T cell antigen receptor. We have previously reported that the activation of Syk is less dependent on the Src family kinase Lck than the activation of Zap. Here we report that overexpression of Syk in the Lck-negative JCaM1 cells enabled the T cell antigen receptor/CD3 complex to induce a normal activation of the mitogen-activated protein kinase (MAPK) pathway and expression of a nuclear factor of activated T cells reporter construct. In contrast, Zap and other protein-tyrosine kinases were unable to reconstitute these signaling pathways when expressed at the same levels. In parallel, Syk was phosphorylated on tyrosine, while Zap was not. The Syk-mediated T cell antigen receptor-induced MAPK activation was detectable within 1 min of receptor stimulation and peaked at 3-5 min. The capacity of Syk to reconstitute the MAPK response required the catalytic activity of Syk, an intact autophosphorylation site (Y518 and Y519), both Src homology 2 domains and it was blocked by the inhibitory N17-mutated dominant-negative Ras construct. A Y341-->F mutant of Syk, which is deficient in its interaction with phospholipase Cy1 and Vav, was less efficient than wild-type Syk. Our results suggest that Syk, in contrast to Zap, can transduce signals from the T cell antigen receptor independently of Lck." 7231;"Integrin-associated protein (CD47) is a comitogenic molecule on CD3-activated human T cells.";"M. Deckert";"Equipe 11, Team 11";8992983;"Journal of immunology (Baltimore, Md. : 1950)";"Ticchioni M, Deckert M, Mary F, Bernard G, Brown EJ, Bernard A";;"Jan 1997";852076800;;"IAP is a glycoprotein functionally and physically associated with some integrins, i.e., the leukocyte response integrin and the beta3 integrin chain on placenta, platelets, and polymorphonuclear cells. IAP may act as a transducer element in activation mediated via these integrins. Since IAP is present at high density on peripheral T lymphocytes we have investigated its involvement in T cell activation. We tested three mAbs against IAP, namely B6H12, BRIC126, and 2D3, which recognize two distinct epitopes. IAP cross-linking with B6H12 or BRIC126, but not 2D3, transduces costimulatory signals within highly purified CD3-activated T lymphocytes, i.e., enhancement of proliferation, CD25 expression, and IL-2 secretion, while no effect was observed upon CD2 stimulation. However, we could not observe any functional association between IAP and integrins on peripheral T cells. In an attempt to explore further the activation signal delivered by IAP, we show here that IAP cross-linking with the comitogenic B6H12 mAb induces the phosphorylation on tyrosine of several proteins, one of which is identified as p56(lck) protein tyrosine kinase. Moreover, we observed that IAP is associated with p56(lck) on PMA-activated, but not on resting, T cells. These data suggest that on T cells, IAP may be involved directly via a specific ligand in cell-matrix or cell-cell interactions. Such interactions could trigger protein tyrosine phosphorylation pathways, which play an important role in both maturation and activation of T cells." 7229;"Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product.";"M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";8986718;Immunity;"Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A";;"Dec 1996";849398400;;"Syk family kinases are essential for lymphocyte development and activation. Therefore the identification of their direct effectors is of critical importance. Here, we report that Syk interacts in the yeast two-hybrid system with Vav, a proto-oncogene product exclusively expressed in hematopoietic cells. This interaction was direct, required the catalytic activity of Syk, the SH2 domain of Vav, and tyrosine residues in the linker domain of Syk. Vav also associated with Syk and Zap in antigen receptor-stimulated B or T cells, respectively. Functionally, Vav was phosphorylated by Syk family kinases both in vivo and in vitro. Furthermore, Syk and Vav cooperated to activate NF-AT synergistically. These results indicate that the interaction between Syk family kinases and Vav plays an important role in coupling immune recognition receptors to signaling pathways involved in lymphokine production." 7227;"Identification of the site in the Syk protein tyrosine kinase that binds the SH2 domain of Lck.";"M. Deckert";"Equipe 11, Team 11";8798676;"The Journal of biological chemistry";"Couture C, Deckert M, Williams S, Russo FO, Altman A, Mustelin T";;"Sep 1996";841536000;;"The Syk protein tyrosine kinase (PTK) is expressed in many hematopoietic cells and is involved in signaling from various receptors for antigen and Fc portions of IgG and IgE. Upon cross-linking of these receptors, Syk is rapidly phosphorylated on tyrosine residues and enzymatically activated. We and others have found that the Lck kinase, a member of the Src family of PTKs, binds through its Src homology (SH) 2 domain to tyrosine phosphorylated Syk and to the related Zap kinase. Here we report that this interaction is direct and identify the two tandem tyrosines at the autophosphorylation site of Syk, Tyr518, and Tyr519, as the binding site for the SH2 domain of Lck. Mutation of either or both tyrosines to phenylalanines abrogated binding, while mutation of a second repetition of the motif at Tyr539 and Tyr540, or of the three tyrosines in the C terminus of Syk, did not. The SH2 domain of Lck bound the autophosphorylation site only when both Tyr518 and Tyr519 were phosphorylated. In intact cells the binding of the SH2 domain of Lck correlated with the ability of Syk to induce tyrosine phosphorylation of cellular proteins." 7225;"Vav: function and regulation in hematopoietic cell signaling.";"M. Deckert";"Equipe 11, Team 11";8724692;"Stem cells (Dayton, Ohio)";"Bonnefoy-Bérard N, Munshi A, Yron I, Wu S, Collins TL, Deckert M, Shalom-Barak T, Giampa L, Herbert E, Hernandez J, Meller N, Couture C, Altman A";;"May 1996";830908800;;"Vav, a 95 kDa proto-oncogene product expressed specifically in hematopoietic cells, was originally isolated as a transforming human oncogene. Vav contains an array of functional domains that are involved in interactions with other proteins and, possibly, with lipids. These include, among others, a putative guanine nucleotide exchange domain, a cysteine-rich region similar to the phorbol ester/diacylglycerol-binding domain of protein kinase C, a pleckstrin-homology domain, and Src-homology 2 and 3 (SH2 and SH3, respectively) domains. The presence of these domains, the transforming activity of the vav oncogene, and the rapid increase in tyrosine phosphorylation of Vav induced by triggering of diverse receptors indicate that it plays an important role in hematopoietic cell signaling pathways. Such a role is supported by recent studies using ""knockout"" mice and transiently transfected T cells, in which Vav deletion or overexpression, respectively, had marked effects on lymphocyte development or activation. The presence of a putative guanine nucleotide exchange domain, the prototype of which is found in the dbl oncogene product, implies that Vav functions as a guanine nucleotide exchange factor (GEF) for one (or more) members of the Ras-like family of small GTP-binding proteins. In support of such a role, Vav preparations were found in some (but not other) studies to mediate in vitro-specific GEF activity for Ras. Additional studies are required to identify the physiological regulators and targets of Vav, and its exact role in hematopoietic cell development and signaling." 7223;"Endocytosis of GPI-anchored proteins in human lymphocytes: role of glycolipid-based domains, actin cytoskeleton, and protein kinases.";"M. Deckert";"Equipe 11, Team 11";8666664;"The Journal of cell biology";"Deckert M, Ticchioni M, Bernard A";;"May 1996";830908800;;"GPI-anchored surface proteins mediate many important functions, including transport, signal transduction, adhesion, and protection against complement. They cluster into glycolipid-based membrane domains and caveolae, plasmalemmal vesicles involved in the transcytosis and endocytosis of these surface proteins. However, in lymphocytes, neither the characteristic flask shaped caveolae nor caveolin, a transmembrane protein typical of caveolae, have been observed. Here, we show that the GPI-anchored CD59 molecule on Jurkat T cells is internalized after cross-linking, a process inhibited by nystatin, a sterol chelating agent. Clustered CD59 molecules mostly accumulate in non-coated invaginations of the lymphocyte membrane before endocytosis, in marked contrast with the pattern of CD3-TCR internalization. Cytochalasin H blocked CD59 internalization in lymphocytes, but neither CD3 internalization nor transferrin uptake. Confocal microscopy analysis of F-actin distribution within lymphocytes showed that CD59 clusters were associated with patches of polymerized actin. Also, we found that internalization of CD59 was prevented by the protein kinase C inhibitor staurosporine and by the protein kinase A activator forskolin. Thus, in lymphocytes, as in other cell types, glycolipid-based domains provide sites of integration of signaling pathways involved in GPI-anchored protein endocytosis. This process, which is regulated by both protein kinase C and A activity, is tightly controlled by the dynamic organization of actin cytoskeleton, and may be critical for polarized contacts of circulating cells." 7221;"CD2-induced apoptosis in activated human peripheral T cells: a Fas-independent pathway that requires early protein tyrosine phosphorylation.";"M. Deckert";"Equipe 11, Team 11";8617939;"Journal of immunology (Baltimore, Md. : 1950)";"Mollereau B, Deckert M, Déas O, Rieux-Laucat F, Hirsch F, Bernard A, Fischer A, Lynch DH, Charpentier B, Le Deist F, Senik A";;"May 1996";830908800;;"Short-term activated peripheral T lymphocytes are susceptible to apoptotic cell death triggered by CD2 mAbs. The aim of this study was to examine whether the CD2-mediated pathway of apoptosis is linked to the Fas death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells. Using T lymphocytes from patients harboring Fas gene mutations and displaying a profound defect in Fas signaling of cell death, we show that CD2- (but not CD3-) mediated apoptosis still proceeds normally. In normal activated T cells, CD3-mediated apoptosis is prevented by reagents that block the Fas/Fas-ligand interaction, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand. In contrast, CD2 signaling of apoptosis resists these blocking agents. Neither new protein synthesis nor the activation of calcineurin was required for CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic ""death"" molecules were activated upon stimulation of the cells. In both cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56lck, yielding overlapping yet nonidentical profiles of protein tyrosine phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 transmembrane signaling of apoptosis, but left intact Fas-induced apoptosis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expanding during an immune reaction." 7219;"Monocyte-independent T cell activation by simultaneous binding of three CD2 monoclonal antibodies (D66 + T11.1 + GT2).";"M. Deckert";"Equipe 11, Team 11";7758133;"Cellular immunology";"Rosenthal-Allieri MA, Ticchioni M, Deckert M, Breittmayer JP, Rochet N, Rouleaux M, Senik A, Bernard A";;"Jun 1995";801964800;;"Mitogenic pairs of CD2 mAb typically transduce activation/proliferation signals within T cells. However, complementary signal(s) provided by accessory cells are required to induce T cell proliferation. We show here that a particular combination of three CD2 mAb, D66 + GT2 + T11.1, leads to the proliferation of highly purified human T lymphocytes, without other complementary signal(s). The CD2 triplets was able to induce CD4+ and, to a lesser extent, CD8+ cells to proliferate. Interestingly, the so-called ""naive"" T cells (CD45RA+) were strongly stimulated, but more immature cells, such as thymocytes, were not. The proliferative response induced by the CD2 triplet was entirely mediated by the IL-2 autocrine pathway, as shown by the complete inhibition with anti-IL2 Ab. T cells stimulated with the CD2 triplet were also able to secrete TNF alpha. We found no evidence for an unusual secretion of cytokines that might explain the lack of requirement of complementary signal(s). As high as it was, the proliferation induced by the CD2 mAb triplet could be further increased by the addition of IL-1, and this proliferative fraction could be inhibited by antibodies against TNF alpha. The CD2 mAb triplet increased [Ca2+]i, while mitogenic CD2 mAb pairs needed the presence of a cross-linking agent. Thus, our data show that T cells can be activated to fully proliferate by this particular CD2 pathway, in the absence of accessory signal(s)." 7217;"The E2 molecule (CD99) specifically triggers homotypic aggregation of CD4+ CD8+ thymocytes.";"M. Deckert";"Equipe 11, Team 11";7527813;"Journal of immunology (Baltimore, Md. : 1950)";"Bernard G, Zoccola D, Deckert M, Breittmayer JP, Aussel C, Bernard A";;"Jan 1995";788918400;;"We have previously described E2 as a 32-kDa transmembrane glycoprotein displaying an isomorphism, as two epitopes (defined by mAbs O662 and L129) are widely distributed on T cells whereas two epitopes are restricted to T cell subsets (defined by mAbs D44 and 12E7). E2, the MIC-2 gene product, is involved in T cell adhesion because anti-E2 mAbs against pan T epitopes block spontaneous T cell rosettes. Pan T E2 mAbs are also able to induce exposure of the phosphatidylserine at the thymocyte surface but not at the surface of mature T lymphocytes, an event most likely linked to adhesion phenomena. We now show here that the anti-E2 mAbs (0662 and L129) that block rosettes and induce phosphatidylserine exposure at the thymocyte surface, and not those reacting with epitopes not involved in adhesion, also trigger aggregation of certain immature T cell lines and no other cell lines tested. Among the normal cells tested, anti-E2 mAbs exclusively induce homotypic aggregation of CD4+ CD8+ human thymocytes. This phenomenon is temperature, energy, and Mg++ dependent, and requires an intact cytoskeleton. These adhesion properties are rather characteristic of integrins. Nevertheless, mAb against beta 1, beta 2, and beta 3 integrin chains, as well as those against alpha-chains known to be present on thymocytes, are unable to block corticothymocyte aggregation. We conclude that E2 triggers on corticothymocytes and no other T cells a homotypic adhesion pathway most likely mediated by an uncharacterized integrin." 7215;"Phenylarsine oxide and phorbol myristate acetate inhibit the CD3-induced rise of cytosolic Ca2+ in Jurkat cells by refilling internal Ca2+ stores.";"M. Deckert";"Equipe 11, Team 11";8110195;"The Biochemical journal";"Deckert M, Aussel C, Bernard A, Breittmayer JP";;"Feb 1994";760060800;;"Phenylarsine oxide (PAO), an inhibitor of tyrosine phosphatases, has been found to inhibit the early elevation in cytosolic Ca2+ concentration ([Ca2+]i), related to the CD3 activation pathway in Jurkat T cells. This inhibition was dose-dependent, consistent with previously reported effects of PAO on tyrosine phosphatases, and reversed by dimercaptopropanol. By contrast, okadaic acid, an inhibitor of serine/threonine phosphatases, had no effect on CD3-induced Ca2+ flux. PAO was compared with phorbol 12-myristate 13-acetate (PMA), which caused a similar, although less potent, inhibition as previously described. The two reagents produced additive inhibition of the CD3-induced [Ca2+]i rise, but did not affect thapsigargin- or ionomycin-driven Ca2+ flux in Jurkat cells. PAO and PMA prevented cells from complete depletion of intracellular Ca2+ stores by an anti-CD3 monoclonal antibody (mAb) and restored, at least partially, the ionomycin-sensitive pool, when added after anti-CD3 mAb. Moreover, the CD3-induced inhibition of phosphatidylserine synthesis, due to depletion of internal Ca2+ stores, is reversed by PAO and PMA. Anti-phosphotyrosine immunoblot analysis show that these effects cannot be accounted for by an inhibition of CD3-induced tyrosine phosphorylations. We propose that PAO and, to a lesser extent, PMA allow the refilling of internal compartments by Ca2+, which consequently abrogates a capacitative entry of external Ca2+." 7213;"CD59 molecule: a second ligand for CD2 in T cell adhesion.";"M. Deckert";"Equipe 11, Team 11";1385156;"European journal of immunology";"Deckert M, Kubar J, Zoccola D, Bernard-Pomier G, Angelisova P, Horejsi V, Bernard A";;"Nov 1992";720576000;;"The T cell surface molecule CD2 forms, with its counter-receptor CD58 (LFA-3), a powerful adhesion/activation pathway. There is some evidence that CD2 might bind more than a single ligand. Chinese hamster ovary cells (CHO) expressing human CD59 after cDNA transfection (CD59+CHO) form rosettes with human T cells; these rosettes are inhibited in a dose-dependent fashion by the CD59 monoclonal antibody (mAb) H19 and by the CD2 mAb O275 known to block natural rosettes, but not by the CD2R mAb D66, a poor rosette blocker. CD2+CHO transfectants form rosettes with human erythrocytes; these rosettes are inhibited by the CD59 mAb H19 in addition to CD2 mAb O275 and CD58 mAb; murine thymoma cells expressing human CD2 form rosettes with CD59+CHO cells that again are blocked by CD59 H19 and by CD2 O275 mAb. In a marked contrast with H19, two others CD59 mAb, YTH 53.1 and MEM 43, which react with a different epitope on CD59, led to a 50%-70% increase of the number of cells forming rosettes. In addition to rosette experiments, the binding of 125I-labeled CD59 molecules to CD2+CHO cells was specifically inhibited by unlabeled CD59 molecule and CD2 mAb. Furthermore, the binding of CD59 molecules to resting T cells induced expression of CD2R epitopes. These results directly show that CD2 binds CD59 and that subtle molecular changes occur upon binding." 7211;"CD58 and CD59 molecules exhibit potentializing effects in T cell adhesion and activation.";"M. Deckert";"Equipe 11, Team 11";1370512;"Journal of immunology (Baltimore, Md. : 1950)";"Deckert M, Kubar J, Bernard A";;"Feb 1992";696902400;;"We have generated stable Chinese hamster ovary (CHO) cell transfectants expressing either CD58 or CD59 or both molecules to compare their respective parts played in T cell adhesion and activation. Using a rosetting assay, we have shown the following: 1) The CD59 molecule was directly responsible for adhesive interaction between human T cells and CD59+ CHO transfectants. CD59-mediated adhesion induced 12 +/- 2% (mean +/- SEM, n = 25) of rosettes. 2) The CD58 molecule expressed on CD58+ CHO transfectants induced 29 +/- 6% (mean +/- SEM, n = 8) of rosettes. 3) Double transfected CD58+CD59+ CHO cells formed up to 80% of rosettes, largely exceeding the sum of rosettes formed by single transfectants, thus disclosing at least an additive and possibly a synergic action of both molecules in mediating adhesion to T cells. Culturing purified human T cells in the presence of fixed CHO transfectants and submitogenic doses of PHA + rIL-1 alpha showed that: 1) CD59+ CHO transfectants induced sevenfold T cell proliferation enhancement, demonstrating the direct involvement of the CD59 molecule in T cell activation; 2) CD58+ CHO transfectants induced 20-fold T cell proliferation increase; and 3) the enhancement induced by CD58+CD59+ CHO cells was more than 40-fold. These results suggest that CD58 and CD59 molecules present on the surface of accessory cells might exert synergic function in T cell adhesive interactions and in the stimulation of T cell activation." 7209;"Insulin-EGF receptor chimerae mediate tyrosine transphosphorylation and serine/threonine phosphorylation of kinase-deficient EGF receptors.";"S. Tartare-Deckert";"Equipe 11, Team 11";1851758;"The Journal of biological chemistry";"Tartare S, Ballotti R, Lammers R, Alengrin F, Dull T, Schlessinger J, Ullrich A, Van Obberghen E";;"May 1991";673056000;;"To study cross-talk between unoccupied epidermal growth factor (EGF) receptors and activated EGF receptor kinases, we have used double-transfected cells, IHE2 cells, expressing both an enzymatically active insulin-EGF chimeric receptor and an inactive kinase EGF receptor mutant. Using immunoaffinity-purified receptors, we show that insulin increased phosphorylation of the insulin-EGF chimeric beta subunit and of the kinase-deficient EGF receptor. Stimulation of intact IHE2 cells with insulin leads to a rapid tyrosine autophosphorylation of the insulin-EGF chimeric beta subunit and to tyrosine phosphorylation of the unoccupied kinase-deficient EGF receptor. Insulin-stimulated transphosphorylation of the kinase-deficient EGF receptor yields the same pattern of tryptic phosphopeptides as those in EGF-induced autophosphorylation of the wild-type human EGF receptor. We conclude that insulin, through activation of the insulin-EGF chimeric receptor, mediates transphosphorylation of the kinase-deficient EGF receptor, further confirming that EGF receptor autophosphorylation may proceed by an intermolecular mechanism. In addition to receptor tyrosine phosphorylation, we find that exposure of cells to insulin results in enhanced phosphorylation on serine and threonine residues of the unoccupied kinase-deficient EGF receptor. These results suggest that insulin-EGF chimeric receptor activation stimulates at least one serine/threonine kinase, which in turn phosphorylates the kinase-deficient EGF receptor. Finally, we show that transphosphorylation and coexpression of an active kinase cause a decrease in the number of cell surface kinase-deficient EGF receptors without increasing their degradation rate." 7207;"Phenylarsine oxide stimulates a cytosolic tyrosine kinase activity and glucose transport in mouse fibroblasts.";"S. Tartare-Deckert";"Equipe 11, Team 11";1659989;"Experimental cell research";"Ballotti R, Tartare S, Chauvel A, Scimeca JC, Alengrin F, Filloux C, Van Obberghen E";;"Dec 1991";691545600;;"In the present report we further approach the mechanism by which insulin and phenylarsine oxide (PAO), a trivalent arsenical compound, regulate glucose transport in mouse fibroblasts (NIH3T3). First, we show that PAO is a powerful stimulatory agent on glucose transport. Second, at least three series of observations indicate that this action of PAO is not mediated through the insulin receptor: (i) the same effect of PAO is observed in NIH3T3 and in transfected cells expressing 6 x 10(6) insulin receptors, while the effect of insulin is markedly increased in the transfected cells; (ii) PAO does not affect the tyrosine phosphorylation of the insulin receptor; (iii) the tyrosine kinase activity of the insulin receptor toward exogenous substrates is not increased by PAO. Since PAO appears to act on glucose transport by a different mechanism than insulin, we have compared the effect of PAO and insulin on tyrosine phosphorylation of cellular proteins. Using Western blot analysis we did not detect common substrates in PAO- and insulin-treated cells. However, we found in cell extracts from both PAO- and insulin-treated cells a 50-kDa protein that is immunoprecipitated by antiphosphotyrosine antibody. In addition, PAO activates a cytosolic tyrosine kinase capable of poly(Glu/Tyr) phosphorylation. As a whole, our data suggest that the 50-kDa protein found in cells incubated with PAO and insulin could be the convergence point of the insulin and PAO signaling pathways." 7205;"Interaction between heterologous receptor tyrosine kinases. Hormone-stimulated insulin receptors activate unoccupied IGF-I receptors.";"S. Tartare-Deckert";"Equipe 11, Team 11";1662646;"FEBS letters";"Tartare S, Ballotti R, Van Obberghen E";;"Dec 1991";691545600;;"To determine whether heterologous receptor tyrosine kinases interact with each other we have investigated the ability of insulin receptors to transphosphorylate and transactivate IGF-I receptors. Using partially purified receptors we show that hormone-stimulated insulin receptors induced a 40% increase in IGF-I receptor phosphorylation. Remarkably, this transphosphorylation of IGF-I receptors by insulin receptors resulted in a 2.5-fold augmentation of the IGF-I receptor tyrosine kinase activity for substrates. Our findings demonstrate that transphosphorylation with transactivation can occur between insulin and IGF-I receptors. We would like to propose that such a phenomenon participates in the insulin-induced pleiotropic program by mediating the growth promoting effects of the hormone." 7203;"Activation of insulin-epidermal growth factor (EGF) receptor chimerae regulates EGF receptor binding affinity.";"S. Tartare-Deckert";"Equipe 11, Team 11";1309816;"The Journal of cell biology";"Tartare S, Ballotti R, Lammers R, Filloux C, Chauvel A, Schlessinger J, Ullrich A, Van Obberghen E";;"Feb 1992";696902400;;"Cell surface tyrosine kinase receptors are subject to a rapid activation by their ligand, which is followed by secondary regulatory processes. The IHE2 cell line is a unique model system to study the regulation of EGF binding to EGF receptors after activation of the EGF receptor kinase. IHE2 cells express both a chimeric insulin-EGF receptor kinase (IER) and a kinase-deficient EGF receptor (HER K721A). We have previously reported that IER is an insulin-responsive EGF receptor tyrosine kinase that activates one or several serine/threonine kinases, which in turn phosphorylate(s) the unoccupied HER K721A. In this article we show that insulin through IER activation induces a decrease in 125I-EGF binding to IHE2 cells. Scatchard analysis indicates that, as for TPA, the effect of insulin can be accounted for by a loss of the high affinity binding of EGF to HER K721A. Since this receptor transmodulation persists in protein kinase C downregulated IHE2 cells, it is likely to be due to a mechanism independent of protein kinase C activation. Using an in vitro system of 125I-EGF binding to transmodulated IHE2 membranes, we illustrate that the inhibition of EGF binding induced by IER activation is related to the phosphorylation state of HER K721A. Further, studies with phosphatase 2A, or at a temperature (4 degrees C) where only IER is functional, strongly suggest that the loss of high affinity EGF binding is related to the serine/threonine phosphorylation of HER K721A after IER activation. Our results provide evidence for a ""homologous desensitization"" of EGF receptor binding after activation of the EGF receptor kinase of the IER receptor." 7201;"The insulin and insulin-like growth factor-I receptor substrate IRS-1 associates with and activates phosphatidylinositol 3-kinase in vitro.";"S. Tartare-Deckert, S. Giorgetti-Peraldi";"Equipe 11, Team 11, Equipe 07, Team 07";8385105;"The Journal of biological chemistry";"Giorgetti S, Ballotti R, Kowalski-Chauvel A, Tartare S, Van Obberghen E";;"Apr 1993";733622400;;"Phosphatidylinositol 3-kinase (PtdIns-3-kinase) is thought to participate in the transductional cascade used by several tyrosine kinase receptors including the insulin-like growth factor (IGF)-I receptor and the insulin receptor. The major insulin receptor cellular substrate IRS-1 (pp185) has been proposed as a possible link between the insulin receptor and PtdIns-3-kinase. In this study we show that both insulin and IGF-I treatment of murine fibroblasts transfected with insulin or IGF-I receptors increase PtdIns-3-kinase activity immunoprecipitated with an antibody directed against the 85-kDa subunit of PtdIns-3-kinase. Whereas only a small amount of PtdIns-3-kinase is found associated with the insulin and IGF-I receptor, a considerable PtdIns-3-kinase activity is immunoprecipitated by an antibody raised against IRS-1. Additionally, insulin and IGF-I stimulation of murine fibroblasts expressing insulin or IGF-I receptors induce tyrosine phosphorylation of IRS-1 and its association with PtdIns-3-kinase. Since IRS-1 seems to be the connection between PtdIns-3-kinase and insulin or IGF-I receptor, we used reconstitution experiments to characterize the implication of IRS-1 in the activation of PtdIns-3-kinase. We show that immunoaffinity-purified IRS-1 can be phosphorylated by ligand-stimulated insulin and IGF-I receptors and that this phosphorylation allows the association of IRS-1 with PtdIns-3-kinase. The interaction between PtdIns-3-kinase and IRS-1 phosphorylated by the insulin or the IGF-I receptor results in the activation of PtdIns-3-kinase. In conclusion, our results demonstrate that IRS-1 is a key component in the signal transduction pathway of PtdIns-3-kinase activation induced by insulin and IGF-I." 7199;"Cross talk among tyrosine kinase receptors in PC12 cells: desensitization of mitogenic epidermal growth factor receptors by the neurotrophic factors, nerve growth factor and basic fibroblast growth factor.";"S. Tartare-Deckert";"Equipe 11, Team 11";8400459;"Molecular biology of the cell";"Mothe I, Ballotti R, Tartare S, Kowalski-Chauvel A, Van Obberghen E";;"Jul 1993";741484800;;"We have studied the effects of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) on epidermal growth factor (EGF) binding to PC12 cells. We show that NGF and bFGF rapidly induce a reduction in 125I-EGF binding to PC12 cells in a dose-dependent manner. This decrease amounts to 50% for NGF and 35% for bFGF. Both factors appear to act through a protein kinase C(PKC)-independent pathway, because their effect persists in PKC-downregulated PC12 cells. Scatchard analysis indicates that NGF and bFGF decrease the number of high affinity EGF binding sites. In addition to their effect on EGF binding, NGF and bFGF activate in intact PC12 cells one or several serine/threonine kinases leading to EGF receptor threonine phosphorylation. Using an in vitro phosphorylation system, we show that NGF- or bFGF-activated extracellular regulated kinase 1 (ERK1) is able to phosphorylate a kinase-deficient EGF receptor. Phosphoamino acid analysis indicates that this phosphorylation occurs mainly on threonine residues. Furthermore, two comparable phosphopeptides are observed in the EGF receptor, phosphorylated either in vivo after NGF treatment or in a cell-free system by NGF-activated ERK1. Finally, a good correlation was found between the time courses of ERK1 activation and 125I-EGF binding inhibition after NGF or bFGF treatment. In conclusion, in PC12 cells the NGF- and bFGF-stimulated ERK1 appears to be involved in the induction of the threonine phosphorylation of the EGF receptor and the decrease in the number of high affinity EGF binding sites." 7197;"Signal transduction by a chimeric insulin-like growth factor-1 (IGF-1) receptor having the carboxyl-terminal domain of the insulin receptor.";"S. Tartare-Deckert";"Equipe 11, Team 11";8157675;"The Journal of biological chemistry";"Tartare S, Mothe I, Kowalski-Chauvel A, Breittmayer JP, Ballotti R, Van Obberghen E";;"Apr 1994";765158400;;"Insulin-like growth factor-1 receptors (IGF-1R) and insulin receptors (IR) are closely related tyrosine kinases. However, the IR plays a major role in metabolism control, whereas the IGF-1R is mainly involved in growth and differentiation. With these observations in mind, we wished to define the regions of IR and IGF-1R responsible for generation of biological specificity. We constructed a chimeric IGF-1R in which the carboxyl-terminal domain was replaced by that of IR. This receptor (IGF/CTIR) was expressed in NIH3T3 cells, and we compared its biological activity with that of wild-type receptors. The IGF/CTIR was fully functional regarding kinase activity and biological properties. Comparison of insulin and IGF-1 effects on IR and IGF-1R cells, respectively, indicated that the IR is more efficient in stimulating glycogen synthesis and p44mapk activity than is the IGF-1R. Interestingly, in IGF/CTIR16 cells expressing only 250,000 receptors glycogen synthesis was better stimulated than in IGF-1R cells with 600,000 receptors. Similarly, p44mapk activation was slightly higher in IGF/CTIR16 cells than in IGF-1R cells. These results suggest that the carboxyl-terminal domain of IR is more tightly coupled to the stimulation of glycogen synthesis and to the p44mapk pathway than is that of IGF-1R. We propose that this domain plays a crucial role in the transmission of biological effects and could account, at least in part, for receptor specificity." 7195;"Tyrosine kinase activity of a chimeric insulin-like-growth-factor-1 receptor containing the insulin receptor C-terminal domain. Comparison with the tyrosine kinase activities of the insulin and insulin-like-growth-factor-1 receptors using a cell-free system.";"S. Tartare-Deckert";"Equipe 11, Team 11";7737184;"European journal of biochemistry";"Mothe I, Tartare S, Kowalski-Chauvel A, Kaliman P, Van Obberghen E, Ballotti R";;"Mar 1995";794016000;;"In a previous study, we showed that a chimeric insulin-like-growth-factor-1 (IGF-1) receptor, with the beta subunit C-terminal part of the insulin receptor was more efficient in stimulating glycogen synthesis and p44mapk activity compared to the wild-type IFG-1 receptor [Tartare, S., Mothe, I., Kowalski-Chauvel, A., Breittmayer, J.-P., Ballotti, R. & Van Obberghen, E. (1994) J. Biol. Chem. 269, 11449-11455]. These data indicate that the receptor C-terminal domain plays an important role in the transmission of biological effects. To understand the molecular basis of the differences in receptor specificity, we studied the characteristics of insulin, IGF-1 and chimeric receptor tyrosine kinase activities in a cell-free system. We found that, compared to wild-type insulin and IGF-1 receptors, the chimeric receptor showed a decrease in (a) autophosphorylation, (b) tyrosine kinase activity towards insulin receptor substrate-1 and the insulin receptor-(1142-1158)-peptide, and (c) the ability to activate phosphatidylinositol 3-kinase. However, for all the effects measured in a cell-free system, the chimeric receptor displayed an increased response to IGF-1 compared to the native IGF-1 receptor. Concerning the cation dependence of the tyrosine kinase activity, we showed that, at 10 mM Mg2+, the ligand-stimulated phosphorylation of poly(Glu80Tyr20) by both insulin receptor and chimeric receptor was increased by Mn2+. Conversely at 50 mM Mg2+, the chimeric receptor behaved like the IGF-1 receptor, since the presence of Mn2+ decreased the stimulatory effect of IGF-1 on their kinase activity. Furthermore, the Km of the chimeric receptor for ATP was increased compared to the wild-type receptors. These data demonstrate that the replacement of the C-terminal tail of the IGF-1 receptor by that of the insulin receptor has changed the receptor characteristics studied in a cell-free system. Our findings indicate that the C-terminal domain of the insulin receptor beta subunit plays a key role in regulation of the tyrosine kinase activity. The fine-tuning of the tyrosine kinase by the C-terminal tail could participate in the receptor specificity." 7193;"The matricellular protein SPARC/osteonectin as a newly identified factor up-regulated in obesity.";"S. Tartare-Deckert";"Equipe 11, Team 11";11294850;"The Journal of biological chemistry";"Tartare-Deckert S, Chavey C, Monthouel MN, Gautier N, Van Obberghen E";;"Jun 2001";991353600;;"Alterations in the expression level of genes may contribute to the development and pathophysiology of obesity. To find genes differentially expressed in adipose tissue during obesity, we performed suppression subtractive hybridization on epididymal fat mRNA from goldthioglucose (GTG) obese mice and from their lean littermates. We identified the secreted protein acidic and rich in cysteine (SPARC), a protein that mediates cell-matrix interactions and plays a role in modulation of cell adhesion, differentiation, and angiogenesis. SPARC mRNA expression in adipose tissue was markedly increased (between 3- and 6-fold) in three different models of obesity, i.e. GTG mice, ob/ob mice, and AKR mice, after 6 weeks of a high fat diet. Immunoblotting of adipocyte extracts revealed a similar increase in protein level. Using a SPARC-specific ELISA, we demonstrated that SPARC is secreted by isolated adipocytes. We found that insulin administration to mice increased SPARC mRNA in the adipose tissue. Food deprivation had no effect on SPARC expression, but after high fat refeeding SPARC mRNA levels were significantly increased. Our results reveal both hormonal and nutritional regulation of SPARC expression in the adipocyte, and importantly, its alteration in obesity. Finally, we show that purified SPARC increased mRNA levels of plasminogen activator inhibitor 1 (PAI-1) in cultured rat adipose tissue suggesting that elevated adipocyte expression of SPARC might contribute to the abnormal expression of PAI-1 observed in obesity. We propose that SPARC is a newly identified autocrine/paracrine factor that could affect key functions in adipose tissue physiology and pathology." 7191;"Dual roles of p300 in chromatin assembly and transcriptional activation in cooperation with nucleosome assembly protein 1 in vitro.";"S. Tartare-Deckert";"Equipe 11, Team 11";11940655;"Molecular and cellular biology";"Asahara H, Tartare-Deckert S, Nakagawa T, Ikehara T, Hirose F, Hunter T, Ito T, Montminy M";;"May 2002";1020211200;;"In a yeast two-hybrid screen to identify proteins that bind to the KIX domain of the coactivator p300, we obtained cDNAs encoding nucleosome assembly protein 1 (NAP-1), a 60-kDa histone H2A-H2B shuttling protein that promotes histone deposition. p300 associates preferentially with the H2A-H2B-bound form of NAP-1 rather than with the unbound form of NAP-1. Formation of NAP-1-p300 complexes was found to increase during S phase, suggesting a potential role for p300 in chromatin assembly. In micrococcal nuclease and supercoiling assays, addition of p300 promoted efficient chromatin assembly in vitro in conjunction with NAP-1 and ATP-utilizing chromatin assembly and remodeling factor; this effect was dependent in part on the intrinsic histone acetyltransferase activity of p300. Surprisingly, NAP-1 potently inhibited acetylation of core histones by p300, suggesting that efficient assembly requires acetylation of either NAP-1 or p300 itself. As p300 acted cooperatively with NAP-1 in stimulating transcription from a chromatin template in vitro, our results suggest a dual role of NAP-1-p300 complexes in promoting chromatin assembly and transcriptional activation." 7187;"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation.";"S. Tartare-Deckert, S. BONNAFOUS";"Equipe 11, Team 11, Equipe 08, Team 08";12529376;"The Journal of biological chemistry";"Chavey C, Mari B, Monthouel MN, Bonnafous S, Anglard P, Van Obberghen E, Tartare-Deckert S";;"Apr 2003";1049155200;;"Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling, a process that takes place during obesity-mediated adipose tissue formation. Here, we examine expression profiles and the potential role of MMPs and their tissue inhibitors (TIMPs) in adipose tissue remodeling during obesity. Expression patterns are studied by Northern blot and real-time PCR in two genetic models of obesity (ob/ob and db/db mice) and in a diet-induced model of obesity (AKR mice). Of the MMPs and TIMPs studied, mRNA levels for MMP-2, MMP-3, MMP-12, MMP-14, MMP-19, and TIMP-1 are strongly induced in obese adipose tissues compared with lean tissues. In contrast, MMP-7 and TIMP-3 mRNAs are markedly decreased in obesity. Interestingly, enzymatic activities of MMP-12 and of a new identified adipocyte-derived 30-kDa metalloproteinase are enhanced in obese adipose tissue fractions, demonstrating that MMP/TIMP balance is shifted toward increased matrix degradation in obesity. Finally, we analyze the modulation of MMP-2, MMP-19, and TIMP-1 during 3T3-L1 preadipocyte differentiation, and we explore the effect of inhibition of MMP activity on in vitro adipogenesis. We find that the synthetic MMP inhibitor BB-94 (Batimastat) decreases adipose conversion of 3T3-L1 and primary rat preadipocytes. BB-94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of CCAAT/enhancer-binding protein beta, a transcription factor that is thought to play a major role in the adipogenic program. Such findings support a role for the MMP/TIMP system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development." 7188;"Prostaglandin E2 induces interaction between hSlo potassium channel and Syk tyrosine kinase in osteosarcoma cells.";"S. Tartare-Deckert";"Equipe 11, Team 11";12009018;"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research";"Rezzonico R, Schmid-Alliana A, Romey G, Bourget-Ponzio I, Breuil V, Breittmayer V, Tartare-Deckert S, Rossi B, Schmid-Antomarchi H";;"May 2002";1021420800;;"Prostaglandins (PGs) are important mediators of bone response to growth factors, hormones, inflammation, or mechanical strains. In this study, we show that in MG63 osteosarcoma cells, prostaglandin E2 (PGE2) produces the opening of a large conductance Ca2+-dependent K+ channel (BK). This PGE2-mediated channel opening induces the recruitment of various tyrosine-phosphorylated proteins on the hSlo alpha-subunit of BK. Because the C-terminal domain of hSlo encompasses an immunoreceptor tyrosine-based activation motif (ITAM), we show that the Syk nonreceptor tyrosine kinase, reported yet to be expressed mainly in hematopoietic cells, is expressed also in osteoblastic cells, and recruited on this ITAM after a PGE2-induced docking/activation process. We show that Syk/hSlo association is dependent of an upstream Src-related tyrosine kinase activity, in accord with the classical two-step model described for immune receptors. Finally, we provide evidence that this Syk/hSlo interaction does not affect the electrical features of BK channels in osteosarcoma cells. With these data, we would like to suggest the new notion that besides its conductance function, hSlo channel can behave in bone cells, as a true transduction protein intervening in the bone remodeling induced by PGE2." 7185;"Regulation of secreted protein acidic and rich in cysteine during adipose conversion and adipose tissue hyperplasia.";"S. Tartare-Deckert";"Equipe 11, Team 11";17135603;"Obesity (Silver Spring, Md.)";"Chavey C, Boucher J, Monthouël-Kartmann MN, Sage EH, Castan-Laurell I, Valet P, Tartare-Deckert S, Van Obberghen E";;"Nov 2006";1162339200;;"To explore the regulation of secreted protein acidic and rich in cysteine (SPARC) expression and its role in adipose tissue." 7183;"LIF mediates proinvasive activation of stromal fibroblasts in cancer.";"S. Tartare-Deckert";"Equipe 11, Team 11";24857661;"Cell reports";"Albrengues J, Bourget I, Pons C, Butet V, Hofman P, Tartare-Deckert S, Feral CC, Meneguzzi G, Gaggioli C";;"May 2014";1401148800;;"Signaling crosstalk between tumor cells and fibroblasts confers proinvasive properties to the tumor microenvironment. Here, we identify leukemia inhibitory factor (LIF) as a tumor promoter that mediates proinvasive activation of stromal fibroblasts independent of alpha-smooth muscle actin (α-SMA) expression. We demonstrate that a pulse of transforming growth factor β (TGF-β) establishes stable proinvasive fibroblast activation by inducing LIF production in both fibroblasts and tumor cells. In fibroblasts, LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, which results in collective carcinoma cell invasion in vitro and in vivo. Accordingly, carcinomas from multiple origins and melanomas display strong LIF upregulation, which correlates with dense collagen fiber organization, cancer cell collective invasion, and poor clinical outcome. Blockade of JAK activity by Ruxolitinib (JAK inhibitor) counteracts fibroblast-dependent carcinoma cell invasion in vitro and in vivo. These findings establish LIF as a proinvasive fibroblast producer independent of α-SMA and may open novel therapeutic perspectives for patients with aggressive primary tumors. " 7179;"SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness.";"S. Tartare-Deckert";"Equipe 11, Team 11";26645564;"Cancer research";"Crottès D, Rapetti-Mauss R, Alcaraz-Perez F, Tichet M, Gariano G, Martial S, Guizouarn H, Pellissier B, Loubat A, Popa A, Paquet A, Presta M, Tartare-Deckert S, Cayuela ML, Martin P, Borgese F, Soriani O";;"Feb 2016";1454284800;;"The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K(+) channel human ether-à-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines. Sig1R promoted the formation of hERG/β1-integrin signaling complexes upon extracellular matrix stimulation, triggering the activation of the PI3K/AKT pathway. Consequently, the presence of Sig1R in cancer cells increased motility and VEGF secretion. In vivo, Sig1R expression enhanced the aggressiveness of tumor cells by potentiating invasion and angiogenesis, leading to poor survival. Collectively, our findings highlight a novel function for Sig1R in mediating cross-talk between cancer cells and their microenvironment, thus driving oncogenesis by shaping cellular electrical activity in response to extracellular signals. Given the involvement of ion channels in promoting several hallmarks of cancer, our study also offers a potential strategy to therapeutically target ion channel function through Sig1R inhibition." 7177;"Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma.";"S. Tartare-Deckert";"Equipe 11, Team 11";28463229;"The Journal of clinical investigation";"Olvedy M, Tisserand JC, Luciani F, Boeckx B, Wouters J, Lopez S, Rambow F, Aibar S, Thienpont B, Barra J, Köhler C, Radaelli E, Tartare-Deckert S, Aerts S, Dubreuil P, van den Oord JJ, Lambrechts D, De Sepulveda P, Marine JC";;"May 2017";1493769600;;"Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer." 7175;"A non-coding function of TYRP1 mRNA promotes melanoma growth.";"S. Tartare-Deckert";"Equipe 11, Team 11";28991221;"Nature cell biology";"Gilot D, Migault M, Bachelot L, Journé F, Rogiers A, Donnou-Fournet E, Mogha A, Mouchet N, Pinel-Marie ML, Mari B, Montier T, Corre S, Gautron A, Rambow F, El Hajj P, Ben Jouira R, Tartare-Deckert S, Marine JC, Felden B, Ghanem G, Galibert MD";;"Nov 2017";1509494400;;"Competition among RNAs to bind miRNA is proposed to influence biological systems. However, the role of this competition in disease onset is unclear. Here, we report that TYRP1 mRNA, in addition to encoding tyrosinase-related protein 1 (TYRP1), indirectly promotes cell proliferation by sequestering miR-16 on non-canonical miRNA response elements. Consequently, the sequestered miR-16 is no longer able to repress its mRNA targets, such as RAB17, which is involved in melanoma cell proliferation and tumour growth. Restoration of miR-16 tumour-suppressor function can be achieved in vitro by silencing TYRP1 or increasing miR-16 expression. Importantly, TYRP1-dependent miR-16 sequestration can also be overcome in vivo by using small oligonucleotides that mask miR-16-binding sites on TYRP1 mRNA. Together, our findings assign a pathogenic non-coding function to TYRP1 mRNA and highlight miRNA displacement as a promising targeted therapeutic approach for melanoma." 7173;"Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas.";"S. Tartare-Deckert";"Equipe 11, Team 11";30482853;"Molecular cancer therapeutics";"Garandeau D, Noujarède J, Leclerc J, Imbert C, Garcia V, Bats ML, Rambow F, Gilhodes J, Filleron T, Meyer N, Brayer S, Arcucci S, Tartare-Deckert S, Ségui B, Marine JC, Levade T, Bertolotto C, Andrieu-Abadie N";;"02 2019";1548979200;;"BRAF inhibitors (BRAFi) are used to treat patients with melanoma harboring the V600E mutation. However, resistance to BRAFi is inevitable. Here, we identified sphingosine 1-phosphate (S1P) receptors as regulators of BRAF-mutant melanoma cell-autonomous resistance to BRAFi. Moreover, our results reveal a distinct sphingolipid profile, that is, a tendency for increased very long-chain ceramide species, in the plasma of patients with melanoma who achieve a response to BRAFi therapy as compared with patients with progressive disease. Treatment with BRAFi resulted in a strong decrease in S1PR1/3 expression in sensitive but not in resistant cells. Genetic and pharmacologic interventions, that increase ceramide/S1P ratio, downregulated S1PR expression and blocked BRAFi-resistant melanoma cell growth. This effect was associated with a decreased expression of MITF and Bcl-2. Moreover, the BH3 mimetic ABT-737 improved the antitumor activity of approaches targeting S1P-metabolizing enzymes in BRAFi-resistant melanoma cells. Collectively, our findings indicate that targeting the S1P/S1PR axis could provide effective therapeutic options for patients with melanoma who relapse after BRAFi therapy." 7171;"Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.";"S. Tartare-Deckert";"Equipe 11, Team 11";31974367;"Nature communications";"Imbert C, Montfort A, Fraisse M, Marcheteau E, Gilhodes J, Martin E, Bertrand F, Marcellin M, Burlet-Schiltz O, Peredo AG, Garcia V, Carpentier S, Tartare-Deckert S, Brousset P, Rochaix P, Puisset F, Filleron T, Meyer N, Lamant L, Levade T, Ségui B, Andrieu-Abadie N, Colacios C";;"01 2020";1577836800;;"Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy." 7169;"Effects on Melanoma Cell Lines Suggest No Significant Risk of Melanoma Under Cladribine Treatment.";"S. Tartare-Deckert";"Equipe 11, Team 11";32712904;"Neurology and therapy";"Lebrun-Frenay C, Berestjuk I, Cohen M, Tartare-Deckert S";;"Dec 2020";1606780800;;"Cladribine is an oral synthetic purine analog that depletes lymphocytes and induces a dose-dependent reduction of T and B cells. It was approved for the therapy of highly active relapsing-remitting multiple sclerosis. Given cladribine's mechanism of action, an increased risk of malignancies was suspected from the number of cancers that occurred in the 3.5 mg/kg-treated arm (CLARITY study). We showed that cladribine inhibits cell proliferation on three melanoma cell lines tested, irrespectively of their mutational oncogenic status and invasive/metastatic potential. Aggregated safety data demonstrated that the risk of melanoma is not confirmed." 7167;"A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment.";"S. Tartare-Deckert";"Equipe 11, Team 11";33995652;Theranostics;"Alcaraz LB, Mallavialle A, David T, Derocq D, Delolme F, Dieryckx C, Mollevi C, Boissière-Michot F, Simony-Lafontaine J, Du Manoir S, Huesgen PF, Overall CM, Tartare-Deckert S, Jacot W, Chardès T, Guiu S, Roger P, Reinheckel T, Moali C, Liaudet-Coopman E";;"Jan 2021";1609459200;;" Alternative therapeutic strategies based on tumor-specific molecular targets are urgently needed for triple-negative breast cancer (TNBC). The protease cathepsin D (cath-D) is a marker of poor prognosis in TNBC and a tumor-specific extracellular target for antibody-based therapy. The identification of cath-D substrates is crucial for the mechanistic understanding of its role in the TNBC microenvironment and future therapeutic developments. : The cath-D substrate repertoire was investigated by N-Terminal Amine Isotopic Labeling of Substrates (TAILS)-based degradome analysis in a co-culture assay of TNBC cells and breast fibroblasts. Substrates were validated by amino-terminal oriented mass spectrometry of substrates (ATOMS). Cath-D and SPARC expression in TNBC was examined using an online transcriptomic survival analysis, tissue micro-arrays, TNBC cell lines, patient-derived xenografts (PDX), human TNBC samples, and mammary tumors from MMTV-PyMT knock-out mice. The biological role of SPARC and its fragments in TNBC were studied using immunohistochemistry and immunofluorescence analysis, gene expression knockdown, co-culture assays, western blot analysis, RT-quantitative PCR, adhesion assays, Transwell motility, trans-endothelial migration and invasion assays. TAILS analysis showed that the matricellular protein SPARC is a substrate of extracellular cath-D. , cath-D induced limited proteolysis of SPARC C-terminal extracellular Ca binding domain at acidic pH, leading to the production of SPARC fragments (34-, 27-, 16-, 9-, and 6-kDa). Similarly, cath-D secreted by TNBC cells cleaved fibroblast- and cancer cell-derived SPARC at the tumor pericellular acidic pH. SPARC cleavage also occurred in TNBC tumors. Among these fragments, only the 9-kDa SPARC fragment inhibited TNBC cell adhesion and spreading on fibronectin, and stimulated their migration, endothelial transmigration, and invasion. Our study establishes a novel crosstalk between proteases and matricellular proteins in the tumor microenvironment through limited SPARC proteolysis, revealing a novel targetable 9-kDa bioactive SPARC fragment for new TNBC treatments. Our study will pave the way for the development of strategies for targeting bioactive fragments from matricellular proteins in TNBC." 7165;"Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration.";"M. Deckert";"Equipe 11, Team 11";11964272;Blood;"Ticchioni M, Charvet C, Noraz N, Lamy L, Steinberg M, Bernard A, Deckert M";;"May 2002";1020211200;;"Transendothelial migration of activated lymphocytes from the blood into the tissues is an essential step for immune functions. The housekeeping chemokine CXCL12 (or stroma cell-derived factor-1alpha), a highly efficient chemoattractant for T lymphocytes, drives lymphocytes to sites where they are highly likely to encounter antigens. This suggests that cross-talk between the T-cell receptor (TCR) and CXCR4 (the CXCL12 receptor) might occur within these sites. Here we show that the zeta-associated protein 70 (ZAP-70), a key element in TCR signaling, is required for CXCR4 signal transduction. The pharmacologic inhibition of ZAP-70, or the absence of ZAP-70 in Jurkat T cells and in primary CD4(+) T cells obtained from a patient with ZAP deficiency, resulted in an impairment of transendothelial migration that was rescued by the transfection of ZAP-70. Moreover, the overexpression of mutated forms of ZAP-70, whose kinase domain was inactivated, also abrogated the migratory response of Jurkat T cells to CXCL12. In contrast, no involvement of ZAP-70 in T-cell arrest on inflammatory endothelium under flow conditions or in CXCL12-induced actin polymerization was observed. Furthermore, CXCL12 induced time-dependent phosphorylation of ZAP-70, Vav1, and extracellular signal-regulated kinases (ERKs); the latter were reduced in the absence of functional ZAP-70. However, though a dominant-negative Vav1 mutant (Vav1 L213A) blocked CXCL12-induced T-cell migration, pharmacologic inhibition of the ERK pathway did not affect migration, suggesting that ERK activation is dispensable for T-cell chemotaxis. We conclude that cross-talk between the ZAP-70 signaling pathway and the chemokine receptor CXCR4 is required for T-cell migration." 7163;"ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1.";"M. Deckert";"Equipe 11, Team 11";12387735;Immunity;"Urzainqui A, Serrador JM, Viedma F, Yáñez-Mó M, Rodríguez A, Corbí AL, Alonso-Lebrero JL, Luque A, Deckert M, Vázquez J, Sánchez-Madrid F";;"Oct 2002";1033430400;;"P-selectin glycoprotein ligand 1 (PSGL-1) is a leukocyte adhesion molecule involved in cell tether and rolling on activated endothelium. Our work shows that PSGL-1 associates with Syk. This association is mediated by the actin-linking proteins moesin and ezrin, which directly interact with Syk in an ITAM-dependent manner. PSGL-1 engagement induces tyrosine phosphorylation of Syk and SRE-dependent transcriptional activity. Treatment of cells with the Syk inhibitor piceatannol and overexpression of either a Syk dead kinase mutant or an ITAM-mutated moesin abrogated PSGL-1-induced transcriptional activation. These data unveil a new functional role for the ERMs (ezrin/radixin/moesin) as adaptor molecules in the interactions of adhesion receptors and intracellular tyrosine kinases and show that PSGL-1 is a signaling molecule in leukocytes." 7161;"The chaperone protein 14-3-3 interacts with 3BP2/SH3BP2 and regulates its adapter function.";"M. Deckert";"Equipe 11, Team 11";12501243;"The Journal of biological chemistry";"Foucault I, Liu YC, Bernard A, Deckert M";;"Feb 2003";1044057600;;"Lymphocyte stimulation by immunoreceptors is achieved through the activation of multiple signaling pathways leading to cytokine gene transcription. Adapter proteins are critical signaling components that can integrate multiple pathways by allowing the assembly of multimolecular signaling complexes. We previously showed that the cytoplasmic adapter 3BP2 (also known as SH3BP2) promotes NFAT/AP-1 transcriptional activities in T cells through the activation of Ras- and calcineurin-dependent pathways. However, the molecular mechanisms by which 3BP2/SH3BP2 regulates cell signaling and activation remain poorly documented. In this study, using a combination of yeast two-hybrid analysis and biochemical approaches, we present evidence for a physical interaction between 3BP2 and the chaperone protein 14-3-3. This interaction was direct and constitutively detected in yeast and in mammalian cells. Phorbol ester, pervanadate, and forskolin/isobutylmethylxanthine stimulations enhanced this interaction, as well as co-expression of constitutive active mutants of serine/threonine kinases, including protein kinase C. We found that dephosphorylation of 3BP2 by alkaline phosphatase disrupted its interaction with 14-3-3 and that 3BP2 was a substrate of purified protein kinase C in vitro, suggesting that the phosphorylation of 3BP2 by upstream kinases was required for 14-3-3 binding. Using deletion mutants of 3BP2, two 14-3-3 binding domains were mapped to two proline-rich (residues 201-240 and 270-310) domains of 3BP2. These domains were shown to contain two 14-3-3 consensus binding motifs. We identified residues Ser(225) and Ser(277) of 3BP2 as being essential for interaction with 14-3-3 family proteins, optimal 3BP2 serine phosphorylation, and then for 3BP2-dependent function. Indeed, a 3BP2 mutant protein incapable of binding 14-3-3 showed increased capacity to stimulate NFAT transcriptional activities, suggesting that 14-3-3 binding to 3BP2 negatively regulates 3BP2 adapter function in lymphocytes." 7159;"Mammalian actin binding protein 1 is essential for endocytosis but not lamellipodia formation: functional analysis by RNA interference.";"M. Deckert";"Equipe 11, Team 11";12565838;"Biochemical and biophysical research communications";"Mise-Omata S, Montagne B, Deckert M, Wienands J, Acuto O";;"Feb 2003";1044057600;;"Mammalian actin binding protein 1 (mAbp1, also called SH3P7/Hip55) is structurally and functionally related to yeast Abp1 and to cortactin, both of which have been implicated in endocytotic processes. mAbp1 associates through its SH3 domain with dynamin, a large GTPase essential for vesicle fission. To clarify the function of mAbp1, we specifically knocked down its expression in human embryonic kidney 293T cells, using RNA interference (RNAi). Co-transfection of a short interfering RNA (siRNA) together with a plasmid coding for a surface marker, followed by purification of transfected cells, enabled us to obtain a cell population having up to 90% inhibition of mAbp1 expression. In mAbp1-knocked down cells, transferrin (Tf) receptor endocytosis was significantly inhibited and intracellular distribution of the early endosomal compartment was modified. In contrast, in these cells actin and microtubule filaments appeared normal, and formation of lamellipodia induced by active Rac was not inhibited. This study provides definitive evidence that mAbp1 is indispensable for receptor-mediated endocytosis." 7157;"CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis.";"M. Deckert";"Equipe 11, Team 11";12690108;"The Journal of biological chemistry";"Lamy L, Ticchioni M, Rouquette-Jazdanian AK, Samson M, Deckert M, Greenberg AH, Bernard A";;"Jun 2003";1054425600;;"CD47 is a surface receptor that induces either coactivation or apoptosis in lymphocytes, depending on the ligand(s) bound. Interestingly, the apoptotic pathway is independent of caspase activation and cytochrome c release and is accompanied by early mitochondrial dysfunction with suppression of mitochondrial membrane potential (Deltapsim). Using CD47 as bait in a yeast two-hybrid system, we identified the Bcl-2 homology 3 (BH3)-only protein 19 kDa interacting protein-3 (BNIP3), a pro-apoptotic member of the Bcl-2 family, as a novel partner. Interaction between CD47 and the BH3-only protein was confirmed by immunoprecipitation analysis, and CD47-induced apoptosis was inhibited by attenuating BNIP3 expression with antisense oligonucleotides. Finally, we showed that the C-terminal domain of thrombospondin-1 (TSP-1), but not signal-regulatory protein (SIRPalpha1), is the ligand for CD47 involved in inducing cell death. Immunofluorescence analysis of CD47 and BNIP3 revealed a partial colocalization of both molecules under basal conditions. After T cell stimulation via CD47, BNIP3 translocates to the mitochondria to induce apoptosis. These results show that the BH3-dependent apoptotic pathways, previously shown to be activated by intracellular pro-apoptotic events, can also be turned on by surface receptors. This new pathway results in a fast induction of cell death resembling necrosis, which is likely to play an important role in lymphocyte regulation at inflammatory sites and/or in the vicinity of thrombosis." 7155;"[Lymphocytes: what is ""Vav""].";"M. Deckert";"Equipe 11, Team 11";12836616;"Medecine sciences : M/S";"Charvet C, Deckert M";;"Feb 2003";1044057600;;"Guanine exchange factors (GEF) of the Vav family are critical activators of Rho GTPases, which control actin cytoskeletal reorganization and gene transcription. Among all GEFs identified, Vav proteins are the only GEFs regulated by tyrosine phosphorylation. Moreover, their structure contains several protein-protein or protein-lipid interaction domains. These domains are involved in the formation of multimolecular signalling complexes, highlighting the adaptor role of Vav proteins. The unique combination of these properties makes Vav proteins privileged integrators of multiple signalling pathways in a broad range of tissues and cells. Lymphocyte function during inflammatory and immune responses requires a dynamic remodeling of cellular architecture. Thus, it is not surprising that Vav proteins have been found to play a central role in the regulation of physiologic and pathologic lymphocyte responses." 7153;"Recruitment of the actin-binding protein HIP-55 to the immunological synapse regulates T cell receptor signaling and endocytosis.";"M. Deckert";"Equipe 11, Team 11";14729663;"The Journal of biological chemistry";"Le Bras S, Foucault I, Foussat A, Brignone C, Acuto O, Deckert M";;"Apr 2004";1080777600;;"Actin cytoskeleton dynamics critically regulate T cell activation. We found that the cytoplasmic adaptor HIP-55, a Src/Syk-kinases substrate and member of the drebrin/Abp1 family of actin-binding proteins, localized to the T cell-antigen-presenting cell (APC) contact site in an antigen-dependent manner. Using green fluorescent protein fusion proteins, both Src homology 3 (SH3) and actin binding domains were found necessary for recruitment at the T cell-APC interface. HIP-55 was not implicated in conjugate formation and actin polymerization but regulated distal signaling events through binding and activation of hematopoietic progenitor kinase 1 (HPK1), a germinal center kinase (GCK) family kinase involved in negative signaling in T cells. Using RNA interference and overexpression experiments, the HIP-55-HPK1 complex was found to negatively regulate nuclear factor of activated T cell (NFAT) activation by the T cell antigen receptor. Moreover, we show that HIP-55, which partly co-localized with early endocytic compartments, promoted both basal and ligand-dependent T cell receptor (TCR) down-modulation, resulting in a decreased TCR expression. SH3 and actin-depolymerizing factor homology domains were required for this function. As controls, the expression of CD28 and the glycosylphosphatidylinositol-linked protein CD59 was not affected by HIP-55 overexpression. These results suggest that, in addition to binding to HPK1, HIP-55 might negatively regulate TCR signaling through down-regulation of TCR expression. Our findings show that HIP-55 is a key novel component of the immunological synapse that modulates T cell activation by connecting actin cytoskeleton and TCRs to gene activation and endocytic processes." 7151;"The adaptor protein 3BP2 associates with VAV guanine nucleotide exchange factors to regulate NFAT activation by the B-cell antigen receptor.";"M. Deckert";"Equipe 11, Team 11";15345594;Blood;"Foucault I, Le Bras S, Charvet C, Moon C, Altman A, Deckert M";;"Feb 2005";1107216000;;"Engagement of the B-cell antigen receptor (BCR) activates kinases of the Src and Syk families and signaling complexes assembled by adaptor proteins, which dictate B-cell fate and function. The adaptor 3BP2/SH3BP2, an Abl Src homology domain 3 (SH3)-binding and Syk-kinases interacting protein, exhibits positive regulatory roles in T, natural killer (NK), and basophilic cells. However, its involvement in BCR signaling is completely unknown. Here we show that 3BP2 is tyrosine phosphorylated following BCR aggregation on B lymphoma cells, and that 3BP2 is a substrate for Syk and Fyn, but not Btk. To further explore the function of 3BP2 in B cells, we screened a yeast 2-hybrid B-lymphocyte library and found 3BP2 as a binding partner of Vav proteins. The interaction between 3BP2 and Vav proteins involved both constitutive and inducible mechanisms. 3BP2 also interacted with other components of the BCR signaling pathway, including Syk and phospholipase C gamma (PLC-gamma). Furthermore, overexpression and RNAi blocking experiments showed that 3BP2 regulated BCR-mediated activation of nuclear factor of activated T cells (NFATs). Finally, evidence was provided that 3BP2 functionally cooperates with Vav proteins and Rho GTPases to activate NFATs. Our results show that 3BP2 may regulate BCR-mediated gene activation through Vav proteins." 7149;"Pathological prion protein exposure switches on neuronal mitogen-activated protein kinase pathway resulting in microglia recruitment.";"M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";15528202;"The Journal of biological chemistry";"Marella M, Gaggioli C, Batoz M, Deckert M, Tartare-Deckert S, Chabry J";;"Jan 2005";1104537600;;"Transmissible spongiform encephalopathies are accompanied by the recruitment of microglial cells in the vicinity of amyloid aggregates of the pathological prion protein (PrPres). We previously showed that PrPres itself triggered the recruitment of microglia by interacting with neurons leading to the up-regulation of the expression level of chemokines, mainly RANTES (regulated on activation normal T cell expressed and secreted). The intracellular mechanisms underlying the PrPres-inducible expression of chemokines in this setting are not clear. Here we demonstrate that the mitogen-activated protein kinase pathway is switched on shortly after PrPres exposure to neurons leading to the expression of early growth response factor-1 (Egr-1), a transcription factor initially linked to differentiation and growth and to up-regulation of RANTES mRNA expression. PD98059, a selective inhibitor of extracellular signal-regulated kinase1/2 activation, resulted in a decrease of RANTES mRNA expression and as a consequence to the lowering of microglial cell migration. Neuronal overexpression of Nab2, a corepressor of Egr-1, produced similar effects. PrPres-induced chemoattraction is independent of the presence of PrPc and the laminin receptor on the neuronal cell surface. Our report is the first demonstration that PrPres exposure on neurons results in the activation of the MAP kinase signaling pathway that acts as a master switch to trigger neuronal expression of regulators of chemoattraction." 7147;"The adapter 3BP2: how it plugs into leukocyte signaling.";"M. Deckert";"Equipe 11, Team 11";16802602;"Advances in experimental medicine and biology";"Deckert M, Rottapel R";;"Jan 2006";1136073600;; 7145;"Vav1 promotes T cell cycle progression by linking TCR/CD28 costimulation to FOXO1 and p27kip1 expression.";"M. Deckert";"Equipe 11, Team 11";17015685;"Journal of immunology (Baltimore, Md. : 1950)";"Charvet C, Canonigo AJ, Bécart S, Maurer U, Miletic AV, Swat W, Deckert M, Altman A";;"Oct 2006";1159660800;;"Vav proteins play a critical role in T cell activation and proliferation by promoting cytoskeleton reorganization, transcription factor activation, and cytokine production. In this study, we investigated the role of Vav in T cell cycle progression. TCR/CD28-stimulated Vav1(-/-) T cells displayed a cell cycle block at the G0-G1 stage, which accounted for their defective proliferation. This defect was associated with impaired TCR/CD28-induced phosphorylation of Akt and the Forkhead family transcription factor, FOXO1. The cytoplasmic localization of FOXO1 and its association with 14-3-3tau were also reduced in Vav1(-/-) T cells. Consistent with the important role of FOXO1 in p27 kip1 transcription, stimulated Vav1(-/-) T cells failed to down-regulate the expression of p27 kip1, explaining their G0-G1 arrest. These defects were more pronounced in Vav1/Vav3 double-deficient T cells, suggesting partial redundancy between Vav1 and Vav3. Importantly, IL-2-induced p27 kip1 down-regulation and cyclin D3 up-regulation and FOXO1 phosphorylation were similar in Vav1(-/-) and wild-type T lymphoblasts, indicating that defective FOXO1 phosphorylation and p27 kip1 and cyclin D3 expression do not result from deficient IL-2 signaling in the absence of Vav1. Thus, Vav1 is a critical regulator of a PI3K/Akt/FOXO1 pathway, which controls T cell cycle progression and proliferation." 7143;"[The adaptor protein 3BP2 in leukocyte signaling].";"M. Deckert";"Equipe 11, Team 11";17156730;"Medecine sciences : M/S";"Deckert M";;"Dec 2006";1164931200;;"Adaptor proteins that do not contain intrinsic enzymatic activity play a critical role in cell biology by regulating the assembly of large multimolecular signaling complexes involved in extracellular signal transduction. The increasing number of diseases associated with aberrant function or expression of adaptor proteins further illustrate their key role in cellular regulation. The adaptor 3BP2 (or SH3BP2) was originally identified more than 10 years ago as an c-Abl binding protein, and next as a partner of Syk family kinases in 1998. 3BP2 displays the typical modular organization of an adapter protein with an amino-terminal PH domain, a central proline rich region and a carboxyl-terminal SH2 domain. Although its physiological function remains unknown, studies have implicated a role for 3BP2 in immunoreceptor signaling through its interaction with a number of signaling molecules including Src and Syk families of protein tyrosine kinases, the membrane adaptor LAT, Vav exchange factors, PLC-gamma, and 14-3-3 proteins. Recently, the 3bp2/sh3bp2 locus was shown to be mutated in a rare human disease involved in cranial-facial development called cherubism, suggesting a role for 3BP2 in regulating osteoclast and hematopoietic cell function." 7141;"Abl-SH3 binding protein 2, 3BP2, interacts with CIN85 and HIP-55.";"M. Deckert";"Equipe 11, Team 11";17306257;"FEBS letters";"Le Bras S, Moon C, Foucault I, Breittmayer JP, Deckert M";;"Mar 2007";1172707200;;"The adapter 3BP2 is involved in leukocyte signaling downstream Src/Syk-kinases coupled immunoreceptors. Here, we show that 3BP2 directly interacts with the endocytic scaffold protein CIN85 and the actin-binding protein HIP-55. 3BP2 co-localized with CIN85 and HIP-55 in T cell rafts and at the T cell/APC synapse, an active zone of receptors and proteins recycling. A binding region of CIN85 SH3 domains on 3BP2 was mapped to a PVPTPR motif in the first proline-rich region of 3BP2, whereas the C-terminal SH3 domain of HIP-55 bound a more distal proline-rich domain of 3BP2. Together, our data suggest an unexpected role of 3BP2 in endocytic and cytoskeletal regulation through its interaction with CIN85 and HIP-55." 7139;"Cell-penetrating TAT-FOXO3 fusion proteins induce apoptotic cell death in leukemic cells.";"M. Deckert";"Equipe 11, Team 11";21220490;"Molecular cancer therapeutics";"Essafi M, Baudot AD, Mouska X, Cassuto JP, Ticchioni M, Deckert M";;"Jan 2011";1293840000;;"FOXO proteins are Akt-regulated transcription factors involved in the control of cell cycle, DNA repair, stress defense, apoptosis, and tumor suppression. We reported that plasmid-based overexpression of constitutively active FOXO3 in cells from chronic lymphocytic leukemia (CLL) reduced their survival, suggesting that increasing FOXO3 activity in hematologic malignancies may represent a promising therapeutic strategy. The transactivating transcription factor (TAT) protein transduction domain (PTD) derived from the HIV TAT protein was shown to efficiently deliver macromolecular cargo in various cell types. In this study, wild-type FOXO3 and FOXO3 mutated on Akt sites [FOXO3 T32A/S253A/S315A or TM (triple mutant)] were fused to the TAT-PTD. Using biochemical techniques, flow cytometry, and microscopy analysis, we found a rapid and dose-dependent cell penetration into leukemic cells of unlabeled and fluorescein isothiocyanate-labeled TAT-FOXO3 fusion proteins followed by their accumulation within nuclear and cytoplasmic compartments. Treatment with TAT-FOXO3 TM-but not wild-type TAT-FOXO3-proteins induced Jurkat and K562 leukemic cell death and affected cell viability of other hematologic malignancies including primary cells from CLL. Cell transduction with TAT-FOXO3 TM induced apoptotic cell death as shown by morphologic changes, Annexin V/7-AAD (7-amino-actinomycin D) staining, activation of effector caspases, and PARP cleavage, caspase blockade through the use of the inhibitor Z-VAD, and expression of Bim and p27(KIP1). By contrast, TAT-FOXO3 TM blocked cell proliferation of primary T cells, without affecting their viability. Together, our data show that cell penetrating TAT-FOXO3 TM fusion proteins constitute novel potential therapeutic agents in the treatment of lymphoproliferative disorders and hematologic malignancies." 7137;"The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development.";"M. Deckert";"Equipe 11, Team 11";21948080;"The Journal of experimental medicine";"Colacios C, Casemayou A, Dejean AS, Gaits-Iacovoni F, Pedros C, Bernard I, Lagrange D, Deckert M, Lamouroux L, Jagodic M, Olsson T, Liblau RS, Fournié GJ, Saoudi A";;"Oct 2011";1317427200;;"CD4(+) regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (T(conv) cells). In this study, we show that a locus on rat chromosome 9 controls the size of the natural T(reg) cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of T(reg) cells in the thymus and peripheral lymphoid organs, without impacting the size of the T(conv) cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reduction in Vav1 cellular contents and a reduction of Ca(2+) flux after TCR engagement. Together, our data reveal a key role for Vav1-dependent T cell antigen receptor signaling in natural T(reg) cell development." 7135;"Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism.";"M. Deckert";"Equipe 11, Team 11";22153076;Cell;"Levaot N, Voytyuk O, Dimitriou I, Sircoulomb F, Chandrakumar A, Deckert M, Krzyzanowski PM, Scotter A, Gu S, Janmohamed S, Cong F, Simoncic PD, Ueki Y, La Rose J, Rottapel R";;"Dec 2011";1322697600;;"Cherubism is an autosomal-dominant syndrome characterized by inflammatory destructive bony lesions resulting in symmetrical deformities of the facial bones. Cherubism is caused by mutations in Sh3bp2, the gene that encodes the adaptor protein 3BP2. Most identified mutations in 3BP2 lie within the peptide sequence RSPPDG. A mouse model of cherubism develops hyperactive bone-remodeling osteoclasts and systemic inflammation characterized by expansion of the myelomonocytic lineage. The mechanism by which cherubism mutations alter 3BP2 function has remained obscure. Here we show that Tankyrase, a member of the poly(ADP-ribose)polymerase (PARP) family, regulates 3BP2 stability through ADP-ribosylation and subsequent ubiquitylation by the E3-ubiquitin ligase RNF146 in osteoclasts. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the SRC, SYK, and VAV signaling pathways." 7131;"Technical advance: actin CytoFRET, a novel FRET flow cytometry method for detection of actin dynamics in resting and activated T cell.";"F. LARBRET, M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";23794712;"Journal of leukocyte biology";"Larbret F, Dubois N, Brau F, Guillemot E, Mahiddine K, Tartare-Deckert S, Verhasselt V, Deckert M";;"Sep 2013";1377993600;;"Actin cytoskeleton plays a critical role in regulating T cell motility and activation. However, the lack of a real-time quantitative method to analyze actin assembly has limited the progress toward understanding actin regulation. Here, we describe a novel approach to probe actin dynamics on living T cells using FRET combined with flow cytometry. We have first generated a Jurkat T cell line stably coexpressing EGFP and mOrange FPs fused to actin. The real-time variation of actin monomer assembly or disassembly into filaments was quantified using a ratiometric flow cytometry method measuring changes in the mOrange/EGFP emission ratio. The method was validated on resting T cells by using chemical compounds with known effects on actin filaments and comparison with conventional microscopy imaging. Our method also detected the rapid and transient actin assembly in T cells stimulated by anti-CD3/CD28-coated beads, demonstrating its robustness and high sensitivity. Finally, we provide evidence that lentiviral-mediated transduction of shRNAs in engineered Jurkat cells could be used as a strategy to identify regulators of actin remodeling. In conclusion, the flow cytometric FRET analysis of actin polymerization represents a new technical advance to study the dynamics of actin regulation in intact cells. " 7129;"Forkhead box O3 (FOXO3) transcription factor mediates apoptosis in BCG-infected macrophages.";"M. Deckert";"Equipe 11, Team 11";24712562;"Cellular microbiology";"Haoues M, Refai A, Mallavialle A, Barbouche MR, Laabidi N, Deckert M, Essafi M";;"Sep 2014";1409529600;;"Enhanced apoptosis of BCG-infected macrophages has been shown to induce stronger dendritic cell-mediated cross-priming of T cells, leading to higher protection against tuberculosis (TB). Uncovering host effectors underlying BCG-induced apoptosis may then prove useful to improve BCG efficacy through priming macrophage apoptosis. Her we report that BCG-mediated apoptosis of human macrophages relies on FOXO3 transcription factor activation. BCG induced a significant apoptosis of THP1 (TDMs) and human monocytes (MDMs)-derived macrophages when a high moi was used, as shown by annexin V/7-AAD staining. BCG-induced apoptosis was associated with dephosphorylation of the prosurvival activated threonine kinase (Akt) and its target FOXO3. Cell fractionation and immunofluorescence microscopy showed translocation of FOXO3 to the nucleus in BCG-infected cells, concomitantly with an increase of FOXO3 transcriptional activity. Moreover, FOXO3 expression knock-down by small interfering RNA (siRNA) partially inhibited the BCG-induced apoptosis. Finally, real-time quantitative PCR (qRT-PCR) analysis of the expression profile of BCG-infected macrophages showed an upregulation of two pro-apoptotic targets of FOXO3, NOXA and p53 upregulated modulator of apoptosis (PUMA). Our results thus indicate that FOXO3 plays an important role in BCG-induced apoptosis of human macrophages and may represent a potential target to improve vaccine efficacy through enhanced apoptosis-mediated cross-priming of T cells. " 7127;"The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism.";"M. Deckert";"Equipe 11, Team 11";25491283;"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research";"Kadlub N, Vazquez MP, Galmiche L, L'Herminé AC, Dainese L, Ulinski T, Fauroux B, Pavlov I, Badoual C, Marlin S, Deckert M, Leboulanger N, Berdal A, Descroix V, Picard A, Coudert AE";;"May 2015";1430438400;;"Cherubism is a rare genetic disorder characterized by extensive growth of a bilateral granuloma of the jaws, resulting in facial disfigurement. Cherubism is caused by gain-of-function mutations in the SH3BP2 gene, leading to overactivation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-dependent osteoclastogenesis. Recent findings in human and mouse cherubism have suggested that calcineurin inhibitors might be drug candidates in cherubism medical treatment. A 4-year-old boy with aggressive cherubism was treated with the calcineurin inhibitor tacrolimus for 1 year, and clinical, radiological, and molecular data were obtained. Immunohistologic analysis was performed to compare preoperative and postoperative NFATc1 staining and tartrate resistant acid phosphatase (TRAP) activity. Real-time PCR was performed to analyze the relative expression levels of OPG and RANKL. After tacrolimus therapy, the patient showed significant clinical improvement, including stabilization of jaw size and intraosseous osteogenesis. Immunohistologic analyses on granuloma showed that tacrolimus caused a significant reduction in the number of TRAP-positive osteoclasts and NFATc1 nuclear staining in multinucleated giant cells. Molecular analysis showed that tacrolimus treatment also resulted in increased OPG expression. We present the first case of effective medical therapy in cherubism. Tacrolimus enhanced bone formation by stimulating osteogenesis and inhibiting osteoclastogenesis." 7125;"Defining a new aggressiveness classification and using NFATc1 localization as a prognostic factor in cherubism.";"M. Deckert";"Equipe 11, Team 11";27498064;"Human pathology";"Kadlub N, Sessiecq Q, Dainese L, Joly A, Lehalle D, Marlin S, Badoual C, Galmiche L, Majoufre-Lefebvre C, Berdal A, Deckert M, Vazquez MP, Descroix V, Coudert AE, Picard A";;"12 2016";1480550400;;"Cherubism is a rare genetic disease characterized by bilateral giant cell reparative granuloma of the jaws consisting of a fibrotic stroma with giant multinucleated cells (GMCs) and osteoclastic features. Cherubism severity is highly variable, and recurrence after surgery is the most important risk. Currently, there are no prognostic indicators. The aims of this study were to evaluate the osteoclastogenesis phenotype by histologic examination of nuclear factor of activated T cells 1 (NFATc1) localization and tartrate-resistant acid phosphatase (TRAP) activity and to correlate the results to disease aggressiveness to define prognostic indicators. Based on cherubism evolution 1 year after surgery, 3 classes of cherubism aggressiveness were identified: mild (group A), moderate (group B), and severe (group C). Histologically, in grade A and B cherubism lesions, GMCs were negative for both TRAP activity and NFATc1 nuclear localization. In contrast, in grade C cherubism lesions, GMCs were all positive for TRAP activity and NFATc1 nuclear localization and displayed osteoclast-like features. Other histopathologic findings were not different among the 3 groups. Our results establish that TRAP activity and NFTAc1 nuclear localization are associated with aggressive cherubism and therefore could be added to routine pathologic examination to aid in prognosis and management of the disease. The finding of NFATc1 nuclear localization in aggressive tumors supports the addition of anticalcineurin treatment to the therapeutic arsenal for cherubism." 7123;"Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies.";"M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";32466585;Cancers;"Diazzi S, Tartare-Deckert S, Deckert M";;"May 2020";1588291200;;"Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by driver mutations. Overall responses from patients with metastatic mutant melanoma are better with therapies combining BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. However, most patients that initially respond to therapies develop drug resistance within months. Acquired resistance to targeted therapies can be due to additional genetic alterations in melanoma cells and to non-genetic events frequently associated with transcriptional reprogramming and a dedifferentiated cell state. In this second scenario, it is possible to identify pro-fibrotic responses induced by targeted therapies that contribute to the alteration of the melanoma tumor microenvironment. A close interrelationship between chronic fibrosis and cancer has been established for several malignancies including breast and pancreatic cancers. In this context, the contribution of fibrosis to drug adaptation and therapy resistance in melanoma is rapidly emerging. In this review, we summarize recent evidence underlining the hallmarks of fibrotic diseases in drug-exposed and resistant melanoma, including increased remodeling of the extracellular matrix, enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues, and the establishment of an inflammatory microenvironment. We also discuss several potential therapeutic options for manipulating this fibrotic-like response to combat drug-resistant and invasive melanoma." 7121;"Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions.";"M. Deckert";"Equipe 11, Team 11";33670716;Biomolecules;"Buffard M, Naldi A, Freiss G, Deckert M, Radulescu O, Coopman PJ, Larive RM";;"02 2021";1612137600;;"Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter. Bioinformatic analyses allowed for unveiling the main differences in signaling pathways, network topology and signal propagation from SYK to its potential effectors. In breast cancer cells, the SYK target-enriched signaling pathways included intercellular adhesion and Hippo signaling components that are often linked to tumor suppression. In Burkitt lymphoma cells, the SYK target-enriched signaling pathways included molecules that could play a role in SYK pro-oncogenic function in B-cell lymphomas. Several protein interactions were profoundly rewired in the breast cancer network compared with the Burkitt lymphoma network. These data demonstrate that proteomic profiling combined with mathematical network modeling allows untangling complex pathway interplays and revealing difficult to discern interactions among the SYK pathways that positively and negatively affect tumor formation and progression." 7119;"p11, an annexin II subunit, an auxiliary protein associated with the background K+ channel, TASK-1.";"C. Girard";"Equipe 11, Team 11";12198146;"The EMBO journal";"Girard C, Tinel N, Terrenoire C, Romey G, Lazdunski M, Borsotto M";;"Sep 2002";1030838400;;"TASK-1 belongs to the 2P domain K+ channel family and is the prototype of background K+ channels that set the resting membrane potential and tune action potential duration. Its activity is highly regulated by hormones and neurotransmitters. Although numerous auxiliary proteins have been described to modify biophysical, pharmacological and expression properties of different voltage- and Ca2+-sensitive K+ channels, none of them is known to modulate 2P domain K+ channel activity. We show here that p11 interacts specifically with the TASK-1 K+ channel. p11 is a subunit of annexin II, a cytoplasmic protein thought to bind and organize specialized membrane cytoskeleton compartments. This association with p11 requires the integrity of the last three C-terminal amino acids, Ser-Ser-Val, in TASK-1. Using series of C-terminal TASK-1 deletion mutants and several TASK-1-GFP chimeras, we demonstrate that association with p11 is essential for trafficking of TASK-1 to the plasma membrane. p11 association with the TASK-1 channel masks an endoplasmic reticulum retention signal identified as Lys-Arg-Arg that precedes the Ser-Ser-Val sequence." 7117;"Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels.";"C. Girard";"Equipe 11, Team 11";14532113;"The EMBO journal";"Chemin J, Girard C, Duprat F, Lesage F, Romey G, Lazdunski M";;"Oct 2003";1064966400;;"Group I metabotropic glutamate receptors (mGluRs) are implicated in diverse processes such as learning, memory, epilepsy, pain and neuronal death. By inhibiting background K(+) channels, group I mGluRs mediate slow and long-lasting excitation. The main neuronal representatives of this K(+) channel family (K(2P) or KCNK) are TASK and TREK. Here, we show that in cerebellar granule cells and in heterologous expression systems, activation of group I mGluRs inhibits TASK and TREK channels. D-myo-inositol-1,4,5-triphosphate and phosphatidyl-4,5-inositol-biphosphate depletion are involved in TASK channel inhibition, whereas diacylglycerols and phosphatidic acids directly inhibit TREK channels. Mechanisms described here with group I mGluRs will also probably stand for many other receptors of hormones and neurotransmitters." 7115;"[Neuronal background two-P-domain potassium channels: molecular and functional aspects].";"C. Girard";"Equipe 11, Team 11";15190472;"Medecine sciences : M/S";"Girard C, Lesage F";;"May 2004";1083369600;;"Background K+ conductances are a major determinant of membrane resting potential and input resistance, two key components of neuronal excitability. Background channels have been cloned and form a K+ channel family structurally different from Kv, KCa and Kir channels. These channels with 2P domains (K2P channels) are voltage- and time-independent. They are relatively insensitive to classical potassium channels blockers such as TEA, 4-AP, Ba2+ and Cs+. TASK and TREK subunits are widely expressed in the nervous system. Open at rest, these channels mainly contribute to the resting potential of somatic motoneurons, brainstem respiratory and chemoreceptor neurones, and cerebellar granule cells. K2P channels are regulated by numerous physical and chemical stimuli including extracellular and intracellular pH, temperature, hypoxia, pressure, bioactive lipids, and neurotransmitters. The regulation of these background K+ channels profoundly alters the neuronal excitability. For example, in Aplysia, regulation of a background potassium conductance by neurotransmitters is involved in synaptic modulation, a simple and primitive form of learning. The recent discovery that clinical compounds such as volatile anaesthetics and other neuroprotective agents including riluzole and unsaturated fatty acids activate K2P channels suggest that neuronal background K+ channels are attractive targets for the development of new drugs." 7113;"Relapsing diabetes can result from moderately activating mutations in KCNJ11.";"C. Girard";"Equipe 11, Team 11";15718250;"Human molecular genetics";"Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT";;"Apr 2005";1112313600;;"Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro." 7111;"A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome.";"C. Girard";"Equipe 11, Team 11";15864298;"EMBO reports";"Proks P, Girard C, Haider S, Gloyn AL, Hattersley AT, Sansom MS, Ashcroft FM";;"May 2005";1114905600;;"Inwardly rectifying potassium (Kir) channels control cell membrane K+ fluxes and electrical signalling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive (K(ATP)) channel, cause permanent neonatal diabetes mellitus. However, the I296L mutation also results in developmental delay, muscle weakness and epilepsy. We investigated the functional effects of the I296L mutation by expressing wild-type or mutant Kir6.2/SUR1 channels in Xenopus oocytes. The mutation caused a marked increase in resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, in both homomeric and simulated heterozygous states. Kinetic analysis showed that the mutation impaired ATP sensitivity indirectly, by stabilizing the open state of the channel and possibly also by means of an allosteric effect on ATP binding and/or transduction. The results implicate a new region in Kir-channel gating and suggest that disease severity is correlated with the extent of reduction in ATP sensitivity." 7109;"Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2-SUR1 interactions.";"C. Girard";"Equipe 11, Team 11";15962003;"The EMBO journal";"Tammaro P, Girard C, Molnes J, Njølstad PR, Ashcroft FM";;"Jul 2005";1120176000;;"ATP-sensitive K(+) (K(ATP)) channels, comprised of pore-forming Kir6.2 and regulatory SUR1 subunits, play a critical role in regulating insulin secretion. Binding of ATP to Kir6.2 inhibits, whereas interaction of MgATP with SUR1 activates, K(ATP) channels. We tested the functional effects of two Kir6.2 mutations (Y330C, F333I) that cause permanent neonatal diabetes mellitus, by heterologous expression in Xenopus oocytes. Both mutations reduced ATP inhibition and increased whole-cell currents, which in pancreatic beta-cells is expected to reduce insulin secretion and precipitate diabetes. The Y330C mutation reduced ATP inhibition both directly, by impairing ATP binding (and/or transduction), and indirectly, by stabilizing the intrinsic open state of the channel. The F333I mutation altered ATP binding/transduction directly. Both mutations also altered Kir6.2/SUR1 interactions, enhancing the stimulatory effect of MgATP (which is mediated via SUR1). This effect was particularly dramatic for the Kir6.2-F333I mutation, and was abolished by SUR1 mutations that prevent MgATP binding/hydrolysis. Further analysis of F333I heterozygous channels indicated that at least three SUR1 must bind/hydrolyse MgATP to open the mutant K(ATP) channel." 7107;"Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP.";"C. Girard";"Equipe 11, Team 11";16087682;"Human molecular genetics";"Proks P, Girard C, Ashcroft FM";;"Sep 2005";1125532800;;"Recent studies have shown that heterozygous mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (K(ATP)) channel, cause permanent neonatal diabetes either alone (R201C, R201H) or in association with developmental delay, muscle weakness and epilepsy (V59G,V59M). Functional analysis in the absence of Mg2+, to isolate the inhibitory effects of ATP on Kir6.2, showed that both types of mutation reduce channel inhibition by ATP. However, in pancreatic beta-cells, K(ATP) channel activity is governed by the balance between ATP inhibition via Kir6.2 and Mg-nucleotide stimulation mediated by an auxiliary subunit, the sulphonylurea receptor SUR1. We therefore studied the MgATP sensitivity of KCNJ11 mutant K(ATP) channels expressed in Xenopus oocytes. In contrast to wild-type channels, Mg2+ dramatically reduced the ATP sensitivity of heterozygous R201C, R201H, V59M and V59G channels. This effect was predominantly mediated via the nucleotide-binding domains of SUR1 and resulted from an enhanced stimulatory action of MgATP. Our results therefore demonstrate that KCNJ11 mutations increase the current magnitude of heterozygous K(ATP) channels in two ways: by increasing MgATP activation and by decreasing ATP inhibition. They further show that the fraction of unblocked K(ATP) current at physiological MgATP concentrations correlates with the severity of the clinical phenotype." 7102;"A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes.";"C. Girard";"Equipe 11, Team 11";16613899;"Human molecular genetics";"Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S";;"Jun 2006";1149120000;;"Neonatal diabetes is a genetically heterogeneous disorder with nine different genetic aetiologies reported to date. Heterozygous activating mutations in the KCNJ11 gene encoding Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (K(ATP)) channel, are the most common cause of permanent neonatal diabetes. The sulphonylurea receptor (SUR) SUR1 serves as the regulatory subunit of the K(ATP) channel in pancreatic beta cells. We therefore hypothesized that activating mutations in the ABCC8 gene, which encodes SUR1, might cause neonatal diabetes. We identified a novel heterozygous mutation, F132L, in the ABCC8 gene of a patient with severe developmental delay, epilepsy and neonatal diabetes (DEND syndrome). This mutation had arisen de novo and was not present in 150 control chromosomes. Residue F132 shows evolutionary conservation across species and is located in the first set of transmembrane helices (TMD0) of SUR1, which is proposed to interact with Kir6.2. Functional studies of recombinant K(ATP) channels demonstrated that F132L markedly reduces the sensitivity of the K(ATP) channel to inhibition by MgATP and this increases the whole-cell K(ATP) current. The functional consequence of this ABCC8 mutation mirrors that of KCNJ11 mutations causing neonatal diabetes and provides new insights into the interaction of Kir6.2 and SUR1. As SUR1 is expressed in neurones as well as in beta cells, this mutation can account for both neonatal diabetes and the neurological phenotype. Our results demonstrate that SUR1 mutations constitute a new genetic aetiology for neonatal diabetes and that they act by reducing the K(ATP) channel's ATP sensitivity." 7098;"Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects.";"C. Girard";"Equipe 11, Team 11";16731833;Diabetes;"Shimomura K, Girard CA, Proks P, Nazim J, Lippiat JD, Cerutti F, Lorini R, Ellard S, Hattersley AT, Barbetti F, Ashcroft FM";;"May 2006";1148947200;;"Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K(+) channel (K(ATP) channel), are a common cause of neonatal diabetes. We identified a novel KCNJ11 mutation, R50Q, that causes permanent neonatal diabetes (PNDM) without neurological problems. We investigated the functional effects this mutation and another at the same residue (R50P) that led to PNDM in association with developmental delay. Wild-type or mutant Kir6.2/SUR1 channels were examined by heterologous expression in Xenopus oocytes. Both mutations increased resting whole-cell currents through homomeric and heterozygous K(ATP) channels by reducing channel inhibition by ATP, an effect that was larger in the presence of Mg(2+). However the magnitude of the reduction in ATP sensitivity (and the increase in the whole-cell current) was substantially larger for the R50P mutation. This is consistent with the more severe phenotype. Single-R50P channel kinetics (in the absence of ATP) did not differ from wild type, indicating that the mutation primarily affects ATP binding and/or transduction. This supports the idea that R50 lies in the ATP-binding site of Kir6.2. The sulfonylurea tolbutamide blocked heterozygous R50Q (89%) and R50P (84%) channels only slightly less than wild-type channels (98%), suggesting that sulfonylurea therapy may be of benefit for patients with either mutation." 7099;"ATP sensitivity of the ATP-sensitive K+ channel in intact and permeabilized pancreatic beta-cells.";"C. Girard";"Equipe 11, Team 11";16936192;Diabetes;"Tarasov AI, Girard CA, Ashcroft FM";;"Sep 2006";1157068800;;"ATP-sensitive K(+) channels (K(ATP) channels) couple cell metabolism to electrical activity and thereby to physiological processes such as hormone secretion, muscle contraction, and neuronal activity. However, the mechanism by which metabolism regulates K(ATP) channel activity, and the channel sensitivity to inhibition by ATP in its native environment, remain controversial. Here, we used alpha-toxin to permeabilize single pancreatic beta-cells and measure K(ATP) channel ATP sensitivity. We show that the channel ATP sensitivity is approximately sevenfold lower in the permeabilized cell than in the inside-out patch and that this is caused by interaction of Mg-nucleotides with the nucleotide-binding domains of the SUR1 subunit of the channel. The ATP sensitivity observed in permeabilized cells accounts quantitatively for K(ATP) channel activity in intact cells. Thus, our results show that the principal metabolic regulators of K(ATP) channel activity are MgATP and MgADP." 7096;"Functional effects of mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11), causing neonatal diabetes, and response to sulfonylurea therapy.";"C. Girard";"Equipe 11, Team 11";16731836;Diabetes;"Proks P, Girard C, Baevre H, Njølstad PR, Ashcroft FM";;"Jun 2006";1149120000;;"Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K(+) channel (K(ATP) channel), cause neonatal diabetes. To date, all mutations increase whole-cell K(ATP) channel currents by reducing channel inhibition by MgATP. Here, we provide functional characterization of two mutations (F35L and F35V) at residue F35 of Kir6.2, which lies within the NH(2)-terminus. We further show that the F35V patient can be successfully transferred from insulin to sulfonylurea therapy. The patient has been off insulin for 24 months and shows improved metabolic control (mean HbA(1c) 7.58 before and 6.18% after sulfonylurea treatment; P < 0.007). Wild-type and mutant Kir6.2 were heterologously coexpressed with SUR1 in Xenopus oocytes. Whole-cell K(ATP) channel currents through homomeric and heterozygous F35V and F35L channels were increased due to a reduced sensitivity to inhibition by MgATP. The mutation also increased the open probability (P(O)) of homomeric F35 mutant channels in the absence of ATP. These effects on P(O) and ATP sensitivity were abolished in the absence of SUR1. Our results suggest that mutations at F35 cause permanent neonatal diabetes by affecting K(ATP) channel gating and thereby, indirectly, ATP inhibition. Heterozygous F35V channels were markedly inhibited by the sulfonylurea tolbutamide, accounting for the efficacy of sulfonylurea therapy in the patient." 7094;"Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes.";"C. Girard";"Equipe 11, Team 11";17021801;"Pflugers Archiv : European journal of physiology";"Girard CA, Shimomura K, Proks P, Absalom N, Castano L, Perez de Nanclares G, Ashcroft FM";;"Dec 2006";1164931200;;"ATP-sensitive potassium (K(ATP)) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.2 inhibits, whereas interaction of Mg-nucleotides with SUR, activates the channel. Heterozygous activating mutations in Kir6.2 (KCNJ11) are a common cause of neonatal diabetes (ND). We assessed the functional effects of six novel Kir6.2 mutations associated with ND: H46Y, N48D, E227K, E229K, E292G, and V252A. K(ATP) channels were expressed in Xenopus oocytes and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of SUR). All mutations reduced the sensitivity of the K(ATP) channel to inhibition by MgATP, and enhanced whole-cell K(ATP) currents. Two mutations (E227K, E229K) also enhanced the intrinsic open probability of the channel, thereby indirectly reducing the channel ATP sensitivity. The other four mutations lie close to the predicted ATP-binding site and thus may affect ATP binding. In pancreatic beta cells, an increase in the K(ATP) current is expected to reduce insulin secretion and thereby cause diabetes. None of the mutations substantially affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting patients carrying these mutations may respond to these drugs." 7092;"Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome.";"C. Girard";"Equipe 11, Team 11";17584766;"Human molecular genetics";"Proks P, Shimomura K, Craig TJ, Girard CA, Ashcroft FM";;"Aug 2007";1185926400;;"Activating mutations in the genes encoding the ATP-sensitive potassium (K(ATP)) channel subunits Kir6.2 and SUR1 are a common cause of neonatal diabetes. Here, we analyse the molecular mechanism of action of the heterozygous mutation F132L, which lies in the first set of transmembrane helices (TMD0) of SUR1. This mutation causes severe developmental delay, epilepsy and permanent neonatal diabetes (DEND syndrome). We show that the F132L mutation reduces the ATP sensitivity of K(ATP) channels indirectly, by altering the intrinsic gating of the channel. Thus, the open probability is markedly increased when Kir6.2 is co-expressed with mutant TMD0 alone or with mutant SUR1. The F132L mutation disrupts the physical interaction between Kir6.2 and TMD0, but does not alter the plasmalemma channel density. Our results explain how a mutation in an accessory subunit can produce enhanced activity of the K(ATP) channel pore (formed by Kir6.2). They also provide further evidence that interactions between TMD0 of SUR1 and Kir6.2 are critical for K(ATP) channel gating and identify a residue crucial for this interaction at both physical and functional levels." 7090;"Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects.";"C. Girard";"Equipe 11, Team 11";17668386;"American journal of human genetics";"Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ, Shield JP, Hattersley AT, Ashcroft FM";;"Aug 2007";1185926400;;"Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present." 7088;"Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy.";"C. Girard";"Equipe 11, Team 11";17942821;Diabetes;"Shield JP, Flanagan SE, Mackay DJ, Harries LW, Proks P, Girard C, Ashcroft FM, Temple IK, Ellard S";;"Jan 2008";1199145600;;"Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic ATP-sensitive K(+) channel are the most common cause of permanent neonatal diabetes. In contrast to KCNJ11, where only dominant heterozygous mutations have been identified, recessively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome 11p15.1, centromeric to the imprinted Beckwith-Wiedemann syndrome (BWS) locus at 11p15.5. We investigated a male with hemihypertrophy, a condition classically associated with neonatal hyperinsulinemia and hypoglycemia, who developed neonatal diabetes at age 5 weeks." 7086;"Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11.";"C. Girard";"Equipe 11, Team 11";17982434;"Nature clinical practice. Neurology";"Mlynarski W, Tarasov AI, Gach A, Girard CA, Pietrzak I, Zubcevic L, Kusmierek J, Klupa T, Malecki MT, Ashcroft FM";;"Nov 2007";1194307200;;"A 12-week-old female presented with neonatal diabetes. Insulin therapy alleviated the diabetes, but the patient showed marked motor and mental developmental delay. The patient underwent genetic evaluation at the age of 6 years, prompted by reports that mutations in the KCNJ11 gene caused neonatal diabetes." 7084;"The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.";"C. Girard";"Equipe 11, Team 11";17991826;"Science (New York, N.Y.)";"Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ";;"Nov 2007";1193875200;;"Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass." 7082;"Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes.";"C. Girard";"Equipe 11, Team 11";19065048;"The Journal of clinical investigation";"Girard CA, Wunderlich FT, Shimomura K, Collins S, Kaizik S, Proks P, Abdulkader F, Clark A, Ball V, Zubcevic L, Bentley L, Clark R, Church C, Hugill A, Galvanovskis J, Cox R, Rorsman P, Brüning JC, Ashcroft FM";;"Jan 2009";1230768000;;"Neonatal diabetes is a rare monogenic form of diabetes that usually presents within the first six months of life. It is commonly caused by gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of the plasmalemmal ATP-sensitive K+ (KATP) channel. To better understand this disease, we generated a mouse expressing a Kir6.2 mutation (V59M) that causes neonatal diabetes in humans and we used Cre-lox technology to express the mutation specifically in pancreatic beta cells. These beta-V59M mice developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Islets isolated from beta-V59M mice secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose. This was due to a reduced sensitivity of KATP channels in pancreatic beta cells to inhibition by ATP or glucose. In contrast, the sulfonylurea tolbutamide, a specific blocker of KATP channels, closed KATP channels, elevated intracellular calcium levels, and stimulated insulin release in beta-V59M beta cells, indicating that events downstream of KATP channel closure remained intact. Expression of the V59M Kir6.2 mutation in pancreatic beta cells alone is thus sufficient to recapitulate the neonatal diabetes observed in humans. beta-V59M islets also displayed a reduced percentage of beta cells, abnormal morphology, lower insulin content, and decreased expression of Kir6.2, SUR1, and insulin mRNA. All these changes are expected to contribute to the diabetes of beta-V59M mice. Their cause requires further investigation." 7080;"Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism.";"C. Girard";"Equipe 11, Team 11";20049716;"EMBO molecular medicine";"Shimomura K, Flanagan SE, Zadek B, Lethby M, Zubcevic L, Girard CA, Petz O, Mannikko R, Kapoor RR, Hussain K, Skae M, Clayton P, Hattersley A, Ellard S, Ashcroft FM";;"Jun 2009";1243814400;;"K(ATP) channels regulate insulin secretion from pancreatic beta-cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism of infancy and neonatal diabetes, respectively. We report two novel mutations in the gating loop of Kir6.2 which cause neonatal diabetes with developmental delay (T293N) and hyperinsulinism (T294M). These mutations increase (T293N) or decrease (T294M) whole-cell K(ATP) currents, accounting for the different clinical phenotypes. The T293N mutation increases the intrinsic channel open probability (Po((0))), thereby indirectly decreasing channel inhibition by ATP and increasing whole-cell currents. T294M channels exhibit a dramatically reduced Po((0)) in the homozygous but not in the pseudo-heterozygous state. Unlike wild-type channels, hetT294M channels were activated by MgADP in the absence but not in the presence of MgATP; however, they are activated by MgGDP in both the absence and presence of MgGTP. These mutations demonstrate the importance of the gating loop of Kir channels in regulating Po((0)) and further suggest that Mg-nucleotide interaction with SUR1 may reduce ATP inhibition at Kir6.2." 7078;"Overexpression of Fto leads to increased food intake and results in obesity.";"C. Girard";"Equipe 11, Team 11";21076408;"Nature genetics";"Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L, Wells S, Brüning JC, Nolan PM, Ashcroft FM, Cox RD";;"Dec 2010";1291161600;;"Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice." 7076;"Control of pancreatic β cell regeneration by glucose metabolism.";"C. Girard";"Equipe 11, Team 11";21459328;"Cell metabolism";"Porat S, Weinberg-Corem N, Tornovsky-Babaey S, Schyr-Ben-Haroush R, Hija A, Stolovich-Rain M, Dadon D, Granot Z, Ben-Hur V, White P, Girard CA, Karni R, Kaestner KH, Ashcroft FM, Magnuson MA, Saada A, Grimsby J, Glaser B, Dor Y";;"Apr 2011";1301616000;;"Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand." 7074;"Emerging roles of secreted phospholipase A2 enzymes: Lessons from transgenic and knockout mice.";"C. Girard";"Equipe 11, Team 11";20347923;Biochimie;"Murakami M, Taketomi Y, Girard C, Yamamoto K, Lambeau G";;"Jun 2010";1275350400;;"Among the emerging phospholipase A(2) (PLA(2)) superfamily, the secreted PLA(2) (sPLA(2)) family consists of low-molecular-mass, Ca(2+)-requiring extracellular enzymes with a His-Asp catalytic dyad. To date, more than 10 sPLA(2) enzymes have been identified in mammals. Individual sPLA(2)s exhibit unique tissue and cellular localizations and enzymatic properties, suggesting their distinct pathophysiological roles. Despite numerous enzymatic and cell biological studies on this enzyme family in the past two decades, their precise in vivo functions still remain largely obscure. Recent studies using transgenic and knockout mice for several sPLA(2) enzymes, in combination with lipidomics approaches, have opened new insights into their distinct contributions to various biological events such as food digestion, host defense, inflammation, asthma and atherosclerosis. In this article, we overview the latest understanding of the pathophysiological functions of individual sPLA(2) isoforms fueled by studies employing transgenic and knockout mice for several sPLA(2)s." 7072;"Group X secreted phospholipase A2 limits the development of atherosclerosis in LDL receptor-null mice.";"C. Girard";"Equipe 11, Team 11";23349189;"Arteriosclerosis, thrombosis, and vascular biology";"Ait-Oufella H, Herbin O, Lahoute C, Coatrieux C, Loyer X, Joffre J, Laurans L, Ramkhelawon B, Blanc-Brude O, Karabina S, Girard CA, Payré C, Yamamoto K, Binder CJ, Murakami M, Tedgui A, Lambeau G, Mallat Z";;"Mar 2013";1362096000;;"Several secreted phospholipases A2 (sPLA2s), including group IIA, III, V, and X, have been linked to the development of atherosclerosis, which led to the clinical testing of A-002 (varespladib), a broad sPLA2 inhibitor for the treatment of coronary artery disease. Group X sPLA2 (PLA2G10) has the most potent hydrolyzing activity toward phosphatidylcholine and is believed to play a proatherogenic role." 7070;"PLA2R1 kills cancer cells by inducing mitochondrial stress.";"C. Girard";"Equipe 11, Team 11";23994771;"Free radical biology & medicine";"Augert A, Vindrieux D, Girard CA, Le Calvé B, Gras B, Ferrand M, Bouchet BP, Puisieux A, de Launoit Y, Simonnet H, Lambeau G, Bernard D";;"Dec 2013";1385856000;;"Little is known about the biological functions of the phospholipase A2 receptor (PLA2R1) except that it has the ability to bind a few secreted phospholipases A2 (sPLA2's). We have previously shown that PLA2R1 regulates senescence in normal human cells. In this study, we investigated the ability of PLA2R1 to control cancer cell growth. Analysis of expression in cancer cells indicates a marked PLA2R1 decrease in breast cancer cell lines compared to normal or nontransformed human mammary epithelial cells. Accordingly, PLA2R1 ectopic expression in PLA2R1-negative breast cancer cell lines led to apoptosis, whereas a prosenescence response was predominantly triggered in normal cells. PLA2R1 structure-function studies and the use of chemical inhibitors of sPLA2-related signaling pathways suggest that the effect of PLA2R1 is sPLA2-independent. Functional experiments demonstrate that PLA2R1 regulation of cell death is driven by a reactive oxygen species (ROS)-dependent mechanism. While screening for ROS-producing complexes involved in PLA2R1 biological responses, we identified a critical role for the mitochondrial electron transport chain in PLA2R1-induced ROS production and cell death. Taken together, this set of data provides evidence for an important role of PLA2R1 in controlling cancer cell death by influencing mitochondrial biology." 7068;"PLA2R1 mediates tumor suppression by activating JAK2.";"C. Girard, S. Aubert";"Equipe 11, Team 11";24008317;"Cancer research";"Vindrieux D, Augert A, Girard CA, Gitenay D, Lallet-Daher H, Wiel C, Le Calvé B, Gras B, Ferrand M, Verbeke S, de Launoit Y, Leroy X, Puisieux A, Aubert S, Perrais M, Gelb M, Simonnet H, Lambeau G, Bernard D";;"Oct 2013";1380585600;;"Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling." 7066;"[New physiopathological roles for the PLA2R1 receptor in cancer and membranous nephropathy].";"C. Girard";"Equipe 11, Team 11";24939538;"Medecine sciences : M/S";"Girard CA, Seitz-Polski B, Dolla G, Augert A, Vindrieux D, Bernard D, Lambeau G";;"May 2014";1398902400;;"PLA2R1 is a large transmembrane receptor of 180-kDa that belongs to the superfamily of C-type lectins. It was discovered because of its high affinity for secreted phospholipases A2 (sPLA2), enzymes that play a key role in lipid mediator synthesis. Early PLA2R1 physiological roles include the clearance of sPLA2 from the extracellular medium and/or promotion of their actions. Over the last four years, two independent studies suggested that PLA2R1 plays a role in cancer as a tumor gene suppressor and is the major target antigen of auto-immune antibodies involved in idiopathic membranous nephropathy, a severe human kidney disease. These novel findings shed light on PLA2R1 and pave the way for its use as a reliable biomarker and an attractive therapeutic target in these diseases." 7064;"Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy.";"C. Girard";"Equipe 11, Team 11";26567246;"Journal of the American Society of Nephrology : JASN";"Seitz-Polski B, Dolla G, Payré C, Girard CA, Polidori J, Zorzi K, Birgy-Barelli E, Jullien P, Courivaud C, Krummel T, Benzaken S, Bernard G, Burtey S, Mariat C, Esnault VL, Lambeau G";;"05 2016";1462060800;;"The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy. However, the value of anti-PLA2R1 antibody titers in predicting patient outcomes is unknown. Here, we screened serum samples from 50 patients positive for PLA2R1 for immunoreactivity against a series of PLA2R1 deletion mutants covering the extracellular domains. We identified reactive epitopes in the cysteine-rich (CysR), C-type lectin domain 1 (CTLD1), and C-type lectin domain 7 (CTLD7) domains and confirmed the reactivity with soluble forms of each domain. We then used ELISAs to stratify 69 patients positive for PLA2R1 by serum reactivity to one or more of these domains: CysR (n=23), CysRC1 (n=14), and CysRC1C7 (n=32). Median ELISA titers measured using the full-length PLA2R1 antigens were not statistically different between subgroups. Patients with anti-CysR-restricted activity were younger (P=0.008), had less nephrotic range proteinuria (P=0.02), and exhibited a higher rate of spontaneous remission (P=0.03) and lower rates of renal failure progression (P=0.002) and ESRD (P=0.01) during follow-up. Overall, 31 of 69 patients had poor renal prognosis (urinary protein/creatinine ratio >4 g/g or eGFR<45 ml/min per 1.73 m(2) at end of follow-up). High anti-PLA2R1 activity and epitope spreading beyond the CysR epitope were independent risk factors of poor renal prognosis in multivariable Cox regression analysis. Epitope spreading during follow-up associated with disease worsening (n=3), whereas reverse spreading from a CysRC1C7 profile back to a CysR profile associated with favorable outcome (n=1). We conclude that analysis of the PLA2R1 epitope profile and spreading is a powerful tool for monitoring disease severity and stratifying patients by renal prognosis." 7062;"Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf Melanoma.";"C. Girard";"Equipe 11, Team 11";32526884;Cancers;"Signetti L, Elizarov N, Simsir M, Paquet A, Douguet D, Labbal F, Debayle D, Di Giorgio A, Biou V, Girard C, Duca M, Bretillon L, Bertolotto C, Verrier B, Azoulay S, Mus-Veteau I";;"Jun 2020";1590969600;;"Melanoma patients harboring the BRAF mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAF melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAF melanoma." 7060;"[Melanoma therapeutic escape: the biomechanical track].";"C. Girard, M. Deckert, S. Tartare-Deckert";"Equipe 11, Team 11";33151853;"Medecine sciences : M/S";"Lecacheur M, Girard CA, Deckert M, Tartare-Deckert S";;"Nov 2020";1604188800;; 6733;"A Lentiviral Vector Allowing Physiologically Regulated Membrane-anchored and Secreted Antibody Expression Depending on B-cell Maturation Status.";"E. Verhoeyen";"Team 03, Equipe 03";26281898;"Molecular therapy : the journal of the American Society of Gene Therapy";"Fusil F, Calattini S, Amirache F, Mancip J, Costa C, Robbins JB, Douam F, Lavillette D, Law M, Defrance T, Verhoeyen E, Cosset FL";;"Nov 2015";1446336000;;"The development of lentiviral vectors (LVs) for expression of a specific antibody can be achieved through the transduction of mature B-cells. This approach would provide a versatile tool for active immunotherapy strategies for infectious diseases or cancer, as well as for protein engineering. Here, we created a lentiviral expression system mimicking the natural production of these two distinct immunoglobulin isoforms. We designed a LV (FAM2-LV) expressing an anti-HCV-E2 surface glycoprotein antibody (AR3A) as a membrane-anchored Ig form or a soluble Ig form, depending on the B-cell maturation status. FAM2-LV induced high-level and functional membrane expression of the transgenic antibody in a nonsecretory B-cell line. In contrast, a plasma cell (PC) line transduced with FAM2-LV preferentially produced the secreted transgenic antibody. Similar results were obtained with primary B-cells transduced ex vivo. Most importantly, FAM2-LV transduced primary B-cells efficiently differentiated into PCs, which secreted the neutralizing anti-HCV E2 antibody upon adoptive transfer into immunodeficient NSG (NOD/SCIDγc(-/-)) recipient mice. Altogether, these results demonstrate that the conditional FAM2-LV allows preferential expression of the membrane-anchored form of an antiviral neutralizing antibody in B-cells and permits secretion of a soluble antibody following B-cell maturation into PCs in vivo. " 6731;"Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors.";"E. Verhoeyen";"Team 03, Equipe 03";26232436;"Journal of immunology (Baltimore, Md. : 1950)";"Zhou Q, Uhlig KM, Muth A, Kimpel J, Lévy C, Münch RC, Seifried J, Pfeiffer A, Trkola A, Coulibaly C, von Laer D, Wels WS, Hartwig UF, Verhoeyen E, Buchholz CJ";;"Sep 2015";1441065600;;"Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy. " 6728;"Surface engineering of lentiviral vectors for gene transfer into gene therapy target cells.";"E. Verhoeyen";"Team 03, Equipe 03";26298515;"Current opinion in pharmacology";"Lévy C, Verhoeyen E, Cosset FL";;"Oct 2015";1443657600;;"Since they allow gene integration into their host genome, lentiviral vectors (LVs) have strong therapeutic potentials, as emphasized by recent clinical trials. The surface-display of the pantropic vesicular stomatitis virus G glycoprotein (VSV-G) on LVs resulted in powerful tools for fundamental and clinical research. However, improved LVs are required either to genetically modify cell types not permissive to classical VSV-G-LVs or to restrict entry to specific cell types. Incorporation of heterologous viral glycoproteins (gps) on LVs often require modification of their cytoplasmic tails and ligands can be inserted into their ectodomain to target LVs to specific receptors. Recently, measles virus (MV) gps have been identified as strong candidates for LV-retargeting to multiple cell types, with the potential to evolve toward clinical applications. " 6727;"Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists.";"E. Verhoeyen";"Team 03, Equipe 03";26331539;Nature;"Prost S, Relouzat F, Spentchian M, Ouzegdouh Y, Saliba J, Massonnet G, Beressi JP, Verhoeyen E, Raggueneau V, Maneglier B, Castaigne S, Chomienne C, Chrétien S, Rousselot P, Leboulch P";;"Sep 2015";1441065600;;"Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool. " 6725;"Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells.";"E. Verhoeyen";"Team 03, Equipe 03";26459632;"Journal of molecular cell biology";"Morozumi Y, Boussouar F, Tan M, Chaikuad A, Jamshidikia M, Colak G, He H, Nie L, Petosa C, de Dieuleveult M, Curtet S, Vitte AL, Rabatel C, Debernardi A, Cosset FL, Verhoeyen E, Emadali A, Schweifer N, Gianni D, Gut M, Guardiola P, Rousseaux S, Gérard M, Knapp S, Zhao Y, Khochbin S";;"08 2016";1470009600;;"Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells Atad2 becomes critical in sustaining specific gene expression programmes, controlling proliferation and differentiation. Altogether, this work defines Atad2 as a facilitator of general chromatin-templated activities such as transcription." 6723;"Cyclic dinucleotides modulate human T-cell response through monocyte cell death.";"E. Verhoeyen";"Team 03, Equipe 03";26460927;"European journal of immunology";"Tosolini M, Pont F, Verhoeyen E, Fournié JJ";;"Dec 2015";1448928000;;"Cyclic dinucleotides, a class of microbial messengers, have been recently identified in bacteria, but their activity in humans remains largely unknown. Here, we have studied the function of cyclic dinucleotides in humans. We found that c-di-AMP and cGAMP, two adenosine-based cyclic dinucleotides, activated T lymphocytes in an unusual manner through monocyte cell death. c-di-AMP and cGAMP induced the selective apoptosis of human monocytes, and T lymphocytes were activated by the direct contact with these dying monocytes. The ensuing T-cell response comprised cell-cycle exit, phenotypic maturation into effector memory cells and proliferation arrest, but not cell death. This quiescence was transient since T cells remained fully responsive to further restimulation. Together, our results depict a novel activation pattern for human T lymphocytes: a transient quiescence induced by c-di-AMP- or cGAMP-primed apoptotic monocytes. " 6722;"Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms.";"E. Verhoeyen, C. Lefebvre";"Team 03, Equipe 03";27060168;Blood;"Emadali A, Hoghoughi N, Duley S, Hajmirza A, Verhoeyen E, Cosset FL, Bertrand P, Roumier C, Roggy A, Suchaud-Martin C, Chauvet M, Bertrand S, Hamaidia S, Rousseaux S, Josserand V, Charles J, Templier I, Maeda T, Bruder-Costa J, Chaperot L, Plumas J, Jacob MC, Bonnefoix T, Park S, Gressin R, Tensen CP, Mecucci C, Macintyre E, Leroux D, Brambilla E, Nguyen-Khac F, Luquet I, Penther D, Bastard C, Jardin F, Lefebvre C, Garnache F, Callanan MB";;"06 2016";1464739200;;"Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN." 6720;"Gene-corrected human Munc13-4-deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice.";"E. Verhoeyen";"Team 03, Equipe 03";27799161;Blood;"Soheili T, Rivière J, Ricciardelli I, Durand A, Verhoeyen E, Derrien AC, Lagresle-Peyrou C, de Saint Basile G, Cosset FL, Amrolia P, André-Schmutz I, Cavazzana M";;"12 2016";1480550400;; 6718;"Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes.";"E. Verhoeyen";"Team 03, Equipe 03";27162078;Biomaterials;"Labenski V, Suerth JD, Barczak E, Heckl D, Levy C, Bernadin O, Charpentier E, Williams DA, Fehse B, Verhoeyen E, Schambach A";;"08 2016";1470009600;;"Primary human T lymphocytes represent an important cell population for adoptive immunotherapies, including chimeric-antigen and T-cell receptor applications, as they have the capability to eliminate non-self, virus-infected and tumor cells. Given the increasing numbers of clinical immunotherapy applications, the development of an optimal vector platform for genetic T lymphocyte engineering, which allows cost-effective high-quality vector productions, remains a critical goal. Alpharetroviral self-inactivating vectors (ARV) have several advantages compared to other vector platforms, including a more random genomic integration pattern and reduced likelihood for inducing aberrant splicing of integrated proviruses. We developed an ARV platform for the transduction of primary human T lymphocytes. We demonstrated functional transgene transfer using the clinically relevant herpes-simplex-virus thymidine kinase variant TK.007. Proof-of-concept of alpharetroviral-mediated T-lymphocyte engineering was shown in vitro and in a humanized transplantation model in vivo. Furthermore, we established a stable, human alpharetroviral packaging cell line in which we deleted the entry receptor (SLC1A5) for RD114/TR-pseudotyped ARVs to prevent superinfection and enhance genomic integrity of the packaging cell line and viral particles. We showed that superinfection can be entirely prevented, while maintaining high recombinant virus titers. Taken together, this resulted in an improved production platform representing an economic strategy for translating the promising features of ARVs for therapeutic T-lymphocyte engineering." 6715;"Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia.";"E. Verhoeyen";"Team 03, Equipe 03";27354269;"Cancer discovery";"Trinquand A, Dos Santos NR, Tran Quang C, Rocchetti F, Zaniboni B, Belhocine M, Da Costa de Jesus C, Lhermitte L, Tesio M, Dussiot M, Cosset FL, Verhoeyen E, Pflumio F, Ifrah N, Dombret H, Spicuglia S, Chatenoud L, Gross DA, Hermine O, Macintyre E, Ghysdael J, Asnafi V";;"09 2016";1472688000;;"Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ε chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse- or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells." 6712;"Twelfth Annual Meeting of the French Society of Cell and Gene Therapy.";"E. Verhoeyen";"Team 03, Equipe 03";27428658;"Human gene therapy";"Verhoeyen E, Gomez S, Galy A, Ayuso E, Midoux P, Pucéat M, Vassaux G, Cordelier P";;"07 2016";1467331200;; 6713;"X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene.";"E. Verhoeyen";"Team 03, Equipe 03";27405666;"The Journal of allergy and clinical immunology";"Lagresle-Peyrou C, Luce S, Ouchani F, Soheili TS, Sadek H, Chouteau M, Durand A, Pic I, Majewski J, Brouzes C, Lambert N, Bohineust A, Verhoeyen E, Cosset FL, Magerus-Chatinet A, Rieux-Laucat F, Gandemer V, Monnier D, Heijmans C, van Gijn M, Dalm VA, Mahlaoui N, Stephan JL, Picard C, Durandy A, Kracker S, Hivroz C, Jabado N, de Saint Basile G, Fischer A, Cavazzana M, André-Schmutz I";;"12 2016";1480550400;;"We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections." 6710;"Gene Therapy in Fanconi Anemia: A Matter of Time, Safety and Gene Transfer Tool Efficiency.";"E. Verhoeyen";"Team 03, Equipe 03";28067165;"Current gene therapy";"Verhoeyen E, Roman-Rodriguez FJ, Cosset FL, Levy C, Rio P";;"Jan 2017";1483228800;;"Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive marrow failure. Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential cure since it is a monogenetic disease with mutations in the FANC genes, coding for DNA repair enzymes [1]. However, the collection of hCD34+-cells in FA patients implies particular challenges because of the reduced numbers of progenitor cells present in their bone marrow (BM) [2] or mobilized peripheral blood [3-5]. In addition, the FA genetic defect fragilizes the HSCs [6]. These particular features might explain why the first clinical trials using murine leukemia virus derived retroviral vectors conducted for FA failed to show engraftment of corrected cells. The gene therapy field is now moving towards the use of lentiviral vectors (LVs) evidenced by recent succesful clinical trials for the treatment of patients suffering from adrenoleukodystrophy (ALD) [7], β-thalassemia [8], metachromatic leukodystrophy [9] and Wiskott-Aldrich syndrome [10]. LV trials for X-linked severe combined immunodificiency and Fanconi anemia (FA) defects were recently initiated [11, 12]. Fifteen years of preclinical studies using different FA mouse models and in vitro research allowed us to find the weak points in the in vitro culture and transduction conditions, which most probably led to the initial failure of FA HSC gene therapy. In this review, we will focus on the different obstacles, unique to FA gene therapy, and how they have been overcome through the development of optimized protocols for FA HSC culture and transduction and the engineering of new gene transfer tools for FA HSCs. These combined advances in the field hopefully will allow the correction of the FA hematological defect in the near future." 6708;"High SYK Expression Drives Constitutive Activation of CD21 B Cells.";"E. Verhoeyen";"Team 03, Equipe 03";28468967;"Journal of immunology (Baltimore, Md. : 1950)";"Keller B, Stumpf I, Strohmeier V, Usadel S, Verhoeyen E, Eibel H, Warnatz K";;"06 2017";1496275200;;"Human CD21 B cells present with an activated phenotype and accumulate in distinct disorders connected with chronic immune stimulation. Signaling studies had revealed an increased basal phosphorylation of spleen tyrosine kinase (SYK) and phospholipase Cγ2. Additional BCR stimulation of these constitutively active cells, however, led to reduced activation of these signaling molecules and subsequently NF-κB and Ca activation. In this article, we demonstrate that high SYK expression is a common feature of CD21 B cells independent of the underlying disorder, and that this high expression is sufficient to drive constitutive phosphorylation of SYK and its immediate targets Bruton's tyrosine kinase and phospholipase Cγ2. Inhibition of SYK activity eliminated features of the constitutive activation in these cells and partly restored BCR signaling. High SYK expression is especially induced by CpG or CD40L in combination with IL-21, but not BCR stimulation, suggesting the importance of the immune-stimulatory context for the induction of this B cell phenotype. In summary, high SYK expression is a common feature of human CD21 B cells and presumably results from chronic activation in inflammatory environments present in a subgroup of patients with heterogeneous disorders like chronic infection, autoimmunity, and immunodeficiency. High SYK expression by itself drives the constitutive activation observed in these B cells, which in turn may contribute to the hyporesponsiveness upon BCR stimulation. Given the high prevalence of autoreactive clones among CD21 B cells in autoimmune disorders, the dominant role of SYK in CD21 B cells may provide a new option for therapeutic interventions in patients with expanded CD21 B cells and humoral autoimmunity." 6705;"Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition.";"E. Verhoeyen";"Team 03, Equipe 03";28481226;"The Journal of clinical investigation";"Elagib KE, Lu CH, Mosoyan G, Khalil S, Zasadzińska E, Foltz DR, Balogh P, Gru AA, Fuchs DA, Rimsza LM, Verhoeyen E, Sansó M, Fisher RP, Iancu-Rubin C, Goldfarb AN";;"Jun 2017";1496275200;;"Hematopoietic transitions that accompany fetal development, such as erythroid globin chain switching, play important roles in normal physiology and disease development. In the megakaryocyte lineage, human fetal progenitors do not execute the adult morphogenesis program of enlargement, polyploidization, and proplatelet formation. Although these defects decline with gestational stage, they remain sufficiently severe at birth to predispose newborns to thrombocytopenia. These defects may also contribute to inferior platelet recovery after cord blood stem cell transplantation and may underlie inefficient platelet production by megakaryocytes derived from pluripotent stem cells. In this study, comparison of neonatal versus adult human progenitors has identified a blockade in the specialized positive transcription elongation factor b (P-TEFb) activation mechanism that is known to drive adult megakaryocyte morphogenesis. This blockade resulted from neonatal-specific expression of an oncofetal RNA-binding protein, IGF2BP3, which prevented the destabilization of the nuclear RNA 7SK, a process normally associated with adult megakaryocytic P-TEFb activation. Knockdown of IGF2BP3 sufficed to confer both phenotypic and molecular features of adult-type cells on neonatal megakaryocytes. Pharmacologic inhibition of IGF2BP3 expression via bromodomain and extraterminal domain (BET) inhibition also elicited adult features in neonatal megakaryocytes. These results identify IGF2BP3 as a human ontogenic master switch that restricts megakaryocyte development by modulating a lineage-specific P-TEFb activation mechanism, revealing potential strategies toward enhancing platelet production." 6703;"Molecular and Functional Characterization of Lymphoid Progenitor Subsets Reveals a Bipartite Architecture of Human Lymphopoiesis.";"E. Verhoeyen";"Team 03, Equipe 03";29045900;Immunity;"Alhaj Hussen K, Vu Manh TP, Guimiot F, Nelson E, Chabaane E, Delord M, Barbier M, Berthault C, Dulphy N, Alberdi AJ, Burlen-Defranoux O, Socié G, Bories JC, Larghero J, Vanneaux V, Verhoeyen E, Wirth T, Dalod M, Gluckman JC, Cumano A, Canque B";;"10 2017";1506816000;;"The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127 and CD127 early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127 and CD127 ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127 ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127 ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a ""two-family"" model of human lymphoid development that differs from the prevailing model of hematopoiesis." 6701;"Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent.";"E. Verhoeyen";"Team 03, Equipe 03";29296856;"Blood advances";"Lévy C, Amirache F, Girard-Gagnepain A, Frecha C, Roman-Rodríguez FJ, Bernadin O, Costa C, Nègre D, Gutierrez-Guerrero A, Vranckx LS, Clerc I, Taylor N, Thielecke L, Cornils K, Bueren JA, Rio P, Gijsbers R, Cosset FL, Verhoeyen E";;"Oct 2017";1506816000;;"Hematopoietic stem cell (HSC)-based gene therapy trials are now moving toward the use of lentiviral vectors (LVs) with success. However, one challenge in the field remains: efficient transduction of HSCs without compromising their stem cell potential. Here we showed that measles virus glycoprotein-displaying LVs (hemagglutinin and fusion protein LVs [H/F-LVs]) were capable of transducing 100% of early-acting cytokine-stimulated human CD34 (hCD34) progenitor cells upon a single application. Strikingly, these H/F-LVs also allowed transduction of up to 70% of nonstimulated quiescent hCD34 cells, whereas conventional vesicular stomatitis virus G (VSV-G)-LVs reached 5% at the most with H/F-LV entry occurring exclusively through the CD46 complement receptor. Importantly, reconstitution of NOD/SCIDγc (NSG) mice with H/F-LV transduced prestimulated or resting hCD34 cells confirmed these high transduction levels in all myeloid and lymphoid lineages. Remarkably, for resting CD34 cells, secondary recipients exhibited increasing transduction levels of up to 100%, emphasizing that H/F-LVs efficiently gene-marked HSCs in the resting state. Because H/F-LVs promoted ex vivo gene modification of minimally manipulated CD34 progenitors that maintained stemness, we assessed their applicability in Fanconi anemia, a bone marrow (BM) failure with chromosomal fragility. Notably, only H/F-LVs efficiently gene-corrected minimally stimulated hCD34 cells in unfractionated BM from these patients. These H/F-LVs improved HSC gene delivery in the absence of cytokine stimulation while maintaining their stem cell potential. Thus, H/F-LVs will facilitate future clinical applications requiring HSC gene modification, including BM failure syndromes, for which treatment has been very challenging up to now." 6699;"Multiplex CRISPR/Cas9 system impairs HCMV replication by excising an essential viral gene.";"E. Verhoeyen";"Team 03, Equipe 03";29447206;"PloS one";"Gergen J, Coulon F, Creneguy A, Elain-Duret N, Gutierrez A, Pinkenburg O, Verhoeyen E, Anegon I, Nguyen TH, Halary FA, Haspot F";;"Jan 2018";1514764800;;"Anti-HCMV treatments used in immunosuppressed patients reduce viral replication, but resistant viral strains can emerge. Moreover, these drugs do not target latently infected cells. We designed two anti-viral CRISPR/Cas9 strategies to target the UL122/123 gene, a key regulator of lytic replication and reactivation from latency. The singleplex strategy contains one gRNA to target the start codon. The multiplex strategy contains three gRNAs to excise the complete UL122/123 gene. Primary fibroblasts and U-251 MG cells were transduced with lentiviral vectors encoding Cas9 and one or three gRNAs. Both strategies induced mutations in the target gene and a concomitant reduction of immediate early (IE) protein expression in primary fibroblasts. Further detailed analysis in U-251 MG cells showed that the singleplex strategy induced 50% of indels in the viral genome, leading to a reduction in IE protein expression. The multiplex strategy excised the IE gene in 90% of all viral genomes and thus led to the inhibition of IE protein expression. Consequently, viral genome replication and late protein expression were reduced by 90%. Finally, the production of new viral particles was nearly abrogated. In conclusion, the multiplex anti-UL122/123 CRISPR/Cas9 system can target the viral genome efficiently enough to significantly prevent viral replication." 6697;"A protein coevolution method uncovers critical features of the Hepatitis C Virus fusion mechanism.";"E. Verhoeyen";"Team 03, Equipe 03";29505618;"PLoS pathogens";"Douam F, Fusil F, Enguehard M, Dib L, Nadalin F, Schwaller L, Hrebikova G, Mancip J, Mailly L, Montserret R, Ding Q, Maisse C, Carlot E, Xu K, Verhoeyen E, Baumert TF, Ploss A, Carbone A, Cosset FL, Lavillette D";;"03 2018";1519862400;;"Amino-acid coevolution can be referred to mutational compensatory patterns preserving the function of a protein. Viral envelope glycoproteins, which mediate entry of enveloped viruses into their host cells, are shaped by coevolution signals that confer to viruses the plasticity to evade neutralizing antibodies without altering viral entry mechanisms. The functions and structures of the two envelope glycoproteins of the Hepatitis C Virus (HCV), E1 and E2, are poorly described. Especially, how these two proteins mediate the HCV fusion process between the viral and the cell membrane remains elusive. Here, as a proof of concept, we aimed to take advantage of an original coevolution method recently developed to shed light on the HCV fusion mechanism. When first applied to the well-characterized Dengue Virus (DENV) envelope glycoproteins, coevolution analysis was able to predict important structural features and rearrangements of these viral protein complexes. When applied to HCV E1E2, computational coevolution analysis predicted that E1 and E2 refold interdependently during fusion through rearrangements of the E2 Back Layer (BL). Consistently, a soluble BL-derived polypeptide inhibited HCV infection of hepatoma cell lines, primary human hepatocytes and humanized liver mice. We showed that this polypeptide specifically inhibited HCV fusogenic rearrangements, hence supporting the critical role of this domain during HCV fusion. By combining coevolution analysis and in vitro assays, we also uncovered functionally-significant coevolving signals between E1 and E2 BL/Stem regions that govern HCV fusion, demonstrating the accuracy of our coevolution predictions. Altogether, our work shed light on important structural features of the HCV fusion mechanism and contributes to advance our functional understanding of this process. This study also provides an important proof of concept that coevolution can be employed to explore viral protein mediated-processes, and can guide the development of innovative translational strategies against challenging human-tropic viruses." 6695;"A kindred with mutant IKAROS and autoimmunity.";"E. Verhoeyen";"Team 03, Equipe 03";29705243;"The Journal of allergy and clinical immunology";"Van Nieuwenhove E, Garcia-Perez JE, Helsen C, Rodriguez PD, van Schouwenburg PA, Dooley J, Schlenner S, van der Burg M, Verhoeyen E, Gijsbers R, Frietze S, Schjerven H, Meyts I, Claessens F, Humblet-Baron S, Wouters C, Liston A";;"08 2018";1533081600;; 6693;"generation of human CD19-CAR T cells results in B-cell depletion and signs of cytokine release syndrome.";"E. Verhoeyen";"Team 03, Equipe 03";30224381;"EMBO molecular medicine";"Pfeiffer A, Thalheimer FB, Hartmann S, Frank AM, Bender RR, Danisch S, Costa C, Wels WS, Modlich U, Stripecke R, Verhoeyen E, Buchholz CJ";;"11 2018";1541030400;;"Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. Notwithstanding, CAR T-cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19-CAR T cells can be generated directly using the lentiviral vector CD8-LV specifically targeting human CD8 cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8 T cells and efficacious elimination of CD19 B cells. Further, upon injection of CD8-LV into mice transplanted with human CD34 cells, induction of CAR T cells and CD19 B-cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue-invading CAR T cells and complete elimination of the B-lymphocyte-rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of reprogramming of human CD8 CAR T cells active against CD19 cells, yet with similar adverse effects currently notorious in the clinical practice." 6690;"A Novel BaEVRless-Pseudotyped γ-Globin Lentiviral Vector Drives High and Stable Fetal Hemoglobin Expression and Improves Thalassemic Erythropoiesis .";"E. Verhoeyen";"Team 03, Equipe 03";30324804;"Human gene therapy";"Drakopoulou E, Georgomanoli M, Lederer CW, Kleanthous M, Costa C, Bernadin O, Cosset FL, Voskaridou E, Verhoeyen E, Papanikolaou E, Anagnou NP";;"05 2019";1556668800;;"It has previously been demonstrated that the self-inactivating γ-globin lentiviral vector GGHI can significantly increase fetal hemoglobin (HbF) in erythroid cells from thalassemia patients and thus improve the disease phenotype In the present study, the GGHI vector was improved further by incorporating novel enhancer elements and also pseudotyping it with the baboon endogenous virus envelope glycoprotein BaEVRless, which efficiently and specifically targets human CD34 cells. We evaluated the hypothesis that the newly constructed vector designated as GGHI-mB-3D would increase hCD34 cell tropism and thus transduction efficiency at low multiplicity of infection, leading to increased transgene expression. High and stable HbF expression was demonstrated in thalassemic cells for the resulting GGHI-mB-3D/BaEVRless vector, exhibiting increased transduction efficiency compared to the original GGHI-mB-3D/VSVG vector, with a concomitant 91% mean HbF increase at a mean vector copy number per cell of 0.86 and a mean transduction efficiency of 56.4%. Transduced populations also exhibited a trend toward late erythroid, orthochromatic differentiation and reduced apoptosis, a further indication of successful gene therapy treatment. Monitoring expression of , a key link between autophagy and apoptosis, it was established that this correction correlates with a reduction of enhanced autophagy activation, a typical feature of thalassemic polychromatophilic normoblasts. This work provides novel mechanistic insights into gene therapy-mediated correction of erythropoiesis and demonstrates the beneficial role of BaEVRless envelope glycoprotein compared to VSVG pseudotyping and of the novel GGHI-mB-3D/BaEVRless lentiviral vector for enhanced thalassemia gene therapy." 6689;"Consensus Statement of European Societies of Gene and Cell Therapy on the Reported Birth of Genome-Edited Babies in China.";"E. Verhoeyen";"Team 03, Equipe 03";30511888;"Human gene therapy";"Büning H, Griesenbach U, Fehse B, Ylä-Herttuala S, Anagnou NP, van Beusechem V, Raya A, Verhoeyen E";;"Dec 2018";1543968000;; 6687;"CD46 Null Packaging Cell Line Improves Measles Lentiviral Vector Production and Gene Delivery to Hematopoietic Stem and Progenitor Cells.";"E. Verhoeyen";"Team 03, Equipe 03";30603655;"Molecular therapy. Methods & clinical development";"Ozog S, Chen CX, Simpson E, Garijo O, Timberlake ND, Minder P, Verhoeyen E, Torbett BE";;"Jun 2019";1559347200;;"Lentiviral vectors (LVs) pseudotyped with the measles virus hemagglutinin (H) and fusion (F) glycoproteins have been reported to more efficiently transduce hematopoietic stem and progenitor cells (HSPCs) compared with vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped LVs. However, a limit to H/F LV use is the low titer of produced vector. Here we show that measles receptor (CD46) expression on H/F transfected HEK293T vector-producing cells caused adjacent cell membrane fusion, resulting in multinucleate syncytia formation and death prior to peak vector production, leading to contaminating cell membranes that co-purified with LV. H/F LVs produced in CD46 null HEK293T cells, generated by CRISPR/Cas9-mediated knockout of CD46, produced 2-fold higher titer vector compared with LVs produced in CD46 HEK293T cells. This resulted in approximately 2- to 3-fold higher transduction of HSPCs while significantly reducing target cell cytotoxicity caused by producer cell contaminates. Improved H/F LV entry into HSPCs and distinct entry mechanisms compared with VSV-G LV were also observed by confocal microscopy. Given that vector production is a major source of cost and variability in clinical trials of gene therapy, we propose that the use of CD46 null packaging cells may help to address these challenges." 6685;"Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency.";"E. Verhoeyen";"Team 03, Equipe 03";30755435;"Blood advances";"Bernadin O, Amirache F, Girard-Gagnepain A, Moirangthem RD, Lévy C, Ma K, Costa C, Nègre D, Reimann C, Fenard D, Cieslak A, Asnafi V, Sadek H, Mhaidly R, Cavazzana M, Lagresle-Peyrou C, Cosset FL, André I, Verhoeyen E";;"02 2019";1548979200;;"T cells represent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-cell therapies would strongly benefit from gene transfer into long-lived persisting naive T cells or T-cell progenitors. Here we demonstrate that baboon envelope glycoprotein pseudotyped lentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypes for transduction of naive adult and fetal interleukin-7-stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitors generated by culture of CD34 cells on Delta-like ligand 4 (Dll4). Upon NOD/SCIDγC engraftment, high transduction levels (80%-90%) were maintained in all T-cell subpopulations. Moreover, T-cell lineage reconstitution was accelerated in NOD/SCIDγC recipients after T-cell progenitor injection compared with hematopoietic stem cell transplantation. Furthermore, γC-encoding BaEV-LVs very efficiently transduced Dll4-generated T-cell precursors from a patient with X-linked severe combined immunodeficiency (SCID-X1), which fully rescued T-cell development in vitro. These results indicate that BaEV-LVs are valuable tools for the genetic modification of naive T cells, which are important targets for gene therapy. Moreover, they allowed for the generation of gene-corrected T-cell progenitors that rescued SCID-X1 T-cell development in vitro. Ultimately, the coinjection of LV-corrected T-cell progenitors and hematopoietic stem cells might accelerate T-cell reconstitution in immunodeficient patients." 6683;"A Recurrent Activating Missense Mutation in Waldenström Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation.";"E. Verhoeyen";"Team 03, Equipe 03";31018969;"Cancer discovery";"Roos-Weil D, Decaudin C, Armand M, Della-Valle V, Diop MK, Ghamlouch H, Ropars V, Hérate C, Lara D, Durot E, Haddad R, Mylonas E, Damm F, Pflumio F, Stoilova B, Metzner M, Elemento O, Dessen P, Camara-Clayette V, Cosset FL, Verhoeyen E, Leblond V, Ribrag V, Cornillet-Lefebvre P, Rameau P, Azar N, Charlotte F, Morel P, Charbonnier JB, Vyas P, Mercher T, Aoufouchi S, Droin N, Guillouf C, Nguyen-Khac F, Bernard OA";;"06 2019";1559347200;;"The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. genes are targeted through genomic rearrangements in oncogenesis. The gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. SIGNIFICANCE: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.." 6681;"The Future: In Vivo CAR T Cell Gene Therapy.";"E. Verhoeyen";"Team 03, Equipe 03";30914238;"Molecular therapy : the journal of the American Society of Gene Therapy";"Mhaidly R, Verhoeyen E";;"04 2019";1554076800;; 6678;"A Distinct Subset of Highly Proliferative and Lentiviral Vector (LV)-Transducible NK Cells Define a Readily Engineered Subset for Adoptive Cellular Therapy.";"E. Verhoeyen";"Team 03, Equipe 03";31507603;"Frontiers in immunology";"Bari R, Granzin M, Tsang KS, Roy A, Krueger W, Orentas R, Schneider D, Pfeifer R, Moeker N, Verhoeyen E, Dropulic B, Leung W";;"Jan 2019";1546300800;;"Genetic engineering is an important tool for redirecting the function of various types of immune cells and their use for therapeutic purpose. Although NK cells have many beneficial therapeutic features, genetic engineering of immune cells for targeted therapy focuses mostly on T cells. One of the major obstacles for NK cell immunotherapy is the lack of an efficient method for gene transfer. Lentiviral vectors have been proven to be a safe tool for genetic engineering, however lentiviral transduction is inefficient for NK cells. We show in this study that lentiviral vectors pseudotyped with a modified baboon envelope glycoprotein can transduce NK cells 20-fold or higher in comparison to VSV-G pseudotyped lentiviral vector. When we investigated the mechanism of transduction, we found that activated NK cells expressed baboon envelope receptor ASCT-2. Further analysis revealed that only a subset of NK cells could be expanded and transduced with an expression profile of NK56, CD16, TRAIL, and CX3CR1. Using CD19-CAR, we could show that CD19 redirected NK cells efficiently and specifically kill cell lines expressing CD19. Taken together, the results from this study will be important for future genetic modification and for redirecting of NK cell function for therapeutic purpose." 6677;"Vectofusin-1 Improves Transduction of Primary Human Cells with Diverse Retroviral and Lentiviral Pseudotypes, Enabling Robust, Automated Closed-System Manufacturing.";"E. Verhoeyen";"Team 03, Equipe 03";31578886;"Human gene therapy";"Radek C, Bernadin O, Drechsel K, Cordes N, Pfeifer R, Sträßer P, Mormin M, Gutierrez-Guerrero A, Cosset FL, Kaiser AD, Schaser T, Galy A, Verhoeyen E, Johnston ICD";;"12 2019";1575158400;;"Cell and gene therapies are finally becoming viable patient treatment options, with both T cell- and hematopoietic stem cell (HSC)-based therapies being approved to market in Europe. However, these therapies, which involve the use of viral vector to modify the target cells, are expensive and there is an urgent need to reduce manufacturing costs. One major cost factor is the viral vector production itself, therefore improving the gene modification efficiency could significantly reduce the amount of vector required per patient. This study describes the use of a transduction enhancing peptide, Vectofusin-1, to improve the transduction efficiency of primary target cells using lentiviral and gammaretroviral vectors (LV and RV) pseudotyped with a variety of envelope proteins. Using Vectofusin-1 in combination with LV pseudotyped with viral glycoproteins derived from baboon endogenous retrovirus, feline endogenous virus (RD114), and measles virus (MV), a strongly improved transduction of HSCs, B cells and T cells, even when cultivated under low stimulation conditions, could be observed. The formation of Vectofusin-1 complexes with MV-LV retargeted to CD20 did not alter the selectivity in mixed cell culture populations, emphasizing the precision of this targeting technology. Functional, ErbB2-specific chimeric antigen receptor-expressing T cells could be generated using a gibbon ape leukemia virus (GALV)-pseudotyped RV. Using a variety of viral vectors and target cells, Vectofusin-1 performed in a comparable manner to the traditionally used surface-bound recombinant fibronectin. As Vectofusin-1 is a soluble peptide, it was possible to easily transfer the T cell transduction method to an automated closed manufacturing platform, where proof of concept studies demonstrated efficient genetic modification of T cells with GALV-RV and RD114-RV and the subsequent expansion of mainly central memory T cells to a clinically relevant dose." 6676;"Humanized mice are precious tools for evaluation of hematopoietic gene therapies and preclinical modeling to move towards a clinical trial.";"E. Verhoeyen";"Team 03, Equipe 03";31726047;"Biochemical pharmacology";"Brendel C, Rio P, Verhoeyen E";;"04 2020";1585699200;;"Over the last decade, incrementally improved xenograft mouse models, which support the engraftment and development of a human hemato-lymphoid system, have been developed and represent an important fundamental and preclinical research tool. Immunodeficient mice can be transplanted with human hematopoietic stem cells (HSCs) and this process is accompanied by HSC homing to the murine bone marrow. This is followed by stem cell expansion, multilineage hematopoiesis, long-term engraftment, and functional human antibody and cellular immune responses. The most significant contributions made by these humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, screening of anti-cancer therapies and their use as preclinical models for gene therapy applications. This review article focuses on several gene therapy applications that have benefited from evaluation in humanized mice such as chimeric antigen receptor (CAR) T cell therapies for cancer, anti-viral therapies and gene therapies for multiple monogenetic diseases. Humanized mouse models have been and still are of great value for the gene therapy field since they provide a more reliable understanding of sometimes complicated therapeutic approaches such as recently developed therapeutic gene editing strategies, which seek to correct a gene at its endogenous genomic locus. Additionally, humanized mouse models, which are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior toclinical trials, help to expedite the critical translation from basic findings to clinical applications. In this review, innovative gene therapies and preclinical studies to evaluate T- and B-cell and HSC-based therapies in humanized mice are discussed and illustrated by multiple examples." 6674;"Corrigendum: A Distinct Subset of Highly Proliferative and Lentiviral Vector (LV)-Transducible NK Cells Define a Readily Engineered Subset for Adoptive Cellular Therapy.";"E. Verhoeyen";"Team 03, Equipe 03";31839796;"Frontiers in immunology";"Bari R, Granzin M, Tsang KS, Roy A, Krueger W, Orentas R, Schneider D, Pfeifer R, Moeker N, Verhoeyen E, Dropulic B, Leung W";;"Jan 2019";1546300800;;"[This corrects the article DOI: 10.3389/fimmu.2019.02001.]." 6672;"CBFβ-SMMHC Affects Genome-wide Polycomb Repressive Complex 1 Activity in Acute Myeloid Leukemia.";"E. Verhoeyen";"Team 03, Equipe 03";31940477;"Cell reports";"Cordonnier G, Mandoli A, Cagnard N, Hypolite G, Lhermitte L, Verhoeyen E, Asnafi V, Dillon N, Macintyre E, Martens JHA, Bond J";;"01 2020";1577836800;;"Mutations and deletions of polycomb repressive complex (PRC) components are increasingly recognized to affect tumor biology in a range of cancers. However, little is known about how genetic alterations of PRC-interacting molecules such as the core binding factor (CBF) complex influence polycomb activity. We report that the acute myeloid leukemia (AML)-associated CBFβ-SMMHC fusion oncoprotein physically interacts with the PRC1 complex and that these factors co-localize across the AML genome in an apparently PRC2-independent manner. Depletion of CBFβ-SMMHC caused substantial increases in genome-wide PRC1 binding and marked changes in the association between PRC1 and the CBF DNA-binding subunit RUNX1. PRC1 was more likely to be associated with actively transcribed genes in CBFβ-SMMHC-expressing cells. CBFβ-SMMHC depletion had heterogeneous effects on gene expression, including significant reductions in transcription of ribosomal loci occupied by PRC1. Our results provide evidence that CBFβ-SMMHC markedly and diversely affects polycomb recruitment and transcriptional regulation across the AML genome." 6670;"Efficient and Robust NK-Cell Transduction With Baboon Envelope Pseudotyped Lentivector.";"E. Verhoeyen";"Team 03, Equipe 03";31921138;"Frontiers in immunology";"Colamartino ABL, Lemieux W, Bifsha P, Nicoletti S, Chakravarti N, Sanz J, Roméro H, Selleri S, Béland K, Guiot M, Tremblay-Laganière C, Dicaire R, Barreiro L, Lee DA, Verhoeyen E, Haddad E";;"Jan 2019";1546300800;;"NK-cell resistance to transduction is a major technical hurdle for developing NK-cell immunotherapy. By using Baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) encoding eGFP, we obtained a transduction rate of 23.0 ± 6.6% (mean ± SD) in freshly-isolated human NK-cells (FI-NK) and 83.4 ± 10.1% (mean ± SD) in NK-cells obtained from the NK-cell Activation and Expansion System (NKAES), with a sustained transgene expression for at least 21 days. BaEV-LVs outperformed Vesicular Stomatitis Virus type-G (VSV-G)-, RD114- and Measles Virus (MV)- pseudotyped LVs ( < 0.0001). mRNA expression of both BaEV receptors, ASCT1 and ASCT2, was detected in FI-NK and NKAES, with higher expression in NKAES. Transduction with BaEV-LVs encoding for CAR-CD22 resulted in robust CAR-expression on 38.3 ± 23.8% (mean ± SD) of NKAES cells, leading to specific killing of NK-resistant pre-B-ALL-RS4;11 cell line. Using a larger vector encoding a dual CD19/CD22-CAR, we were able to transduce and re-expand dual-CAR-expressing NKAES, even with lower viral titer. These dual-CAR-NK efficiently killed both CD19- and CD22-RS4;11 cells. Our results suggest that BaEV-LVs may efficiently enable NK-cell biological studies and translation of NK-cell-based immunotherapy to the clinic." 6666;"Combining T-cell-specific activation and in vivo gene delivery through CD3-targeted lentiviral vectors.";"E. Verhoeyen";"Team 03, Equipe 03";33216892;"Blood advances";"Frank AM, Braun AH, Scheib L, Agarwal S, Schneider IC, Fusil F, Perian S, Sahin U, Thalheimer FB, Verhoeyen E, Buchholz CJ";;"11 2020";1604188800;;"Genetic modification of T lymphocytes is a key issue in research and therapy. Conventional lentiviral vectors (LVs) are neither selective for T cells nor do they modify resting or minimally stimulated cells, which is crucial for applications, such as efficient in vivo modification of T lymphocytes. Here, we introduce novel CD3-targeted LVs (CD3-LVs) capable of genetically modifying human T lymphocytes without prior activation. For CD3 attachment, agonistic CD3-specific single-chain variable fragments were chosen. Activation, proliferation, and expansion mediated by CD3-LVs were less rapid compared with conventional antibody-mediated activation owing to lack of T-cell receptor costimulation. CD3-LVs delivered genes not only selectively into T cells but also under nonactivating conditions, clearly outperforming the benchmark vector vesicular stomatitis-LV glycoproteins under these conditions. Remarkably, CD3-LVs were properly active in gene delivery even when added to whole human blood in absence of any further stimuli. Upon administration of CD3-LV into NSG mice transplanted with human peripheral blood mononuclear cells, efficient and exclusive transduction of CD3+ T cells in all analyzed organs was achieved. Finally, the most promising CD3-LV successfully delivered a CD19-specific chimeric antigen receptor (CAR) into T lymphocytes in vivo in humanized NSG mice. Generation of CAR T cells was accompanied by elimination of human CD19+ cells from blood. Taken together, the data strongly support implementation of T-cell-activating properties within T-cell-targeted vector particles. These particles may be ideally suited for T-cell-specific in vivo gene delivery." 6667;"Development of a Model for Chemical Screening Based on Collateral Sensitivity to Target BTK C481S Mutant.";"E. Verhoeyen";"Team 03, Equipe 03";32272741;Cancers;"Libre C, Moro-Sibilot L, Giraud S, Martin L, Verhoeyen E, Costa C, Chebel A, Bissay N, Salles G, Genestier L, Sujobert P";;"Apr 2020";1586563200;;"Targeted therapies have improved the outcome of cancer, but their efficacy is intrinsically limited by the emergence of subclones with a mutation in the gene encoding the target protein. A few examples of collateral sensitivity have demonstrated that the conformational changes induced by these mutations can create unexpected sensitivity to other kinase inhibitors, but whether this concept can be generalized is unknown. Here is described the development of a model to screen a library of kinase inhibitors for collateral sensitivity drugs active on the Bruton Tyrosine Kinase (BTK) protein with the ibrutinib resistance mutation C481S. First, we demonstrate that overexpression of the constitutively active mutant of BTK harboring the E41K mutation in Ba/F3 cells creates an oncogenic addiction to BTK. Then, we have exploited this phenotype to perform a screen of a kinase inhibitor library on cells with or without the ibrutinib resistance mutation. The BTK inhibitors showed the expected sensitivity profile, but none of the drugs tested had a specific activity against the C481S mutant of BTK, suggesting that extending the collateral sensitivity paradigm to all kinases targeted by cancer therapy might not be trivial." 6664;"Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8 T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy.";"E. Verhoeyen";"Team 03, Equipe 03";33053331;Immunity;"Weulersse M, Asrir A, Pichler AC, Lemaitre L, Braun M, Carrié N, Joubert MV, Le Moine M, Do Souto L, Gaud G, Das I, Brauns E, Scarlata CM, Morandi E, Sundarrajan A, Cuisinier M, Buisson L, Maheo S, Kassem S, Agesta A, Pérès M, Verhoeyen E, Martinez A, Mazieres J, Dupré L, Gossye T, Pancaldi V, Guillerey C, Ayyoub M, Dejean AS, Saoudi A, Goriely S, Avet-Loiseau H, Bald T, Smyth MJ, Martinet L";;"10 2020";1601510400;;"CD8 T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8 T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8 T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226 CD8 T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8 tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226 mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy." 6662;"Genetic in vivo engineering of human T lymphocytes in mouse models.";"E. Verhoeyen";"Team 03, Equipe 03";33846629;"Nature protocols";"Weidner T, Agarwal S, Perian S, Fusil F, Braun G, Hartmann J, Verhoeyen E, Buchholz CJ";;"07 2021";1625097600;;"Receptor targeting of vector particles is a key technology to enable cell type-specific in vivo gene delivery. For example, T cells in humanized mouse models can be modified by lentiviral vectors (LVs) targeted to human T-cell markers to enable them to express chimeric antigen receptors (CARs). Here, we provide detailed protocols for the generation of CD4- and CD8-targeted LVs (which takes ~9 d in total). We also describe how to humanize immunodeficient mice with hematopoietic stem cells (which takes 12-16 weeks) and precondition (over 5 d) and administer the vector stocks. Conversion of the targeted cell type is monitored by PCR and flow cytometry of blood samples. A few weeks after administration, ~10% of the targeted T-cell subtype can be expected to have converted to CAR T cells. By closely following the protocol, sufficient vector stock for the genetic manipulation of 10-15 humanized mice is obtained. We also discuss how the protocol can be easily adapted to use LVs targeted to other types of receptors and/or for delivery of other genes of interest." 6660;"Recent Progress in Genome Editing for Gene Therapy Applications: The French Perspective.";"E. Verhoeyen";"Team 03, Equipe 03";34494480;"Human gene therapy";"Amendola M, Bedel A, Buj-Bello A, Carrara M, Concordet JP, Frati G, Gilot D, Giovannangeli C, Gutierrez-Guerrero A, Laurent M, Miccio A, Moreau-Gaudry F, Sourd C, Valton J, Verhoeyen E";;"Oct 2021";1633046400;;"Recent advances in genome editing tools, especially novel developments in the clustered regularly interspaced short palindromic repeats associated to Cas9 nucleases (CRISPR/Cas9)-derived editing machinery, have revolutionized not only basic science but, importantly, also the gene therapy field. Their flexibility and ability to introduce precise modifications in the genome to disrupt or correct genes or insert expression cassettes in safe harbors in the genome underline their potential applications as a medicine of the future to cure many genetic diseases. In this review, we give an overview of the recent progress made by French researchers in the field of therapeutic genome editing, while putting their work in the general context of advances made in the field. We focus on recent hematopoietic stem cell gene editing strategies for blood diseases affecting the red blood cells or blood coagulation as well as lysosomal storage diseases. We report on a genome editing-based therapy for muscular dystrophy and the potency of T cell gene editing to increase anticancer activity of chimeric antigen receptor T cells to combat cancer. We will also discuss technical obstacles and side effects such as unwanted editing activity that need to be surmounted on the way toward a clinical implementation of genome editing. We propose here improvements developed today, including by French researchers to overcome the editing-related genotoxicity and improve editing precision by the use of novel recombinant nuclease-based systems such as nickases, base editors, and prime editors. Finally, a solution is proposed to resolve the cellular toxicity induced by the systems employed for gene editing machinery delivery." 6658;"Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL.";"E. Verhoeyen";"Team 03, Equipe 03";34587248;Blood;"Sasaki K, Yamauchi T, Semba Y, Nogami J, Imanaga H, Terasaki T, Nakao F, Akahane K, Inukai T, Verhoeyen E, Akashi K, Maeda T";;"Sep 2021";1630454400;;"Acute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. To identify molecules/pathways relevant for IgH-CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which enabled, for the first time, highly efficient transduction of human B cells. While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that STAT signaling is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that blocks CRKL phosphorylation, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes." 6656;"Baboon Envelope Pseudotyped ""Nanoblades"" Carrying Cas9/gRNA Complexes Allow Efficient Genome Editing in Human T, B, and CD34 Cells and Knock-in of AAV6-Encoded Donor DNA in CD34 Cells.";"E. Verhoeyen";;34713246;"Frontiers in genome editing";"Gutierrez-Guerrero A, Abrey Recalde MJ, Mangeot PE, Costa C, Bernadin O, Périan S, Fusil F, Froment G, Martinez-Turtos A, Krug A, Martin F, Benabdellah K, Ricci EP, Giovannozzi S, Gijsbers R, Ayuso E, Cosset FL, Verhoeyen E";;"Jan 2021";1609459200;;"Programmable nucleases have enabled rapid and accessible genome engineering in eukaryotic cells and living organisms. However, their delivery into human blood cells can be challenging. Here, we have utilized ""nanoblades,"" a new technology that delivers a genomic cleaving agent into cells. These are modified murine leukemia virus (MLV) or HIV-derived virus-like particle (VLP), in which the viral structural protein Gag has been fused to Cas9. These VLPs are thus loaded with Cas9 protein complexed with the guide RNAs. Highly efficient gene editing was obtained in cell lines, IPS and primary mouse and human cells. Here, we showed that nanoblades were remarkably efficient for entry into human T, B, and hematopoietic stem and progenitor cells (HSPCs) thanks to their surface co-pseudotyping with baboon retroviral and VSV-G envelope glycoproteins. A brief incubation of human T and B cells with nanoblades incorporating two gRNAs resulted in 40 and 15% edited deletion in the Wiskott-Aldrich syndrome (WAS) gene locus, respectively. CD34 cells (HSPCs) treated with the same nanoblades allowed 30-40% exon 1 drop-out in the WAS gene locus. Importantly, no toxicity was detected upon nanoblade-mediated gene editing of these blood cells. Finally, we also treated HSPCs with nanoblades in combination with a donor-encoding rAAV6 vector resulting in up to 40% of stable expression cassette knock-in into the WAS gene locus. Summarizing, this new technology is simple to implement, shows high flexibility for different targets including primary immune cells of human and murine origin, is relatively inexpensive and therefore gives important prospects for basic and clinical translation in the area of gene therapy." 6654;"Disruption of HIV-1 co-receptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing.";"E. Verhoeyen";"Team 03, Equipe 03";34737067;"Molecular therapy : the journal of the American Society of Gene Therapy";"Knipping F, Newby GA, Eide CR, McElroy AN, Nielsen SC, Smith K, Fang Y, Cornu TI, Costa C, Gutierrez-Guerrero A, Bingea SP, Feser CJ, Steinbeck B, Hippen KL, Blazar BR, McCaffrey A, Mussolino C, Verhoeyen E, Tolar J, Liu DR, Osborn MJ";;"Jan 2022";1640995200;;"Disruption of CCR5 or CXCR4, the main human immunodeficiency virus type 1 (HIV-1) co-receptors, has been shown to protect primary human CD4 T cells from HIV-1 infection. Base editing can install targeted point mutations in cellular genomes, and can thus efficiently inactivate genes by introducing stop codons or eliminating start codons without double-stranded DNA break formation. Here, we applied base editors for individual and simultaneous disruption of both co-receptors in primary human CD4 T cells. Using cytosine base editors we observed premature stop codon introduction in up to 89% of sequenced CCR5 or CXCR4 alleles. Using adenine base editors we eliminated the start codon in CCR5 in up to 95% of primary human CD4 T cell and up to 88% of CD34 hematopoietic stem and progenitor cell target alleles. Genome-wide specificity analysis revealed low numbers of off-target mutations that were introduced by base editing, located predominantly in intergenic or intronic regions. We show that our editing strategies prevent transduction with CCR5-tropic and CXCR4-tropic viral vectors in up to 79% and 88% of human CD4 T cells, respectively. The engineered T cells maintained functionality and overall our results demonstrate the effectiveness of base-editing strategies for efficient and specific ablation of HIV co-receptors in clinically relevant cell types." 6652;"Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma.";"E. Verhoeyen";"Team 03, Equipe 03";34858727;Oncoimmunology;"Stirm K, Leary P, Bertram K, Núñez NG, Wüst D, Boudesco C, Verhoeyen E, Zenz T, Becher B, Menter T, Tzankov A, Müller A";;"Jan 2021";1609459200;;"Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy arising from germinal center or post-germinal center B-cells that retain many of the properties of normal B-cells. Here we show that a subset of DLBCL express the cytokine IL-10 and its receptor. The genetic ablation of IL-10 receptor signaling abrogates the autocrine STAT3 phosphorylation triggered by tumor cell-intrinsic IL-10 expression and impairs growth of DLBCL cell lines in subcutaneous and orthotopic xenotransplantation models. Furthermore, we demonstrate using an immunocompetent Myc-driven model of DLBCL that neutralization of IL-10 signaling reduces tumor growth, which can be attributed to reduced Treg infiltration, stronger intratumoral effector T-cell responses, and restored tumor-specific MHCII expression. The effects of IL-10R neutralization were phenocopied by the genetic ablation of IL-10 signaling in the Treg compartment and could be reversed by MHCII blockade. The BTK inhibitor ibrutinib effectively blocked tumor cell-intrinsic IL-10 expression and tumor growth in this Myc-driven model. Tumors from patients with high IL-10RA expression are infiltrated by higher numbers of Tregs than IL-10RA patients. Finally, we show in 16 cases of DLBCL derived from transplant patients on immunosuppressive therapy that IL-10RA expression is less common in this cohort, and Treg infiltration is not observed." 6646;"Effects of polyamines on cyclic AMP-mediated stimulation of amino acid transport in isolated rat hepatocytes.";"P. Auberger";"Equipe 02, Team 02";6313702;"Journal of cellular physiology";"Auberger P, Samson M, Le Cam G, Le Cam A";;"Nov 1983";436492800;;"The effects of natural polyamines on cyclic AMP-mediated stimulation of amino acid transport in isolated rat hepatocytes were analyzed. Despite the fact that polyamines could directly compete with alpha-aminoisobutyric acid (AIB) for uptake, preincubation of hepatocytes with polyamines did not significantly alter basal AIB transport. The stimulatory effect of glucagon or cyclic AMP analogs was differently affected by polyamines, since it was reduced in the presence of spermine and, inversely, potentiated by spermidine, putrescine, and cadaverine. Dose-dependence analysis showed that half maximal and maximal effects occurred with 2-3 and 6-10 mM external concentrations, respectively. None of the polyamine effects could be ascribed to transstimulation or transinhibition of amino acid uptake. The inhibitory effect exerted by spermine correlated its capacity to inhibit [3H]-leucine incorporation into proteins partially. The potentiating effect of the other polyamines did not result from stabilization of newly synthesized carrier proteins. Instead, the increase in Vmax of the high affinity transport component suggested that more carriers became available, presumably because polyamines facilitated their synthesis by interacting directly with one or several steps controlled by cyclic AMP. Polyamines appear to represent a new class of factors capable of modulating the cyclic AMP-mediated stimulation of amino acid transport, in hepatocytes." 6647;"Insulin regulation of protein phosphorylation in hepatocytes. Studies using two effectors: amiloride and natural aliphatic polyamines.";"P. Auberger";"Equipe 02, Team 02";3907716;Biochimie;"Le Cam A, Auberger P, Samson M, Le Cam G";;"Oct 1985";496972800;;"The effects of amiloride and of natural aliphatic polyamines on basal and hormone-stimulated protein phosphorylations in hepatocytes were studied. Cells isolated from adult rats were incubated in suspension with (32P)-orthophosphate, in the absence or presence of the effectors at varying concentrations and for different times; hepatocytes were then exposed to various hormones for 10 min. Phosphoproteins contained in total cell lysates were analyzed by one- and two-dimensional gel electrophoresis and autoradiography. Amiloride and spermine (the most effective amine) decreased the basal level of phosphorylation of proteins of 46, 34 and 22 kDal, and increased that of 18 kDal and 93 kDal proteins. These effects were maximal with external concentrations of 1 mM and 7.5-10 mM amiloride and spermine, respectively. They were detectable after a lag period of about 10 min and reached a plateau after 45 min. Pretreatment of cells with these effectors almost completely prevented stimulation of the phosphorylation of the 46 and 34 kDal proteins by insulin. In contrast, the effects of vasopressin on the same proteins were only partly inhibited, whereas those of glucagon appeared largely unaffected. The major effect observed in intact cells (i.e., decreased phosphorylation) could be reproduced in a cell-free system where no kinase activity persisted. Amiloride or spermine added directly to cell extracts strongly accelerated the dephosphorylation of 46 kDal protein and also of the 61 kDal protein identified as pyruvate kinase. Furthermore, restoration of the activity of this enzyme occurred concomitantly with dephosphorylation of the 61 kDal protein, an observation supporting the notion that amiloride and spermine could activate a phosphoprotein phosphatase." 6644;"Regulation of protein phosphorylation by polyamines in hepatocytes.";"P. Auberger";"Equipe 02, Team 02";6487653;"Biochimica et biophysica acta";"Auberger P, Samson M, Le Cam G, Le Cam A";;"Oct 1984";465436800;;"The effects of natural aliphatic polyamines on basal and hormone-stimulated protein phosphorylations in hepatocytes were studied. Cells isolated from adult rats were incubated in suspension with [32P]orthophosphate, in the absence or presence of polyamines at varying concentrations and for different times; hepatocytes were then exposed to various hormones for 10 min. Phosphoproteins contained in total cell lysates were analyzed by one- and two-dimensional gel electrophoresis and autoradiography. Spermine, the most effective amine, decreased the basal level of phosphorylation of proteins with 46, 34 and 22 kDa, and increased that of a 18 kDa protein. These effects, maximal with an external concentration of 7.5-10 mM, were detectable after a lag period of about 10 min and reached a plateau after 45 min. Pretreatment of cells with the polyamine almost completely prevented stimulation of the phosphorylation of the 46 and 34 kDa proteins by insulin; in contrast, the effects of phenylephrine on the same proteins were only partly inhibited, whereas those of glucagon appeared largely unaffected. The major polyamine effect observed in intact cells (i.e., decreased phosphorylation) could be reproduced in a cell-free system where no kinase activity persisted. Indeed, spermine added directly to cell extracts strongly accelerated dephosphorylation of the 46 kDa protein and also of the 61 kDa protein identified as pyruvate kinase; furthermore, restoration of the activity of this enzyme occurred concomitantly with dephosphorylation of the 61 kDa protein in the presence of spermine." 6642;"Pretranslational regulation of tyrosine aminotransferase and phosphoenolpyruvate carboxykinase (GTP) synthesis by glucagon and dexamethasone in adult rat hepatocytes.";"P. Auberger";"Equipe 02, Team 02";2858199;"The Biochemical journal";"Iynedjian PB, Auberger P, Guigoz Y, Le Cam A";;"Jan 1985";473385600;;"The regulation of synthesis of the gluconeogenic cytosolic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and of tyrosine aminotransferase (TAT) by glucagon and glucocorticoid hormones was studied in hepatocytes maintained in suspension culture for 7 h. Specific antibodies were used to measure relative rates of enzyme synthesis after pulse-labelling of the cells with [3H]leucine or [35S]methionine. Concomitantly, amounts of mRNA were quantified after translation in vitro in a reticulocyte lysate and specific immunoprecipitation of the proteins. Glucagon stimulated the rate of synthesis of PEPCK by 4-6-fold and that of TAT by 6-8-fold in 2h. In contrast, dexamethasone had little effect on PEPCK synthesis, whereas it increased TAT synthesis by 5-9-fold. When used in combination, the two hormones displayed additive effects on TAT synthesis, whereas the glucocorticoid hormone strongly potentiated stimulation of PEPCK synthesis by glucagon. In every instance, changes in rates of synthesis of the two enzymes were totally accounted for by increases in amounts of the corresponding functional mRNA, suggesting a pretranslational site of action for both glucagon and dexamethasone." 6640;"Secretion of a major phosphorylated glycoprotein by hepatocytes. Characterization of specific antibodies and investigations of the processing, excretion kinetics, and phosphorylation.";"P. Auberger";"Equipe 02, Team 02";4066700;"The Journal of biological chemistry";"Le Cam A, Magnaldo I, Le Cam G, Auberger P";;"Dec 1985";502243200;;"Isolated rat hepatocytes secreted a major phosphorylated glycoprotein (PP63) with apparent Mr = 63,000 and isoelectric point ranging from 4.8 to 5.3. Specific antibodies were raised in a rabbit using material obtained from plasma as an antigen. The biosynthesis of PP63 was studied in vitro in a cell-free system and in intact hepatocytes incubated with or without tunicamycin. The mRNA translation product had a Mr = 43,000 and was of the same size as the major unglycosylated precursor found in intact cells. This precursor was rapidly processed into two major intracellular forms of Mr = 53,000 and 56,000. These species were insensitive to neuraminidase but susceptible to endoglycosidase H, indicating that they contained oligosaccharide side chains of the high mannose-type. Terminal glycosylation gave rise to the mature Mr = 63,000 protein that contained sialic acid and fucose. This species represented the exportable form of the protein and was the only one to be phosphorylated. The charge heterogeneity observed for the mature protein already existed in all the precursors, indicating that it could not be ascribed to sialylation or to phosphorylation. However, these covalent modifications were mainly responsible for the acidic character of PP63. PP63 secretion was altered by tunicamycin. Pulse-chase experiments showed that the phosphorylated glycoprotein was secreted according to kinetics similar to that described for other liver glycoprotein, with slower kinetics than albumin. Permanent phosphorylation did not appear mandatory for excretion since the dephosphorylated PP63 was excreted with an efficacy comparable to that of the phosphorylated protein. Phosphorylation of PP63 was shown to occur on a single tryptic peptide, at a serine residue." 6638;"Study of a growth hormone-regulated protein secreted by rat hepatocytes: cDNA cloning, anti-protease activity and regulation of its synthesis by various hormones.";"P. Auberger";"Equipe 02, Team 02";2440672;"The EMBO journal";"Le Cam A, Pages G, Auberger P, Le Cam G, Leopold P, Benarous R, Glaichenhaus N";;"May 1987";546825600;;"GHR-P63 ('growth hormone-regulated protein of 63,000 daltons') is an acidic glycoprotein secreted by rat hepatocytes whose synthesis is abolished upon hypophysectomy. The sequence of its mRNA including the entire coding and 3' untranslated regions was determined from a nearly full-length lambda gt11-cDNA clone. The sequence contained two ATGs in frame giving rise to two overlapping coding regions which could encode precursor polypeptides of 416 and 406 amino acid residues (MrS = 46549 and 45371). These potential translation initiation codons appeared to be functional both in vitro and in intact cells since two precursors of the correct size were immunoprecipitated as products of mRNA translation. The unglycosylated precursors were converted into intermediate intracellular forms of about 56,000 daltons containing N-linked oligosaccharide side chains and thereafter into the secretory form of approximately equal to 63,000 daltons. Strong sequence homologies, both at the nucleotide and the amino acid levels were found between GHR-P63 and several serum protease inhibitors, more particularly mouse contrapsin and human alpha 1-antichymotrypsin. In agreement with sequence data, GHR-P63 purified from rat blood by affinity chromatography was found to carry an anti-trypsin activity. GHR-P63 mRNA, virtually undetectable in hepatocytes from hypophysectomized rats, could be hormonally re-induced to subnormal levels both in vivo by treating animals with hormones and in vitro by incubating the defective cells with hormones. Growth hormone was absolutely required but had a weak effect when used alone. Glucocorticoids which had no effect per se, strongly potentiated the action of growth hormone. Nuclear run-off experiments suggest that hormones regulated GHR-P63 mRNA levels by acting mostly, if not exclusively, on gene transcription." 6636;"A chymotryptic-type protease inhibitor decreases interleukin 2 synthesis and induces prostaglandin production in Jurkat T cells.";"P. Auberger";"Equipe 02, Team 02";2641884;"Cellular signalling";"Auberger P, Didier M, Didier J, Aussel C, Fehlmann M";;"Jan 1989";599616000;;"TPCK (N-alpha-p-tosyl-L-phenylalanine chloromethylketone), a potent inhibitor of chymotryptic-type serine proteases, was found to decrease IL2 synthesis in Jurkat T cells. Conversely, the tryptic-type protease inhibitor, TLCK (N-alpha-p-tosyl-lysine chloromethylketone), which structurally is very similar to TPCK, had no effect on IL2 synthesis. Prostaglandin synthesis, a process that is known to reduce IL2 production in T cells, was increased by TPCK but not by TLCK, suggesting that this process could be, at least in part, responsible for the inhibition of IL2 production. Our results imply that a chymotryptic-type serine protease plays an active role in the regulation of IL2 synthesis and thus in the whole process of T-lymphocyte activation." 6634;"Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity.";"P. Auberger";"Equipe 02, Team 02";2766355;Cell;"Auberger P, Falquerho L, Contreres JO, Pages G, Le Cam G, Rossi B, Le Cam A";;"Aug 1989";617932800;;"Amino acid sequence of the precursor of the phosphorylated N-glycoprotein (pp63) secreted by rat hepatocytes was deduced from the cDNA sequence. This polypeptide (Mr = 40,586) was rich in both cysteine and proline and contained three potential N-glycosylation sites. A single pp63 mRNA species (approximately 2000 bp), found in normal hepatocytes but not in FaO hepatoma cells, appeared to result from transcription of a single gene. pp63 purified by affinity chromatography inhibited insulin receptor tyrosine kinase and receptor autophosphorylation. Only the phosphorylated form of the protein was active. In additon, pp63 antagonized the growth-promoting action of insulin in FaO cells but did not affect hormone-mediated increase in amino acid transport capacity or tyrosine aminotransferase induction in these cells." 6632;"Inhibitors of chymotrypsin-like activities selectively block the mitotic pathway in rat hepatoma cells.";"P. Auberger";"Equipe 02, Team 02";1982214;"Growth factors (Chur, Switzerland)";"Ponzio G, Contreres JO, Debant A, Auberger P, Farahifar D, Rossi B";;"Jan 1990";631152000;;"We provide evidence that both covalent and non-covalent inhibitors of chymotrypsin-like activities inhibit the insulin-induced DNA replication, while the hormonal metabolic effects such as induction of tyrosine aminotransferase activity or increase of amino-acid transport remain unchanged. Besides, the protease inhibitors that we tested were without any effect on both the autocatalytic phosphorylation of insulin receptors and the tyrosine kinase activity towards poly(glutamate/tyrosine). The inhibitory effect of protease inhibitors on DNA synthesis was also visible when fibroblast growth factor (FGF) was used to commit cells in the proliferative cycle. This observation proves that the involvement of a putative protease is not restricted to the insulin mitogenic pathway. Finally, we observed that Fao cells totally escaped the inhibitory action of a covalent inhibitor of chymotrypsin after having been exposed to insulin for 10 h. We propose that a chymotrypsin-like activity is involved in the intracellular signalling leading to the proliferation of rat hepatoma cells up to a non-return point situated in the middle of G1 (6-8 h)." 6630;"Characterization and purification of a guanidinobenzoatase: a possible marker of human renal carcinoma.";"P. Auberger";"Equipe 02, Team 02";1617634;"Cancer research";"Poustis-Delpont C, Descomps R, Auberger P, Delque-Bayer P, Sudaka P, Rossi B";;"Jul 1992";709948800;;"Guanidinobenzoatases are cell surface-associated proteinases supposed to be involved in cancer metastasis, cell migration, and tissue remodeling. The main features of the guanidinobenzoatase associated with human renal carcinoma plasma membrane are weak membrane association, continuous cleavage of p-nitrophenyl-p'-guanidinobenzoate conversely to the site titration effect of this compound when used with trypsin, and a peculiar sensitivity to serine protease inhibitors, compatible with a poorly active form. Plasma membrane preparation followed by agmatine-trisacryl affinity chromatography allows the purification of guanidinobenzoatase to homogeneity with an apparent enrichment factor of 450. Purified guanidinobenzoatase appears as a single polypeptide chain of M(r) 80,000, likely stabilized by intrachain disulfides bonds. The properties of purified guanidinobenzoatase indicate that it is an original enzyme in spite of some similarities with plasminogen activators. Indeed, in addition to differences in substrate and inhibitor specificity, guanidinobenzoatase is not recognized by specific monoclonal antibodies directed against plasminogen activators or their single-chain precursors. Thus, human renal carcinoma guanidinobenzoatase appears to be an original enzyme whose activity is undetectable in the nontumoral tissue of origin. In this respect, use of purified guanidinobenzoatase would allow us to obtain specific tools to give new insights in cancer cell metastasis." 6628;"Characterization and purification of T lymphocyte aminopeptidase B: a putative marker of T cell activation.";"P. Auberger";"Equipe 02, Team 02";8344358;"European journal of immunology";"Belhacene N, Mari B, Rossi B, Auberger P";;"Aug 1993";744163200;;"We have previously described that human T lymphocytes express membrane-associated peptidase activities (Mari et al., EMBO J., 1992, 11:3875). We show in this report that intact Jurkat T cells readily cleaved H-Arg-paranitroanilide, an aminopeptidase B (AP-B) substrate. The identification of the hydrolyzing activity as AP-B was confirmed by its sensitivity to both arphamenine B and bestatin in the nanomolar range. Significant AP-B activity was released in the supernatant upon incubation of intact T lymphocytes at 37 degrees C. However, AP-B activity was found mainly in the cytosolic fraction of Jurkat T cells. Cytosolic T cell AP-B was purified to homogeneity and exhibited a molecular mass of 72 kDa. Purified AP-B cleaved N-terminal basic amino acid-containing peptides such as thymopentin (H-Arg-Lys-Asp-Val-Tyr-OH), indicating that it might play a role in the regulation of the concentration of important soluble mediators of T cell activation. A rabbit polyclonal antibody was shown to recognize AP-B as assessed by both immunoprecipitation and Western blot experiments. Finally, we found that AP-B was up-regulated during activation of normal and leukemic T lymphocytes." 6625;"Monomeric 55-kDa guanidinobenzoatase switches to a serine proteinase activity upon tetramerization. Tetrameric proteinase SP 220 K appears as the native form.";"P. Auberger";"Equipe 02, Team 02";8182074;"The Journal of biological chemistry";"Poustis-Delpont C, Thaon S, Auberger P, Gerardi-Laffin C, Sudaka P, Rossi B";;"May 1994";767750400;;"Guanidinobenzoatases are cell surface enzymes present in cells capable of migration or remodeling. The guanidinobenzoatase purified to homogeneity from human renal carcinoma did not display gelatinase activity under the 55-kDa form (Poustis-Delpont, C., Descomps, R., Auberger, P., Delque-Bayer, P., Sudaka, P., and Rossi, B. (1992) Cancer Res. 52, 3622-3628). We bring new insights into the structure-activity relationships of this enzyme using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, [3H]diisopropyl fluorophosphate labeling, gelatin zymography, and immunodetection using a polyclonal antibody raised against the 55-kDa entity. Upon aggregation into a 220-kDa form, the enzyme exhibited [3H]diisopropyl fluorophosphate labeling and diisopropyl fluorophosphate-inhibitable gelatinase activity whereas its capability to cleave p-nitrophenyl p'-guanidinobenzoate as a substrate was abolished. Thus, the guanidinobenzoatase property appears as a feature of a 55-kDa inactive form of a serine proteinase subunit. After boiling in the presence of sodium dodecyl sulfate (3% w/v), the 220-kDa entity subjected to SDS-polyacrylamide gel electrophoresis could be dissociated into a 55-kDa protein as shown by silver staining. The resulting 55-kDa band remained [3H]diisopropyl fluorophosphate-labeled and reacted with anti-55-kDa guanidinobenzoatase antibodies, strongly suggesting that the 220-kDa proteinase was a noncovalently associated tetramer. Interestingly, Triton X-100 extracts of renal carcinoma plasma membranes exhibited a 220-kDa serine proteinase activity, as expressed in gelatin zymography, which was barely detectable in the non-tumoral counterpart. It is noteworthy that an anti-55-kDa guanidinobenzoatase reactive 220-kDa species was also observed in renal carcinoma plasma membranes extracts as assessed by Western blot, whereas it was hardly visible in the non-tumoral counterpart. No signal was immunodetected at M(r) 55,000 in renal carcinoma and kidney cortex membranes in Western blot experiments. Taken together, our data support the idea that the enzyme is expressed under its tetrameric form in the membrane. The purified enzyme is able to exhibit a serine proteinase activity when it recovers its native tetrameric form. This high molecular weight tetrameric proteinase SP 220 K appears as a new member of the cell surface serine protease family." 6624;"Insulin and interleukin-1 differentially regulate pp63, an acute phase phosphoprotein in hepatoma cell line.";"P. Auberger";"Equipe 02, Team 02";7515065;"The Journal of biological chemistry";"Akhoundi C, Amiot M, Auberger P, Le Cam A, Rossi B";;"Jun 1994";770428800;;"We have reported previously that the phosphoprotein pp63, an acute phase protein, which has been recently identified as the rat fetuin, was capable of blocking the mitogenic effect of insulin on the rat Fao hepatoma cell line, without affecting metabolic effects of the hormone. Only the phosphorylated form of the protein has been shown to exhibit both anti-tyrosine kinase and growth inhibitory properties. In this study, we used the FTO-2B rat hepatoma cell line to analyze the mechanisms involved in the control of synthesis and/or phosphorylation of pp63. For this purpose, we investigated the action of effectors known to modulate hepatic functions, such as cytokines (interleukin (IL)-1 beta and IL-6), which regulate the production of acute phase proteins, and insulin, which elicits profound effects on hepatocyte metabolism. Here, we demonstrate that IL-1 beta diminished markedly the pp63 production by affecting its mRNA transcription and that the cytokine was able to modify the N-glycosylation process of the protein. In contrast, insulin did not affect the biosynthesis of pp63 but dramatically decreased its extent of phosphorylation." 6620;"Effects of growth factors on hormonal stimulation of amino acid transport in primary cultures of rat hepatocytes.";"P. Auberger";"Equipe 02, Team 02";6134522;"The Biochemical journal";"Auberger P, Samson M, Le Cam A";;"Feb 1983";412905600;;"In primary cultures of rat hepatocytes, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and foetal-calf serum (FCS) prevented the stimulation of amino acid transport by glucagon (cyclic AMP-dependent) and by catecholamines (cyclic AMP-independent), but not by insulin. The insulin effect, as well as the effect of other hormones, were totally inhibited by thrombin through a mechanism independent of its proteolytic activity. The inhibitory effect of growth factors, not found in freshly isolated hepatocytes, was expressed very early in culture (4h). Induction of tyrosine aminotransferase by glucagon or dexamethasone, which, like stimulation of transport, represents a late hormonal effect, was not affected by EGF, PDGF or FCS, but was inhibited by thrombin. In contrast, none of the rapid changes in protein phosphorylation caused by hormones was altered by growth factors. Thus the inhibition by growth factors of hormonal stimulation of transport presumably involves late step(s) in the cascade of events implicated in this hormonal effect." 6621;"Inhibition of hormonal induction of tyrosine aminotransferase by polyamines in freshly isolated rat hepatocytes.";"P. Auberger";"Equipe 02, Team 02";6138028;"The Biochemical journal";"Auberger P, Samson M, Le Cam A";;"Sep 1983";431222400;;"We have analysed the effects of natural aliphatic polyamines on hormonal induction of tyrosine aminotransferase (TAT) in suspensions of hepatocytes isolated from adult fed rats. Glucagon or cyclic AMP derivatives (dibutyryl and 8-bromo) used alone caused a 4-5 fold increase in enzyme activity within 4h. This effect was independent of glucocorticoids, which also increased TAT activity (2.5-fold); when combined, the effects of the two inducers were additive. Spermine and putrescine totally inhibited the hormonally-mediated increase in enzyme activity when added at the onset of incubation with the inducers. Furthermore, polyamines could block the hormonal effect at any time during the course of TAT induction, with, however, a 30 min lag period, suggesting that they must enter the cells. Hepatocytes were indeed shown to take up spermine. At low external concentrations (less than 50 microM), an Na+-dependent, saturable and concentrative mechanism was predominant; at high concentrations (greater than 0.5 mM) transport occurred mainly through a non-saturable, Na+-independent mechanism, building up intracellular concentrations slightly lower than those in the medium. Dose-dependence analysis of the polyamine effect on enzyme induction indicated that half-maximal and maximal inhibition occurred with 0.75 mM- and 2.5 mM-spermine respectively, whereas 2.5mM- and 7.5 mM-putrescine were required respectively to obtain similar effects. Spermidine was much less effective and cadaverine had virtually no effect. None of the polyamines affected the rate of decay of TAT, nor did they directly or indirectly cause enzyme inactivation, indicating that a post-translational modification was unlikely to account for the polyamine effects. Similarly, these effects could not be ascribed to a non-specific inhibition of overall protein synthesis. We conclude that, in hepatocytes, polyamines (or their metabolites) directly interfere with one or several steps controlled by hormones in the synthesis of tyrosine aminotransferase." 6618;"Comparative analysis of proteins labelled with [35S]methionine in the liver in vivo and in freshly isolated and short-term-cultured hepatocytes in vitro.";"P. Auberger";"Equipe 02, Team 02";6753943;"Biochimica et biophysica acta";"Auberger P, Le Cam A";;"Sep 1982";399686400;;"[35S]Methionine-labelled liver proteins, analysed by one- or two-dimensional gel electrophoresis showed a strikingly similar pattern whether synthesized in vivo or by freshly isolated hepatocytes. In contrast, major qualitative and quantitative differences were observed with the patterns of labelled proteins found in cultured hepatocytes. The changes detectable very early (within 1 h) in culture affected preferentially the synthesis of cytoskeleton proteins (cytokeratins, actin, myosin), which was dramatically increased. Physical factors like cell attachment appear to be responsible for these changes which, however, occurred more rapidly in the presence of serum. Freshly isolated hepatocytes and short-term-cultured cells responded similarly to insulin and glucagon, which respectively increased and decreased the labelling of the whole set of cellular and exported proteins. Glucocorticoids caused either an increase or a decrease in the labelling of several proteins, but the effects were detectable only under chronic exposure of cultured hepatocytes. Based on these results, freshly isolated hepatocytes appear more representative of the liver in vivo than cultured hepatocytes, and therefore seem more suitable for short-term studies. However, cultured hepatocytes can be used for long-term studies since they maintain many specific liver functions and remain hormonally sensitive." 6616;"Insulin enhances protein phosphorylation in isolated hepatocytes by inhibiting an amiloride sensitive phosphatase.";"P. Auberger";"Equipe 02, Team 02";6288029;"Biochemical and biophysical research communications";"Le Cam A, Auberger P, Samson M";;"Jun 1982";391737600;; 6613;"Rat liver injury after normothermic ischemia is prevented by a phosphinic matrix metalloproteinase inhibitor.";"P. Auberger, P. ROSTAGNO";"Equipe 02, Team 02";11709491;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Cursio R, Mari B, Louis K, Rostagno P, Saint-Paul MC, Giudicelli J, Bottero V, Anglard P, Yiotakis A, Dive V, Gugenheim J, Auberger P";;"Jan 2002";1009843200;;"Hepatic ischemia occurs in liver transplantation, hemodynamic or cardiogenic shock, and liver resection associated with trauma or tumor. Ischemia/reperfusion (I/R) injury results in microcirculation failure followed by apoptosis and necrosis. Matrix metalloproteinases (MMPs) are involved in many physiological and pathological processes, but their expression and function during liver I/R remains poorly documented. In this study, we evaluated the expression of nine MMPs and their natural inhibitors, tissue inhibitors of MMPs (TIMPs), in a rat model of liver I/R. Analysis of MMP and TIMP expression show that although most of these genes are not constitutively expressed in the normal liver, they are induced in a specific time-dependent manner following I/R. Stromelysin-1, gelatinase B, and collagenase-3 are induced during the early phase of acute liver injury associated with inflammation and increased necrosis/apoptosis, whereas gelatinase A, membrane type-MMP, stromelysin-3, metalloelastase, TIMP-1, and TIMP-2 are essentially detectable during the recovery phase of liver injury corresponding to hepatocyte regeneration. This observation suggested that MMPs and TIMPs could play both deleterious and beneficial roles following I/R. We thus tested the effect of a specific phosphinic MMP inhibitor on acute liver I/R injury. Inhibition of MMP activity was shown to significantly decrease liver injury in ischemic/reperfused liver tissue as assessed by histological studies and serum hepatic enzyme levels. We therefore propose that MMP inhibitors may be of clinical relevance in liver-associated ischemic diseases or after liver transplantation." 6611;"RelB reduces thymocyte apoptosis and regulates terminal thymocyte maturation.";"P. Auberger";"Equipe 02, Team 02";11753998;"European journal of immunology";"Guerin S, Baron ML, Valero R, Herrant M, Auberger P, Naquet P";;"01 2002";1009843200;;"Thymocyte maturation is controlled by successive developmental checkpoints connected to the acquisition of a functional T cell receptor (TCR). During thymocyte selection, engagement of the TCR regulates the fine balance between death and survival signals. At the final stages of single-positive (SP) thymocyte maturation, the coupling of the TCR changes from death- to proliferation-inducing signals, a competence required for optimal effector functions in the periphery. We show here that in RelB mutant thymuses, thymocyte differentiation of CD24(-) SP cells is partially impaired. Competitive bone marrow reconstitution experiments show that this defect is constitutive to the lymphoid compartment. This is accompanied by an increased proportion of apoptotic thymocytes and a drastically reduced proliferation upon activation with anti-CD3 antibody/PMA stimulation. Thus, the RelB protein contributes to the quality of cell signaling in thymocytes by providing anti-apoptotic signals. These results suggest that in addition to its major role on the activation of antigen-presenting cell function, the RelB protein is intrinsically required for terminal thymocyte differentiation and activation." 6609;"The protective effect of phorbol esters on Fas-mediated apoptosis in T cells. Transcriptional and postranscriptional regulation.";"P. Auberger";"Equipe 02, Team 02";12118374;Oncogene;"Herrant M, Luciano F, Loubat A, Auberger P";;"Jul 2002";1025481600;;"Phorbol esters are tumor promoters that bind and activate both conventional and new Protein kinase C (PKC) isoforms. In various circumstances, PKC-dependent signaling pathways can promote cell survival and protect against cell death. This was first analysed in Jurkat T cells where Phorbol Myristate Acetate (PMA) was found to inhibit Fas-mediated apoptosis as judged by DiOC6(3) staining, caspase activation and DNA fragmentation, indicating that PMA exerts its protective effect upstream or at the mitochondrial level in these cells. PMA activated most of the main kinase pathways in T cells such as PKCs, p42/44MAPK, p38MAPK and p90Rsk but not JNK and Akt. A pharmacological approach allowed us to identify that nPKCs are both necessary and likely sufficient to promote T cell survival. Besides this post-transcriptional regulation, nPKCs may also regulate apoptosis at the transcriptional level. cDNA arrays were used to identify a set of genes whose expression was modulated in death versus survival conditions. Following PMA treatment, expression of Mcl-1 and Bcl-x increased while that of c-Myc was significantly reduced. Moreover, survivin expression decreased upon CH11 or PMA treatment. c-Myc, survivin and Bcl-x modulation seems to be regulated at the transcriptional level while decrease in Mcl-1 protein in CH11-treated cells resulted especially from a caspase-dependent proteolysis. Taken together, our data demonstrate that PMA-mediated inhibition of apoptosis is a complex process that is integrated at both the transcriptional and post-transcriptional level and point out to the potential role of Mcl-1, Bcl-x, c-Myc and survivin in this process." 6607;"Vav1 couples T cell receptor to serum response factor-dependent transcription via a MEK-dependent pathway.";"M. Deckert, P. Auberger, S. Tartare-Deckert";"Equipe 11, Team 11, Equipe 02, Team 02";11859076;"The Journal of biological chemistry";"Charvet C, Auberger P, Tartare-Deckert S, Bernard A, Deckert M";;"May 2002";1020211200;;"The Vav family of guanine nucleotide exchange factors for Rho family GTPases plays a critical role in lymphocyte proliferation, gene transcription, and cytoskeleton reorganization following immunoreceptor stimulation. However, its role in immediate early gene activation is unclear. In this study, we have investigated the mechanisms by which Vav1 can regulate c-fos serum response element transcriptional activity. We show that T cell antigen receptor (TCR) stimulation induces the phosphorylation of serum response factor (SRF) on serine 103 and increases the binding of SRF complexes on serum response element in a MEK- and p38-dependent pathway. The physiological relevance of our findings is supported by the inhibition of the interleukin-2 gene transcriptional activity by a dominant negative SRF mutant. Overexpression of Vav1, which partially mimics TCR stimulation, promotes SRF-dependent transcription, and dominant negative Vav1 mutants block SRF activation by TCR. SRF activation by Vav1 occurs through a signaling cascade consisting of Rac1/Cdc42 and the serine/threonine kinases Pak1 and MEK, but independently of the phosphatidylinositol 3-kinase pathway. Interestingly, Vav2 also enhances SRF through Rho GTPases, suggesting that Vav proteins are general regulators of SRF activation in lymphocytes. This report establishes Vav proteins as a direct link between antigen receptors and SRF-dependent early gene expression." 6605;"Rho GTPase is activated by cytotoxic necrotizing factor 1 in peripheral blood T lymphocytes: potential cytotoxicity for intestinal epithelial cells.";"P. Auberger";"Equipe 02, Team 02";12595428;"Infection and immunity";"Brest P, Mograbi B, Hofman V, Loubat A, Rossi B, Auberger P, Hofman P";;"Mar 2003";1046476800;;"Some strains of Escherichia coli related to acute cystitis or colitis produce a toxin named cytotoxic necrotizing factor 1 (CNF-1). CNF-1 mediates its effects on epithelial cells or phagocytes via the permanent activation of small GTP-binding proteins, caused by the toxin-induced deamidation of Glu(63) of p21 Rho. The behavior of peripheral blood T lymphocytes during the acute phase of bacterial colitis has been poorly investigated. Our study was conducted to test whether (i) peripheral blood T lymphocytes can be activated by CNF-1 and (ii) CNF-1-activated T lymphocytes are cytotoxic against intestinal epithelial cells. Activation of T lymphocytes by CNF-1 was assessed by electrophoresis, flow cytometry, confocal microscopy, and electron microscopy studies. Assays for migration and adherence of CNF-1-treated T lymphocytes were performed in Transwell chambers with T84 intestinal epithelial cells grown on polycarbonate semipermeable filters. CNF-1 induced a decrease in the electrophoretic mobility of the GTP-binding protein Rho in treated T lymphocytes. CNF-1 provoked an increase in the content of actin stress fibers and pseudopodia in T lymphocytes. Several adherence molecules were clustered into cytoplasmic projections in CNF-1-treated T lymphocytes and adherence of such lymphocytes on the basolateral pole of T84 was increased, resulting in cytotoxicity toward epithelial cells. Such enhanced adherence in response to CNF-1 was dependent on p42-44(MAP) kinase activation of T lymphocytes. Taken together, these results suggest that CNF-1, by acting on T lymphocytes, may increase in an important fashion the virulence of certain strains of E. coli against the intestinal epithelia." 6603;"Active stromelysin-3 (MMP-11) increases MCF-7 survival in three-dimensional Matrigel culture via activation of p42/p44 MAP-kinase.";"P. Auberger";"Equipe 02, Team 02";12845673;"International journal of cancer";"Fromigué O, Louis K, Wu E, Belhacène N, Loubat A, Shipp M, Auberger P, Mari B";;"Sep 2003";1062374400;;"Stromelysin-3 (ST3) has the characteristic structure of matrix metalloproteinases (MMP), but its substrate specificity and pattern of expression differ markedly from that of other MMP family members. ST3 was originally isolated on the basis of its expression in primary breast cancers and has been shown to be overexpressed in virtually all primary carcinomas, suggesting that ST3 participates in the initial development of epithelial malignancies. Recent data using murine models reported that ST3 expression was able to increase tumor take by suppressing cell apoptosis. Our present goal was to set up an in vitro model in which we could study this new function. For this purpose, we analyzed survival of MCF-7 transfectants expressing either wild-type or catalytically inactive ST3 (ST3wt or ST3cat-) in three-dimensional (3-D) culture conditions by inclusion in Matrigel. In such conditions, that mimic the in vivo microenvironment, we found a marked decrease in the percentage of cell death when active ST3 was expressed (ST3wt transfectants vs. ST3cat- or vector only transfectants) as assessed by FACS and TUNEL analysis. The addition of batimastat, a broad spectrum MMP inhibitor, reversed the increased cell survival in ST3wt transfectants, confirming that ST3 enzymatic activity was required for this effect. Finally, we analyzed the expression of anti- and pro-apoptotic proteins as well as activation of cell survival pathways and we found that ST3-mediated cell survival was accompanied by activation of both p42/p44 MAPK and AKT. Our data confirm and extend the anti-apoptotic function of ST3 and provide a useful model to dissect this new role and identify new physiological substrates." 6601;"Altered T cell surface glycosylation in HIV-1 infection results in increased susceptibility to galectin-1-induced cell death.";"P. Auberger";"Equipe 02, Team 02";12925577;Glycobiology;"Lantéri M, Giordanengo V, Hiraoka N, Fuzibet JG, Auberger P, Fukuda M, Baum LG, Lefebvre JC";;"Dec 2003";1070236800;;"The massive T cell death that occurs in HIV type 1 (HIV-1) infection contributes profoundly to the pathophysiology associated with AIDS. The mechanisms controlling cell death of both infected and uninfected T cells (""bystander"" death) are not completely understood. We have shown that HIV-1 infection of T cells results in altered glycosylation of cell surface glycoproteins; specifically, it decreased sialylation and increased expression of core 2 O-glycans. Galectin-1 is an endogenous human lectin that recognizes these types of glycosylation changes and induces cell death of activated lymphocytes. Therefore we studied the possible contribution of galectin-1 in the pathophysiology of AIDS. O-glycan modifications were investigated on peripheral lymphocytes from AIDS patients. Oligosaccharides from CD43 and CD45 of CEM cells latently infected with HIV-1 were chemically analyzed. Consistent with our previous results, we show that HIV-1 infection results in accumulation of exposed lactosamine residues, oligosaccharides recognized by galectin-1 on cell surface glycoproteins. Both latently HIV-1-infected T cell lines and peripheral CD4 and CD8 T cells from AIDS patients exhibited exposed lactosamine residues and demonstrated marked susceptibility to galectin-1-induced cell death, in contrast to control cultures or cells from uninfected donors. The fraction of cells that died in response to galectin-1 exceeded the fraction of infected cells, indicating that death of uninfected cells occurred. Altered cell surface glycosylation of T cells during HIV-1 infection increases the susceptibility to galectin-1-induced cell death, and this death pathway can contribute to loss of both infected and uninfected T cells in AIDS." 6599;"Increased rate of apoptosis and diminished phagocytic ability of human neutrophils infected with Afa/Dr diffusely adhering Escherichia coli strains.";"P. Auberger";"Equipe 02, Team 02";15385473;"Infection and immunity";"Brest P, Bétis F, Cuburu N, Selva E, Herrant M, Servin A, Auberger P, Hofman P";;"Oct 2004";1096588800;;"The proinflammatory effect of Afa/Dr diffusely adhering Escherichia coli (Afa/Dr DAEC) strains have been recently demonstrated in vitro by showing that polymorphonuclear leukocyte (PMN) transepithelial migration is induced after bacterial colonization of apical intestinal monolayers. The effect of Afa/Dr DAEC-PMN interaction on PMN behavior has been not investigated. Because of the putative virulence mechanism of PMN apoptosis during infectious diseases and taking into account the high level of expression of the decay-accelerating factor (DAF, or CD55), the receptor of Afa/Dr DAEC on PMNs, we sought to determine whether infection of PMNs by Afa/Dr DAEC strains could promote cell apoptosis. We looked at the behavior of PMNs incubated with Afa/Dr DAEC strains once they had transmigrated across polarized monolayers of intestinal (T84) cells. Infection of PMNs by Afa/Dr DAEC strains induced PMN apoptosis characterized by morphological nuclear changes, DNA fragmentation, caspase activation, and a high level of annexin V expression. However, transmigrated and nontransmigrated PMNs incubated with Afa/Dr DAEC strains showed similar elevated global caspase activities. PMN apoptosis depended on their agglutination, induced by Afa/Dr DAEC, and was still observed after preincubation of PMNs with anti-CD55 and/or anti-CD66 antibodies. Low levels of phagocytosis of Afa/Dr DAEC strains were observed both in nontransmigrated and in transmigrated PMNs compared to that observed with the control E. coli DH5alpha strain. Taken together, these data strongly suggest that interaction of Afa/Dr DAEC with PMNs may increase the bacterial virulence both by inducing PMN apoptosis through an agglutination process and by diminishing their phagocytic capacity." 6597;"Gene expression profiling of normal human pulmonary fibroblasts following coculture with non-small-cell lung cancer cells reveals alterations related to matrix degradation, angiogenesis, cell growth and survival.";"P. Auberger, S. Tartare-Deckert";"Equipe 02, Team 02, Equipe 11, Team 11";14627989;Oncogene;"Fromigué O, Louis K, Dayem M, Milanini J, Pages G, Tartare-Deckert S, Ponzio G, Hofman P, Barbry P, Auberger P, Mari B";;"Nov 2003";1069718400;;"Increasing evidence supports a major role for the microenvironment in carcinoma formation and progression. The influence of the stroma is partly mediated by signalling between epithelial tumor cells and neighboring fibroblasts. However, the molecular mechanisms underlying these interactions are largely unknown. To mimic the initial steps of invasive carcinoma in which tumor cells come in contact with normal stromal cells, we used a coculture model of non-small-cell lung cancer tumor cells and normal pulmonary fibroblasts. Using DNA filter arrays, we first analysed the overall modification of gene expression profile after a 24 h period of coculture. Next, we focused our interest on the transcriptome of the purified fibroblastic fraction of coculture using both DNA filter arrays and a laboratory-made DNA microarray. These experiments allowed the identification of a set of modulated genes coding for growth and survival factors, angiogenic factors, proteases and protease inhibitors, transmembrane receptors, kinases and transcription regulators that can potentially affect the regulation of matrix degradation, angiogenesis, invasion, cell growth and survival. This study represents to our knowledge the first attempt to dissect early global gene transcription occurring in a tumor-stroma coculture model and should help to understand better some of the molecular mechanisms involved in heterotypic signalling between epithelial tumor cells and fibroblasts." 6596;"Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway.";"P. Auberger";"Equipe 02, Team 02";15034012;"Journal of immunology (Baltimore, Md. : 1950)";"Py B, Slomianny C, Auberger P, Petit PX, Benichou S";;"Apr 2004";1080777600;;"Siva-1 is a death domain-containing proapoptotic protein identified as an intracellular ligand of CD27 and of the glucocorticoid-induced TNFR family-related gene, which are two members of the TNFR family expressed on lymphoid cells. Although Siva-1 expression is up-regulated in multiple pathological processes, little is known about the signaling pathway underlying the Siva-induced apoptosis. In this study, we investigated the mechanism of the proapoptotic activity of Siva-1 and an alternative splice form lacking the death domain of Siva-1, Siva-2, in T lymphocytes in which Siva proteins, CD27, and glucocorticoid-induced TNFR family-related gene are primarily expressed. Overexpression of Siva proteins triggers a typical apoptotic process manifested by cell shrinkage and surface exposure of phosphatidylserine, and confirmed by ultrastructural features. Siva-induced apoptosis is related to the CD27-mediated apoptotic pathway and results in activation of both initiator and effector caspases. This pathway involves a mitochondrial step evidenced by activation of Bid and cytochrome c release, and is modulated by overexpression of Bcl-2 or Bcl-x(L). The determinants for Siva-induced apoptosis are not contained within the death domain found in the central part of Siva-1, but rather in both the N-terminal and C-terminal regions shared by both Siva proteins. The N-terminal region also participates in the translocation of both Siva proteins into the nuclear compartment. These results indicate that Siva-1 and Siva-2 mediate apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway that likely involves both cytoplasmic and nuclear events." 6592;"Tumor cell-mediated induction of the stromal factor stromelysin-3 requires heterotypic cell contact-dependent activation of specific protein kinase C isoforms.";"P. Auberger";"Equipe 02, Team 02";15509588;"The Journal of biological chemistry";"Louis K, Guérineau N, Fromigué O, Defamie V, Collazos A, Anglard P, Shipp MA, Auberger P, Joubert D, Mari B";;"Jan 2005";1104537600;;"Stromelysin-3 (ST3, MMP-11) has been shown to be strongly overexpressed in stromal fibroblasts of most invasive human carcinomas. However, the molecular mechanisms leading to ST3 expression in nonmalignant fibroblasts remain unknown. The aim of the present study was to analyze the signaling pathways activated in normal pulmonary fibroblasts after their interaction with non-small cell lung cancer (NSCLC) cells and leading to ST3 expression. The use of selective signaling pathway inhibitors showed that conventional and novel protein kinase Cs (PKC) were required for ST3 induction, whereas Src kinases exerted a negative control. We observed by both conventional and real time confocal microscopy that green fluorescent protein-tagged PKCalpha and PKCepsilon, but not PKCdelta, transfected in fibroblasts, accumulate selectively at the cell-cell contacts between fibroblasts and tumor cells. In agreement, RNAi-mediated depletion of PKCalpha and PKCepsilon, but not PKCdelta significantly decreased co-culture-dependent ST3 production. Finally, a tetracycline-inducible expression model allowed us to confirm the central role of these PKC isoforms and the negative regulatory function of c-Src in the control of ST3 expression. Altogether, our data emphasize signaling changes occurring in the tumor microenvironment that may define new stromal targets for therapeutic intervention." 6593;"Cooperation of amphiregulin and insulin-like growth factor-1 inhibits Bax- and Bad-mediated apoptosis via a protein kinase C-dependent pathway in non-small cell lung cancer cells.";"P. Auberger";"Equipe 02, Team 02";15767261;"The Journal of biological chemistry";"Hurbin A, Coll JL, Dubrez-Daloz L, Mari B, Auberger P, Brambilla C, Favrot MC";;"May 2005";1114905600;;"Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) are growth factors known to promote non-small cell lung cancer (NSCLC) survival. We have previously published that 1) AR and IGF1, secreted by H358 NSCLC cells, cooperate to protect those cells and H322 NSCLC cells from serum-starved apoptosis; 2) H358 cells resist Bax-induced apoptosis through an inhibition of Bax conformational change. We show here that the antiapoptotic activity of the AR/IGF1 combination is specifically abolished by the PKC inhibitors calphostin C and staurosporine, but not by the MAPK and phosphatidylinositol 3-kinase inhibitors PD98059 and wortmannin, suggesting the involvement of a PKC-dependent and MAPK- and phosphatidylinositol 3-kinase-independent survival pathway. The PKCdelta inhibitor rottlerin restores apoptosis induced by serum deprivation. In addition, phosphorylation of PKCdelta and PKCzeta/lambda, but not of PKCalpha/beta(II), increases in serum-starved H358 cells and in H322 cells treated with an AR/IGF1 combination and is blocked by calphostin C. The combination of AR and IGF1 increases p90(rsk) and Bad phosphorylation as well as inhibiting the conformational change of Bax by a PKC-dependent mechanism. Finally, PKCdelta, PKCzeta, or p90(rsk) small interfering RNAs block the antiapoptotic activity of AR/IGF1 combination but have no effect on partial apoptosis inhibition observed with each factor used alone. Constitutively active PKC expression inhibits serum deprivation-induced apoptosis, whereas a catalytically inactive form of p90(rsk) restores it. Thus, AR and IGF1 cooperate to prevent apoptosis by activating a specific PKC-p90(rsk)-dependent pathway, which leads to Bad and Bax inactivation. This signaling pathway is different to that used by single factor." 6590;"Fas ligand expression following normothermic liver ischemia-reperfusion.";"P. Auberger";"Equipe 02, Team 02";15836847;"The Journal of surgical research";"Cursio R, Filippa N, Miele C, Colosetti P, Auberger P, Van Obberghen E, Gugenheim J";;"May 2005";1114905600;;"The aim of this study was to evaluate the role of the pro-apoptotic molecule Fas Ligand (FasL) in 120 min normothermic ischemia-reperfusion (I-R) induced apoptosis in rat liver treated or not with Z-Asp-cmk caspase inhibitor." 6588;"Human polymorphonuclear leukocytes are sensitive in vitro to Helicobacter pylori vaca toxin.";"P. Auberger";"Equipe 02, Team 02";17083376;Helicobacter;"Brest P, Hofman V, Lassalle S, Césaro A, Ricci V, Selva E, Auberger P, Hofman P";;"Dec 2006";1164931200;;"Interactions between bacterial components and polymorphonuclear leukocytes (PMNL) play a major pathogenic role in Helicobacter pylori-associated diseases. Activation of PMNL can be induced by contact with whole bacteria or by different H. pylori products released in the extracellular space either by active secretion or by bacterial autolysis. Among these products, H. pylori VacA is a secreted toxin inducing vacuolation and apoptosis of epithelial cells." 6585;"The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis.";"P. Auberger";"Equipe 02, Team 02";16140982;"Genes & development";"Larribere L, Hilmi C, Khaled M, Gaggioli C, Bille K, Auberger P, Ortonne JP, Ballotti R, Bertolotto C";;"Sep 2005";1125532800;;"Microphthalmia-associated transcription factor (MITF) M-form is a melanocyte-specific transcription factor that plays a key role in melanocyte development, survival, and differentiation. Here, we identified MITF as a new substrate of caspases and we characterized the cleavage site after Asp 345 in the C-terminal domain. We show that expression of a noncleavable form of MITF renders melanoma cells resistant to apoptotic stimuli, and we found that the C-terminal fragment generated upon caspase cleavage is endowed with a proapoptotic activity that sensitizes melanoma cells to death signals. The proapoptotic function gained by MITF following its processing by caspases provides a tissue-restricted means to modulate death in melanocyte and melanoma cells." 6583;"Caspase-3-derived C-terminal product of synphilin-1 displays antiapoptotic function via modulation of the p53-dependent cell death pathway.";"P. Auberger";"Equipe 02, Team 02";16495229;"The Journal of biological chemistry";"Giaime E, Sunyach C, Herrant M, Grosso S, Auberger P, McLean PJ, Checler F, da Costa CA";;"Apr 2006";1143849600;;"Parkinson disease is the second most frequent neurodegenerative disorder after Alzheimer disease. A subset of genetic forms of Parkinson disease has been attributed to alpha-synuclein, a synaptic protein with remarkable chaperone properties. Synphilin-1 is a cytoplasmic protein that has been identified as a partner of alpha-synuclein (Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., Margolis, R. L., Troncoso, J. C., Lanahan, A. A., Worley, P. F., Dawson, V. L., Dawson, T. M., and Ross, C. A. (1999) Nat. Gen. 22, 110-114), but its function remains totally unknown. We show here for the first time that synphilin-1 displays an antiapoptotic function in the control of cell death. We have established transient and stable transfectants overexpressing wild-type synphilin-1 in human embryonic kidney 293 cells, telecephalon-specific murine 1 neurons, and SH-SY5Y neuroblastoma cells, and we show that both cell systems display lower responsiveness to staurosporine and 6-hydroxydopamine. Thus, synphilin-1 reduces procaspase-3 hydrolysis and thereby caspase-3 activity and decreases poly(ADP-ribose) polymerase cleavage, two main indicators of apoptotic cell death. Furthermore, we establish that synphilin-1 drastically reduces p53 transcriptional activity and expression and lowers p53 promoter transactivation and mRNA levels. Interestingly, we demonstrate that synphilin-1 catabolism is enhanced by staurosporine and blocked by caspase-3 inhibitors. Accordingly, we show by transcription/translation assay that recombinant caspase-3 and, to a lesser extent, caspase-6 but not caspase-7 hydrolyze synphilin-1. Furthermore, we demonstrate that mutated synphilin-1, in which a consensus caspase-3 target sequence has been disrupted, resists proteolysis by cellular and recombinant caspases and displays drastically reduced antiapoptotic phenotype. We further show that the caspase-3-derived C-terminal fragment of synphilin-1 was probably responsible for the antiapoptotic phenotype elicited by the parent wild-type protein. Altogether, our study is the first demonstration that synphilin-1 harbors a protective function that is controlled by the C-terminal fragment generated by its proteolysis by caspase-3." 6580;"Inhibition of apoptosis induced by heat shock preconditioning is associated with decreased phagocytosis in human polymorphonuclear leukocytes through inhibition of Rac and Cdc42.";"P. Auberger";"Equipe 02, Team 02";17228324;"Immunology and cell biology";"Selva E, Brest P, Loubat A, Lassalle S, Auberger P, Hofman P";;"May Apr 2007";1175731200;;"The functionality of polymorphonuclear leukocytes (PMNL) and the exact process of the protective program employed by these cells in response to the heat shock (HS) remain ill-defined and debated. Particularly, the mechanism of phagocytic impairment induced by the HS and the molecular events associated with the delay of apoptosis used by these cells in such condition have given conflictual data. The aim of the present work is to study the consequences of the HS in different pathways involved in human PMNL apoptosis and subsequently in human PMNL phagocytic function. We demonstrated that HS (41 degrees C, 1 h) preconditioning induced inhibition of spontaneous PMNL apoptosis observed at 18 h in control cells incubated at 37 degrees C. This inhibition was characterized by absence of morphological nuclear changes, decrease of DNA fragmentation, low level of annexin V expression and decrease of caspase-3 activity. In parallel, HS increased both Hsp70 and Mcl-1 protein levels in PMNL. Phagocytosis of latex beads by PMNL was inhibited by HS (41 degrees C, 1 h) preconditioning despite an upregulation of CD11b, CD16 and CD47. Moreover, HS induced prolonged F actin depolymerization and inhibited both Rac and Cdc42 activation in PMNL. Finally, our results identify a new function of Mcl-1 in HS protection against apoptosis." 6578;"Nephroblastoma overexpressed/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 (NOV/CCN3), a selective adrenocortical cell proapoptotic factor, is down-regulated in childhood adrenocortical tumors.";"P. Auberger";"Equipe 02, Team 02";17566092;"The Journal of clinical endocrinology and metabolism";"Doghman M, Arhatte M, Thibout H, Rodrigues G, De Moura J, Grosso S, West AN, Laurent M, Mas JC, Bongain A, Zambetti GP, Figueiredo BC, Auberger P, Martinerie C, Lalli E";;"Aug 2007";1185926400;;"Childhood adrenocortical tumors (ACTs) have a fetal adrenal phenotype and overexpress steroidogenic factor-1 (SF-1). Nephroblastoma overexpressed (NOV)/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 mRNA is significantly down-regulated in childhood ACTs." 6576;"Effect of caspase inhibition on thymic apoptosis in hemorrhagic shock.";"P. Auberger";"Equipe 02, Team 02";17454394;"Journal of investigative surgery : the official journal of the Academy of Surgical Research";"Bini R, Cursio R, Belhacene N, Giudicelli J, Ferruà B, Olivero G, Auberger P, Mari B, Gugenheim J, Cotogni P";;"Apr Mar 2007";1172966400;;"In hemorrhagic shock (HS) an increased thymic apoptosis (TA) was described. The aim of this study was to evaluate the effect of administration of the caspase inhibitor N-benzyloxy-carbonil-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) during the resuscitation phase on TA, organ dysfunctions, and tumor necrosis factor (TNF)-alpha release in HS. Forty rats were randomly assigned to four groups: no HS/resuscitation (sham); HS/resuscitation with shed blood and normal saline (control); HS/resuscitation with shed blood and phosphate-buffered solution (PBS) (vehicle); and HS/resuscitation with shed blood and Z-VAD-FMK (inhibitor). Rats were subjected to HS by blood removal to a MAP of 35-40 mmHg. After a 1-h shock period, the animals were resuscitated according to the protocol. At 1 and 3 h after resuscitation, transaminases, creatinine, urea, lipase, TNF-alpha, and TA were evaluated. Our study showed that a nonlethal HS is early able to induce organ dysfunctions and increased TA. Administration of Z-VAD-FMK did not significantly decrease organ dysfunctions, while it induced a significant TNF-alpha release. TA was significantly reduced by Z-VAD-FMK after 1 h, but not after 3 h. Our results suggest that postinjury caspase inhibition does not attenuate organ dysfunctions, and also does not permanently reduce TA induced by HS and resuscitation in rats." 6574;"Involvement of mast cells in gastritis caused by Helicobacter pylori: a potential role in epithelial cell apoptosis.";"P. Auberger";"Equipe 02, Team 02";17557865;"Journal of clinical pathology";"Hofman V, Lassalle S, Selva E, Kalem K, Steff A, Hébuterne X, Sicard D, Auberger P, Hofman P";;"Jun 2007";1180656000;;"The role(s) of mast cells (MC) in gastric mucosal inflammation caused by Helicobacterpylori is (are) still debated." 6572;"Tyrosine phosphorylation of insulin receptor substrates during ischemia/reperfusion-induced apoptosis in rat liver.";"P. Auberger";"Equipe 02, Team 02";18679708;"Langenbeck's archives of surgery";"Cursio R, Miele C, Filippa N, Colosetti P, Auberger P, Van Obberghen E, Gugenheim J";;"Jan 2009";1230768000;;"Phosphoregulation of signal transduction pathways is a complex series of reactions that may modulate the cellular response to ischemia-reperfusion (I-R). The aim of this study was to evaluate the effect of normothermic liver I/R-induced apoptosis on phosphorylation and activation of signal proteins in tyrosine kinase pathways." 6570;"Isoform-specific contribution of protein kinase C to prion processing.";"P. Auberger";"Equipe 02, Team 02";18722532;"Molecular and cellular neurosciences";"Alfa Cissé M, Louis K, Braun U, Mari B, Leitges M, Slack BE, Fisher A, Auberger P, Checler F, Vincent B";;"Aug 2008";1220054400;;"The cellular prion protein (PrP(c)) undergoes a physiological cleavage between amino acids 111 and 112, thereby leading to the secretion of an amino-terminal fragment referred to as N1. This proteolytic event is either constitutive or regulated by protein kinase C (PKC) and is operated by the disintegrins ADAM9/ADAM10 or ADAM17 respectively. We recently showed that the stimulation of the M1/M3 muscarinic receptors potentiates this cleavage via the phosphorylation and activation of ADAM17. We have examined the contribution of various PKC isoforms in the regulated processing of PrP(c). First we show that the PDBu- and carbachol-stimulated N1 secretions are blocked by the general PKC inhibitor GF109203X. We establish that HEK293 and human-derived rhabdhomyosarcoma cells over-expressing constitutively active PKCalpha, PKCdelta or PKCepsilon, but not PKCzeta, produce increased amounts of N1 and harbor enhanced ability to hydrolyze the fluorimetric substrate of ADAM17, JMV2770. Conversely, over-expression of the corresponding dominant negative proteins abolishes PDBU-stimulated N1 secretion and restores N1 to levels comparable to constitutive production. Moreover, deletion of PKCalpha lowers N1 recovery in primary cultured fibroblasts. Importantly, mutation of threonine 735 of ADAM17 significantly lowers the PDBu-induced N1 formation while transient over-expression of constitutively active PKCalpha, PKCdelta or PKCepsilon, but not PKCzeta, induced both the phosphorylation of ADAM17 on its threonine residues and N1 secretion. As a corollary, T735A mutation concomitantly reversed PKCalpha-, PKCdelta- and PKCepsilon-induced ADAM17 phosphorylation and N1 recovery. Finally, we established that PKCepsilon-dependent N1 production is fully prevented by ADAM17 deficiency. Altogether, the present results provide strong evidence that the activation of PKCalpha, delta and epsilon, but not zeta, isoforms leads to increased N1 secretion via the phosphorylation and activation of ADAM17, a process that likely accounts for M1/M3 muscarinic receptors-mediated control of N1 production." 6568;"Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells: reversal of mitogen-mediated repression of Fas DISC assembly.";"P. Auberger";"Equipe 02, Team 02";19112091;"Journal of leukocyte biology";"Engedal N, Auberger P, Blomhoff HK";;"Mar 2009";1235865600;;"The effect of the immune regulator vitamin A on T cell death has been poorly characterized. In the present study, we demonstrate that an active metabolite of vitamin A, retinoic acid (RA), promotes cell death in Jurkat leukemic T cells by counteracting mitogen-mediated repression of Fas-induced apoptosis. The effect of RA was dose-dependent, and at the optimal concentration of 1 muM, repression of Fas-induced cell death by the mitogens 12-O-tetradecanoylphorbol 13-acetate (TPA) or Con A was reversed by approximately 50% and 30%, respectively. RA promoted apoptosis rather than necrosis, as judged by analysis of cell morphology, mitochondrial membrane depolarization, and DNA fragmentation. TPA-mediated protection from Fas-induced apoptosis is dependent on ERK and NF-kappaB. However, analyses of ERK and NF-kappaB activities and expression of target genes indicated that RA-mediated counteraction of the protective effect of TPA did not involve negative crosstalk with ERK or NF-kappaB survival pathways. RA-induced cell death was accompanied by enhanced cleavage of procaspase-3, -6, and -8, as well as enhanced cleavage of DNA fragmentation factor 45. Interestingly, RA-mediated cleavage of procaspase-8 occurred very early and before any effect of RA could be detected on procaspase-3 cleavage, suggesting that RA might act at the level of the Fas death-inducing signaling complex (DISC). Indeed, DISC immunoprecipitation studies revealed that RA treatment reversed the inhibitory effect of TPA on CH11-induced recruitment and processing of procaspase-8 at the DISC. In conclusion, we have identified a role of RA in abrogating mitogen-mediated repression of Fas DISC assembly, thus enhancing Fas-induced apoptosis in leukemic T cells." 6567;"Injection of Staphylococcus aureus EDIN by the Bacillus anthracis protective antigen machinery induces vascular permeability.";"P. Auberger";"Equipe 02, Team 02";19546197;"Infection and immunity";"Rolando M, Munro P, Stefani C, Auberger P, Flatau G, Lemichez E";;"Sep 2009";1251763200;;"Systemic injection of Bacillus anthracis lethal toxin (LT) produces vascular leakage and animal death. Recent studies suggest that LT triggers direct endothelial cell cytotoxicity that is responsible for the vascular leakage. LT is composed of heptamers of protective antigen (PA), which drives the endocytosis and translocation into host cells of the lethal factor (LF), a mitogen-activated protein kinase kinase protease. Here we investigated the consequences of injection of an endothelium-permeabilizing factor using LT as a ""molecular syringe."" To this end, we generated the chimeric factor LE, corresponding to the PA-binding domain of LF (LF(1-254)) fused to EDIN exoenzyme. EDIN ADP ribosylates RhoA, leading to actin cable disruption and formation of transcellular tunnels in endothelial cells. We report that systemic injection of LET (LE plus PA) triggers a PA-dependent increase in the pulmonary endothelium permeability. We also report that native LT induces a progressive loss of endothelium barrier function. We established that there is a direct correlation between the extent of endothelium permeability induced by LT and the cytotoxic activity of LT. This suggests new ways to design therapeutic drugs against anthrax directed toward vascular permeability." 6566;"Transcriptome dysregulation by anthrax lethal toxin plays a key role in induction of human endothelial cell cytotoxicity.";"P. Auberger";"Equipe 02, Team 02";20088950;"Cellular microbiology";"Rolando M, Stefani C, Flatau G, Auberger P, Mettouchi A, Mhlanga M, Rapp U, Galmiche A, Lemichez E";;"Jan 2010";1264118400;;"We have investigated how Bacillus anthracis lethal toxin (LT) triggers caspase-3 activation and the formation of thick actin cables in human endothelial cells. By DNA array analysis we show that LT has a major impact on the cell transcriptome and we identify key host genes involved in LT cytotoxic effects. Indeed, upregulation of TRAIL and downregulation of XIAP both participate in LT-induced caspase-3 activation. LT induces a downregulation of the immediate early gene and master regulator of transcription egr1. Importantly, its re-expression in LT-intoxicated cells blocks caspase-3 activation. In parallel, we found that the formation of actin cables induced by LT occurs in the absence of direct activation of RhoA/ROCK signalling. We show that knock-down of cortactin and rhophilin-2 under conditions of calponin-1 expression defines the minimal set of genes regulated by LT for actin cable formation. Together our data establish that the modulation of the cell transcriptome by LT plays a key role in triggering human endothelial cell toxicity." 6564;"AMPK- and p62/SQSTM1-dependent autophagy mediate resveratrol-induced cell death in chronic myelogenous leukemia.";"P. Auberger";"Equipe 02, Team 02";20458181;Autophagy;"Puissant A, Auberger P";;"Jul 2010";1277942400;;"Resveratrol (RSV) is an attractive candidate for cancer therapy via its ability to intervene at different levels in the AMPK/mTOR pathway. Indeed, RSV is unique in its capacity to inhibit both mTOR and S6 kinase and to activate AMPK. Our recent data reveals that RSV triggered autophagic cell death (ACD) in Chronic Myelogenous Leukemia (CML) cells, via both AMPK activation and JNK-mediated p62/SQSTM1 expression. Here we discuss how Resveratrol can mediate ACD in CML cells and the possibility of utilizing the AMPK/mTOR and JNK/p62 pathways via Resveratrol to combat CML and other hematopoietic malignancies." 6562;"Structure elucidation of the new citharoxazole from the Mediterranean deep-sea sponge Latrunculia (Biannulata) citharistae.";"P. Auberger";"Equipe 02, Team 02";21761452;"Magnetic resonance in chemistry : MRC";"Genta-Jouve G, Francezon N, Puissant A, Auberger P, Vacelet J, Pérez T, Fontana A, Mourabit AA, Thomas OP";;"Aug 2011";1312156800;;"Citharoxazole (1), a new batzelline derivative featuring a benzoxazole moiety, was isolated from the Mediterranean deep-sea sponge Latrunculia (Biannulata) citharistae Vacelet, 1969, together with the known batzelline C (2). This is the first chemical study of a Mediterranean Latrunculia species and the benzoxazole moiety is unprecedented for this family of marine natural products. The structure was mainly elucidated by the interpretation of NMR spectra and especially HMBC correlations." 6560;"Hypomethylating agents reactivate FOXO3A in acute myeloid leukemia.";"P. Auberger, T. Cluzeau";"Equipe 02, Team 02";21654193;"Cell cycle (Georgetown, Tex.)";"Thépot S, Lainey E, Cluzeau T, Sébert M, Leroy C, Adès L, Tailler M, Galluzzi L, Baran-Marszak F, Roudot H, Eclache V, Gardin C, de Botton S, Auberger P, Fenaux P, Kroemer G, Boehrer S";;"Jul 2011";1309478400;;"The deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agent, notably azacitidine, constitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine, and to a lesser degree azacitidine, induced the activation of checkpoint kinases Chk-1 and Chk-2 and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box O3, best known as FOXO3A, whose phosphorylation has been related to poor prognosis in AML. The dephoasphorylation of FOXO3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FOXO3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML-derived, azacitidine-sensitive SKM-1S cells upregulated FOXO3A and the pro-apoptotic FOXO3A targets BIM and PUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the reactivation of FOXO3A may contribute to the effects of hypomethylating agents in malignant blasts." 6556;"BCR-ABL/p62/SQSTM1: a cannibal embrace.";"P. Auberger";"Equipe 02, Team 02";23100300;Blood;"Auberger P";;"Oct 2012";1349049600;;"In this issue of Blood, Goussetis et al identify autophagy as a new pathway for the degradation of the oncoprotein BCR-ABL. They show that the therapeutic drug arsenic trioxide (AS(2)O(3)) targets BCR-ABL for autophagic degradation via a p62/SQSTM1-dependent mechanism that is critical for the antileukemic effect of the drug." 6557;"When autophagy meets cancer through p62/SQSTM1.";"P. Auberger";"Equipe 02, Team 02";22860231;"American journal of cancer research";"Puissant A, Fenouille N, Auberger P";;"Jan 2012";1325376000;;"Although p62/SQSTM1 was initially identified as an essential mediator of NFκB signaling, several recent studies have also highlighted its important role at the crossroad between the mTOR or MAPK signaling pathways and selective autophagy. The p62 structure containing important interaction domains attests to the ability of this protein to regulate and modulate the activation of these signaling pathways during tumor formation and propagation. The second very important function of this protein is to act as a molecular adaptor between the autophagic machinery and its substrates. Consequently, p62 is degraded following an increase in autophagic flux for which this protein currently serves as an indicator. However, the measurement of p62 expression strictly as a marker of autophagic flux is still controversial and can be misinterpreted mainly because this protein is subject to complex regulation at both the transcriptional and post-translational levels. Finally, because p62 is an autophagic substrate, it acts as a molecular link between cancer and autophagy by conferring a high level of selectivity through the degradation of important signaling molecules." 6554;"Monosomal karyotype improves IPSS-R stratification in MDS and AML patients treated with Azacitidine.";"P. Auberger, T. Cluzeau";"Equipe 02, Team 02";23757315;"American journal of hematology";"Cluzeau T, Mounier N, Karsenti JM, Richez V, Legros L, Gastaud L, Garnier G, Re D, Montagne N, Gutnecht J, Gabriel Fuzibet J, Auberger P, Raynaud S, Cassuto JP";;"Sep 2013";1377993600;;"IPSS-R classifies cytogenetic abnormalities into five prognostic groups for survival. Monosomal karyotype (MK) is not a subgroup of IPSS-R. Additional prognostic information from MK in poor and very poor karyotype has been recently shown. The aim of our study was to determine the prognostic value of IPSS-R and MK for response and survival in AZA-treated high-risk MDS and AML with 20-30% of blasts patients. The study population included 154 patients who were classified according to IPSS-R. IPSS-R was not predictive of response (intermediate, 64%; poor, 44%; very poor, 56%; P = 0.28) or survival (intermediate, 25 months; poor, 12 months; very poor, 11 months; P = 0.14). Twenty-one patients (15%) presented with MK and had a median OS of 9 months. Patients with a very high IPSS-R score without MK had a median OS of 15 months, while patients with a high IPSS-R score without MK had a median OS of 13 months (P = 0.18). We reclassified patients into the following three groups to include MK status: very high (MK only; OS median: 9 months), high (very high IPSS-R without MK and high IPSS-R without MK; OS median: 14 months) and intermediate (OS median: 25 months). As in recent publication including MK prognostic, we confirmed that this classification was predictive for survival in AZA treated patients (P = 0.008). IPSS-R failed to discriminate between the prognostic subgroups. Stratification with MK has value in the prognosis of our cohort of AZA-treated patients." 6552;"Nepheliosyne B, a new polyacetylenic acid from the new caledonian marine sponge Niphates sp.";"P. Auberger";"Equipe 02, Team 02";23807547;"Marine drugs";"Legrave N, Hamrouni-Buonomo S, Dufies M, Guérineau V, Vacelet J, Auberger P, Amade P, Mehiri M";;"Jun 2013";1370044800;;"A new C47 polyoxygenated acetylenic acid, nepheliosyne B (2), along with the previously described nepheliosyne A (1), have been isolated from the New Caledonian marine sponge Niphates sp. Their structures have been elucidated on the basis of extensive spectroscopic analyses. These metabolites exhibited a moderate cytotoxicity against K562, U266, SKM1, and Kasumi cancer cell lines. " 6550;"Tumor suppressor function of miR-483-3p on squamous cell carcinomas due to its pro-apoptotic properties.";"P. Auberger";"Equipe 02, Team 02";24067364;"Cell cycle (Georgetown, Tex.)";"Bertero T, Bourget-Ponzio I, Puissant A, Loubat A, Mari B, Meneguzzi G, Auberger P, Barbry P, Ponzio G, Rezzonico R";;"Jul 2013";1372636800;;"The frequent alteration of miRNA expression in many cancers, together with our recent reports showing a robust accumulation of miR-483-3p at the final stage of skin wound healing, and targeting of CDC25A leading to an arrest of keratinocyte proliferation, led us to hypothesize that miR-483-3p could also be endowed with antitumoral properties. We tested that hypothesis by documenting the in vitro and in vivo impacts of miR-483-3p in squamous cell carcinoma (SCC) cells. miR-483-3p sensitized SCC cells to serum deprivation- and drug-induced apoptosis, thus exerting potent tumor suppressor activities. Its pro-apoptotic activity was mediated by a direct targeting of several anti-apoptotic genes, such as API5, BIRC5, and RAN. Interestingly, an in vivo delivery of miR-483-3p into subcutaneous SCC xenografts significantly hampered tumor growth. This effect was explained by an inhibition of cell proliferation and an increase of apoptosis. This argues for its further use as an adjuvant in the many instances of cancers characterized by a downregulation of miR-483-3p. " 6548;"Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux.";"N. Mazure, P. Auberger";"Equipe 05, Team 05, Equipe 02, Team 02";26312386;Autophagy;"Giuliano S, Cormerais Y, Dufies M, Grépin R, Colosetti P, Belaid A, Parola J, Martin A, Lacas-Gervais S, Mazure NM, Benhida R, Auberger P, Mograbi B, Pagès G";;"Jan 2015";1420070400;;"Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome. " 6546;"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).";"P. Auberger";"Equipe 02, Team 02";26799652;Autophagy;"Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, Adhihetty PJ, Adler SG, Agam G, Agarwal R, Aghi MK, Agnello M, Agostinis P, Aguilar PV, Aguirre-Ghiso J, Airoldi EM, Ait-Si-Ali S, Akematsu T, Akporiaye ET, Al-Rubeai M, Albaiceta GM, Albanese C, Albani D, Albert ML, Aldudo J, Algül H, Alirezaei M, Alloza I, Almasan A, Almonte-Beceril M, Alnemri ES, Alonso C, Altan-Bonnet N, Altieri DC, Alvarez S, Alvarez-Erviti L, Alves S, Amadoro G, Amano A, Amantini C, Ambrosio S, Amelio I, Amer AO, Amessou M, Amon A, An Z, Anania FA, Andersen SU, Andley UP, Andreadi CK, Andrieu-Abadie N, Anel A, Ann DK, Anoopkumar-Dukie S, Antonioli M, Aoki H, Apostolova N, Aquila S, Aquilano K, Araki K, Arama E, Aranda A, Araya J, Arcaro A, Arias E, Arimoto H, Ariosa AR, Armstrong JL, Arnould T, Arsov I, Asanuma K, Askanas V, Asselin E, Atarashi R, Atherton SS, Atkin JD, Attardi LD, Auberger P, Auburger G, Aurelian L, Autelli R, Avagliano L, Avantaggiati ML, Avrahami L, Awale S, Azad N, Bachetti T, Backer JM, Bae DH, Bae JS, Bae ON, Bae SH, Baehrecke EH, Baek SH, Baghdiguian S, Bagniewska-Zadworna A, Bai H, Bai J, Bai XY, Bailly Y, Balaji KN, Balduini W, Ballabio A, Balzan R, Banerjee R, Bánhegyi G, Bao H, Barbeau B, Barrachina MD, Barreiro E, Bartel B, Bartolomé A, Bassham DC, Bassi MT, Bast RC, Basu A, Batista MT, Batoko H, Battino M, Bauckman K, Baumgarner BL, Bayer KU, Beale R, Beaulieu JF, Beck GR, Becker C, Beckham JD, Bédard PA, Bednarski PJ, Begley TJ, Behl C, Behrends C, Behrens GM, Behrns KE, Bejarano E, Belaid A, Belleudi F, Bénard G, Berchem G, Bergamaschi D, Bergami M, Berkhout B, Berliocchi L, Bernard A, Bernard M, Bernassola F, Bertolotti A, Bess AS, Besteiro S, Bettuzzi S, Bhalla S, Bhattacharyya S, Bhutia SK, Biagosch C, Bianchi MW, Biard-Piechaczyk M, Billes V, Bincoletto C, Bingol B, Bird SW, Bitoun M, Bjedov I, Blackstone C, Blanc L, Blanco GA, Blomhoff HK, Boada-Romero E, Böckler S, Boes M, Boesze-Battaglia K, Boise LH, Bolino A, Boman A, Bonaldo P, Bordi M, Bosch J, Botana LM, Botti J, Bou G, Bouché M, Bouchecareilh M, Boucher MJ, Boulton ME, Bouret SG, Boya P, Boyer-Guittaut M, Bozhkov PV, Brady N, Braga VM, Brancolini C, Braus GH, Bravo-San Pedro JM, Brennan LA, Bresnick EH, Brest P, Bridges D, Bringer MA, Brini M, Brito GC, Brodin B, Brookes PS, Brown EJ, Brown K, Broxmeyer HE, Bruhat A, Brum PC, Brumell JH, Brunetti-Pierri N, Bryson-Richardson RJ, Buch S, Buchan AM, Budak H, Bulavin DV, Bultman SJ, Bultynck G, Bumbasirevic V, Burelle Y, Burke RE, Burmeister M, Bütikofer P, Caberlotto L, Cadwell K, Cahova M, Cai D, Cai J, Cai Q, Calatayud S, Camougrand N, Campanella M, Campbell GR, Campbell M, Campello S, Candau R, Caniggia I, Cantoni L, Cao L, Caplan AB, Caraglia M, Cardinali C, Cardoso SM, Carew JS, Carleton LA, Carlin CR, Carloni S, Carlsson SR, Carmona-Gutierrez D, Carneiro LA, Carnevali O, Carra S, Carrier A, Carroll B, Casas C, Casas J, Cassinelli G, Castets P, Castro-Obregon S, Cavallini G, Ceccherini I, Cecconi F, Cederbaum AI, Ceña V, Cenci S, Cerella C, Cervia D, Cetrullo S, Chaachouay H, Chae HJ, Chagin AS, Chai CY, Chakrabarti G, Chamilos G, Chan EY, Chan MT, Chandra D, Chandra P, Chang CP, Chang RC, Chang TY, Chatham JC, Chatterjee S, Chauhan S, Che Y, Cheetham ME, Cheluvappa R, Chen CJ, Chen G, Chen GC, Chen G, Chen H, Chen JW, Chen JK, Chen M, Chen M, Chen P, Chen Q, Chen Q, Chen SD, Chen S, Chen SS, Chen W, Chen WJ, Chen WQ, Chen W, Chen X, Chen YH, Chen YG, Chen Y, Chen Y, Chen Y, Chen YJ, Chen YQ, Chen Y, Chen Z, Chen Z, Cheng A, Cheng CH, Cheng H, Cheong H, Cherry S, Chesney J, Cheung CH, Chevet E, Chi HC, Chi SG, Chiacchiera F, Chiang HL, Chiarelli R, Chiariello M, Chieppa M, Chin LS, Chiong M, Chiu GN, Cho DH, Cho SG, Cho WC, Cho YY, Cho YS, Choi AM, Choi EJ, Choi EK, Choi J, Choi ME, Choi SI, Chou TF, Chouaib S, Choubey D, Choubey V, Chow KC, Chowdhury K, Chu CT, Chuang TH, Chun T, Chung H, Chung T, Chung YL, Chwae YJ, Cianfanelli V, Ciarcia R, Ciechomska IA, Ciriolo MR, Cirone M, Claerhout S, Clague MJ, Clària J, Clarke PG, Clarke R, Clementi E, Cleyrat C, Cnop M, Coccia EM, Cocco T, Codogno P, Coers J, Cohen EE, Colecchia D, Coletto L, Coll NS, Colucci-Guyon E, Comincini S, Condello M, Cook KL, Coombs GH, Cooper CD, Cooper JM, Coppens I, Corasaniti MT, Corazzari M, Corbalan R, Corcelle-Termeau E, Cordero MD, Corral-Ramos C, Corti O, Cossarizza A, Costelli P, Costes S, Cotman SL, Coto-Montes A, Cottet S, Couve E, Covey LR, Cowart LA, Cox JS, Coxon FP, Coyne CB, Cragg MS, Craven RJ, Crepaldi T, Crespo JL, Criollo A, Crippa V, Cruz MT, Cuervo AM, Cuezva JM, Cui T, Cutillas PR, Czaja MJ, Czyzyk-Krzeska MF, Dagda RK, Dahmen U, Dai C, Dai W, Dai Y, Dalby KN, Dalla Valle L, Dalmasso G, D'Amelio M, Damme M, Darfeuille-Michaud A, Dargemont C, Darley-Usmar VM, Dasarathy S, Dasgupta B, Dash S, Dass CR, Davey HM, Davids LM, Dávila D, Davis RJ, Dawson TM, Dawson VL, Daza P, de Belleroche J, de Figueiredo P, de Figueiredo RC, de la Fuente J, De Martino L, De Matteis A, De Meyer GR, De Milito A, De Santi M, de Souza W, De Tata V, De Zio D, Debnath J, Dechant R, Decuypere JP, Deegan S, Dehay B, Del Bello B, Del Re DP, Delage-Mourroux R, Delbridge LM, Deldicque L, Delorme-Axford E, Deng Y, Dengjel J, Denizot M, Dent P, Der CJ, Deretic V, Derrien B, Deutsch E, Devarenne TP, Devenish RJ, Di Bartolomeo S, Di Daniele N, Di Domenico F, Di Nardo A, Di Paola S, Di Pietro A, Di Renzo L, DiAntonio A, Díaz-Araya G, Díaz-Laviada I, Diaz-Meco MT, Diaz-Nido J, Dickey CA, Dickson RC, Diederich M, Digard P, Dikic I, Dinesh-Kumar SP, Ding C, Ding WX, Ding Z, Dini L, Distler JH, Diwan A, Djavaheri-Mergny M, Dmytruk K, Dobson RC, Doetsch V, Dokladny K, Dokudovskaya S, Donadelli M, Dong XC, Dong X, Dong Z, Donohue TM, Doran KS, D'Orazi G, Dorn GW, Dosenko V, Dridi S, Drucker L, Du J, Du LL, Du L, du Toit A, Dua P, Duan L, Duann P, Dubey VK, Duchen MR, Duchosal MA, Duez H, Dugail I, Dumit VI, Duncan MC, Dunlop EA, Dunn WA, Dupont N, Dupuis L, Durán RV, Durcan TM, Duvezin-Caubet S, Duvvuri U, Eapen V, Ebrahimi-Fakhari D, Echard A, Eckhart L, Edelstein CL, Edinger AL, Eichinger L, Eisenberg T, Eisenberg-Lerner A, Eissa NT, El-Deiry WS, El-Khoury V, Elazar Z, Eldar-Finkelman H, Elliott CJ, Emanuele E, Emmenegger U, Engedal N, Engelbrecht AM, Engelender S, Enserink JM, Erdmann R, Erenpreisa J, Eri R, Eriksen JL, Erman A, Escalante R, Eskelinen EL, Espert L, Esteban-Martínez L, Evans TJ, Fabri M, Fabrias G, Fabrizi C, Facchiano A, Færgeman NJ, Faggioni A, Fairlie WD, Fan C, Fan D, Fan J, Fang S, Fanto M, Fanzani A, Farkas T, Faure M, Favier FB, Fearnhead H, Federici M, Fei E, Felizardo TC, Feng H, Feng Y, Feng Y, Ferguson TA, Fernández ÁF, Fernandez-Barrena MG, Fernandez-Checa JC, Fernández-López A, Fernandez-Zapico ME, Feron O, Ferraro E, Ferreira-Halder CV, Fesus L, Feuer R, Fiesel FC, Filippi-Chiela EC, Filomeni G, Fimia GM, Fingert JH, Finkbeiner S, Finkel T, Fiorito F, Fisher PB, Flajolet M, Flamigni F, Florey O, Florio S, Floto RA, Folini M, Follo C, Fon EA, Fornai F, Fortunato F, Fraldi A, Franco R, Francois A, François A, Frankel LB, Fraser ID, Frey N, Freyssenet DG, Frezza C, Friedman SL, Frigo DE, Fu D, Fuentes JM, Fueyo J, Fujitani Y, Fujiwara Y, Fujiya M, Fukuda M, Fulda S, Fusco C, Gabryel B, Gaestel M, Gailly P, Gajewska M, Galadari S, Galili G, Galindo I, Galindo MF, Galliciotti G, Galluzzi L, Galluzzi L, Galy V, Gammoh N, Gandy S, Ganesan AK, Ganesan S, Ganley IG, Gannagé M, Gao FB, Gao F, Gao JX, García Nannig L, García Véscovi E, Garcia-Macía M, Garcia-Ruiz C, Garg AD, Garg PK, Gargini R, Gassen NC, Gatica D, Gatti E, Gavard J, Gavathiotis E, Ge L, Ge P, Ge S, Gean PW, Gelmetti V, Genazzani AA, Geng J, Genschik P, Gerner L, Gestwicki JE, Gewirtz DA, Ghavami S, Ghigo E, Ghosh D, Giammarioli AM, Giampieri F, Giampietri C, Giatromanolaki A, Gibbings DJ, Gibellini L, Gibson SB, Ginet V, Giordano A, Giorgini F, Giovannetti E, Girardin SE, Gispert S, Giuliano S, Gladson CL, Glavic A, Gleave M, Godefroy N, Gogal RM, Gokulan K, Goldman GH, Goletti D, Goligorsky MS, Gomes AV, Gomes LC, Gomez H, Gomez-Manzano C, Gómez-Sánchez R, Gonçalves DA, Goncu E, Gong Q, Gongora C, Gonzalez CB, Gonzalez-Alegre P, Gonzalez-Cabo P, González-Polo RA, Goping IS, Gorbea C, Gorbunov NV, Goring DR, Gorman AM, Gorski SM, Goruppi S, Goto-Yamada S, Gotor C, Gottlieb RA, Gozes I, Gozuacik D, Graba Y, Graef M, Granato GE, Grant GD, Grant S, Gravina GL, Green DR, Greenhough A, Greenwood MT, Grimaldi B, Gros F, Grose C, Groulx JF, Gruber F, Grumati P, Grune T, Guan JL, Guan KL, Guerra B, Guillen C, Gulshan K, Gunst J, Guo C, Guo L, Guo M, Guo W, Guo XG, Gust AA, Gustafsson ÅB, Gutierrez E, Gutierrez MG, Gwak HS, Haas A, Haber JE, Hadano S, Hagedorn M, Hahn DR, Halayko AJ, Hamacher-Brady A, Hamada K, Hamai A, Hamann A, Hamasaki M, Hamer I, Hamid Q, Hammond EM, Han F, Han W, Handa JT, Hanover JA, Hansen M, Harada M, Harhaji-Trajkovic L, Harper JW, Harrath AH, Harris AL, Harris J, Hasler U, Hasselblatt P, Hasui K, Hawley RG, Hawley TS, He C, He CY, He F, He G, He RR, He XH, He YW, He YY, Heath JK, Hébert MJ, Heinzen RA, Helgason GV, Hensel M, Henske EP, Her C, Herman PK, Hernández A, Hernandez C, Hernández-Tiedra S, Hetz C, Hiesinger PR, Higaki K, Hilfiker S, Hill BG, Hill JA, Hill WD, Hino K, Hofius D, Hofman P, Höglinger GU, Höhfeld J, Holz MK, Hong Y, Hood DA, Hoozemans JJ, Hoppe T, Hsu C, Hsu CY, Hsu LC, Hu D, Hu G, Hu HM, Hu H, Hu MC, Hu YC, Hu ZW, Hua F, Hua Y, Huang C, Huang HL, Huang KH, Huang KY, Huang S, Huang S, Huang WP, Huang YR, Huang Y, Huang Y, Huber TB, Huebbe P, Huh WK, Hulmi JJ, Hur GM, Hurley JH, Husak Z, Hussain SN, Hussain S, Hwang JJ, Hwang S, Hwang TI, Ichihara A, Imai Y, Imbriano C, Inomata M, Into T, Iovane V, Iovanna JL, Iozzo RV, Ip NY, Irazoqui JE, Iribarren P, Isaka Y, Isakovic AJ, Ischiropoulos H, Isenberg JS, Ishaq M, Ishida H, Ishii I, Ishmael JE, Isidoro C, Isobe K, Isono E, Issazadeh-Navikas S, Itahana K, Itakura E, Ivanov AI, Iyer AK, Izquierdo JM, Izumi Y, Izzo V, Jäättelä M, Jaber N, Jackson DJ, Jackson WT, Jacob TG, Jacques TS, Jagannath C, Jain A, Jana NR, Jang BK, Jani A, Janji B, Jannig PR, Jansson PJ, Jean S, Jendrach M, Jeon JH, Jessen N, Jeung EB, Jia K, Jia L, Jiang H, Jiang H, Jiang L, Jiang T, Jiang X, Jiang X, Jiang X, Jiang Y, Jiang Y, Jiménez A, Jin C, Jin H, Jin L, Jin M, Jin S, Jinwal UK, Jo EK, Johansen T, Johnson DE, Johnson GV, Johnson JD, Jonasch E, Jones C, Joosten LA, Jordan J, Joseph AM, Joseph B, Joubert AM, Ju D, Ju J, Juan HF, Juenemann K, Juhász G, Jung HS, Jung JU, Jung YK, Jungbluth H, Justice MJ, Jutten B, Kaakoush NO, Kaarniranta K, Kaasik A, Kabuta T, Kaeffer B, Kågedal K, Kahana A, Kajimura S, Kakhlon O, Kalia M, Kalvakolanu DV, Kamada Y, Kambas K, Kaminskyy VO, Kampinga HH, Kandouz M, Kang C, Kang R, Kang TC, Kanki T, Kanneganti TD, Kanno H, Kanthasamy AG, Kantorow M, Kaparakis-Liaskos M, Kapuy O, Karantza V, Karim MR, Karmakar P, Kaser A, Kaushik S, Kawula T, Kaynar AM, Ke PY, Ke ZJ, Kehrl JH, Keller KE, Kemper JK, Kenworthy AK, Kepp O, Kern A, Kesari S, Kessel D, Ketteler R, Kettelhut Ido C, Khambu B, Khan MM, Khandelwal VK, Khare S, Kiang JG, Kiger AA, Kihara A, Kim AL, Kim CH, Kim DR, Kim DH, Kim EK, Kim HY, Kim HR, Kim JS, Kim JH, Kim JC, Kim JH, Kim KW, Kim MD, Kim MM, Kim PK, Kim SW, Kim SY, Kim YS, Kim Y, Kimchi A, Kimmelman AC, Kimura T, King JS, Kirkegaard K, Kirkin V, Kirshenbaum LA, Kishi S, Kitajima Y, Kitamoto K, Kitaoka Y, Kitazato K, Kley RA, Klimecki WT, Klinkenberg M, Klucken J, Knævelsrud H, Knecht E, Knuppertz L, Ko JL, Kobayashi S, Koch JC, Koechlin-Ramonatxo C, Koenig U, Koh YH, Köhler K, Kohlwein SD, Koike M, Komatsu M, Kominami E, Kong D, Kong HJ, Konstantakou EG, Kopp BT, Korcsmaros T, Korhonen L, Korolchuk VI, Koshkina NV, Kou Y, Koukourakis MI, Koumenis C, Kovács AL, Kovács T, Kovacs WJ, Koya D, Kraft C, Krainc D, Kramer H, Kravic-Stevovic T, Krek W, Kretz-Remy C, Krick R, Krishnamurthy M, Kriston-Vizi J, Kroemer G, Kruer MC, Kruger R, Ktistakis NT, Kuchitsu K, Kuhn C, Kumar AP, Kumar A, Kumar A, Kumar D, Kumar D, Kumar R, Kumar S, Kundu M, Kung HJ, Kuno A, Kuo SH, Kuret J, Kurz T, Kwok T, Kwon TK, Kwon YT, Kyrmizi I, La Spada AR, Lafont F, Lahm T, Lakkaraju A, Lam T, Lamark T, Lancel S, Landowski TH, Lane DJ, Lane JD, Lanzi C, Lapaquette P, Lapierre LR, Laporte J, Laukkarinen J, Laurie GW, Lavandero S, Lavie L, LaVoie MJ, Law BY, Law HK, Law KB, Layfield R, Lazo PA, Le Cam L, Le Roch KG, Le Stunff H, Leardkamolkarn V, Lecuit M, Lee BH, Lee CH, Lee EF, Lee GM, Lee HJ, Lee H, Lee JK, Lee J, Lee JH, Lee JH, Lee M, Lee MS, Lee PJ, Lee SW, Lee SJ, Lee SJ, Lee SY, Lee SH, Lee SS, Lee SJ, Lee S, Lee YR, Lee YJ, Lee YH, Leeuwenburgh C, Lefort S, Legouis R, Lei J, Lei QY, Leib DA, Leibowitz G, Lekli I, Lemaire SD, Lemasters JJ, Lemberg MK, Lemoine A, Leng S, Lenz G, Lenzi P, Lerman LO, Lettieri Barbato D, Leu JI, Leung HY, Levine B, Lewis PA, 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Sanchez-Prieto R, Sandri M, Sanjuan MA, Santaguida S, Santambrogio L, Santoni G, Dos Santos CN, Saran S, Sardiello M, Sargent G, Sarkar P, Sarkar S, Sarrias MR, Sarwal MM, Sasakawa C, Sasaki M, Sass M, Sato K, Sato M, Satriano J, Savaraj N, Saveljeva S, Schaefer L, Schaible UE, Scharl M, Schatzl HM, Schekman R, Scheper W, Schiavi A, Schipper HM, Schmeisser H, Schmidt J, Schmitz I, Schneider BE, Schneider EM, Schneider JL, Schon EA, Schönenberger MJ, Schönthal AH, Schorderet DF, Schröder B, Schuck S, Schulze RJ, Schwarten M, Schwarz TL, Sciarretta S, Scotto K, Scovassi AI, Screaton RA, Screen M, Seca H, Sedej S, Segatori L, Segev N, Seglen PO, Seguí-Simarro JM, Segura-Aguilar J, Seki E, Sell C, Seiliez I, Semenkovich CF, Semenza GL, Sen U, Serra AL, Serrano-Puebla A, Sesaki H, Setoguchi T, Settembre C, Shacka JJ, Shajahan-Haq AN, Shapiro IM, Sharma S, She H, Shen CK, Shen CC, Shen HM, Shen S, Shen W, Sheng R, Sheng X, Sheng ZH, Shepherd TG, Shi J, Shi Q, Shi Q, Shi Y, Shibutani S, 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L, Steffan J, Stellrecht CM, Stenmark H, Stepkowski TM, Stern ST, Stevens C, Stockwell BR, Stoka V, Storchova Z, Stork B, Stratoulias V, Stravopodis DJ, Strnad P, Strohecker AM, Ström AL, Stromhaug P, Stulik J, Su YX, Su Z, Subauste CS, Subramaniam S, Sue CM, Suh SW, Sui X, Sukseree S, Sulzer D, Sun FL, Sun J, Sun J, Sun SY, Sun Y, Sun Y, Sun Y, Sundaramoorthy V, Sung J, Suzuki H, Suzuki K, Suzuki N, Suzuki T, Suzuki YJ, Swanson MS, Swanton C, Swärd K, Swarup G, Sweeney ST, Sylvester PW, Szatmari Z, Szegezdi E, Szlosarek PW, Taegtmeyer H, Tafani M, Taillebourg E, Tait SW, Takacs-Vellai K, Takahashi Y, Takáts S, Takemura G, Takigawa N, Talbot NJ, Tamagno E, Tamburini J, Tan CP, Tan L, Tan ML, Tan M, Tan YJ, Tanaka K, Tanaka M, Tang D, Tang D, Tang G, Tanida I, Tanji K, Tannous BA, Tapia JA, Tasset-Cuevas I, Tatar M, Tavassoly I, Tavernarakis N, Taylor A, Taylor GS, Taylor GA, Taylor JP, Taylor MJ, Tchetina EV, Tee AR, Teixeira-Clerc F, Telang S, Tencomnao T, Teng BB, Teng RJ, Terro F, 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G, Weis SN, Wen L, Wen X, Wen Y, Westermann B, Weyand CM, White AR, White E, Whitton JL, Whitworth AJ, Wiels J, Wild F, Wildenberg ME, Wileman T, Wilkinson DS, Wilkinson S, Willbold D, Williams C, Williams K, Williamson PR, Winklhofer KF, Witkin SS, Wohlgemuth SE, Wollert T, Wolvetang EJ, Wong E, Wong GW, Wong RW, Wong VK, Woodcock EA, Wright KL, Wu C, Wu D, Wu GS, Wu J, Wu J, Wu M, Wu M, Wu S, Wu WK, Wu Y, Wu Z, Xavier CP, Xavier RJ, Xia GX, Xia T, Xia W, Xia Y, Xiao H, Xiao J, Xiao S, Xiao W, Xie CM, Xie Z, Xie Z, Xilouri M, Xiong Y, Xu C, Xu C, Xu F, Xu H, Xu H, Xu J, Xu J, Xu J, Xu L, Xu X, Xu Y, Xu Y, Xu ZX, Xu Z, Xue Y, Yamada T, Yamamoto A, Yamanaka K, Yamashina S, Yamashiro S, Yan B, Yan B, Yan X, Yan Z, Yanagi Y, Yang DS, Yang JM, Yang L, Yang M, Yang PM, Yang P, Yang Q, Yang W, Yang WY, Yang X, Yang Y, Yang Y, Yang Z, Yang Z, Yao MC, Yao PJ, Yao X, Yao Z, Yao Z, Yasui LS, Ye M, Yedvobnick B, Yeganeh B, Yeh ES, Yeyati PL, Yi F, Yi L, Yin XM, Yip CK, Yoo YM, Yoo YH, Yoon SY, Yoshida K, Yoshimori T, Young KH, Yu H, Yu JJ, Yu JT, Yu J, Yu L, Yu WH, Yu XF, Yu Z, Yuan J, Yuan ZM, Yue BY, Yue J, Yue Z, Zacks DN, Zacksenhaus E, Zaffaroni N, Zaglia T, Zakeri Z, Zecchini V, Zeng J, Zeng M, Zeng Q, Zervos AS, Zhang DD, Zhang F, Zhang G, Zhang GC, Zhang H, Zhang H, Zhang H, Zhang H, Zhang J, Zhang J, Zhang J, Zhang J, Zhang JP, Zhang L, Zhang L, Zhang L, Zhang L, Zhang MY, Zhang X, Zhang XD, Zhang Y, Zhang Y, Zhang Y, Zhang Y, Zhang Y, Zhao M, Zhao WL, Zhao X, Zhao YG, Zhao Y, Zhao Y, Zhao YX, Zhao Z, Zhao ZJ, Zheng D, Zheng XL, Zheng X, Zhivotovsky B, Zhong Q, Zhou GZ, Zhou G, Zhou H, Zhou SF, Zhou XJ, Zhu H, Zhu H, Zhu WG, Zhu W, Zhu XF, Zhu Y, Zhuang SM, Zhuang X, Ziparo E, Zois CE, Zoladek T, Zong WX, Zorzano A, Zughaier SM";;"Jan 2016";1451606400;; 6544;"[Nobel prizes in medicine 2016].";"P. Auberger";"Equipe 02, Team 02";27816170;"Bulletin du cancer";"Auberger P";;"Nov 2016";1477958400;; 6542;"Autophagy, a key mechanism of oncogenesis and resistance in leukemia.";"P. Auberger";"Equipe 02, Team 02";27956388;Blood;"Auberger P, Puissant A";;"02 2017";1485907200;;"Autophagy is a lysosomal pathway involved in degradation of intracellular material. It appears as an adaptation mechanism that is essential for cellular homeostasis in response to various stress conditions. Over the past decade, many studies have linked alteration of autophagy with cancer initiation and progression, autoimmune, inflammatory, metabolic, and degenerative diseases. This review highlights recent findings on the impact of autophagy on leukemic transformation of normal hematopoietic stem cells and summarizes its role on leukemic cell response to chemotherapy." 6540;"The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia.";"P. Auberger";"Equipe 02, Team 02";28191887;"Nature medicine";"Fenouille N, Bassil CF, Ben-Sahra I, Benajiba L, Alexe G, Ramos A, Pikman Y, Conway AS, Burgess MR, Li Q, Luciano F, Auberger P, Galinsky I, DeAngelo DJ, Stone RM, Zhang Y, Perkins AS, Shannon K, Hemann MT, Puissant A, Stegmaier K";;"Mar 2017";1488326400;;"Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens." 6538;"Pro-inflammatory proteins S100A9 and tumor necrosis factor-α suppress erythropoietin elaboration in myelodysplastic syndromes.";"P. Auberger, T. Cluzeau";"Equipe 02, Team 02";28983059;Haematologica;"Cluzeau T, McGraw KL, Irvine B, Masala E, Ades L, Basiorka AA, Maciejewski J, Auberger P, Wei S, Fenaux P, Santini V, List A";;"12 2017";1512086400;;"Accumulating evidence implicates innate immune activation in the pathobiology of myelodysplastic syndromes. A key myeloid-related inflammatory protein, S100A9, serves as a Toll-like receptor ligand regulating tumor necrosis factor-α and interleukin-1β production. The role of myelodysplastic syndrome-related inflammatory proteins in endogenous erythropoietin regulation and response to erythroid-stimulating agents or lenalidomide has not been investigated. The HepG2 hepatoma cell line was used to investigate erythropoietin elaboration. Serum samples collected from 311 patients with myelodysplastic syndrome were investigated (125 prior to treatment with erythroid-stimulating agents and 186 prior to lenalidomide therapy). Serum concentrations of S100A9, S100A8, tumor necrosis factor-α, interleukin-1β and erythropoietin were analyzed by enzyme-linked immunosorbent assay. Using erythropoietin-producing HepG2 cells, we show that S100A9, tumor necrosis factor-α and interleukin-1β suppress transcription and cellular elaboration of erythropoietin. Pre-incubation with lenalidomide significantly diminished suppression of erythropoietin production by S100A9 or tumor necrosis factor-α. Moreover, in peripheral blood mononuclear cells from patients with myelodysplastic syndromes, lenalidomide significantly reduced steady-state S100A9 generation (=0.01) and lipopolysaccharide-induced tumor necrosis factor-α elaboration (=0.002). Enzyme-linked immunosorbent assays of serum from 316 patients with non-del(5q) myelodysplastic syndromes demonstrated a significant inverse correlation between tumor necrosis factor-α and erythropoietin concentrations (=0.006), and between S100A9 and erythropoietin (=0.01). Moreover, baseline serum tumor necrosis factor-α concentration was significantly higher in responders to erythroid-stimulating agents (=0.03), whereas lenalidomide responders had significantly lower tumor necrosis factor-α and higher S100A9 serum concentrations (=0.03). These findings suggest that S100A9 and its nuclear factor-κB transcriptional target, tumor necrosis factor-α, directly suppress erythropoietin elaboration in myelodysplastic syndromes. These cytokines may serve as rational biomarkers of response to lenalidomide and erythroid-stimulating agent treatments. Therapeutic strategies that either neutralize or suppress S100A9 may improve erythropoiesis in patients with myelodysplastic syndromes." 6536;"Targeting the Proteasome-Associated Deubiquitinating Enzyme USP14 Impairs Melanoma Cell Survival and Overcomes Resistance to MAPK-Targeting Therapies.";"M. Deckert, M. Ohanna, P. Auberger, S. Tartare-Deckert";"Equipe 11, Team 11, Equipe 02, Team 02";29703842;"Molecular cancer therapeutics";"Didier R, Mallavialle A, Ben Jouira R, Domdom MA, Tichet M, Auberger P, Luciano F, Ohanna M, Tartare-Deckert S, Deckert M";;"07 2018";1530403200;;"Advanced cutaneous melanoma is one of the most challenging cancers to treat because of its high plasticity, metastatic potential, and resistance to treatment. New targeted therapies and immunotherapies have shown remarkable clinical efficacy. However, such treatments are limited to a subset of patients and relapses often occur, warranting validation of novel targeted therapies. Posttranslational modification of proteins by ubiquitin coordinates essential cellular functions, including ubiquitin-proteasome system (UPS) function and protein homeostasis. Deubiquitinating enzymes (DUB) have been associated to multiple diseases, including cancer. However, their exact involvement in melanoma development and therapeutic resistance remains poorly understood. Using a DUB trap assay to label cellular active DUBs, we have observed an increased activity of the proteasome-associated DUB, USP14 (Ubiquitin-specific peptidase 14) in melanoma cells compared with melanocytes. Our survey of public gene expression databases indicates that high expression of correlates with melanoma progression and with a poorer survival rate in metastatic melanoma patients. Knockdown or pharmacologic inhibition of USP14 dramatically impairs viability of melanoma cells irrespective of the mutational status of , or and their transcriptional cell state, and overcomes resistance to MAPK-targeting therapies both and in human melanoma xenografted mice. At the molecular level, we find that inhibition of USP14 rapidly triggers accumulation of poly-ubiquitinated proteins and chaperones, mitochondrial dysfunction, ER stress, and a ROS production leading to a caspase-independent cell death. Our results provide a rationale for targeting the proteasome-associated DUB USP14 to treat and combat melanomas. ." 6534;"ZNF224 is a transcriptional repressor of AXL in chronic myeloid leukemia cells.";"P. Auberger";"Equipe 02, Team 02";30176265;Biochimie;"Sodaro G, Blasio G, Fiorentino F, Auberger P, Costanzo P, Cesaro E";;"Nov 2018";1541030400;;"ZNF224 is a KRAB-zinc finger transcription factor that exerts a key tumor suppressive role in chronic myelogenous leukemia. In this study, we identify the receptor tyrosine kinase Axl as a novel target of ZNF224 transcriptional repression activity. Axl overexpression is found in many types of cancer and is frequently associated with drug resistance. Interestingly, we also found that sensitivity to imatinib can be partly restored in imatinib-resistant chronic myelogenous leukemia cells by ZNF224 overexpression and the resulting suppression of Axl expression. These results, in accordance with our previous findings, support the role of ZNF224 in imatinib responsiveness and shed new insights into potential therapeutic use of ZNF224 in imatinib-resistant chronic myelogenous leukemia." 6532;"New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments.";"P. Auberger";"Equipe 02, Team 02";31410218;Theranostics;"Dufies M, Grytsai O, Ronco C, Camara O, Ambrosetti D, Hagege A, Parola J, Mateo L, Ayrault M, Giuliano S, Grépin R, Lagarde N, Montes M, Auberger P, Demange L, Benhida R, Pagès G";;"Jan 2019";1546300800;;"Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyrosine kinase inhibitor for RCC or cisplatin for HNSCC) are urgently needed on relapse. Here, we described the relevance of targeting the ELR+CXCL cytokines receptors, CXCR1/2, for the treatment of these two cancer types. : The relevance to patient treatment was evaluated by correlating the ELRCXCL/CXCR1/2 levels to survival using online available data. We report herein the synthesis of new pharmacological inhibitors of CXCR1/2 with anti-proliferation/survival activity. The latter was evaluated with the XTT assay with leukemic, breast, RCC and HNSCC cell lines. Their relevance as an alternative treatment was tested on sunitinib- and cisplatin- resistant cells. The most efficient compound was then tested in a mouse model of RCC and HNSCC. : RCC and HNSCC expressed the highest amounts of CXCR1/2 of all cancers. High levels of ELRCXCL cytokines (CXCL1, 2, 3, 5, 6, 7, 8) correlated to shorter survival. Among the 33 synthesized and tested molecules, compound C29 reduced ELRCXCL/CXCR1/2-dependent proliferation and migration of endothelial cells. C29 exerted an anti-proliferation/survival activity on a panel of cancer cells including naive and resistant RCC and HNSCC cells. C29 reduced the growth of experimental RCC and HNSCC tumors by decreasing tumor cell proliferation, angiogenesis and ELR/CXCL-mediated inflammation. : Our study highlights the relevance of new CXCR1/2 inhibitors for the treatment of RCC or HNSCC as first-line treatment or at relapse on reference therapies." 6530;"Drug Resistance in Hematological Malignancies.";"P. Auberger";"Equipe 02, Team 02";32847013;"International journal of molecular sciences";"Auberger P, Tamburini-Bonnefoy J, Puissant A";;"Aug 2020";1596240000;;"Hematological malignancies define a highly heterogeneous set of blood-, bone marrow-, and organ-associated diseases with highly variable prognoses that constantly relapse upon treatment [...]." 6527;"Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma.";"N. Mazure, P. Auberger";"Equipe 05, Team 05, Equipe 02, Team 02";33547392;"Communications biology";"Dufies M, Verbiest A, Cooley LS, Ndiaye PD, He X, Nottet N, Souleyreau W, Hagege A, Torrino S, Parola J, Giuliano S, Borchiellini D, Schiappa R, Mograbi B, Zucman-Rossi J, Bensalah K, Ravaud A, Auberger P, Bikfalvi A, Chamorey E, Rioux-Leclercq N, Mazure NM, Beuselinck B, Cao Y, Bernhard JC, Ambrosetti D, Pagès G";;"02 2021";1612137600;;"Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients." 6526;"Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort.";"M. Loschi, P. Auberger, T. Cluzeau";"Equipe 02, Team 02";33570629;"Blood advances";"Chiche E, Rahmé R, Bertoli S, Dumas PY, Micol JB, Hicheri Y, Pasquier F, Peterlin P, Chevallier P, Thomas X, Loschi M, Genthon A, Legrand O, Mohty M, Raffoux E, Auberger P, Caulier A, Joris M, Bonmati C, Roth-Guepin G, Lejeune C, Pigneux A, Vey N, Recher C, Ades L, Cluzeau T";;"01 2021";1609459200;;"CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD <10-3 was achieved in 57% of complete response (CR)/CR with incomplete hematological recovery (CRi) patients. Only the presence of mutated TP53 (P = .02) or PTPN11 (P = .004) predicted lower response in multivariate analysis. Interestingly, high-risk molecular prognosis subgroups defined by 2017 European LeukemiaNet risk stratification, including ASXL1 and RUNX1 mutations, were not associated with a significantly lower response rate using CPX-351. With a median follow-up of 8.6 months, median overall survival (OS) was 16.1 months. Thirty-six patients underwent allogeneic stem cell transplantation with a significantly longer median OS compared with nontransplanted patients (P < .001). In multivariate analyses, only spliceosome mutations were associated with better OS (P = .04). In comparison with intensive chemotherapy, there was no difference in OS for patients <60 years. These data confirm the efficacy and safety of CPX-351 in high-risk AML (t-AML and MRC-AML) in a real-life setting. CPX-351 is a treatment of choice for patients aged ≥60 years." 6524;"Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor.";"P. Auberger";"Equipe 02, Team 02";33790022;"Science translational medicine";"Roux B, Vaganay C, Vargas JD, Alexe G, Benaksas C, Pardieu B, Fenouille N, Ellegast JM, Malolepsza E, Ling F, Sodaro G, Ross L, Pikman Y, Conway AS, Tang Y, Wu T, Anderson DJ, Le Moigne R, Zhou HJ, Luciano F, Hartigan CR, Galinsky I, DeAngelo DJ, Stone RM, Auberger P, Schenone M, Carr SA, Guirouilh-Barbat J, Lopez B, Khaled M, Lage K, Hermine O, Hemann MT, Puissant A, Stegmaier K, Benajiba L";;"03 2021";1614556800;;"The development and survival of cancer cells require adaptive mechanisms to stress. Such adaptations can confer intrinsic vulnerabilities, enabling the selective targeting of cancer cells. Through a pooled in vivo short hairpin RNA (shRNA) screen, we identified the adenosine triphosphatase associated with diverse cellular activities (AAA-ATPase) valosin-containing protein (VCP) as a top stress-related vulnerability in acute myeloid leukemia (AML). We established that AML was the most responsive disease to chemical inhibition of VCP across a panel of 16 cancer types. The sensitivity to VCP inhibition of human AML cell lines, primary patient samples, and syngeneic and xenograft mouse models of AML was validated using -directed shRNAs, overexpression of a dominant-negative VCP mutant, and chemical inhibition. By combining mass spectrometry-based analysis of the VCP interactome and phospho-signaling studies, we determined that VCP is important for ataxia telangiectasia mutated (ATM) kinase activation and subsequent DNA repair through homologous recombination in AML. A second-generation VCP inhibitor, CB-5339, was then developed and characterized. Efficacy and safety of CB-5339 were validated in multiple AML models, including syngeneic and patient-derived xenograft murine models. We further demonstrated that combining DNA-damaging agents, such as anthracyclines, with CB-5339 treatment synergizes to impair leukemic growth in an MLL-AF9-driven AML murine model. These studies support the clinical testing of CB-5339 as a single agent or in combination with standard-of-care DNA-damaging chemotherapy for the treatment of AML." 6522;"The p54 cleaved form of the tyrosine kinase Lyn generated by caspases during BCR-induced cell death in B lymphoma acts as a negative regulator of apoptosis.";"A. Jacquel, JE. Ricci, P. Auberger";"Equipe 02, Team 02, Equipe 03";12586738;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Luciano F, Herrant M, Jacquel A, Ricci JE, Auberger P";;"Apr 2003";1049155200;;"Engagement of the B cell receptor antigen (BCR) triggers apoptosis on immature B cell lines. We report here that BCR triggering leads to caspase activation followed by Lyn cleavage and induction of apoptosis. The cleavage process is mitochondrion-dependent and involves caspases 9 and 7. Stable expression of the cleaved form of Lyn (Lyn-Delta-N) in Ramos B cells impairs BCR-mediated apoptosis as judged by loss of Delta(psi)m, caspase activation and PARP cleavage. Activation of the main survival pathways upon BCR-triggering was unaltered in both cell variants. However, the PI3-K inhibitor Ly294002 resensitizes Lyn-Delta-N cells to apoptosis. Selected cDNA expression arrays revealed that anti-IgM modulates the expression of approximately 20 genes in both cell variants. Among them, only c-Myc was found to be differentially regulated, which suggests a role for c-Myc in the B cell apoptotic response. Interestingly, c-Myc expression decreased more rapidly in Lyn-Delta-N compared with Lyn-WT cells during the first hours of anti-IgM stimulation. Nevertheless, rapid down-regulation of c-Myc following BCR engagement seems to correlate with the resistance of B cells to apoptosis. Thus, the soluble form of Lyn generated by caspases following BCR triggering acts as an inhibitor of B lymphocyte death likely through the modulation of c-Myc expression." 6520;"Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases.";"A. Jacquel, M. Deckert, P. Auberger";"Equipe 02, Team 02, Equipe 11, Team 11";12881712;Oncogene;"Charvet C, Alberti I, Luciano F, Jacquel A, Bernard A, Auberger P, Deckert M";;"Jul 2003";1057017600;;"Forkhead family transcription factors are critical regulators of cell cycle progression and apoptosis in hematopoietic cells. Here, we show that FOXO3a (also known as FKHRL1) is a new substrate of caspase-3-like proteases during apoptosis in T lymphocytes. FOXO3a was cleaved in vivo by caspases in leukemic Jurkat cells following engagement of Fas (CD95) receptor, staurosporine, and etoposide treatment, but not following engagement of CD99, a caspase-independent cell death inducer. Caspase-mediated cleavage of FOXO3a was also observed in CD4+ peripheral T cells subjected to activation-induced cell death. The expression of the death adapter FADD and caspase-8 was required for Fas-induced FOXO3a cleavage, but activation of survival pathways by overexpression of FLICE-inhibitory protein or phorbol myristate acetate treatment prevented it. FOXO3a was cleaved in vitro by caspase-3-like proteases at the consensus sequence DELD304A, releasing the N-terminal DNA-binding domain of FOXO3a from its C-terminal transactivating domain. Whereas full-length FOXO3a enhanced Forkhead response element-dependent transcription and apoptosis in Jurkat cells, both fragments were inactive to promote gene activation and cell death. In contrast, a caspase-resistant FOXO3a mutant exhibited enhanced transcriptional and proapoptotic activities. Together, these results indicate that the proteolytic cleavage of FOXO3a by caspases may represent a novel regulatory mechanism of FOXO3a activity during death receptors signaling." 6518;"Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";14555991;Oncogene;"Luciano F, Jacquel A, Colosetti P, Herrant M, Cagnol S, Pages G, Auberger P";;"Oct 2003";1064966400;;"Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation." 6515;"Imatinib induces mitochondria-dependent apoptosis of the Bcr-Abl-positive K562 cell line and its differentiation toward the erythroid lineage.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";14597677;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Jacquel A, Herrant M, Legros L, Belhacene N, Luciano F, Pages G, Hofman P, Auberger P";;"Nov 2003";1067644800;; 6513;"Imatinib mesylate (STI571) decreases the vascular endothelial growth factor plasma concentration in patients with chronic myeloid leukemia.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";14976047;Blood;"Legros L, Bourcier C, Jacquel A, Mahon FX, Cassuto JP, Auberger P, Pagès G";;"Jul 2004";1088640000;;"Increased angiogenesis in bone marrow (BM) is one of the characteristics of chronic myeloid leukemia (CML), a clonal myeloproliferative disorder that expresses a chimeric Bcr/Abl protein. Recently, the therapeutic strategy in CML has been totally modified with the development of a new drug: imatinib mesylate (STI571), a specific inhibitor of Bcr/Abl tyrosine kinase activity. The aim of our study was to determine, in patients with CML, the capacity of imatinib mesylate to modulate one of the most potent regulators of angiogenesis, the vascular endothelial growth factor (VEGF). In newly diagnosed CML, we observed significantly increased VEGF secretion by CML BM cells and significantly increased VEGF plasma concentrations. We showed that low plasma VEGF concentrations could be one of the characteristics of complete cytogenetic remission. To understand the molecular mechanisms leading to the inhibition of VEGF production by imatinib, we focused our experiments on the human cell line K562, which is Bcr/Abl positive. We demonstrated that imatinib inhibits VEGF gene transcription by targeting the Sp1 and Sp3 transcription factors. Taken together, our results highlight the potential prognostic value of VEGF concentrations in evaluating the evolution of CML patients treated with imatinib." 6511;"Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis.";"A. Jacquel, P. Auberger, S. Marchetti";"Equipe 02, Team 02, Team 03";15378010;Oncogene;"Herrant M, Jacquel A, Marchetti S, Belhacène N, Colosetti P, Luciano F, Auberger P";;"Oct 2004";1096588800;;"Mcl-1 is an antiapoptotic member of the Bcl-2 family that can promote cell viability. We report here that Mcl-1 is a new substrate for caspases during induction of apoptosis. Mcl-1 cleavage occurs after Asp127 and Asp157 and generates four fragments of 24, 19, 17 and 12 kDa in both intact cells and in vitro, an effect prevented by selective caspase inhibitors. As a consequence, the resulting protein that lacks the first 127 or 157 amino acids contains only the BH1-BH3 domains of Bcl-2 family members. Mutation of Asp127 and Asp157 abolishes the generation of the 24 and 12 kDa fragments and that of the 19 and 17 kDa fragments, respectively. Interestingly, when expressed in HeLa cells Mcl-1 wt and Mcl-1 Delta127 showed a markedly different intracellular distribution. Mcl-1 wt colocalized with alpha-Tubulin near the internal face of the plasma membrane, while Mcl-1 Delta127 coassociated with Bim-EL at the mitochondrial level. Coimmunoprecipitation experiments also demonstrated that Mcl1 Delta127 exhibited increased binding to Bim when compared to Mcl-1 wt. Finally, Mcl-1 wt unlike Mcl-1 Delta127 inhibited Bim-EL-induced caspase activation. Altogether, our findings demonstrate that cleavage of Mcl-1 by caspases modifies its subcellular localization, increases its association with Bim and inhibits its antiapoptotic function." 6509;"p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1)-dependent signaling contributes to epithelial skin carcinogenesis.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";16510590;"Cancer research";"Bourcier C, Jacquel A, Hess J, Peyrottes I, Angel P, Hofman P, Auberger P, Pouysségur J, Pagès G";;"Mar 2006";1141171200;;"Extracellular signal-regulated kinases (ERK) regulate cellular functions in response to a variety of external signals. However, the specific functions of individual ERK isoforms are largely unknown. Hence, we have investigated the specific function of ERK1 in skin homeostasis and tumorigenesis in ERK1 knockout mice. They spontaneously develop cutaneous lesions and hyperkeratosis with epidermis thickness. Skin hyperproliferation and inflammation induced by application of 12-O-tetradecanoylphorbol-13-acetate (TPA) is strongly reduced in mutant mice. ERK1(-/-) mice are resistant to development of skin papillomas induced by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by TPA. Tumor appearance was delayed, their formation was less frequent, and their number and size were reduced. Keratinocytes obtained from knockout mice showed reduced growth and resistance to apoptotic signals, accompanied by an impaired expression of genes implicated in growth control and invasiveness. These results highlight the importance of ERK1 in skin homeostasis and in the process of skin tumor development." 6507;"A role for caspases in the differentiation of erythroid cells and macrophages.";"A. Jacquel";"Equipe 02, Team 02";17905508;Biochimie;"Droin N, Cathelin S, Jacquel A, Guéry L, Garrido C, Fontenay M, Hermine O, Solary E";;"Feb 2008";1201824000;;"Several cysteine proteases of the caspase family play a central role in many forms of cell death by apoptosis. Other enzymes of the family are involved in cytokine maturation along inflammatory response. In recent years, several caspases involved in cell death were shown to play a role in other cellular processes such as proliferation and differentiation. In the present review, we summarize the current knowledge of the role of caspases in the differentiation of erythroid cells and macrophages. Based on these two examples, we show that the nature of involved enzymes, the pathways leading to their activation in response to specific growth factors, and the specificity of the target proteins that are cleaved by the activated enzymes strongly differ from one cell type to another. Deregulation of these pathways is thought to play a role in the pathophysiology of low-grade myelodysplastic syndromes, characterized by excessive activation of caspases and erythroid precursor apoptosis, and that of chronic myelomonocytic leukemia, characterized by a defective activation of caspases in monocytes exposed to M-CSF, which blocks their differentiation." 6505;"Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";18245170;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Puissant A, Grosso S, Jacquel A, Belhacene N, Colosetti P, Cassuto JP, Auberger P";;"Jun 2008";1212278400;;"Imatinib is successfully used in the treatment of chronic myelogenous leukemia (CML), and the main mechanisms of resistance in refractory patients are now partially understood. In the present study, we investigated the mechanism of action of resveratrol in imatinib-sensitive (IM-S) and -resistant (IM-R) CML cell lines. Resveratrol induced loss of viability and apoptosis in IM-S and IM-R in a time- and dose-dependent fashion. Inhibition of cell viability was detected for concentrations of resveratrol as low as 5 microM, and the IC(50) values for viability, clonogenic assays, apoptosis, and erythroid differentiation were in the 10-25 microM range. The effect of imatinib and resveratrol was additive in IM-S but not in IM-R clones in which the resveratrol effect was already maximal. The effect of resveratrol on apoptosis was partially rescued by zVAD-fmk, suggesting a caspase-independent contribution. Resveratrol action was independent of BCR-ABL expression and phosphorylation, and in agreement was additive to BCR-ABL silencing. Finally, phytoalexin inhibited the growth of BaF3 cells expressing mutant BCR-ABL proteins found in resistant patients, including the multiresistant T315I mutation. Our findings show that resveratrol induces apoptosis, caspase-independent death, and differentiation that collectively contribute to the specific elimination of CML cells. Resveratrol should provide therapeutic benefits in IM-R patients and in other hematopoietic malignancies." 6503;"Various functions of caspases in hematopoiesis.";"A. Jacquel";"Equipe 02, Team 02";19273205;"Frontiers in bioscience (Landmark edition)";"Droin N, Jacquel A, Guery L, Dufour E, Garrido C, Solary E";;"Jan 2009";1230768000;;"The role of cysteine proteases of the caspase family in apoptosis is well defined. Some caspases were initially shown to be involved in cytokine maturation along inflammatory response. In the recent years, several other non apoptotic functions of caspases were identified. In hematopoietic cells, caspases play a role in specific pathways of differentiation (erythropoiesis, differentiation of monocytes into macrophages, formation of proplatelets by megakaryocytes). These enzymes also play a non-apoptotic and complex role in regulating the maturation and proliferation of specific lymphocytes. Lastly, the apoptotic functions of caspases regulate the life span of several but not all blood cell types. The present review summarizes the current knowledge in these different functions. We show that the nature of involved enzymes, the pathways leading to their activation and the specificity of their cellular target proteins varies strongly from a cell type to another. We indicate also that, in most situations, specific Bcl-2-related proteins are involved in the control of caspase activation. Lastly, we discuss the deregulation of these pathways in hematopoietic diseases, including those in which an excess in caspase activation leads to cell death and those in which a default in caspase activation could block cell differentiation." 6501;"Gene expression profiling of imatinib and PD166326-resistant CML cell lines identifies Fyn as a gene associated with resistance to BCR-ABL inhibitors.";"A. Jacquel, M. Deckert, P. Auberger";"Equipe 02, Team 02, Equipe 11, Team 11";19567819;"Molecular cancer therapeutics";"Grosso S, Puissant A, Dufies M, Colosetti P, Jacquel A, Lebrigand K, Barbry P, Deckert M, Cassuto JP, Mari B, Auberger P";;"Jul 2009";1246406400;;"Imatinib is used to treat chronic myelogenous leukemia (CML), but resistance develops in all phases of this disease. The purpose of the present study was to identify the mode of resistance of newly derived imatinib-resistant (IM-R) and PD166326-resistant (PD-R) CML cells. IM-R and PD-R clones exhibited an increase in viability and a decrease in caspase activation in response to various doses of imatinib and PD166326, respectively, as compared with parental K562 cells. Resistance involved neither mutations in BCR-ABL nor increased BCR-ABL, MDR1 or Lyn expression, all known modes of resistance. To gain insight into the resistance mechanisms, we used pangenomic microarrays and identified 281 genes modulated in parental versus IM-R and PD-R cells. The gene signature was similar for IM-R and PD-R cells, accordingly with the cross-sensitivity observed for both inhibitors. These genes were functionally associated with pathways linked to development, cell adhesion, cell growth, and the JAK-STAT cascade. Especially relevant were the increased expression of the tyrosine kinases AXL and Fyn as well as CD44 and HMGA2. Small interfering RNA experiments and pharmacologic approaches identified FYN as a candidate for resistance to imatinib. Our findings provide a comprehensive picture of the transcriptional events associated with imatinib and PD166326 resistance and identify Fyn as a new potential target for therapeutic intervention in CML." 6499;"Colony-stimulating factor-1-induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages.";"A. Jacquel";"Equipe 02, Team 02";19721010;Blood;"Jacquel A, Benikhlef N, Paggetti J, Lalaoui N, Guery L, Dufour EK, Ciudad M, Racoeur C, Micheau O, Delva L, Droin N, Solary E";;"Oct 2009";1254355200;;"The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves of AKT activation with increasing amplitude and duration are required to provoke the formation of the caspase-8-activating molecular platform. CSF-1 and its receptor are both required for oscillations in AKT activation to occur, and expression of a constitutively active AKT mutant prevents the macrophage differentiation process. The extracellular receptor kinase 1/2 pathway is activated with a coordinated oscillatory kinetics in a CSF-1R-dependent manner but plays an accessory role in caspase activation and nucleophosmin cleavage. Altogether, CSF-1 stimulation activates a molecular clock that involves phosphatidylinositol-3 kinase and AKT to promote caspase activation. This oscillatory signaling pathway, which is coordinated with extracellular receptor kinase 1/2 oscillatory activation, involves CSF-1 and CSF-1R and controls the terminal differentiation of macrophages." 6497;"Alpha-defensins secreted by dysplastic granulocytes inhibit the differentiation of monocytes in chronic myelomonocytic leukemia.";"A. Jacquel";"Equipe 02, Team 02";19864642;Blood;"Droin N, Jacquel A, Hendra JB, Racoeur C, Truntzer C, Pecqueur D, Benikhlef N, Ciudad M, Guery L, Jooste V, Dufour E, Fenaux P, Quesnel B, Kosmider O, Fontenay M, Ducoroy P, Solary E";;"Jan 2010";1262304000;;"Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that occurs in elderly patients. One of the main diagnostic criteria is the accumulation of heterogeneous monocytes in the peripheral blood. We further explored this cellular heterogeneity and observed that part of the leukemic clone in the peripheral blood was made of immature dysplastic granulocytes with a CD14(-)/CD24(+) phenotype. The proteome profile of these cells is dramatically distinct from that of CD14(+)/CD24(-) monocytes from CMML patients or healthy donors. More specifically, CD14(-)/CD24(+) CMML cells synthesize and secrete large amounts of alpha-defensin 1-3 (HNP1-3). Recombinant HNPs inhibit macrophage colony-stimulating factor (M-CSF)-driven differentiation of human peripheral blood monocytes into macrophages. Using transwell, antibody-mediated depletion, suramin inhibition of purinergic receptors, and competitive experiments with uridine diphosphate (UDP)/uridine triphosphate (UTP), we demonstrate that HNP1-3 secreted by CD14(-)/CD24(+) cells inhibit M-CSF-induced differentiation of CD14(+)/CD24(-) cells at least in part through P2Y6, a receptor involved in macrophage differentiation. Altogether, these observations suggest that a population of immature dysplastic granulocytes contributes to the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the differentiation capabilities of monocytes." 6496;"Leukemic cell xenograft in zebrafish embryo for investigating drug efficacy.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";21228037;Haematologica;"Pruvot B, Jacquel A, Droin N, Auberger P, Bouscary D, Tamburini J, Muller M, Fontenay M, Chluba J, Solary E";;"Jan 2011";1294963200;;"Zebrafish were proposed as an alternative to mammalian models to assess the efficacy and toxicity of antileukemic drugs. Due to the limited number of transgenic zebrafish leukemia models, we explored human leukemic cell xenograft in zebrafish embryos. Human leukemic cell lines and blast cells sorted from patients with acute myelogenous leukemia were injected 48 hours post-fertilization and remained in the circulation of zebrafish embryos for several days without affecting their development. Imatinib and oxaphorines did not demonstrate any toxicity on normal zebrafish embryos and decreased the leukemic burden in animals xenografted with sensitive leukemic cell lines. Two other molecules, all-trans retinoic acid and the translation inhibitor 4EGI-1, demonstrated teratogenic effects at concentrations shown to be efficient in vitro, which precluded investigation of their antileukemic activity in such models. Altogether, xenografted leukemic cells in zebrafish embryos are a pharmacologically relevant model for screening non-teratogenic drugs." 6494;"Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells.";"A. Jacquel";"Equipe 02, Team 02";21467134;"Cancer prevention research (Philadelphia, Pa.)";"Colin D, Limagne E, Jeanningros S, Jacquel A, Lizard G, Athias A, Gambert P, Hichami A, Latruffe N, Solary E, Delmas D";;"Jul 2011";1309478400;;"trans-Resveratrol has been proposed to prevent tumor growth and to sensitize cancer cells to anticancer agents. Polyphenol entry into the cells has remained poorly understood. Here, we show that [(3)H]-resveratrol enters colon cancer cells (SW480, SW620, HT29) and leukemia U937 cells through a monensin (5-20 μmol/L) -sensitive process that suggests clathrin-independent endocytosis. Uptake of the molecule can be prevented by methyl-β-cyclodextrin (2-12 mg/mL), nystatin (12 ng/mL), and filipin (1 μg/mL), which all disrupt plasma membrane lipid rafts. Accordingly, radiolabeled resveratrol accumulates in sphingomyelin- and cholesterol-enriched cell fractions. Interestingly, extracellular signal-regulated kinases (ERK), c-Jun NH(2)-terminal kinases (JNK), and Akt also accumulate in lipid rafts on resveratrol exposure (IC(50) at 48 h ≈ 30 μmol/L in SW480 and U937 cells). In these rafts also, resveratrol promotes the recruitment, by the integrin α(V)β(3) (revealed by coimmunoprecipitation with an anti-integrin α(V)β(3) antibody), of signaling molecules that include the FAK (focal adhesion kinase), Fyn, Grb2, Ras, and SOS proteins. Resveratrol-induced activation of downstream signaling pathways and caspase-dependent apoptosis is prevented by endocytosis inhibitors, lipid raft-disrupting molecules, and the integrin antagonist peptide arginine-glycine-aspartate (500 nmol/L). Altogether, these data show the role played by lipid rafts in resveratrol endocytosis and activation of downstream pathways leading to cell death." 6492;"Fine-tuning nucleophosmin in macrophage differentiation and activation.";"A. Jacquel";"Equipe 02, Team 02";21876121;Blood;"Guery L, Benikhlef N, Gautier T, Paul C, Jego G, Dufour E, Jacquel A, Cally R, Manoury B, Vanden Berghe T, Vandenabeele P, Droin N, Solary E";;"Oct 2011";1317427200;;"M-CSF-driven differentiation of peripheral blood monocytes is one of the sources of tissue macrophages. In humans and mice, the differentiation process involves the activation of caspases that cleave a limited number of proteins. One of these proteins is nucleophosmin (NPM1), a multifunctional and ubiquitous protein. Here, we show that caspases activated in monocytes exposed to M-CSF cleave NPM1 at D213 to generate a 30-kDa N-terminal fragment. The protein is further cleaved into a 20-kDa fragment, which involves cathepsin B. NPM1 fragments contribute to the limited motility, migration, and phagocytosis capabilities of resting macrophages. Their activation with lipopolysaccharides inhibits proteolytic processes and restores expression of the full-length protein that negatively regulates the transcription of genes encoding inflammatory cytokines (eg, NPM1 is recruited with NF-κB on the MCP1 gene promoter to decrease its transcription). In mice with heterozygous npm gene deletion, cytokine production in response to lipopolysaccharides, including CXCL1 (KC), MCP1, and MIP2, is dramatically enhanced. These results indicate a dual function of NPM1 in M-CSF-differentiated macrophages. Proteolysis of the protein participates in the establishment of a mature macrophage phenotype. In response to inflammatory stimuli, the full-length protein negatively regulates inflammatory cytokine production." 6490;"Proper macrophagic differentiation requires both autophagy and caspase activation.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";22751215;Autophagy;"Jacquel A, Obba S, Solary E, Auberger P";;"Jul 2012";1341100800;;"Autophagy allows the elimination of superfluous or damaged macromolecules or organelles. Genetic evidence indicates that autophagy plays essential functions during differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process triggered by colony stimulating factor1 (CSF1/CSF-1). We have established, using pharmacological inhibitors, siRNA approaches and Atg7 (-/-) mice, that autophagy is required for proper CSF1/CSF-1-driven differentiation of human and murine monocytes and acquisition of phagocytic functions. Collectively, these findings highlight an essential role of autophagy during monocyte differentiation and acquisition of macrophage functions. Deciphering the complex interplay between caspase and autophagy that occurs during this process will undoubtedly bring new insights in our understanding of monocyte differentiation." 6488;"Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";24014241;Blood;"Willems L, Jacque N, Jacquel A, Neveux N, Maciel TT, Lambert M, Schmitt A, Poulain L, Green AS, Uzunov M, Kosmider O, Radford-Weiss I, Moura IC, Auberger P, Ifrah N, Bardet V, Chapuis N, Lacombe C, Mayeux P, Tamburini J, Bouscary D";;"Nov 2013";1383264000;;"Cancer cells require nutrients and energy to adapt to increased biosynthetic activity, and protein synthesis inhibition downstream of mammalian target of rapamycin complex 1 (mTORC1) has shown promise as a possible therapy for acute myeloid leukemia (AML). Glutamine contributes to leucine import into cells, which controls the amino acid/Rag/mTORC1 signaling pathway. We show in our current study that glutamine removal inhibits mTORC1 and induces apoptosis in AML cells. The knockdown of the SLC1A5 high-affinity transporter for glutamine induces apoptosis and inhibits tumor formation in a mouse AML xenotransplantation model. l-asparaginase (l-ase) is an anticancer agent also harboring glutaminase activity. We show that l-ases from both Escherichia coli and Erwinia chrysanthemi profoundly inhibit mTORC1 and protein synthesis and that this inhibition correlates with their glutaminase activity levels and produces a strong apoptotic response in primary AML cells. We further show that l-ases upregulate glutamine synthase (GS) expression in leukemic cells and that a GS knockdown enhances l-ase-induced apoptosis in some AML cells. Finally, we observe a strong autophagic process upon l-ase treatment. These results suggest that l-ase anticancer activity and glutamine uptake inhibition are promising new therapeutic strategies for AML. " 6486;"cIAPs and XIAP reduce RIPKs to silence.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";24744249;Blood;"Jacquel A, Auberger P";;"Apr 2014";1396310400;; 6484;"CD271 is an imperfect marker for melanoma initiating cells.";"A. Jacquel";"Equipe 02, Team 02";25105565;Oncotarget;"Cheli Y, Bonnazi VF, Jacquel A, Allegra M, De Donatis GM, Bahadoran P, Bertolotto C, Ballotti R";;"Jul 2014";1404172800;;"Understanding the molecular and cellular processes underlying melanoma plasticity and heterogeneity is of paramount importance to improve the efficiency of current treatment and to overcome resistance to chemotherapy drugs. The notion of plasticity and heterogeneity implies the existence of melanoma cell populations with different phenotypic and tumorigenic properties. Using melanoma cell lines and melanoma cells freshly isolated from patient biopsies, we investigated the relationship between ABCB5+, CD271+ and low-MITF, expressing populations that were reported to display melanoma initiating cell properties. Here, we showed that ABCB5+ and CD271+ populations poorly overlap. However, we found that the CD271+ population is enriched in low-MITF cells and expresses a higher level of stemness genes, such as OCT4, NANOG and NES. These features could explain the increased tumorigenicity of the CD271+ cells. The rapid conversion of CD271+ to CD271- cells in vitro demonstrates the plasticity ability of melanoma cells. Finally, we observed that the transient slow-growing population contains only CD271+ cells that are highly tumorigenic. However, the fast growing/CD271+ population exhibits a poor tumorigenic ability. Taking together, our data show that CD271 is an imperfect marker for melanoma initiating cells, but may be useful to identify melanoma cells with an increased stemness and tumorigenic potential." 6482;"Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";26601252;"Science advances";"Green AS, Maciel TT, Hospital MA, Yin C, Mazed F, Townsend EC, Pilorge S, Lambert M, Paubelle E, Jacquel A, Zylbersztejn F, Decroocq J, Poulain L, Sujobert P, Jacque N, Adam K, So JC, Kosmider O, Auberger P, Hermine O, Weinstock DM, Lacombe C, Mayeux P, Vanasse GJ, Leung AY, Moura IC, Bouscary D, Tamburini J";;"Sep 2015";1441065600;;"Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD-induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3-ITD(+) cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy. " 6480;"CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";28850564;"British journal of cancer";"Dufies M, Giuliano S, Viotti J, Borchiellini D, Cooley LS, Ambrosetti D, Guyot M, Ndiaye PD, Parola J, Claren A, Schiappa R, Gal J, Frangeul A, Jacquel A, Cassuto O, Grépin R, Auberger P, Bikfalvi A, Milano G, Escudier B, Rioux-Leclercq N, Porta C, Negrier S, Chamorey E, Ferrero JM, Pagès G";;"Sep 2017";1504224000;;"Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis." 6477;"Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic myeloid leukemia.";"A. Jacquel";"Equipe 02, Team 02";29423056;Oncotarget;"Sodaro G, Cesaro E, Montano G, Blasio G, Fiorentino F, Romano S, Jacquel A, Aurberger P, Costanzo P";;"Jan 2018";1514764800;;"The transcription factor ZNF224 plays a key proapoptotic role in chronic myelogenous leukemia (CML), by modulating Wilms Tumor protein 1 (WT1) dependent apoptotic genes transcription. Recently, we demonstrated that Bcr-Abl signaling represses ZNF224 expression in Bcr-Abl positive CML cell lines and in CML patients. Interestingly, Imatinib and second-generation tyrosine kinase inhibitors specifically increase ZNF224 expression. On the other hand, Bcr-Abl positively modulates, via JAK2 activation, the expression of the c-Myc oncogene, which is required for Bcr-Abl oncogenic transformation in CML. Consequently, JAK2 inhibitors represent promising molecular therapeutic tools in CML. In this work, we demonstrate that ZNF224 is a novel transcriptional repressor of c-Myc in CML. We also show that ZNF224 induction by Imatinib and AG490, a specific JAK2 inhibitor, is responsible for the transcriptional repression of c-MYC, thus highlighting the crucial role of the ZNF224/c-Myc axis in Imatinib responsiveness. Interestingly, we also report that ZNF224 is induced by AG490 in Imatinib-resistant CML cells, leading to c-Myc repression and apoptosis induction. These findings suggest that the development of molecular tools able to induce ZNF224 expression could provide promising means to bypass Imatinib resistance in CML." 6475;"Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice.";"A. Jacquel, E. Verhoeyen, G. MICHEL, P. Chaintreuil, S. Marchetti";"Equipe 02, Team 02, Team 03, Equipe 06, Team 06";33432150;"Nature microbiology";"Dufies O, Doye A, Courjon J, Torre C, Michel G, Loubatier C, Jacquel A, Chaintreuil P, Majoor A, Guinamard RR, Gallerand A, Saavedra PHV, Verhoeyen E, Rey A, Marchetti S, Ruimy R, Czerucka D, Lamkanfi M, Py BF, Munro P, Visvikis O, Boyer L";;"03 2021";1614556800;;"Inflammasomes are signalling platforms that are assembled in response to infection or sterile inflammation by cytosolic pattern recognition receptors. The consequent inflammasome-triggered caspase-1 activation is critical for the host defence against pathogens. During infection, NLRP3, which is a pattern recognition receptor that is also known as cryopyrin, triggers the assembly of the inflammasome-activating caspase-1 through the recruitment of ASC and Nek7. The activation of the NLRP3 inflammasome is tightly controlled both transcriptionally and post-translationally. Despite the importance of the NLRP3 inflammasome regulation in autoinflammatory and infectious diseases, little is known about the mechanism controlling the activation of NLRP3 and the upstream signalling that regulates the NLRP3 inflammasome assembly. We have previously shown that the Rho-GTPase-activating toxin from Escherichia coli cytotoxic necrotizing factor-1 (CNF1) activates caspase-1, but the upstream mechanism is unclear. Here, we provide evidence of the role of the NLRP3 inflammasome in sensing the activity of bacterial toxins and virulence factors that activate host Rho GTPases. We demonstrate that this activation relies on the monitoring of the toxin's activity on the Rho GTPase Rac2. We also show that the NLRP3 inflammasome is activated by a signalling cascade that involves the p21-activated kinases 1 and 2 (Pak1/2) and the Pak1-mediated phosphorylation of Thr 659 of NLRP3, which is necessary for the NLRP3-Nek7 interaction, inflammasome activation and IL-1β cytokine maturation. Furthermore, inhibition of the Pak-NLRP3 axis decreases the bacterial clearance of CNF1-expressing UTI89 E. coli during bacteraemia in mice. Taken together, our results establish that Pak1 and Pak2 are critical regulators of the NLRP3 inflammasome and reveal the role of the Pak-NLRP3 signalling axis in vivo during bacteraemia in mice." 6474;"AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.";"A. Jacquel, P. Auberger";"Equipe 02, Team 02";34986346;"Cell reports";"Grenier A, Poulain L, Mondesir J, Jacquel A, Bosc C, Stuani L, Mouche S, Larrue C, Sahal A, Birsen R, Ghesquier V, Decroocq J, Mazed F, Lambert M, Andrianteranagna M, Viollet B, Auberger P, Lane AA, Sujobert P, Bouscary D, Sarry JE, Tamburini J";;"Jan 2022";1641340800;;"AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML." 6465;"Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness.";"G. Robert, M. Deckert, P. Auberger";"Equipe 02, Team 02, Equipe 11, Team 11";19212434;"PloS one";"Essafi-Benkhadir K, Grosso S, Puissant A, Robert G, Essafi M, Deckert M, Chamorey E, Dassonville O, Milano G, Auberger P, Pagès G";;"Jan 2009";1230768000;;"The ambiguous role of transcription factor Sp3 for tumour progression is still debated since it was described as a transcriptional repressor or activator. Here we tried to decipher the molecular mechanisms implicated in Sp3 accumulation observed in aggressive tumours." 6462;"Autophagy is an important event for megakaryocytic differentiation of the chronic myelogenous leukemia K562 cell line.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";19786835;Autophagy;"Colosetti P, Puissant A, Robert G, Luciano F, Jacquel A, Gounon P, Cassuto JP, Auberger P";;"Nov 2009";1257033600;;"Autophagy is a highly conserved catabolic process for the elimination and recycling of organelles and macromolecules, characterized by the formation of double-membrane vesicles called autophagosomes. To date, the function of autophagy in cell differentiation is poorly documented. Here, we investigated the possibility that megakaryocytic differentiation of the Chronic Myelogenous Leukemia (CML) cell line K562, a process known to be accompanied by accumulation of vacuoles inside the cells, might involve autophagy. Using various complementary approaches, we show that the combination of the phorbol ester PMA and the p38(MAPK) inhibitor SB202190 (SB), which engaged a majority of K562 cells towards the megakaryocytic lineage, also triggered vacuolization and autophagy. The combination of PMA + SB appears to induce both increase in autophagic fluxes and an autophagic degradation blockage. Induction of autophagy was accompanied also by increased expression of Beclin 1 and p62/SQSTM1 and was found to precede the onset of megakaryocytic differentiation. Moreover, knockdown of LC3 and Beclin 1 by specific siRNAs impaired PMA + SB-mediated vacuolization, LC3-II accumulation and megakaryocytic differentiation, as well. To the best of our knowledge, this is the first description that induction of autophagy is involved in megakaryocytic differentiation of K562 CML cells." 6460;"Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.";"F. BOST, G. Robert, P. Auberger";"Equipe 02, Team 02";19924252;"PloS one";"Robert G, Ben Sahra I, Puissant A, Colosetti P, Belhacene N, Gounon P, Hofman P, Bost F, Cassuto JP, Auberger P";;"Nov 2009";1257033600;;"CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients." 6458;"Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation.";"G. Robert, P. Auberger";"Equipe 02, Team 02";20103647;"Cancer research";"Puissant A, Robert G, Fenouille N, Luciano F, Cassuto JP, Raynaud S, Auberger P";;"Feb 2010";1264982400;;"Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy." 6456;"Targeting autophagy to fight hematopoietic malignancies.";"G. Robert, P. Auberger";"Equipe 02, Team 02";20703092;"Cell cycle (Georgetown, Tex.)";"Puissant A, Robert G, Auberger P";;"Sep 2010";1283299200;;"Macroautophagy, referred hereafter to as autophagy is an evolutionary conserved catabolic process for the degradation and recycling of macromolecules, bulk cytoplasm and dammaged organelles. Autophagy is activated under stress conditions induced by nutrient deprivation, hypoxia and drug treatments. Morphologically, autophagic cells are characterized by the accumulation of double membrane cytoplasmic vesicules called autophagosomes that surrounds cytoplasmic proteins and/or organelles. Autophagosomes next fuse with lysosomes to generate autolysosomes, the structures in which the retained constituents are digested before recycling into the cytoplasm. In this context, autophagy promotes cell survival under adverse conditions. In contrast, under certain circumstances autophagic cells may engage a specific mode of cell death called type II cell death or autophagic cell death (ACD). Considering the strategic positionnement of this process at the crossroads of cell death and survival, it is not surprising that defects in autophagy have been linked to a plethora of human diseases, including hematopoietic malignancies. Finally, autophagy induction is repressed by the mammalian target of rapamycin complex 1 (mTORC1) and favored by the adenosine-monophosphate activated-protein kinase (AMPK). In the present review, we focus on the functions of autophagy in normal and malignant hematopoiesis and discuss the opportunity to target the AMPK/mTOR pathways as a new therapeutic strategy to fight hematopoietic malignancies with a special emphasis on Chronic Myelogenous Leukemia (CML)." 6452;"Persistent activation of the Fyn/ERK kinase signaling axis mediates imatinib resistance in chronic myelogenous leukemia cells through upregulation of intracellular SPARC.";"A. Jacquel, G. Robert, M. Deckert, M. Ohanna, P. Auberger, S. Tartare-Deckert";"Equipe 02, Team 02, Equipe 11, Team 11";21098700;"Cancer research";"Fenouille N, Puissant A, Dufies M, Robert G, Jacquel A, Ohanna M, Deckert M, Pasquet JM, Mahon FX, Cassuto JP, Raynaud S, Tartare-Deckert S, Auberger P";;"Dec 2010";1291161600;;"SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)-resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC." 6450;"Azacitidine-resistant SKM1 myeloid cells are defective for AZA-induced mitochondrial apoptosis and autophagy.";"G. Robert, P. Auberger, T. Cluzeau";"Equipe 02, Team 02";21654192;"Cell cycle (Georgetown, Tex.)";"Cluzeau T, Robert G, Puissant A, Jean-Michel K, Cassuto JP, Raynaud S, Auberger P";;"Jul 2011";1309478400;;"Azacitidine (AZA) is the current treatment for patients with high-risk myelodysplastic syndrome, but resistance is a common feature of AZA-treated patients. To investigate the mechanisms associated with AZA resistance in vitro, we generated AZA-resistant SKM1 myeloid cells, called hereafter AZA-R. AZA-R cells exhibit impaired mitochondrial membrane permeabilization and caspase activation in response to AZA compared to their AZA-sensitive (AZA-S) counterpart. AZA induced LC3-II accumulation and cathepsin B activity in AZA-S cells, two hallmarks of autophagy. AZA-R cells displayed increased basal autophagy but are resistant to AZA-mediated autophagy. Inhibition of autophagy using LC3 siRNA revealed that autophagy is protective in AZA-S cells and AZA-R cells in basal conditions. By contrast, AZA-R cells exhibited impaired autophagy in response to AZA. Collectively, our findings indicate that AZA promotes apoptosis and autophagy in SKM1 cells, and that AZA-R cells are resistant to both apoptosis and autophagy induced by AZA." 6448;"A new hydroxylated nonaprenylhydroquinone from the Mediterranean marine sponge Sarcotragus spinosulus.";"G. Robert, P. Auberger";"Equipe 02, Team 02";21822411;"Marine drugs";"Abed C, Legrave N, Dufies M, Robert G, Guérineau V, Vacelet J, Auberger P, Amade P, Mehiri M";;"Jan 2011";1293840000;;"Chemical investigation of the Mediterranean sponge Sarcotragus spinosulus led to the isolation of a new hydroxylated nonaprenylhydroquinone, along with two known metabolites, hepta- and octaprenylhydroquinones. The structure of the new metabolite was assigned by extensive 1D and 2D NMR analyses and MS studies. The antileukemic effect of the three compounds towards the chronic myelogenous leukemia (CML) cells line K562 was also evaluated." 6446;"Mechanism of action of the multikinase inhibitor Foretinib.";"A. Jacquel, G. Robert, P. Auberger, T. Cluzeau";"Equipe 02, Team 02";22101270;"Cell cycle (Georgetown, Tex.)";"Dufies M, Jacquel A, Robert G, Cluzeau T, Puissant A, Fenouille N, Legros L, Raynaud S, Cassuto JP, Luciano F, Auberger P";;"Dec 2011";1322697600;;"Mitotic catastrophe (MC) is induced when stressed cells enter prematurely or inappropriately into mitosis and can be caused by ionizing radiation and anticancer drugs. Foretinib is a multikinase inhibitor whose mechanism of action is incompletely understood. We investigated here the effect of Foretinib on chronic myelogenous leukemia (CML) cell lines either sensitive (IM-S) or resistant (IM-R) to the tyrosine kinase inhibitor Imatinib. Foretinib decreased viability and clonogenic potential of IM-S and IM-R CML cells as well. Foretinib-treated cells exhibited increased size, spindle assembly checkpoint anomalies and enhanced ploidy that collectively evoked mitotic catastrophe (MC). Accordingly, Foretinib-stimulated CML cells displayed decreased expression of Cdk1, Cyclin B1 and Plk1. In addition, Foretinib triggered caspase-2 activation that precedes mitochondrial membrane permeabilization. Accordingly, z-VAD-fmk and a caspase-2 siRNA abolished Foretinib-mediated cell death but failed to affect MC, indicating that Foretinib-mediated apoptosis and MC are two independent events. Anisomycin, a JNK activator, impaired Foretinib-induced MC and inhibition or knockdown of JNK phenotyped its effect on MC. Moreover, we found that Foretinib acted as a potent inhibitor of JNK. Importantly, Foretinib exhibited no or very little effect on normal peripheral blood mononuclear cells, monocytes or melanocytes cells but efficiently inhibited the clonogenic potential of CD34+ cell from CML patients. Collectively, our data show that the multikinase inhibitor Foretinib induces MC in CML cells and other cell lines via JNK-dependent inhibition of Plk1 expression and triggered apoptosis by a caspase 2-mediated mechanism. This unusual mechanism of action may have important implications for the treatment of cancer." 6444;"Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells.";"A. Jacquel, G. Robert, P. Auberger, T. Cluzeau";"Equipe 02, Team 02";22141136;Oncotarget;"Dufies M, Jacquel A, Belhacene N, Robert G, Cluzeau T, Luciano F, Cassuto JP, Raynaud S, Auberger P";;"Nov 2011";1320105600;;"AXL is a receptor tyrosine kinase of the TAM family, the function of which is poorly understood. We previously identified AXL overexpression in Imatinib (IM)-resistant CML cell lines and patients. The present study was conducted to investigate the role of AXL and the mechanisms underlying AXL overexpression in Tyrosine Kinase Inhibitor (TKI)-resistant CML cells. We present evidence that high AXL expression level is a feature of TKI-resistant CML cells and knockdown of AXL sensitized TKI-resistant cells to IM. In addition, expression of wild-type AXL but not a dominant negative form of AXL confers IM-sensitive CML cells the capacity to resist IM effect. AXL overexpression required PKCα and β and constitutive activation of ERK1/2. Accordingly, GF109203X a PKC inhibitor, U0126 a MEK1 inhibitor and PKCα/β knockdown restore sensitivity to IM while PKCα or PKCβ overexpression in CML cells promotes protection against IM-induced cell death. Finally, using luciferase promoter activity assays we established that AXL is regulated transcriptionally through the AP1 transcription factor. Our findings reveal an unexpected role of AXL in resistance to TKI in CML cells, identify the molecular mechanisms involved in its overexpression and support the notion that AXL is a new marker of resistance to TKI in CML." 6441;"Autophagy is required for CSF-1-induced macrophagic differentiation and acquisition of phagocytic functions.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";22452982;Blood;"Jacquel A, Obba S, Boyer L, Dufies M, Robert G, Gounon P, Lemichez E, Luciano F, Solary E, Auberger P";;"Mar 2012";1332979200;;"Autophagy is the process by which superfluous or damaged macromolecules or organelles are degraded by the lysosome. Pharmacologic and genetic evidence indicates that autophagy plays pleiotropic functions in cellular homeostasis, development, survival, and differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by colony stimulating factor-1. We show here, using pharmacologic inhibitors, siRNA approaches, and Atg7-/- mice, that autophagy initiated by ULK1 is required for proper colony stimulating factor-1-driven differentiation of human and murine monocytes. We also unravel a role for autophagy in macrophage acquisition of phagocytic functions. Collectively, these findings highlight an unexpected and essential role of autophagy during monocyte differentiation and acquisition of macrophage functions." 6439;"Imatinib triggers mesenchymal-like conversion of CML cells associated with increased aggressiveness.";"A. Jacquel, G. Robert, M. Deckert, P. Auberger, T. Cluzeau";"Equipe 02, Team 02, Equipe 11, Team 11";22467682;"Journal of molecular cell biology";"Puissant A, Dufies M, Fenouille N, Ben Sahra I, Jacquel A, Robert G, Cluzeau T, Deckert M, Tichet M, Chéli Y, Cassuto JP, Raynaud S, Legros L, Pasquet JM, Mahon FX, Luciano F, Auberger P";;"Aug 2012";1343779200;;"Chronic myelogenous leukemia (CML) is a cytogenetic disorder resulting from the expression of p210BCR-ABL. Imatinib, an inhibitor of BCR-ABL, has emerged as the leading compound to treat CML patients. Despite encouraging clinical results, resistance to imatinib represents a major drawback for therapy, as a substantial proportion of patients are refractory to this treatment. Recent publications have described the existence of a small cancer cell population with the potential to exhibit the phenotypic switch responsible for chemoresistance. To investigate the existence of such a chemoresistant cellular subpopulation in CML, we used a two-step approach of pulse and continuous selection by imatinib in different CML cell lines that allowed the emergence of a subpopulation of adherent cells (IM-R Adh) displaying an epithelial-mesenchymal transition (EMT)-like phenotype. Overexpression of several EMT markers was observed in this CML subpopulation, as well as in CD34(+) CML primary cells from patients who responded poorly to imatinib treatment. In response to imatinib, this CD44(high)/CD24(low) IM-R Adh subpopulation exhibited increased adhesion, transmigration and invasion in vitro and in vivo through specific overexpression of the αVβ3 receptor. FAK/Akt pathway activation following integrin β3 (ITGβ3) engagement mediated the migration and invasion of IM-R Adh cells, whereas persistent activation of ERK counteracted BCR-ABL inhibition by imatinib, promoting cell adhesion-mediated resistance." 6438;"BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients.";"A. Jacquel, G. Robert, P. Auberger, T. Cluzeau";"Equipe 02, Team 02";22577154;Oncotarget;"Cluzeau T, Robert G, Mounier N, Karsenti JM, Dufies M, Puissant A, Jacquel A, Renneville A, Preudhomme C, Cassuto JP, Raynaud S, Luciano F, Auberger P";;"Apr 2012";1333238400;;"Azacitidine is the leading compound to treat patients suffering myelodysplastic syndrome (MDS) or AML with less than 30% of blasts, but a majority of patients is primary refractory or rapidly relapses under treatment. These patients have a drastically reduced life expectancy as compared to sensitive patients. Therefore identifying predictive factors for AZA resistance is of great interest to propose alternative therapeutic strategies for non-responsive patients. We generated AZA-resistant myeloid cell line (SKM1-R) that exhibited increased expression of BCL2L10 an anti-apoptotic Bcl-2 member. Importantly, BCL2L10 knockdown sensitized SKM1-R cells to AZA effect suggesting that increased BCL2L10 expression is linked to AZA resistance in SKM1-R. We next established in 77 MDS patients that resistance to AZA is significantly correlated with the percentage of MDS or AML cells expressing BCL2L10. In addition, we showed that the proportion of BCL2L10 positive bone marrow cells can predict overall survival in MDS or AML patients. We propose a convenient assay in which the percentage of BCL2L10 expressing cells as assessed by flow cytometry is predictive of whether or not a patient will become resistant to AZA. Therefore, systematic determination of BCL2L10 expression could be of great interest in newly diagnosed and AZA-treated MDS patients." 6436;"The anti-apoptotic Bcl-B protein inhibits BECN1-dependent autophagic cell death.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";22498477;Autophagy;"Robert G, Gastaldi C, Puissant A, Hamouda A, Jacquel A, Dufies M, Belhacene N, Colosetti P, Reed JC, Auberger P, Luciano F";;"Apr 2012";1333238400;;"Bcl-2 family members are key modulators of apoptosis that have recently been shown to also regulate autophagy. It has been previously reported that Bcl-2 and Bcl-X(L) bind and inhibit BECN1, an essential mediator of autophagy. Bcl-B is an anti-apoptotic member of the Bcl-2 family that possesses the four BH (Bcl-2 homology) domains (BH1, BH2, BH3 and BH4) and a predicted C-terminal trans-membrane domain. Although the anti-apoptotic properties of Bcl-B are well characterized, its physiological function remains to be established. In the present study, we first established that Bcl-B interacts with the BH3 domain of BECN1. We also showed that Bcl-B overexpression reduces autophagy triggered by a variety of pro-autophagic stimuli. This impairment of autophagy was closely related to the capacity of Bcl-B to bind to BECN1. Importantly, we have demonstrated that Bcl-B knockdown triggers autophagic cell death and sensitizes cells to amino acid starvation. The cell death induced by Bcl-B knockdown was partially dependent on components of the autophagy machinery (LC3; BECN1; ATG5). These findings reveal a new role of Bcl-B in the regulation of autophagy." 6433;"Ultrasound-assisted one-pot synthesis of anti-CML nucleosides featuring 1,2,3-triazole nucleobase under iron-copper catalysis.";"G. Robert, P. Auberger";"Equipe 02, Team 02";22595539;"Ultrasonics sonochemistry";"Driowya M, Puissant A, Robert G, Auberger P, Benhida R, Bougrin K";;"Nov 2012";1351728000;;"A simple and efficient synthesis of modified 1,2,3-triazole nucleosides was developed. The strategy involved sequential one-pot acetylation-azidation-cycloaddition procedure and was found to be highly effective under a cooperative effect of ultrasound activation and iron/copper catalysis. The reactions were carried out under both conventional and ultrasonic irradiation conditions. In general, improvement in rates and yields were observed when reactions were carried out under sonication compared with conventional conditions. This one-pot procedure provides several advantages such as operational simplicity, high yield, safety and environment friendly protocol. The resulting substituted nucleosides were evaluated for their anticancer activity against K562 chronic myelogenous leukemia (CML) cell line." 6431;"All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to ponatinib.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";23238683;Oncotarget;"Cassuto O, Dufies M, Jacquel A, Robert G, Ginet C, Dubois A, Hamouda A, Puissant A, Luciano F, Karsenti JM, Legros L, Cassuto JP, Lenain P, Auberger P";;"Dec 2012";1354320000;;"The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients." 6429;"Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E mutation.";"G. Robert, P. Auberger";"Equipe 02, Team 02";23300174;Haematologica;"Peyrade F, Re D, Ginet C, Gastaud L, Allegra M, Ballotti R, Thyss A, Zenz T, Auberger P, Robert G";;"Feb 2013";1359676800;; 6427;"How recent advances in high-risk myelodysplastic syndrome physiopathology may impact future treatments.";"A. Jacquel, G. Robert, P. Auberger, T. Cluzeau";"Equipe 02, Team 02";23394086;"Current pharmaceutical design";"Cluzeau T, Robert G, Jacquel A, Auberger P";;"Jan 2013";1356998400;;"Myelodysplastic Syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis that often develop into acute myeloid leukemia (AML). MDSs are predominant in the elderly with an incidence of 20/100000 at 70 years of age. To date, the only curative treatment is allogeneic stem cell transplantation; however, a majority of patients are not eligible for this therapy. Azacitidine (AZA), a hypomethylating agent, remains the primary treatment for MDS patients, which leads to a significant increase in overall survival (OS), although it is not curative. Although it is well known that the impairment of apoptosis and differentiation are important features of this complex disease, the implication of autophagy in the pathogenesis of MDS is an emerging concept. Another significant advance in MDS pathogenesis research is the recent identification of mutations in genes encoding transcription factors implicated in hematopoiesis and proteins involved in splicing (SF3B1), methylation (DNMT3A), regulation of methylation (TET2 and IDH), DNA conformation (EZH2 and ASXL1) and differentiation (N- and K-RAS). Additionally, BCL2 family member expression and regulation may also affect the physiopathology of this disease. We have recently reported that targeting autophagy may be an interesting option for the treatment of AZA-resistant patients. Thus, targeting the products of the above-mentioned genes or the signaling pathways affected by the corresponding proteins may be of great interest for the development of a new arsenal of molecules to fight MDS. In this review, we discuss the new aspects of MDS physiopathology and how recent advances in MDS pathogenesis research may impact future treatments to improve the outcome of MDS patients. " 6425;"Simalikalactone E (SkE), a new weapon in the armamentarium of drugs targeting cancers that exhibit constitutive activation of the ERK pathway.";"A. Jacquel, G. Robert, P. Auberger, S. Tartare-Deckert";"Equipe 02, Team 02, Equipe 11, Team 11";23518796;Oncotarget;"Robert G, Jullian V, Jacquel A, Ginet C, Dufies M, Torino S, Pottier A, Peyrade F, Tartare-Deckert S, Bourdy G, Deharo E, Auberger P";;"Dec 2012";1354320000;;"Simalikalactone E (SkE) is a quassinoid extracted from a widely used Amazonian antimalarial remedy. Although SkE has previously been shown to have cytostatic and/or cytotoxic activities in some tumor cell lines, its mechanism of action has not yet been characterized. We show here that SkE in the high nanomolar range inhibited the growth of various leukemic and solid tumor cell lines. Importantly, SkE was highly efficient at inhibiting chronic myelogenous leukemia (CML) cells that exhibit constitutive activation of the MAPK pathway and, accordingly, it impaired the phosphorylation of ERK1/2. SkE also abrogated MEK1/2 and B-Raf phosphorylation but had no effect on Ras activity. Moreover, SkE was particularly effective against melanoma cell lines carrying the B-Raf-V600E mutation. Importantly, SkE resensitized the PLX-4032-resistant 451Lu melanoma cell line (451Lu-R) and was more efficient than U0126, a MEK inhibitor, and PLX-4032 (PLX) at inducing the apoptosis of two hairy cell leukemia (HCL) patient samples carrying the B-Raf-V600E mutation. Finally, SkE was as efficient as imatinib at inhibiting tumor formation in a xenograft model of CML cells in athymic mice. In conclusion, we show that SkE, a very potent inhibitor of B-Raf-V600E, is highly effective against cancer cell lines that exhibit constitutive activation of the ERK1/2 pathway." 6423;"Ponatinib circumvents all types of imatinib resistance in chronic myelogenous leukemia cell lines.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";23673326;"Cell cycle (Georgetown, Tex.)";"Dufies M, Cassuto O, Jacquel A, Robert G, Auberger P";;"Jun 2013";1370044800;; 6421;"FeCl3-promoted and ultrasound-assisted synthesis of resveratrol O-derived glycoside analogs.";"G. Robert, P. Auberger";"Equipe 02, Team 02";24961448;"Ultrasonics sonochemistry";"Marzag H, Robert G, Dufies M, Bougrin K, Auberger P, Benhida R";;"Jan 2015";1420070400;;"Phenol derived O-glycosides were synthesized using a direct and convenient O-glycosidation, starting from acetylated sugars in the presence of FeCl3, an inexpensive, mild and benign Lewis acid catalyst. The reactions were carried out under both conventional and ultrasonic irradiation conditions. In general, improvement in rates and yields were observed when reactions were carried out under sonication compared with conventional conditions leading to the corresponding β-O-glycosides as the major anomer. Post-synthetic transformations of iodophenol intermediates led to new resveratrol O-glycoside analogs in good overall yields. " 6420;"Phenotypic and genotypic characterization of azacitidine-sensitive and resistant SKM1 myeloid cell lines.";"A. Jacquel, G. Robert, P. Auberger, PS. ROHRLICH, T. Cluzeau";"Equipe 02, Team 02, Equipe 04, Team 04";24962689;Oncotarget;"Cluzeau T, Dubois A, Jacquel A, Luciano F, Renneville A, Preudhomme C, Karsenti JM, Mounier N, Rohrlich P, Raynaud S, Mari B, Robert G, Auberger P";;"Jun 2014";1403740800;;"In the present study, we provide a comparative phenotypic and genotypic analysis of azacitidine-sensitive and resistant SKM-1 cell lines. Morphologically, SKM1-R exhibited increase in cell size that accounts for by enhanced ploidy in a majority of cells as shown by cell cycle and karyotype analysis. No specific Single Nucleotide Polymorphism (SNP) alteration was found in SKM1-R cells compared to their SKM1-S counterpart. Comparative pangenomic profiling revealed the up-regulation of a panel of genes involved in cellular movement, cell death and survival and down-regulation of genes required for cell to cell signaling and free radical scavenging in SKM1-R cells. We also searched for mutations frequently associated with myelodysplastic syndromes (MDS) and found that both cell lines harbored mutations in TET2, ASLX1 and TP53. Collectively, our data show that despite their different morphological and phenotypic features, SKM1-S and SKM1-R cells exhibited similar genotypic characteristics. Finally, pangenomic profiling identifies new potential pathways to be targeted to circumvent AZA-resistance. In conclusion, SKM1-R cells represent a valuable tool for the validation of new therapeutic intervention in MDS. " 6418;"The small heat shock protein B8 (HSPB8) confers resistance to bortezomib by promoting autophagic removal of misfolded proteins in multiple myeloma cells.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";25051369;Oncotarget;"Hamouda MA, Belhacene N, Puissant A, Colosetti P, Robert G, Jacquel A, Mari B, Auberger P, Luciano F";;"Aug 2014";1406851200;;"Velcade is one of the inescapable drug to treat patient suffering from multiple myeloma (MM) and resistance to this drug represents a major drawback for patients. However, the mechanisms underlying velcade resistance remain incompletely understood. We derived several U266 MM cell clones that resist to velcade. U266-resistant cells were resistant to velcade-induced cell death but exhibited a similar sensitivity to various proapoptotic stimuli. Careful analysis of proteosomal subunits and proteasome enzymatic activities showed that neither the composition nor the activity of the proteasome was affected in velcade-resistant cells. Elimination of velcade-induced poly-ubiquitinated proteins and protein aggregates was drastically stimulated in the resistant cells and correlated with increased cell survival. Inhibition of the lysosomal activity in velcade-resistant cells resulted in an increase of cell aggregates and decrease survival, indicating that aggregates are eliminated through lysosomal degradation. In addition, pangenomic profiling of velcade-sensitive and resistant cells showed that the small heat shock protein HSPB8 was overexpressed in resistant cells. Finally, gain and loss of function experiment demonstrated that HSPB8 is a key factor for velcade resistance. In conclusion, HSPB8 plays an important role for the elimination of aggregates in velcade-resistant cells that contributes to their enhanced survival. " 6416;"Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib.";"G. Robert, P. Auberger";"Equipe 02, Team 02";25815361;Oncoscience;"Bailleux C, Robert G, Ginet C, Re D, Thyss A, Sudaka I, Peyrottes I, Hofman P, Auberger P, Peyrade F";;"Jan 2015";1420070400;;"Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder that accounts for 2% of all leukemia. Recent identification of the recurrent V600E BRAF mutation in a majority of HCL patients has led some teams to evaluate the clinical potential of vemurafenib, a BRAF V600 specific inhibitor in a limited number of refractory HCL patients. Recently, we published the case of an HCL patient successfully treated with a low dose of vemurafenib. Eight months after the ending of treatment this patient relapsed. We present here the successful retreatment of this patient with a second line of vemurafenib. Our data suggest for the first time that vemurafenib at the dose of 240 mg once a day could be sufficient to maintain a complete hematological remission after an initial induction treatment with low-dose vemurafenib (2 × 240 mg) daily without inducing major toxicity. " 6413;"An miRNA-DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia.";"G. Robert, P. Auberger";"Equipe 02, Team 02";27881579;"Clinical cancer research : an official journal of the American Association for Cancer Research";"Solly F, Koering C, Mohamed AM, Maucort-Boulch D, Robert G, Auberger P, Flandrin-Gresta P, Adès L, Fenaux P, Kosmider O, Tavernier-Tardy E, Cornillon J, Guyotat D, Campos L, Mortreux F, Wattel E";;"Nov 2016";1480032000;;" Azacitidine inhibits DNA methyltransferases, including DNMT1, and is currently the standard of care for patients with higher-risk myelodysplastic syndrome (HRMDS) or low blast count acute myeloid leukemia (AML). The expression of 754 miRNAs was compared in azacitidine-resistant and azacitidine-sensitive myelodysplastic syndrome cells. We investigated the role of differentially expressed miRNAs on DNMT1 expression and azacitidine resistance We next evaluated anti-DNMT1 miRNA expression in pretreatment bone marrow samples derived from 75 patients treated with azacitidine for HRMDS or AML. Seven miRNAs, including 5 that targeted the DNMT1 3' UTR, were repressed in azacitidine-resistant cells in which DNMT1 protein levels were significantly higher. Ectopic anti-DNMT1 miRNA expression decreased DNMT1 expression and increased azacitidine sensitivity, whereas specific inhibition of endogenous anti-DNMT1 miRNAs increased DNMT1 expression and triggered azacitidine resistance. In patients treated with azacitidine, decreased expression of anti-DNMT1 miRNAs was associated with poor outcome. miR-126* had the strongest prognostic impact. Patients with miR-126* myelodysplastic syndrome had significantly lower response rates ( = 0.04) and higher relapse rates ( = 0.03), as well as shorter progression-free (PFS; = 0.004) and overall survival (OS; = 0.004). Multivariate analysis showed that age, miR-126* expression, and revised International Prognostic Scoring System risk independently predicted PFS and OS. In 15 patient samples collected over time, decreased miRNA expression levels were associated with secondary resistance. A decreased expression of anti-DNMT1 miRNAs might account for azacitidine resistance in HRMDS and AML, and measuring miRNA expression before and during treatment might help predict primary or secondary azacitidine resistance. ." 6411;"In Vitro and in Vivo Evaluation of Fully Substituted (5-(3-Ethoxy-3-oxopropynyl)-4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as Original Nucleoside Analogues to Circumvent Resistance in Myeloid Malignancies.";"G. Robert, P. Auberger";"Equipe 02, Team 02";28094938;"Journal of medicinal chemistry";"Amdouni H, Robert G, Driowya M, Furstoss N, Métier C, Dubois A, Dufies M, Zerhouni M, Orange F, Lacas-Gervais S, Bougrin K, Martin AR, Auberger P, Benhida R";;"02 2017";1485907200;;"A series of nucleoside analogues bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl-1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy. Compound 4a also proved efficient in vivo on mice xenografted with SKM1-R MDS cell line. Additionally, some insights in its mode of action revealed that this compound induced cell death by caspase and autophagy induction." 6409;"Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides.";"G. Robert, P. Auberger";"Equipe 02, Team 02";28325600;"Bioorganic & medicinal chemistry letters";"Alaoui S, Dufies M, Driowya M, Demange L, Bougrin K, Robert G, Auberger P, Pagès G, Benhida R";;"05 2017";1493596800;;"Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization." 6408;"[Autophagy, a key player in leukemogenesis and a therapeutic target in hematopoietic malignancies].";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";28367807;"Medecine sciences : M/S";"Jacquel A, Luciano F, Puissant A, Robert G, Auberger P";;"Mar 2017";1488326400;; 6406;"Modular synthesis of new C-aryl-nucleosides and their anti-CML activity.";"G. Robert, P. Auberger";"Equipe 02, Team 02";29655981;"Bioorganic & medicinal chemistry letters";"Marzag H, Zerhouni M, Tachallait H, Demange L, Robert G, Bougrin K, Auberger P, Benhida R";;"06 2018";1527811200;;"The C-aryl-ribosyles are of utmost interest for the development of antiviral and anticancer agents. Even if several synthetic pathways have been disclosed for the preparation of these nucleosides, a direct, few steps and modular approaches are still lacking. In line with our previous efforts, we report herein a one step - eco-friendly β-ribosylation of aryles and heteroaryles through a direct Friedel-Craft ribosylation mediated by bismuth triflate, Bi(OTf). The resulting carbohydrates have been functionalized by cross-coupling reactions, leading to a series of new C-aryl-nucleosides (32 compounds). Among them, we observed that 5d exerts promising anti-proliferative effects against two human Chronic Myeloid Leukemia (CML) cell lines, both sensitive (K562-S) or resistant (K562-R) to imatinib, the ""gold standard of care"" used in this pathology. Moreover, we demonstrated that 5d kills CML cells by a non-conventional mechanism of cell death." 6404;"BCL2L10 positive cells in bone marrow are an independent prognostic factor of azacitidine outcome in myelodysplastic syndrome and acute myeloid leukemia.";"G. Robert, P. Auberger, PS. ROHRLICH, T. Cluzeau";"Equipe 02, Team 02, Equipe 04, Team 04";28514758;Oncotarget;"Vidal V, Robert G, Goursaud L, Durand L, Ginet C, Karsenti JM, Luciano F, Gastaud L, Garnier G, Braun T, Hirsch P, Raffoux E, Nloga AM, Padua RA, Dombret H, Rohrlich P, Ades L, Chomienne C, Auberger P, Fenaux P, Cluzeau T";;"Jul 2017";1498867200;;"Azacitidine (AZA), the reference treatment for most higher-risk myelodysplastic (MDS) patients can also improve overall survival (OS) in elderly acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy, but reliable biological markers predicting response and OS in patients treated with AZA are lacking. In a preliminary study, we found that an increase of the percentage of BCL2L10, an anti-apoptotic member of the bcl-2 family, was correlated with AZA resistance. In this study, we assessed prospectively by flow cytometry the prognostic value of BCL2L10 positive bone marrow mononuclear cells in 70 patients (42 MDS and 28 AML), prior to AZA treatment.In patients with baseline marrow blasts below 30%, the baseline percentage of bone marrow BCL2L10 positive cells inversely correlated with response to AZA and OS independently of the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R). Specifically, OS was significantly lower in patients with more than 10% BCL2L10 positive cells (median 8.3 vs 22.9 months in patients with less than 10% positivity, p = 0,001). In summary, marrow BCL2L10 positive cells may be a biomarker for azacitidine response and OS, with a potential impact in clinical practice." 6401;"IL-34 and CSF-1 display an equivalent macrophage differentiation ability but a different polarization potential.";"A. Jacquel, E. Verhoeyen, G. Robert, P. Auberger, P. Chaintreuil, S. Marchetti";"Equipe 02, Team 02, Team 03";29321503;"Scientific reports";"Boulakirba S, Pfeifer A, Mhaidly R, Obba S, Goulard M, Schmitt T, Chaintreuil P, Calleja A, Furstoss N, Orange F, Lacas-Gervais S, Boyer L, Marchetti S, Verhoeyen E, Luciano F, Robert G, Auberger P, Jacquel A";;"01 2018";1514764800;;"CSF-1 and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes. IL-34 promotes the differentiation and survival of monocytes, macrophages and osteoclasts, as CSF-1 does. However, IL-34 binds other receptors, suggesting that differences exist in the effect of both cytokines. In the present study, we compared the differentiation and polarization abilities of human primary monocytes in response to CSF-1 or IL-34. CSF-1R engagement by one or the other ligands leads to AKT and caspase activation and autophagy induction through expression and activation of AMPK and ULK1. As no differences were detected on monocyte differentiation, we investigated the effect of CSF-1 and IL-34 on macrophage polarization into the M1 or M2 phenotype. We highlighted a striking increase in IL-10 and CCL17 secretion in M1 and M2 macrophages derived from IL-34 stimulated monocytes, respectively, compared to CSF-1 stimulated monocytes. Variations in the secretome induced by CSF-1 or IL-34 may account for their different ability to polarize naïve T cells into Th1 cells. In conclusion, our findings indicate that CSF-1 and IL-34 exhibit the same ability to induce human monocyte differentiation but may have a different ability to polarize macrophages." 6399;"ATP-competitive Plk1 inhibitors induce caspase 3-mediated Plk1 cleavage and activation in hematopoietic cell lines.";"A. Jacquel, C. Savy, G. Robert, P. Auberger, S. Marchetti";"Equipe 02, Team 02, Team 03";29541386;Oncotarget;"Dufies M, Ambrosetti D, Boulakirba S, Calleja A, Savy C, Furstoss N, Zerhouni M, Parola J, Aira-Diaz L, Marchetti S, Orange F, Lacas-Gervais S, Luciano F, Jacquel A, Robert G, Pagès G, Auberger P";;"Feb 2018";1517443200;;"Polo-like kinases (Plks) define a highly conserved family of Ser/Thr kinases with crucial roles in the regulation of cell division. Here we show that Plk1 is cleaved by caspase 3, but not by other caspases in different hematopoietic cell lines treated with competitive inhibitors of the ATP-binding pocket of Plk1. Intriguingly, Plk1 was not cleaved in cells treated with Rigosertib, a non-competitive inhibitor of Plk1, suggesting that binding of the inhibitor to the ATP binding pocket of Plk1 triggers a conformational change and unmasks a cryptic caspase 3 cleavage site on the protein. Cleavage occurs after Asp-404 in a DYSD/K sequence and separates the kinase domain from the two PBDs of Plk1. All Plk1 inhibitors triggered G2/M arrest, activation of caspases 2 and 3, polyploidy, multiple nuclei and mitotic catastrophe, albeit at higher concentrations in the case of Rigosertib. Upon BI-2536 treatment, Plk1 cleavage occurred only in the cytosolic fraction and cleaved Plk1 accumulated in this subcellular compartment. Importantly, the cleaved N-Terminal fragment of Plk1 exhibited a higher enzymatic activity than its non-cleaved counterpart and accumulated into the cytoplasm conversely to the full length and the C-Terminal Plk1 fragments that were found essentially into the nucleus. Finally, the DYSD/K cleavage site was highly conserved during evolution from to human. In conclusion, we described herein for the first time a specific cleavage of Plk1 by caspase 3 following treatment of cancer cells with ATP-competitive inhibitors of Plk1." 6395;"Implication and Regulation of AMPK during Physiological and Pathological Myeloid Differentiation.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";30274374;"International journal of molecular sciences";"Jacquel A, Luciano F, Robert G, Auberger P";;"Sep 2018";1535760000;;"AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase consisting of the arrangement of various α β, and γisoforms that are expressed differently depending on the tissue or the cell lineage. AMPK is one of the major sensors of energy status in mammalian cells and as such plays essential roles in the regulation of cellular homeostasis, metabolism, cell growth, differentiation, apoptosis, and autophagy. AMPK is activated by two upstream kinases, the tumor suppressor liver kinase B1 (LKB1) and the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) through phosphorylation of the kinase on Thr172, leading to its activation. In addition, AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. Although it is well established that AMPK can control the differentiation of different cell lineages, including hematopoietic stem cells (HSCs), progenitors, and mature hematopoietic cells, the role of AMPK regarding myeloid cell differentiation is less documented. The differentiation of monocytes into macrophages triggered by colony stimulating factor 1 (CSF-1), a process during which both caspase activation (independently of apoptosis induction) and AMPK-dependent stimulation of autophagy are necessary, is one noticeable example of the involvement of AMPK in the physiological differentiation of myeloid cells. The present review focuses on the role of AMPK in the regulation of the physiological and pathological differentiation of myeloid cells. The mechanisms of autophagy induction by AMPK will also be addressed, as autophagy has been shown to be important for differentiation of hematopoietic cells. In addition, myeloid malignancies (myeloid leukemia or dysplasia) are characterized by profound defects in the establishment of proper differentiation programs. Reinduction of a normal differentiation process in myeloid malignancies has thus emerged as a valuable and promising therapeutic strategy. As AMPK seems to exert a key role in the differentiation of myeloid cells, notably through induction of autophagy, we will also discuss the potential to target this pathway as a pro-differentiating and anti-leukemic strategy in myeloid malignancies." 6394;"Azacitidine resistance caused by LAMP2 deficiency: a therapeutic window for the use of autophagy inhibitors in MDS/AML patients?";"G. Robert, P. Auberger";"Equipe 02, Team 02";30806567;Autophagy;"Robert G, Auberger P";;"05 2019";1556668800;;"Chaperone-mediated autophagy (CMA) is a selective form of autophagy that allows the elimination and recycling of cytosolic proteins endowed with a KFERQ-like motif into the lysosome. During this process, the proteins to be degraded are recognized by cellular chaperones such as HSC70 and presented to the CMA receptor LAMP2A, which then translocate them into lysosomes for degradation. In this punctum, we discuss the mechanisms underlying the response and resistance to Azacitidine (Aza) in MDS/AML cell lines and bone marrow CD34+ blasts from MDS/AML patients. We show that treatment of MDS/AML cell lines and bone marrow samples from MDS/AML patients with Aza triggers loss of LAMP2 expression leading to CMA defects. LAMP2 deficiency is responsible for CMA defects, Aza resistance and hypersensitivity to lysosome and autophagy inhibitors. Low levels of LAMP2 expression in CD34+ blasts from MDS/AML patients correlate with an absence of response to Aza and are associated to a pejorative overall survival. We propose that CD34+/LAMP2Low patients at diagnosis or who become CD34+/LAMP2Low during the course of treatment with Aza could receive an autophagy inhibitor available in the clinic." 6392;"Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells.";"G. Robert";"Equipe 02, Team 02";30759257;"Nucleic acids research";"Beauvarlet J, Bensadoun P, Darbo E, Labrunie G, Rousseau B, Richard E, Draskovic I, Londono-Vallejo A, Dupuy JW, Nath Das R, Guédin A, Robert G, Orange F, Croce S, Valesco V, Soubeyran P, Ryan KM, Mergny JL, Djavaheri-Mergny M";;"04 2019";1554076800;;"G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound." 6390;"Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies.";"A. Jacquel, G. Robert, P. Auberger";"Equipe 02, Team 02";31623164;Cells;"Robert G, Jacquel A, Auberger P";;"10 2019";1569888000;;"Chaperone-mediated autophagy (CMA) ensures the selective degradation of cellular proteins endowed with a KFERQ-like motif by lysosomes. It is estimated that 30% of all cellular proteins can be directed to the lysosome for CMA degradation, but only a few substrates have been formally identified so far. Mechanistically, the KFERQ-like motifs present in substrate proteins are recognized by the molecular chaperone Hsc70c (Heat shock cognate 71 kDa protein cytosolic), also known as HSPA8, and directed to LAMP2A, which acts as the CMA receptor at the lysosomal surface. Following linearization, the protein substrate is next transported to the lumen of the lysosomes, where it is degraded by resident proteases, mainly cathepsins and eventually recycled to sustain cellular homeostasis. CMA is induced by different stress conditions, including energy deprivation that also activates macro-autophagy (MA), that may make it difficult to decipher the relative impact of both pathways on cellular homeostasis. Besides common inducing triggers, CMA and MA might be induced as compensatory mechanisms when either mechanism is altered, as it is the often the case in different pathological settings. Therefore, CMA activation can compensate for alterations of MA and vice versa. In this context, these compensatory mechanisms, when occurring, may be targeted for therapeutic purposes. Both processes have received particular attention from scientists and clinicians, since modulation of MA and CMA may have a profound impact on cellular proteostasis, metabolism, death, differentiation, and survival and, as such, could be targeted for therapeutic intervention in degenerative and immune diseases, as well as in cancer, including hematopoietic malignancies. The role of MA in cancer initiation and progression is now well established, but whether and how CMA is involved in tumorigenesis has been only sparsely explored. In the present review, we encompass the description of the mechanisms involved in CMA, its function in the physiology and pathogenesis of hematopoietic cells, its emerging role in cancer initiation and development, and, finally, the potential therapeutic opportunity to target CMA or CMA-mediated compensatory mechanisms in hematological malignancies." 6388;"Clonal selection in therapy-related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment.";"G. Robert, P. Auberger, T. Cluzeau";"Equipe 02, Team 02";31990086;"European journal of haematology";"Calleja A, Yun S, Moreilhon C, Karsenti JM, Gastaud L, Mannone L, Komrokji R, Al Ali N, Dadone-Montaudie B, Robert G, Auberger P, Raynaud S, Sallman DA, Cluzeau T";;"May 2020";1588291200;;"Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) are defined as complications of previous cytotoxic therapy. Azacitidine (AZA), a hypomethylating agent, has showed activity in t-MDS/AML." 6386;"Ultrasound-assisted one-pot three-component synthesis of new isoxazolines bearing sulfonamides and their evaluation against hematological malignancies.";"C. Favreau, G. Robert, M. Bourgoin, P. Auberger";"Equipe 02, Team 02";34520963;"Ultrasonics sonochemistry";"Talha A, Favreau C, Bourgoin M, Robert G, Auberger P, El Ammari L, Saadi M, Benhida R, Martin AR, Bougrin K";;"Oct 2021";1633046400;;"In the present study, following a one-pot two-step protocol, we have synthesized novel sulfonamides-isoxazolines hybrids (3a-r) via a highly regioselective 1,3-dipolar cycloaddition. The present methodology capitalized on trichloroisocyanuric acid (TCCA) as a safe and ecological oxidant and chlorinating agent for the in-situ conversion of aldehydes to nitrile oxides in the presence of hydroxylamine hydrochloride, under ultrasound activation. These nitrile oxides could be engaged in 1,3-dipolar cycloaddition reactions with various alkene to afford the targeted sulfonamides-isoxazolines hybrids (3a-r). The latter were assessed for their antineoplastic activity against model leukemia cell lines (Chronic Myeloid Leukemia, K562 and Promyelocytic Leukemia, HL-60)." 6342;"Galanin can inhibit insulin release by a mechanism other than membrane hyperpolarization or inhibition of adenylate cyclase.";"M. Cormont";"Equipe 07, Team 07";2468668;"The Journal of biological chemistry";"Sharp GW, Le Marchand-Brustel Y, Yada T, Russo LL, Bliss CR, Cormont M, Monge L, Van Obberghen E";;"May 1989";609984000;;"Studies on the mode of action of galanin to inhibit insulin release in RINm5F cells have shown that basal and glyceraldehyde-stimulated release were both inhibited. Galanin was inhibitory at concentrations in the low nanomolar range. Binding studies with 125I-labeled galanin indicated that the RINm5F cells exhibit a single set of sites estimated to be of the order of 30,000 sites/cell. Displacement of 125I-galanin by galanin from the receptor sites occurred over a similar concentration range to that which inhibited insulin release. Half-displacement was achieved with 2 nM galanin. Measurements of bis-(1,3-diethylthiobarbiturate) trimethineoxonol (bis-oxonol) fluorescence showed that galanin hyperpolarized the RINm5F cell plasma membrane. Measurements of intracellular free calcium, [Ca2+]i by means of the fluorescent indicator fura-2 showed that galanin decreased [Ca2+]i. As galanin did not inhibit either basal or glyceraldehyde-stimulated insulin release in the presence of the Ca2+ channel blocker nitrendipine, the hyperpolarization and reduction of Ca2+ entry appear to be a possible explanation for the galanin effects. However, quantitatively, the effects on membrane potential and [Ca2+]i appear to be insufficient to account for the potent inhibition of insulin release. Furthermore, evidence for an additional mechanism of action was obtained from experiments with 12-O-tetradecanoylphorbol-13-acetate (TPA), a phorbol ester which stimulates insulin secretion by at least two mechanisms, one Ca2+ dependent and one Ca2+ independent. TPA-stimulated insulin release was inhibited by galanin over the same concentration range as for the inhibition of glyceraldehyde-stimulated release. Galanin inhibited TPA-stimulated release in the presence of maximally effective concentrations of nitrendipine and in the absence of extracellular Ca2+. These effects cannot be explained by hyperpolarization of the plasma membrane and consequent reduction of Ca2+ entry via the voltage-dependent Ca2+ channels. One suggested mechanism for the action of galanin is inhibition of adenylate cyclase. However, it was found that galanin inhibits insulin release even in the presence of 8-Br-cAMP, an agent which effectively bypasses adenylate cyclase. Therefore, an additional mechanism for the inhibitory effect of galanin must be present. All of the effects of galanin were sensitive to pertussis toxin. These data suggest two G-protein-dependent actions of galanin, one to hyperpolarize the plasma membrane and one at a distal point in stimulus-secretion coupling, close to the exocytotic event." 6340;"Identification of G protein alpha-subunits in RINm5F cells and their selective interaction with galanin receptor.";"M. Cormont";"Equipe 07, Team 07";1718802;Diabetes;"Cormont M, Le Marchand-Brustel Y, Van Obberghen E, Spiegel AM, Sharp GW";;"Sep 1991";683683200;;"Galanin, an inhibitor of insulin secretion in pancreatic beta-cells, exerts its multiple effects through mechanisms that are sensitive to pertussis toxin (PTX). G proteins have been characterized in RINm5F cells. By ADP ribosylation and immunoblotting, the alpha-subunits of Gi1, Gi2, Gi3, and two forms of Go were identified, Gi alpha 2 being predominant. As expected from a G protein-linked receptor, GTP and its nonhydrolyzable analogue GTP-gamma-S decreased tracer galanin binding to cell membranes. This resulted from a change in receptor affinity without any modification in the number of sites. Selective antibodies against the COOH-terminal decapeptide of the alpha-subunits of the Gi and Go proteins were used to block G protein interaction before we studied galanin binding. Antibody AS, which selectively recognizes Gi alpha 1 and Gi alpha 2, decreased tracer galanin binding to membranes at concentrations where there were no effects of other antibodies specifically directed against Gi alpha 3 or G alpha o. These data suggest that Gi1 and/or Gi2 interact with the galanin receptor and probably mediate the effects of galanin in pancreatic beta-cells." 6338;"Insulin stimulates phosphatidylinositol-3-kinase activity in rat adipocytes.";"M. Cormont, S. Giorgetti-Peraldi";"Equipe 07, Team 07";1321717;"European journal of biochemistry";"Giorgetti S, Ballotti R, Kowalski-Chauvel A, Cormont M, Van Obberghen E";;"Jul 1992";709948800;;"Phosphatidylinositol (PtdIns) 3-kinase is thought to participate in the signal transduction pathways initiated by the activation of receptor tyrosine kinases including the insulin receptor. To approach the physiological relevance of this enzyme in insulin signaling, we studied the activation of PtdIns-3-kinase in adipocytes, a major insulin target tissue for glucose transport and utilisation. To analyze possible interactions of the enzyme with cellular proteins, immunoprecipitations with the following antibodies were performed: (a) anti-phosphotyrosine antibodies, (b) two antibodies to the 85-kDa subunit of PtdIns-3-kinase (p85) and (c) an antibody to the 185-kDa major insulin receptor substrate (p185). We show that in cell extracts from adipocytes exposed to insulin, and after immunoprecipitation with an anti-phosphotyrosine antibody and an antibody to p85, we are able to detect a PtdIns-3-kinase activity stimulated by the hormone. Similarly, after immunoprecipitation with an antibody to p185, an increase in the PtdIns-3-kinase activity could be demonstrated. Taken together these results suggest that, upon insulin stimulation of fat cells, PtdIns-3-kinase itself is tyrosine phosphorylated and/or associated with an insulin receptor substrate, such as p185, which could function as a link between the insulin receptor and PtdIns-3-kinase. The PtdIns-3-kinase was activated within 1 min of exposure to insulin, and the half-maximal effect was reached at the same concentration, i.e. 3 nM, as for stimulation of the insulin receptor kinase. Subcellular fractionation showed that PtdIns-3-kinase activity was found both in the membranes and in the cytosol. Further, immunoprecipitation with an antibody to p85, which possesses the capacity to activate PtdIns-3-kinase, suggests that the presence of the enzyme in the membrane may be due to an insulin-induced recruitment of the PtdIns-3-kinase from the cytosol to the membrane. Finally, we used isoproterenol, which exerts antagonistic effects on insulin action. This drug was found to inhibit both the PtdIns-3-kinase and the insulin receptor activation by insulin, suggesting that the activation of the PtdIns-3-kinase was closely regulated by the insulin receptor tyrosine kinase. The occurrence of an insulin-stimulated PtdIns-3-kinase in adipocytes leads us to propose that this enzyme might be implicated in the generation of metabolic responses induced by insulin." 6336;"Wortmannin inhibits the action of insulin but not that of okadaic acid in skeletal muscle: comparison with fat cells.";"M. Cormont";"Equipe 07, Team 07";7628394;Endocrinology;"Le Marchand-Brustel Y, Gautier N, Cormont M, Van Obberghen E";;"Aug 1995";807235200;;"To look for the possible involvement of phosphatidylinositol-3-kinase (PI3-kinase) in insulin action in muscle, we have used wortmannin, described as a specific inhibitor of the enzyme, and compared its effect in muscle and in adipose cells. Both in intact mouse soleus muscle and in isolated rat adipocytes, wortmannin blocked insulin effect on glucose uptake, without markedly altering basal glucose uptake. In adipocyte, this effect results from a blockade of the translocation process because wortmannin inhibited the stimulatory action of insulin on both the Glut 4 movement from the internal compartment to the plasma membranes and the Rab4 departure from the microsomes. In a similar fashion, two other insulin effects, the activation of glycogen synthase and the stimulation of amino acid uptake, were blocked by wortmannin in skeletal muscle. Lipogenesis from acetate was also inhibited by wortmannin in adipocytes. By contrast, wortmannin did not affect muscle deoxglucose uptake when it was stimulated either by okadaic acid or by the protein kinase C activator tumor promoting agent. These results suggest that, in muscle and adipocyte, PI3-kinase inhibition causes a blockade of all insulin effects studied. By contrast, wortmannin did not affect the same responses elicited in muscle by okadaic acid or tumor promoting agent." 6334;"Potential role of Rab4 in the regulation of subcellular localization of Glut4 in adipocytes.";"M. Cormont";"Equipe 07, Team 07";8943343;"Molecular and cellular biology";"Cormont M, Bortoluzzi MN, Gautier N, Mari M, van Obberghen E, Le Marchand-Brustel Y";;"Dec 1996";849398400;;"A role for Rab4 in the translocation of the glucose transporter Glut4 induced by insulin has been recently proposed. To study more directly the role of this small GTPase, freshly isolated adipocytes were transiently transfected with the cDNAs of both an epitope-tagged Glut4-myc and Rab4, a system which allows direct measurement of the concentration of Glut4 molecules at the cell surface. When cells were cotransfected with Glut4-myc and Rab4, the concentration of Glut4-myc at the cell surface decreased in parallel with the increased expression of Rab4, suggesting that Rab4 participates in the intracellular retention of Glut4. In parallel, the amount of Rab4 associated with the Glut4-containing vesicles increased. When Rab4 was moderately overexpressed, the number of Glut4-myc molecules recruited to the cell surface in response to insulin was similar to that observed in mock-transfected cells, and thus the insulin efficiency was increased. When Rab4 was expressed at a higher level, the amount of Glut4-myc present at the cell surface in response to insulin decreased. Since the overexpressed protein was predominantly cytosolic, this suggests that the cytosolic Rab4 might complex some factor(s) necessary for insulin action. This hypothesis was strengthened by the fact that Rab4 deltaCT, a Rab4 mutant lacking the geranylgeranylation sites, inhibited insulin-induced recruitement of Glut4-myc to the cell surface, even when moderately overexpressed. Rab3D was without effect on Glut4-myc subcellular distribution in basal or insulin-stimulated conditions. While two mutated proteins unable to bind GTP did not decrease the number of Glut4-myc molecules in basal or insulin-stimulated conditions at the plasma membrane, the behavior of a mutated Rab4 protein without GTPase activity was similar to that of the wild-type Rab4 protein, indicating that GTP binding but not its hydrolysis was required for the observed effects. Altogether, our results suggest that Rab4, but not Rab3D, participates in the molecular mechanism involved in the subcellular distribution of the Glut4 molecules both in basal and in insulin-stimulated conditions in adipocytes." 6332;"Differential effects of insulin and exercise on Rab4 distribution in rat skeletal muscle.";"M. Cormont";"Equipe 07, Team 07";8536622;Endocrinology;"Sherman LA, Hirshman MF, Cormont M, Le Marchand-Brustel Y, Goodyear LJ";;"Jan 1996";820454400;;"Insulin and exercise cause the translocation of GLUT4 from an intracellular location to the plasma membrane in skeletal muscle. The purpose of this study was to determine if Rab4, a small GTP binding protein that has been implicated in the insulin-stimulated translocation of GLUT4 in adipose cells, is involved in the regulation of transporter translocation in skeletal muscle. Male rats were injected with insulin (20 U i.p.) or exercised on a treadmill(1 h, 20 m/min, 10% grade). Rats were killed 30 min after insulin injection or immediately after exercise, and the hind limb muscles dissected. Plasma membrane and intracellular microsomal membrane fractions were prepared, and the distribution of GLUT4 and Rab4 was determined by immunoblotting. Both insulin and exercise caused GLUT4 translocation as demonstrated by a decrease in microsomal membrane GLUT4 and an increase in plasma membrane GLUT4. In contrast, only insulin caused a decrease in Rab4 in the microsomal membrane. Rab4 was associated with GLUT4-containing vesicles isolated by immunoprecipitation. Rab4 was not detected in plasma membrane under any condition. These data demonstrate that insulin modulates the subcellular distribution of both GLUT4 and Rab4 in rats skeletal muscle, suggesting that Rab4 may play a role in the insulin-stimulated movement of GLUT4-containing vesicles. Although both insulin and exercise increase skeletal muscle glucose uptake by the translocation of GLUT4, the regulation of translocation may occur by different mechanisms." 6330;"Insulin induces a change in Rab5 subcellular localization in adipocytes independently of phosphatidylinositol 3-kinase activation.";"M. Cormont";"Equipe 07, Team 07";8754768;Endocrinology;"Cormont M, Van Obberghen E, Zerial M, Le Marchand-Brustel Y";;"Aug 1996";838857600;;"We investigated whether Rab5, a small guanosine triphosphatase that regulates early endocytic transport in different cell types is involved in the insulin-regulated endocytic pathways in adipocytes. Rab5 was detected in freshly isolated adipocytes and 3T3-L1 adipocytes, but its expression level was not markedly increased with adipocyte differentiation. After subcellular fractionation of adipocytes incubated in the absence of insulin, Rab5 was found to be abundant in plasma membrane and cytosol, but was also present in high and low density microsomes. This subcellular distribution was compatible with a role in early endocytosis. When cells were incubated with insulin, the concentration of Rab5 decreased by about 50% in the internal compartments. In contrast to Rab4, which also leaves the low density microsomes in response to insulin, Rab5 was not found in Glut4-containing vesicles purified by immunoadsorption on antibodies to Glut4. When adipocytes were treated with wortmannin, an inhibitor of phosphatidylinositol 3-kinase, the effect of insulin on Rab5 movement was not affected, whereas the insulin-induced movements of Rab4 and Glut4 were abolished. In parallel, wortmannin inhibited the increase in horseradish peroxidase uptake induced by insulin, an index of fluid phase endocytosis, but did not prevent the endocytosis of the glucose transporters. As a whole, our results suggest that Rab5 is not involved in insulin-stimulated Glut4 exocytosis. These results are compatible with the postulated role of Rab5 in the endocytotic pathway, at a step that does not require phosphatidyl-inositol 3-kinase activation." 6328;"GTPase activating protein activity for Rab4 is enriched in the plasma membrane of 3T3-L1 adipocytes. Possible involvement in the regulation of Rab4 subcellular localization.";"M. Cormont";"Equipe 07, Team 07";8858211;Diabetologia;"Bortoluzzi MN, Cormont M, Gautier N, Van Obberghen E, Le Marchand-Brustel Y";;"Aug 1996";838857600;;"The small guanosine 5'-triphosphate (GTP)ase Rab4 has been suggested to play a role in insulin-induced GLUT4 translocation. Under insulin stimulation, GLUT4 translocates to the plasma membranes, while Rab4 leaves the GLUT4-containing vesicles and becomes cytosolic. Rab proteins cycle between a GTP-bound active form and a guanosine 5'-diphosphate (GDP)-bound inactive form. The intrinsic GTPase activity of Rab proteins is low and the interconversion between the two forms is dependent on accessory factors. In the present work, we searched for a GTPase activating protein (GAP) for Rab4 in 3T3-L1 adipocytes. We used a glutathione-S-transferase (GST)-Rab4 protein which possesses the properties of a small GTPase (ability to bind GDP and GTP and to hydrolyse GTP) and can be isolated in a rapid and efficient way. This GAP activity was observed in 3T3-L1 adipocyte lysates, and was able to accelerate the hydrolysis of the [alpha-32P]GTP bound to GST-Rab4 into [alpha-32P]GDP. This activity, tentatively called Rab4-GAP, was also present in 3T3-L1 fibroblasts. The Rab4-GAP activity was present in total membrane fractions and nearly undetectable in cytosol. Following subcellular fractionation, Rab4-GAP was found to be enriched in plasma membranes when compared to internal microsomes. Insulin treatment of the cells had no effect on the total Rab4-GAP activity or on its subcellular localization. Taking our results together with the accepted model of Rab cycling in intracellular traffic, we propose that Rab4-GAP activity plays a role in the cycling between the GTP- and GDP-bound forms of Rab4, and thus possibly in the traffic of GLUT4-containing vesicles." 6326;"The small guanosine triphosphate-binding protein Rab4 is involved in insulin-induced GLUT4 translocation and actin filament rearrangement in 3T3-L1 cells.";"M. Cormont";"Equipe 07, Team 07";9348225;Endocrinology;"Vollenweider P, Martin SS, Haruta T, Morris AJ, Nelson JG, Cormont M, Le Marchand-Brustel Y, Rose DW, Olefsky JM";;"Nov 1997";878342400;;"Insulin's stimulation of glucose transport involves the translocation of vesicles containing the glucose transporter GLUT4 to the plasma membrane. Small GTP-binding proteins have been implicated in the regulation of vesicular traffic. We studied the effects of microinjection of wild-type Rab4 glutathione S-transferase fusion protein (WT Rab4), a GTP-binding defective mutant (Rab4 N121I), a guanosine triphosphatase-defective mutant (Rab4 Q67L), and a Rab4 antibody on insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Microinjection of Rab4 N121I and Rab4 antibodies had no effect on basal GLUT4 staining, but inhibited insulin-induced GLUT4 translocation by 50% compared with that in control IgG-injected cells. WT Rab4 and Rab4 Q67L microinjection had no effect on either basal or insulin-induced GLUT4 translocation. Premixing and coinjection of the Rab4 antibody with WT Rab4 almost completely abolished its inhibitory effect on insulin-induced GLUT4 translocation. In contrast, microinjection of an antibody directed against the highly conserved region of Rab3 proteins had no effect on insulin-induced GLUT4. These results point to a direct role of Rab4 in insulin-induced GLUT4 translocation, and that this effect is dependent on nucleotide binding to the protein. We also studied the effect of microinjection of the same proteins on insulin-induced actin filament rearrangement (membrane ruffling) in the same cell line. Microinjection of Rab4 N121I and Rab4 antibodies inhibited insulin-induced membrane ruffling by 40%, whereas WT Rab4 or a Rab3 antibody injection had no effect on cytoskeletal rearrangement. In summary, 1) Rab4 is a necessary component of the insulin/GLUT4 translocation signaling pathway; 2) the function of Rab4 in this pathway requires GTP binding; 3) Rab4 also participates in the process of insulin-induced membrane ruffling; and 4) Rab3 proteins do not seem to be involved in these processes." 6324;"Insulin promotes phosphorylation and activation of geranylgeranyltransferase II. Studies with geranylgeranylation of rab-3 and rab-4.";"M. Cormont";"Equipe 07, Team 07";9915824;"The Journal of biological chemistry";"Goalstone ML, Leitner JW, Golovchenko I, Stjernholm MR, Cormont M, Le Marchand-Brustel Y, Draznin B";;"Jan 1999";915148800;;"Rab proteins play a crucial role in the trafficking of intracellular vesicles. Rab proteins are GTPases that cycle between an inactive GDP-bound form and an active GTP-bound conformation. A prerequisite to Rab activation by GTP loading is its post-translational modification by the addition of geranylgeranyl moieties to highly conserved C-terminal cysteine residues. We examined the effect of insulin on the activity of geranylgeranyltransferase II (GGTase II) in 3T3-L1 fibroblasts and adipocytes. In fibroblasts, insulin increased the enzymatic activity of GGTase II 2.5-fold after 1 h of incubation, an effect that is blocked by perillyl alcohol, an inhibitor of prenyltransferases, but not by the geranylgeranyltransferase I inhibitor, GGTI-298, or the farnesyltransferase inhibitor, alpha-hydroxyfarnesylphosphonic acid. Concomitantly, insulin stimulated the phosphorylation of the GGTase II alpha-subunit without any effect on the GGTase II beta-subunit. At the same time, insulin also increased the amounts of geranylgeranylated Rab-3 in 3T3-L1 fibroblasts from 44 +/- 1.2% in control cells to 63 +/- 3.8 and 64 +/- 6.1% after 1 and 24 h of incubation, respectively. In adipocytes, insulin increased the amounts of geranylgeranylated Rab-4 from 38 +/- 0.6% in control cells to 56 +/- 1.7 and 60 +/- 2.6% after 1 and 24 h of incubation, respectively. In both fibroblasts and adipocytes, the presence of perillyl alcohol blocked the ability of insulin to increase geranylgeranylation of Rab-4, whereas GGTI-298 and alpha-hydroxyfarnesylphosphonic acid were without effect, indicating that insulin activates GGTase II. In summary, insulin promotes phosphorylation and activation of GGTase II in both 3T3 L1 fibroblasts and adipocytes and increases the amounts of geranylgeranylated Rab-3 and Rab-4 proteins." 6322;"A FYVE-finger-containing protein, Rabip4, is a Rab4 effector involved in early endosomal traffic.";"M. Cormont";"Equipe 07, Team 07";11172003;"Proceedings of the National Academy of Sciences of the United States of America";"Cormont M, Mari M, Galmiche A, Hofman P, Le Marchand-Brustel Y";;"Feb 2001";980985600;;"The small GTPase Rab4 is implicated in endocytosis in all cell types, but also plays a specific role in some regulated processes. To better understand the role of Rab4 in regulation of vesicular trafficking, we searched for an effector(s) that specifically recognizes its GTP-bound form. We cloned a ubiquitous 69-kDa protein, Rabip4, that behaves as a Rab4 effector in the yeast two-hybrid system and in the mammalian cell. Rabip4 contains two coiled-coil domains and a FYVE-finger domain. When expressed in CHO cells, Rabip4 is present in early endosomes, because it is colocated with endogenous Early Endosome Antigen 1, although it is absent from Rab11-positive recycling endosomes and Rab-7 positive late endosomes. The coexpression of Rabip4 with active Rab4, but not with inactive Rab4, leads to an enlargement of early endosomes. It strongly increases the degree of colocalization of markers of sorting (Rab5) and recycling (Rab11) endosomes with Rab4. Furthermore, the expression of Rabip4 leads to the intracellular retention of a recycling molecule, the glucose transporter Glut 1. We propose that Rabip4, an effector of Rab4, controls early endosomal traffic possibly by activating a backward transport step from recycling to sorting endosomes." 6320;"Expression of a prenylation-deficient Rab4 inhibits the GLUT4 translocation induced by active phosphatidylinositol 3-kinase and protein kinase B.";"M. Cormont";"Equipe 07, Team 07";11336646;"The Biochemical journal";"Cormont M, Gautier N, Ilc K, le Marchand-Brustel Y";;"May 2001";988675200;;"The small GTPase Rab4 has been shown to participate in the subcellular distribution of GLUT4 under both basal and insulin-stimulated conditions in adipocytes. In the present work, we have characterized the effect of Rab4 DeltaCT, a prenylation-deficient and thus cytosolic form of Rab4, in this process. We show that the expression of Rab4 DeltaCT in freshly isolated adipocytes inhibits insulin-induced GLUT4 translocation, but only when this protein is in its GTP-bound active form. Further, it not only blocks the effect of insulin, but also that of a hyperosmotic shock, but does not interfere with the effect of zinc ions on GLUT4 translocation. Rab4 DeltaCT was then shown to prevent GLUT4 translocation induced by the expression of an active form of phosphatidylinositol 3-kinase or of protein kinase B, without altering the activities of the enzymes. Our results are consistent with a role of Rab4 DeltaCT acting as a dominant negative protein towards Rab4, possibly by binding to Rab4 effectors." 6316;"Role of the FYVE finger and the RUN domain for the subcellular localization of Rabip4.";"M. Cormont";"Equipe 07, Team 07";11509568;"The Journal of biological chemistry";"Mari M, Macia E, Le Marchand-Brustel Y, Cormont M";;"Nov 2001";1004572800;;"Rabip4 is a Rab4 effector, which possesses a RUN domain, two coiled-coil domains, and a FYVE finger. It is associated with the early endosomes and leads, in concert with Rab4, to the enlargement of endosomes, resulting in the fusion of sorting and recycling endosomes. Our goal was to characterize the role of these various domains in Rabip4 subcellular localization and their function in Chinese hamster ovary cells. Although the FYVE finger domain specifically bound phosphatidylinositol 3-phosphate and was necessary for the function of Rabip4, it was not sufficient for the protein association with membranes. Indeed a protein containing the FYVE finger and the Rab4-binding site was cytosolic, whereas the total protein was mostly associated to the membrane fraction, whether or not cells were pretreated with wortmannin. By contrast, a construct corresponding to the N-terminal end, Rabip4-(1-212), and containing the RUN domain was membrane-associated. The complete protein partitioned between the Triton X-100-insoluble and -soluble fractions and a wortmannin treatment increased the amount of the protein in the Triton X-100 fraction. Rabip4-(1-212) was totally Triton X-100-insoluble, and confocal microscopic examination showed that it labeled not only the endosomes, positive for Rabip4, but also a filamentous network with a honeycomb appearance. The Triton X-100-insoluble fraction that contains Rabip4 did not correspond to the caveolin or glycosylphosphatidylinositol-enriched lipid rafts. Rabip4 did not appear directly linked to actin but seemed associated to the actin network. We propose that the subcellular localization of the protein is primarily driven by the RUN domain to endosomal microdomains characterized by Triton X-100 insolubility and that the FYVE domain and the Rab4-binding domain then allow for the recruitment of the protein to lipophilic microdomains enriched in phosphatidylinositol 3-phosphate." 6317;"The role of small G-proteins in the regulation of glucose transport (review).";"M. Cormont";"Equipe 07, Team 07";11681788;"Molecular membrane biology";"Cormont M, Le Marchand-Brustel Y";;"Sep Jul 2001";994636800;;"Insulin increases the rate of glucose transport into fat and muscle cells by stimulating the translocation of intracellular Glut 4-containing vesicles to the plasma membrane. This results in a marked increase in the amount of the facilitative glucose transporter Glut 4 at the cell surface, allowing for an enhanced glucose uptake. This process requires a continuous cycling through the early endosomes, a Glut 4 specific storage compartment and the plasma membrane. The main effect of insulin is to increase the rate of Glut 4 trafficking from its specific storage compartment to the plasma membrane. The whole phenomenon involves signal transduction from the insulin receptor, vesicle trafficking (sorting and fusion processes) and actin cytoskeleton modifications, which are all supposed to require small GTPases. This review describes the potential role of the various members of the Ras, Rad, Rho, Arf and Rab families in the traffic of the Glut 4-containing vesicles." 6314;"Rab proteins in endocytosis and Glut4 trafficking.";"M. Cormont";"Equipe 07, Team 07";18171431;"Acta physiologica (Oxford, England)";"Kaddai V, Le Marchand-Brustel Y, Cormont M";;"Jan 2008";1199145600;;"The intracellular trafficking of numerous proteins requires a tight control to fulfil their physiological functions. It is the case of the adipocyte and muscle glucose transporter Glut4 that is retained intracellularly until insulin induces its recruitment to the plasma membrane. Rabs are evolutionarily conserved small GTPases that control intracellular traffic events from yeast to mammalian cells. In the past few decades, considerable progresses have been made in identifying the route of Glut4, the Rabs involved in controlling it, and more recently the connection between insulin signalling and Glut4 trafficking through Rab activity control." 6312;"The nitric oxide-donating derivative of acetylsalicylic acid, NCX 4016, stimulates glucose transport and glucose transporters translocation in 3T3-L1 adipocytes.";"M. Cormont";"Equipe 07, Team 07";18492771;"American journal of physiology. Endocrinology and metabolism";"Kaddai V, Gonzalez T, Bolla M, Le Marchand-Brustel Y, Cormont M";;"Jul 2008";1214870400;;"NCX 4016 is a nitric oxide (NO)-donating derivative of acetylsalicylic acid. NO and salicylate, in vivo metabolites of NCX 4016, were shown to be potential actors in controlling glucose homeostasis. In this study, we evaluated the action of NCX 4016 on the capacity of 3T3-L1 adipocytes to transport glucose in basal and insulin-stimulated conditions. NCX 4016 induced a twofold increase in glucose uptake in parallel with the translocation of the glucose transporters GLUT1 and GLUT4 to the plasma membrane, leaving unaffected their total expression levels. Importantly, NCX 4016 further increased glucose transport induced by a physiological concentration of insulin. The stimulatory effect of NCX 4016 on glucose uptake appears to be mediated by its NO moiety. Indeed, it is inhibited by a NO scavenger and treatment with acetylsalicylic or salicylic acid had no effect. Although NO is involved in the action of NCX 4016, it did not mainly depend on the soluble cGMP cyclase/protein kinase G pathway. Furthermore, NCX 4016-stimulated glucose transport did not involve the insulin-signaling cascade required to stimulate glucose transport. NCX 4016 induces a small activation of the mitogen-activated protein kinases p38 and c-Jun NH(2)-terminal kinase and no activation of other stress-activated signaling molecules, including extracellular signal-regulated kinase, inhibitory factor kappaB, or AMP-activated kinases. Interestingly, NCX 4016 modified the content of S-nitrosylated proteins in adipocytes. Taken together, our results indicate that NCX 4016 induced glucose transport in adipocytes through a novel mechanism possibly involving S-nitrosylation. NCX 4016 thus possesses interesting characteristics to be considered as a candidate molecule for the treatment of patients suffering from metabolic syndrome and type 2 diabetes." 6310;"Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma.";"M. Cormont, T. Strub";"Equipe 07, Team 07, Equipe 01, Team 01";21258399;Oncogene;"Strub T, Giuliano S, Ye T, Bonet C, Keime C, Kobi D, Le Gras S, Cormont M, Ballotti R, Bertolotto C, Davidson I";;"May 2011";1304208000;;"Malignant melanoma is an aggressive cancer known for its notorious resistance to most current therapies. The basic helix-loop-helix microphthalmia transcription factor (MITF) is the master regulator determining the identity and properties of the melanocyte lineage, and is regarded as a lineage-specific 'oncogene' that has a critical role in the pathogenesis of melanoma. MITF promotes melanoma cell proliferation, whereas sustained supression of MITF expression leads to senescence. By combining chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) and RNA sequencing analyses, we show that MITF directly regulates a set of genes required for DNA replication, repair and mitosis. Our results reveal how loss of MITF regulates mitotic fidelity, and through defective replication and repair induces DNA damage, ultimately ending in cellular senescence. These findings reveal a lineage-specific control of DNA replication and mitosis by MITF, providing new avenues for therapeutic intervention in melanoma. The identification of MITF-binding sites and gene-regulatory networks establish a framework for understanding oncogenic basic helix-loop-helix factors such as N-myc or TFE3 in other cancers." 6308;"UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling.";"F. BOST, J. GILLERON, M. IRONDELLE, M. Cormont, C. Hinault";"Equipe 05, Team 05, Equipe 07, Team 07";33884955;eLife;"Torrino S, Tiroille V, Dolfi B, Dufies M, Hinault C, Bonesso L, Dagnino S, Uhler J, Irondelle M, Gay AS, Fleuriot L, Debayle D, Lacas-Gervais S, Cormont M, Bertero T, Bost F, Gilleron J, Clavel S";;"04 2021";1617235200;;"To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that ubiquitin domain-containing protein 1 (UBTD1) plays a crucial role in both the epidermal growth factor receptor (EGFR) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through N-acylsphingosine amidohydrolase 1 (ASAH1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of Sequestosome 1 (SQSTM1/p62) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation." 6305;"CD2AP, Rabip4, and Rabip4': analysis of interaction with Rab4a and regulation of endosomes morphology.";"M. Cormont";"Equipe 07, Team 07";16473581;"Methods in enzymology";"Monzo P, Mari M, Kaddai V, Gonzalez T, Le Marchand-Brustel Y, Cormont M";;"Jan 2005";1104537600;;"In this chapter, we describe various approaches that allow us to study interactions between the small GTPase Rab4a and its two effectors, Rabip4 and CD2AP. Two complementary approaches, one using the yeast two-hybrid system and the other using a GST pull-down assay, are described. We document the studies of the localization of these proteins by cellular fractionation. Finally, we develop cellular imaging techniques to study the morphology of vesicular structures containing Rab4a. We show that the coexpression of Rab4a with its effectors affects Rab4a-containing structures, giving a clear indication of their interaction in the mammalian cellular context." 6304;"The Rab4 effector Rabip4 plays a role in the endocytotic trafficking of Glut 4 in 3T3-L1 adipocytes.";"M. Cormont";"Equipe 07, Team 07";16522682;"Journal of cell science";"Mari M, Monzo P, Kaddai V, Keslair F, Gonzalez T, Le Marchand-Brustel Y, Cormont M";;"Apr 2006";1143849600;;"Insulin regulates glucose uptake in the adipocytes by modulating Glut 4 localization, a traffic pathway involving the endocytic small GTPases Rab4, Rab5, and RabThe expression of the Rab4 effector Rabip4 leads to a 30% increase in glucose uptake and Glut 4 translocation in the presence of insulin, without modifications in the basal condition. This effect was not due to modifications of Glut 4 expression or insulin signaling, suggesting that Rabip4 controls Glut 4 trafficking. We present evidence that Rabip4 defines a subdomain of early endosomes and that Rabip4 is redistributed to the plasma membrane by insulin. Rabip4 is mostly absent from structures positive for early endosome antigen 1, Rab11 or transferrin receptors and from Glut 4 sequestration compartments. However, Rabip4 vesicles can be reached by internalized transferrin and Glut 4. Thus, Rabip4 probably defines an endocytic sorting platform for Glut 4 towards its sequestration pool. The expression of a form of Rabip4 unable to bind Rab4 does not modify basal and insulin-induced glucose transport. However, it induces an increase in the amount of Glut 4 at the plasma membrane and perturbs Glut 4 traffic from endosomes towards its sequestration compartments. These observations suggest that the uncoupling between Rabip4 and Rab4 induces the insertion of Glut 4 molecules that are unable to transport glucose into the plasma membrane." 6302;"[CD2AP, a molecule adaptator between endocytosis and actin cytoskeleton in the cell in interphase and during cytokinesis?].";"M. Cormont";"Equipe 07, Team 07";16324643;"Medecine sciences : M/S";"Monzo P, Cormont M";;"Dec 2005";1133395200;; 6300;"Clues to CD2-associated protein involvement in cytokinesis.";"M. Cormont";"Equipe 07, Team 07";15800069;"Molecular biology of the cell";"Monzo P, Gauthier NC, Keslair F, Loubat A, Field CM, Le Marchand-Brustel Y, Cormont M";;"Jun 2005";1117584000;;"Cytokinesis requires membrane trafficking coupled to actin remodeling and involves a number of trafficking molecules. CD2-associated protein (CD2AP) has been implicated in dynamic actin remodeling and membrane trafficking that occurs during endocytosis leading to the degradative pathway. In this study, we present several arguments for its implication in cytokinesis. First, endogenous CD2AP was found concentrated in the narrow region of the midzone microtubules during anaphase and in the midbody during late telophase. Moreover, we found that CD2AP is a membrane- and not a microtubule-associated protein. Second, the overexpression of the first two Src homology 3 domains of CD2AP, which are responsible for this localization, led to a significant increase in the rate of cell multinucleation. Third, the CD2AP small interfering RNA interfered with the cell separation, indicating that CD2AP is required for HeLa cells cytokinesis. Fourth, using the yeast two-hybrid system, we found that CD2AP interacted with anillin, a specific cleavage furrow component, and the two proteins colocalized at the midbody. Both CD2AP and anillin were found phosphorylated early in mitosis and also CD2AP phosphorylation was coupled to its delocalization from membrane to cytosol. All these observations led us to propose CD2AP as a new player in cytokinesis." 6298;"CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl.";"M. Cormont";"Equipe 07, Team 07";12559036;"Traffic (Copenhagen, Denmark)";"Cormont M, Metón I, Mari M, Monzo P, Keslair F, Gaskin C, McGraw TE, Le Marchand-Brustel Y";;"Feb 2003";1044057600;;"The small GTPase Rab4 is involved in endocytosis through sorting and recycling early endosomes. To better understand the role of Rab4 in regulation of vesicular trafficking, we searched for effectors that specifically interact with Rab4-Q67L, the GTP-bound form of Rab4. We cloned an ubiquitous 80-kDa protein, identical to CD2-associated protein/Cas ligand with multiple SH3 domains (CD2AP/CMS), that interacts with Rab4-Q67L in the yeast two-hybrid system and in vitro. CD2AP/CMS expressed in mammalian cells was localized to punctate structures and along actin filaments. None of the known markers of early endosomes [Early Endosomes Antigen 1 (EEA1), Rab5 and Rab11] colocalized with the CD2AP/CMS-positive vesicles. However, coexpression of Rab4-Q67L with CD2AP/CMS induces a significant enlargement of EEA1-positive early endosomes. Rab4, CD2AP/CMS and Rab7 colocalized in these modified endosomes. Coexpression of c-Cbl and CD2AP/CMS also resulted in an enlargement of early endosomes. Using various truncated forms of CD2AP/CMS, we demonstrate that early endosomes enlargement requires that CD2AP/CMS interacts with both Rab4 and c-Cbl. The expression of a truncated form of CD2AP/CMS that retains the ability to interact with Rab4 but not c-Cbl inhibits ligand-induced PDGF receptor degradation. We propose that CD2AP/CMS, through interactions with Rab4 and c-Cbl, controls early endosome morphology and may play a role in traffic between early and late endosomes, and thus in the degradative pathway." 6296;"The Rab4A effector protein Rabip4 is involved in migration of NIH 3T3 fibroblasts.";"M. Cormont";"Equipe 07, Team 07";17001082;"The Journal of biological chemistry";"Vukmirica J, Monzo P, Le Marchand-Brustel Y, Cormont M";;"Nov 2006";1162339200;;"The small GTP-binding protein Rab4 has been involved in the recycling of alphavbeta3 integrins in response to platelet-derived growth factor (PDGF) stimulation suggesting a role for Rab4 in cell adhesion and migration. In this study, we explored the role of Rabip4 and Rabip4', two Rab4 effector proteins, in migration of NIH 3T3 fibroblasts. In these cells, Rabip4 and Rabip4', collectively named Rabip4s, were partially co-localized with the early endosomal marker EEA1. PDGF treatment re-distributed endogenous Rabip4s toward the cell periphery where they colocalized with F-actin. In cells expressing green fluorescent protein (GFP)-Rabip4 or GFP-Rabip4', constitutive appearance of GFP-Rabip4s at the cell periphery was accompanied by local increase in cortical F-actin in membrane ruffles at the leading edge. The expression of GFP-Rabip4 induced an increased migration compared with control cells expressing GFP alone, even in the absence of PDGF stimulation. On the contrary, in cells expressing a mutated form of Rabip4s unable to interact with Rab4, lack of typical leading edge was observed. Furthermore, PDGF treatment did not stimulate the migration of these cells. Furthermore, down-regulation of the expression of Rabip4s inhibited PDGF-stimulated cell migration. Endogenous Rabip4s were localized with alphav integrins at the leading edge following PDGF treatment, whereas in cells expressing GFP-Rabip4s, alphav integrins, together with GFP-Rabip4s, were constitutively localized at the leading edge. In contrast, reduction in Rabip4s expression levels using small interfering RNA was associated with impaired PDGF-induced translocation of alphav integrins toward the leading edge. Taken together, our data provide evidence that Rabip4s, possibly via their interaction with Rab4, regulate integrin trafficking and are involved in the migration of NIH 3T3 fibroblasts." 6294;"Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin.";"M. Cormont";"Equipe 07, Team 07";17438076;"The Journal of cell biology";"Gauthier NC, Monzo P, Gonzalez T, Doye A, Oldani A, Gounon P, Ricci V, Cormont M, Boquet P";;"Apr 2007";1175385600;;"Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are endocytosed by a clathrin- independent pathway into vesicles named GPI-AP-enriched early endosomal compartments (GEECs). We recently showed that the vacuolating toxin VacA secreted by Helicobacter pylori is endocytosed into the GEECs (Gauthier, N.C., P. Monzo, V. Kaddai, A. Doye, V. Ricci, and P. Boquet. 2005. Mol. Biol. Cell. 16:4852-4866). Unlike GPI-APs that are mostly recycled back to the plasma membrane, VacA reaches early endosomes (EEs) and then late endosomes (LEs), where vacuolation occurs. In this study, we used VacA to study the trafficking pathway between GEECs and LEs. We found that VacA routing from GEECs to LEs required polymerized actin. During this trafficking, VacA was transferred from GEECs to EEs associated with polymerized actin structures. The CD2-associated protein (CD2AP), a docking protein implicated in intracellular trafficking, bridged the filamentous actin (F-actin) structures with EEs containing VacA. CD2AP regulated those F-actin structures and was required to transfer VacA from GEECs to LEs. These results demonstrate that sorting from GEECs to LEs requires dynamic F-actin structures on EEs." 6292;"Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells.";"M. Cormont";"Equipe 07, Team 07";19798427;"PLoS pathogens";"Oldani A, Cormont M, Hofman V, Chiozzi V, Oregioni O, Canonici A, Sciullo A, Sommi P, Fabbri A, Ricci V, Boquet P";;"Oct 2009";1254355200;;"Infection with Helicobacter pylori is responsible for gastritis and gastroduodenal ulcers but is also a high risk factor for the development of gastric adenocarcinoma and lymphoma. The most pathogenic H. pylori strains (i.e., the so-called type I strains) associate the CagA virulence protein with an active VacA cytotoxin but the rationale for this association is unknown. CagA, directly injected by the bacterium into colonized epithelium via a type IV secretion system, leads to cellular morphological, anti-apoptotic and proinflammatory effects responsible in the long-term (years or decades) for ulcer and cancer. VacA, via pinocytosis and intracellular trafficking, induces epithelial cell apoptosis and vacuolation. Using human gastric epithelial cells in culture transfected with cDNA encoding for either the wild-type 38 kDa C-terminal signaling domain of CagA or its non-tyrosine-phosphorylatable mutant form, we found that, depending on tyrosine-phosphorylation by host kinases, CagA inhibited VacA-induced apoptosis by two complementary mechanisms. Tyrosine-phosphorylated CagA prevented pinocytosed VacA to reach its target intracellular compartments. Unphosphorylated CagA triggered an anti-apoptotic activity blocking VacA-induced apoptosis at the mitochondrial level without affecting the intracellular trafficking of the toxin. Assaying the level of apoptosis of gastric epithelial cells infected with wild-type CagA(+)/VacA(+)H. pylori or isogenic mutants lacking of either CagA or VacA, we confirmed the results obtained in cells transfected with the CagA C-ter constructions showing that CagA antagonizes VacA-induced apoptosis. VacA toxin plays a role during H. pylori stomach colonization. However, once bacteria have colonized the gastric niche, the apoptotic action of VacA might be detrimental for the survival of H. pylori adherent to the mucosa. CagA association with VacA is thus a novel, highly ingenious microbial strategy to locally protect its ecological niche against a bacterial virulence factor, with however detrimental consequences for the human host." 6290;"Decrease in αβ/γδ T-cell ratio is accompanied by a reduction in high-fat diet-induced weight gain, insulin resistance, and inflammation.";"M. Cormont, J. Neels, J. Murdaca";"Equipe 07, Team 07, Team 09, Equipe 09";30285581;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Le Menn G, Sibille B, Murdaca J, Rousseau AS, Squillace R, Vergoni B, Cormont M, Niot I, Grimaldi PA, Mothe-Satney I, Neels JG";;"02 2019";1548979200;;"The implication of αβ and γδ T cells in obesity-associated inflammation and insulin resistance (IR) remains uncertain. Mice lacking γδ T cells show either no difference or a decrease in high-fat diet (HFD)-induced IR, whereas partial depletion in γδ T cells does not protect from HFD-induced IR. αβ T-cell deficiency leads to a decrease in white adipose tissue (WAT) inflammation and IR without weight change, but partial depletion of these cells has not been studied. We previously described a mouse model overexpressing peroxisome proliferator-activated receptor β (PPAR-β) specifically in T cells [transgenic (Tg) T-PPAR-β] that exhibits a partial depletion in αβ T cells and no change in γδ T-cell number. This results in a decreased αβ/γδ T-cell ratio in lymphoid organs. We now show that Tg T-PPAR-β mice are partially protected against HFD-induced weight gain and exhibit decreased IR and liver steatosis independently of animal weight. These mice display an alteration of WAT-depots distribution with an increased epididymal-WAT mass and a decreased subcutaneous WAT mass. Immune cell number is decreased in both WAT-depots, except for γδ T cells, which are increased in epididymal-WAT. Overall, we show that decreasing αβ/γδ T-cell ratio in WAT-depots alters their inflammatory state and mass repartition, which might be involved in improvement of insulin sensitivity.-Le Menn, G., Sibille, B., Murdaca, J., Rousseau, A.-S., Squillace, R., Vergoni, B., Cormont, M., Niot, I., Grimaldi, P. A., Mothe-Satney, I., Neels, J. G. Decrease in αβ/γδ T-cell ratio is accompanied by a reduction in high-fat diet-induced weight gain, insulin resistance, and inflammation." 6285;"REDD1 deficiency protects against nonalcoholic hepatic steatosis induced by high-fat diet.";"A. TRAN, JF. Tanti, J. GILLERON, L. Yvan-Charvet, M. Cormont, N. Vaillant, S. PATOURAUX, P. GUAL, R. ANTY, S. Giorgetti-Peraldi";"Equipe 08, Team 08, Equipe 07, Team 07, Equipe 13, Team 13";32043636;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Dumas K, Ayachi C, Gilleron J, Lacas-Gervais S, Pastor F, Favier FB, Peraldi P, Vaillant N, Yvan-Charvet L, Bonnafous S, Patouraux S, Anty R, Tran A, Gual P, Cormont M, Tanti JF, Giorgetti-Peraldi S";;"04 2020";1585699200;;"Nonalcoholic fatty liver disease is a chronic liver disease which is associated with obesity and insulin resistance. We investigated the implication of REDD1 (Regulated in development and DNA damage response-1), a stress-induced protein in the development of hepatic steatosis. REDD1 expression was increased in the liver of obese mice and morbidly obese patients, and its expression correlated with hepatic steatosis and insulin resistance in obese patients. REDD1 deficiency protected mice from the development of hepatic steatosis induced by high-fat diet (HFD) without affecting body weight gain and glucose intolerance. This protection was associated with a decrease in the expression of lipogenic genes, SREBP1c, FASN, and SCD-1 in liver of HFD-fed REDD1-KO mice. Healthy mitochondria are crucial for the adequate control of lipid metabolism and failure to remove damaged mitochondria is correlated with liver steatosis. Expression of markers of autophagy and mitophagy, Beclin, LC3-II, Parkin, BNIP3L, was enhanced in liver of HFD-fed REDD1-KO mice. The number of mitochondria showing colocalization between LAMP2 and AIF was increased in liver of HFD-fed REDD1-KO mice. Moreover, mitochondria in liver of REDD1-KO mice were smaller than in WT. These results are correlated with an increase in PGC-1α and CPT-1 expression, involved in fatty acid oxidation. In conclusion, loss of REDD1 protects mice from the development of hepatic steatosis." 6271;"Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway.";"JF. Louet";"Equipe 07, Team 07";11171094;"The Biochemical journal";"Louet JF, Chatelain F, Decaux JF, Park EA, Kohl C, Pineau T, Girard J, Pegorier JP";;"Feb 2001";980985600;;"Liver carnitine palmitoyltransferase I (L-CPT I) catalyses the transfer of long-chain fatty acid (LCFA) for translocation across the mitochondrial membrane. Expression of the L-CPT I gene is induced by LCFAs as well as by lipid-lowering compounds such as clofibrate. Previous studies have suggested that the peroxisome-proliferator-activated receptor alpha (PPARalpha) is a common mediator of the transcriptional effects of LCFA and clofibrate. We found that free LCFAs rather than acyl-CoA esters are the signal metabolites responsible for the stimulation of L-CPT I gene expression. Using primary culture of hepatocytes we found that LCFAs failed to stimulate L-CPT I gene expression both in wild-type and PPARalpha-null mice. These results suggest that the PPARalpha-knockout mouse does not represent a suitable model for the regulation of L-CPT I gene expression by LCFAs in the liver. Finally, we determined that clofibrate stimulates L-CPT I through a classical direct repeat 1 (DR1) motif in the promoter of the L-CPT I gene while LCFAs induce L-CPT I via elements in the first intron of the gene. Our results demonstrate that LCFAs can regulate gene expression through PPARalpha-independent pathways and suggest that the regulation of gene expression by dietary lipids is more complex than previously proposed." 6269;"Regulation of liver carnitine palmitoyltransferase I gene expression by hormones and fatty acids.";"JF. Louet";"Equipe 07, Team 07";11356173;"Biochemical Society transactions";"Louet JF, Le May C, Pégorier JP, Decaux JF, Girard J";;"May 2001";988675200;;"This brief review focuses on the transcriptional regulation of liver carnitine palmitoyltransferase I (L-CPT I) by pancreatic and thyroid hormones and by long-chain fatty acids (LCFA). Both glucagon and 3,3',5-tri-iodothyronine (T(3)) enhanced the transcription of the gene encoding L-CPT I, whereas insulin had the opposite effect. Interestingly, the transcriptional effect of T(3) required, in addition to the thyroid-responsive element, the co-operation of a sequence located in the first intron of L-CPT I gene. Non-esterified fatty acids rather than acyl-CoA ester or intra-mitochondrial metabolite were responsible for the transcriptional effect on the gene encoding L-CPT I. It was shown that LCFA and peroxisome proliferators stimulated L-CPT I gene transcription by distinct mechanisms. Peroxisome proliferator stimulated L-CPT I gene transcription through a peroxisome-proliferator-responsive element (PPRE) located at -2846 bp, whereas LCFA induced L-CPT I gene transcription through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent mechanism owing to a sequence located in the first intron of the gene." 6267;"The coactivator PGC-1 is involved in the regulation of the liver carnitine palmitoyltransferase I gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB).";"JF. Louet";"Equipe 07, Team 07";12107181;"The Journal of biological chemistry";"Louet JF, Hayhurst G, Gonzalez FJ, Girard J, Decaux JF";;"Oct 2002";1033430400;;"Liver carnitine palmitoyltransferase I catalyzes the transfer of long-chain fatty acids into mitochondria. L-CPT I is considered the rate-controlling enzyme in fatty acid oxidation. Expression of the L-CPT I gene is induced by starvation in response to glucagon secretion from the pancreas, an effect mediated by cAMP. Here, the molecular mechanisms underlying the induction of L-CPT I gene expression by cAMP were characterized. We demonstrate that the cAMP response unit of the L-CPT I gene is composed of a cAMP-response element motif and a DR1 sequence located 3 kb upstream of the transcription start site. Our data strongly suggest that the coactivator PGC-1 is involved in the regulation of this gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). Indeed, (i) cotransfection of CREB or HNF4 alpha dominant negative mutants completely abolishes the effect of cAMP on the L-CPT I promoter, and (ii) the cAMP-responsive unit binds HNF4 alpha and CREB through the DR1 and the cAMP-response element sequences, respectively. Moreover, cotransfection of PGC-1 strongly activates the L-CPT I promoter through HNF4 alpha bound at the DR1 element. Finally, we show that the transcriptional induction of the PGC-1 gene by glucagon through cAMP in hepatocytes precedes that of L-CPT-1. In addition to the key role that PGC-1 plays in glucose homeostasis, it may also be critical for lipid homeostasis. Taken together these observations suggest that PGC-1 acts to coordinate the process of metabolic adaptation in the liver." 6265;"Antidiabetic actions of estrogen: insight from human and genetic mouse models.";"JF. Louet";"Equipe 07, Team 07";15068742;"Current atherosclerosis reports";"Louet JF, LeMay C, Mauvais-Jarvis F";;"May 2004";1083369600;;"There is increasing evidence both in humans and rodents linking the endogenous estrogen 17b-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic b-cell function/survival and insulin secretion in conditions of oxidative stress." 6263;"Oncogenic steroid receptor coactivator-3 is a key regulator of the white adipogenic program.";"JF. Louet";"Equipe 07, Team 07";17098861;"Proceedings of the National Academy of Sciences of the United States of America";"Louet JF, Coste A, Amazit L, Tannour-Louet M, Wu RC, Tsai SY, Tsai MJ, Auwerx J, O'Malley BW";;"Nov 2006";1162339200;;"The white adipocyte is at the center of dysfunctional regulatory pathways in various pathophysiological processes, including obesity, diabetes, inflammation, and cancer. Here, we show that the oncogenic steroid receptor coactivator-3 (SRC-3) is a critical regulator of white adipocyte development. Indeed, in SRC-3(-/-) mouse embryonic fibroblasts, adipocyte differentiation was severely impaired, and reexpression of SRC-3 was able to restore it. The early stages of adipocyte differentiation are accompanied by an increase in nuclear levels of SRC-3, which accumulates to high levels specifically in the nucleus of differentiated fat cells. Moreover, SRC-3(-/-) animals showed reduced body weight and adipose tissue mass with a significant decrease of the expression of peroxisome proliferator-activated receptor gamma2 (PPARgamma2), a master gene required for adipogenesis. At the molecular level, SRC-3 acts synergistically with the transcription factor CAAT/enhancer-binding protein to control the gene expression of PPARgamma2. Collectively, these data suggest a crucial role for SRC-3 as an integrator of the complex transcriptional network controlling adipogenesis." 6261;"Coregulators in adipogenesis: what could we learn from the SRC (p160) coactivator family?";"JF. Louet";"Equipe 07, Team 07";17704643;"Cell cycle (Georgetown, Tex.)";"Louet JF, O'Malley BW";;"Oct 2007";1191196800;;"Strong epidemiological studies clearly show that reduction in body fat content decreases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease and some forms of cancer. Therefore, detailed understanding of the mechanisms underlying how fat pads expand appears crucial. Extensive studies already identified a cohort of transcription factors involved in adipocyte differentiation but the fine interrelationship between the myriads of cellular and molecular events occurring during this complex biological process is far from being completely understood. Since the cloning of the first coregulator, the impact of those molecules has dramatically increased. In this review, we will summarize the emerging impact of coregulators on energy balance with a specific interest for fat formation. Emphasis will be given to the coactivators of the SRC (p160) family." 6259;"Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes.";"JF. Louet";"Equipe 07, Team 07";18093211;"Diabetes, obesity & metabolism";"Louet JF, Smith SB, Gautier JF, Molokhia M, Virally ML, Kevorkian JP, Guillausseau PJ, Vexiau P, Charpentier G, German MS, Vaisse C, Urbanek M, Mauvais-Jarvis F";;"Sep 2008";1220227200;;"Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population." 6257;"The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1{alpha}.";"JF. Louet";"Equipe 07, Team 07";18957541;"Proceedings of the National Academy of Sciences of the United States of America";"Coste A, Louet JF, Lagouge M, Lerin C, Antal MC, Meziane H, Schoonjans K, Puigserver P, O'Malley BW, Auwerx J";;"Nov 2008";1225497600;;"Transcriptional control of metabolic circuits requires coordination between specific transcription factors and coregulators and is often deregulated in metabolic diseases. We characterized here the mechanisms through which the coactivator SRC-3 controls energy homeostasis. SRC-3 knock-out mice present a more favorable metabolic profile relative to their wild-type littermates. This metabolic improvement in SRC-3(-/-) mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1alpha. By controlling the expression of the only characterized PGC-1alpha acetyltransferase GCN5, SRC-3 induces PGC-1alpha acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1alpha activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1alpha activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1alpha as an effector to control mitochondrial function and energy homeostasis." 6255;"Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.";"JF. Louet";"Equipe 07, Team 07";19039140;"Science (New York, N.Y.)";"Chopra AR, Louet JF, Saha P, An J, Demayo F, Xu J, York B, Karpen S, Finegold M, Moore D, Chan L, Newgard CB, O'Malley BW";;"Nov 2008";1225497600;;"Hepatic glucose production is critical for basal brain function and survival when dietary glucose is unavailable. Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serves as a terminal gatekeeper for hepatic glucose release into the plasma. Mutations in G6Pase result in Von Gierke's disease (glycogen storage disease-1a), a potentially fatal genetic disorder. We have identified the transcriptional coactivator SRC-2 as a regulator of fasting hepatic glucose release, a function that SRC-2 performs by controlling the expression of hepatic G6Pase. SRC-2 modulates G6Pase expression directly by acting as a coactivator with the orphan nuclear receptor RORalpha. In addition, SRC-2 ablation, in both a whole-body and liver-specific manner, resulted in a Von Gierke's disease phenotype in mice. Our results position SRC-2 as a critical regulator of mammalian glucose production." 6253;"Identification of de novo copy number variants associated with human disorders of sexual development.";"JF. Louet";"Equipe 07, Team 07";21048976;"PloS one";"Tannour-Louet M, Han S, Corbett ST, Louet JF, Yatsenko S, Meyers L, Shaw CA, Kang SH, Cheung SW, Lamb DJ";;"Oct 2010";1285891200;;"Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened 116 children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital defects were used to compare with our cohort of affected patients. Clinically relevant imbalances were found in 21.5% of the analyzed patients. Most anomalies (74.2%) evaded detection by the routinely ordered karyotype and were scattered across the genome in gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication and deletion events were noted on 1p36.33, 9p24.3 and 19q12-q13.11 for ambiguous genitalia, 10p14 and Xq28 for cryptorchidism and 12p13 and 16p11.2 for hypospadias. These variants were significantly associated with genitourinary defects (P = 6.08×10(-12)). The causality of defects observed in 5p15.3, 9p24.3, 22q12.1 and Xq28 was supported by the presence of overlapping chromosomal rearrangements in several unrelated patients. In addition to known gonad determining genes including SRY and DMRT1, novel candidate genes such as FGFR2, KANK1, ADCY2 and ZEB2 were encompassed. The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development." 6251;"The coactivator SRC-1 is an essential coordinator of hepatic glucose production.";"JF. Louet";"Equipe 07, Team 07";21109193;"Cell metabolism";"Louet JF, Chopra AR, Sagen JV, An J, York B, Tannour-Louet M, Saha PK, Stevens RD, Wenner BR, Ilkayeva OR, Bain JR, Zhou S, DeMayo F, Xu J, Newgard CB, O'Malley BW";;"Dec 2010";1291161600;;"Gluconeogenesis makes a major contribution to hepatic glucose production, a process critical for survival in mammals. In this study, we identify the p160 family member, SRC-1, as a key coordinator of the hepatic gluconeogenic program in vivo. SRC-1-null mice displayed hypoglycemia secondary to a deficit in hepatic glucose production. Selective re-expression of SRC-1 in the liver restored blood glucose levels to a normal range. SRC-1 was found induced upon fasting to coordinate in a cell-autonomous manner, the gene expression of rate-limiting enzymes of the gluconeogenic pathway. At the molecular level, the main role of SRC-1 was to modulate the expression and the activity of C/EBPα through a feed-forward loop in which SRC-1 used C/EBPα to transactivate pyruvate carboxylase, a crucial gene for initiation of the gluconeogenic program. We propose that SRC-1 acts as a critical mediator of glucose homeostasis in the liver by adjusting the transcriptional activity of key genes involved in the hepatic glucose production machinery." 6249;"Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption.";"JF. Louet";"Equipe 07, Team 07";21195347;"Cell metabolism";"Chopra AR, Kommagani R, Saha P, Louet JF, Salazar C, Song J, Jeong J, Finegold M, Viollet B, DeMayo F, Chan L, Moore DD, O'Malley BW";;"Jan 2011";1293840000;;"All organisms have devised strategies to counteract energy depletion and promote fitness for survival. We show here that cellular energy depletion puts into play a surprising strategy that leads to absorption of exogenous fuel for energy repletion. The energy-depletion-sensing kinase AMPK binds, phosphorylates, and activates the transcriptional coactivator SRC-2, which in a liver-specific manner promotes absorption of dietary fat from the gut. Hepatocyte-specific deletion of SRC-2 results in intestinal fat malabsorption and attenuated entry of fat into the blood stream. This defect can be attributed to AMPK- and SRC-2-mediated transcriptional regulation of hepatic bile acid (BA) secretion into the gut, as it can be completely rescued by replenishing intestinal BA or by genetically restoring the levels of hepatic bile salt export pump (BSEP). Our results position the hepatic AMPK-SRC-2 axis as an energy rheostat, which upon cellular energy depletion resets whole-body energy by promoting absorption of dietary fuel." 6247;"Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy.";"JF. Louet";"Equipe 07, Team 07";22560224;"Cell metabolism";"York B, Reineke EL, Sagen JV, Nikolai BC, Zhou S, Louet JF, Chopra AR, Chen X, Reed G, Noebels J, Adesina AM, Yu H, Wong LJ, Tsimelzon A, Hilsenbeck S, Stevens RD, Wenner BR, Ilkayeva O, Xu J, Newgard CB, O'Malley BW";;"May 2012";1335830400;;"Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypoglycemia, hyperammonemia, and impaired neurologic, cardiac and skeletal muscle performance, each of which is apparent in mice lacking SRC-3 expression. Consistent with human cases of CACT deficiency, dietary rescue with short chain fatty acids drastically attenuates the clinical hallmarks of the disease in mice devoid of SRC-3. Collectively, our results position SRC-3 as a key regulator of β-oxidation. Moreover, these findings allow us to consider platform coactivators such as the SRCs as potential contributors to syndromes such as CACT deficiency, previously considered as monogenic." 6245;"Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family.";"JF. Louet";"Equipe 07, Team 07";23315938;"Molecular endocrinology (Baltimore, Md.)";"York B, Sagen JV, Tsimelzon A, Louet JF, Chopra AR, Reineke EL, Zhou S, Stevens RD, Wenner BR, Ilkayeva O, Bain JR, Xu J, Hilsenbeck SG, Newgard CB, O'Malley BW";;"Feb 2013";1359676800;;"The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, including the p160 steroid receptor coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis, fat absorption and storage in the liver, and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of the SRC family members, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockouts (KOs) of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 KO mice and their wild-type littermates under fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC. Specifically, SRC-1 ablation revealed the most significant impact on hepatic metabolism, whereas SRC-2 appeared to impact cardiac metabolism. Conversely, ablation of SRC-3 primarily affected brain and skeletal muscle metabolism. Surprisingly, we identified very few metabolites that changed universally across the three SRC KO models. The findings of this Research Resource demonstrate that coactivator function has very limited metabolic redundancy even within the homologous SRC family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators." 6243;"Increased expression of CYP24A1 correlates with advanced stages of prostate cancer and can cause resistance to vitamin D3-based therapies.";"JF. Louet";"Equipe 07, Team 07";24081904;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Tannour-Louet M, Lewis SK, Louet JF, Stewart J, Addai JB, Sahin A, Vangapandu HV, Lewis AL, Dittmar K, Pautler RG, Zhang L, Smith RG, Lamb DJ";;"Jan 2014";1388534400;;"A major limitation of exogenous vitamin D3 administration for the treatment of prostate cancer is the marginal, if any, clinical efficacy. We dissected the basis for the resistance to the vitamin D3 antitumor properties and specifically examined the effect of its major catabolic enzyme, CYP24A1, in prostate cancer. Local CYP24A1 expression levels and the effect of selective modulation were analyzed using tissue microarrays from needle core biopsy specimens and xenograft-bearing mouse models. CYP24A1 mRNA was elevated in malignant human prostate tissues compared to benign lesions. High CYP24A1 protein levels were seen in poorly differentiated and highly advanced stages of prostate cancer and correlated with parallel increase in the tumor proliferation rate. The use of CYP24A1 RNAi enhanced the cytostatic effects of vitamin D3 in human prostate cancer cells. Remarkably, subcutaneous and orthotopic xenografts of prostate cancer cells harboring CYP24A1 shRNA resulted in a drastic reduction in tumor volume when mice were subjected to vitamin D3 supplementation. CYP24A1 may be a predictive marker of vitamin D3 clinical efficacy in patients with advanced prostate cancer. For those with up-regulated CYP24A1, combination therapy with RNAi targeting CYP24A1 could be considered to improve clinical responsiveness to vitamin D3." 6241;"Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action.";"JF. Louet";"Equipe 07, Team 07";24880616;"Nature medicine";"Tannour-Louet M, Han S, Louet JF, Zhang B, Romero K, Addai J, Sahin A, Cheung SW, Lamb DJ";;"Jul 2014";1404172800;;"Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor α (ESR1) in the presence of its cognate ligand, 17β-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans." 6239;"Hepatic SRC-1 activity orchestrates transcriptional circuitries of amino acid pathways with potential relevance for human metabolic pathogenesis.";"JF. Louet";"Equipe 07, Team 07";25148457;"Molecular endocrinology (Baltimore, Md.)";"Tannour-Louet M, York B, Tang K, Stashi E, Bouguerra H, Zhou S, Yu H, Wong LJ, Stevens RD, Xu J, Newgard CB, O'Malley BW, Louet JF";;"Oct 2014";1412121600;;"Disturbances in amino acid metabolism are increasingly recognized as being associated with, and serving as prognostic markers for chronic human diseases, such as cancer or type 2 diabetes. In the current study, a quantitative metabolomics profiling strategy revealed global impairment in amino acid metabolism in mice deleted for the transcriptional coactivator steroid receptor coactivator (SRC)-1. Aberrations were hepatic in origin, because selective reexpression of SRC-1 in the liver of SRC-1 null mice largely restored amino acids concentrations to normal levels. Cistromic analysis of SRC-1 binding sites in hepatic tissues confirmed a prominent influence of this coregulator on transcriptional programs regulating amino acid metabolism. More specifically, SRC-1 markedly impacted tyrosine levels and was found to regulate the transcriptional activity of the tyrosine aminotransferase (TAT) gene, which encodes the rate-limiting enzyme of tyrosine catabolism. Consequently, SRC-1 null mice displayed low TAT expression and presented with hypertyrosinemia and corneal alterations, 2 clinical features observed in the human syndrome of TAT deficiency. A heterozygous missense variant of SRC-1 (p.P1272S) that is known to alter its coactivation potential, was found in patients harboring idiopathic tyrosinemia-like disorders and may therefore represent one risk factor for their clinical symptoms. Hence, we reinforce the concept that SRC-1 is a central factor in the fine orchestration of multiple pathways of intermediary metabolism, suggesting it as a potential therapeutic target that may be exploitable in human metabolic diseases and cancer." 6237;"Leptin decreases BC cell susceptibility to NK lysis via PGC1A pathway.";"JF. Louet";"Equipe 07, Team 07";32449691;"Endocrine connections";"Bouguerra H, Amal G, Clavel S, Boussen H, Louet JF, Gati A";;"Jun 2020";1590969600;;"Large prospective studies established a link between obesity and breast cancer (BC) development. Yet, the mechanisms underlying this association are not fully understood. Among the diverse adipocytokine secreted by hypertrophic adipose tissue, leptin is emerging as a key candidate molecule linking obesity and cancer, since it promotes proliferation and invasiveness of tumors. However, the potential implication of leptin on tumor escape mechanisms remains unknown. This study aims to explore the effect of leptin on tumor resistance to NK lysis and the underlying mechanism. We found that leptin promotes both BC resistance to NK92-mediated lysis and β oxidation on MCF-7, by the up-regulation of a master regulator of mitochondrial biogenesis, the peroxisome proliferator activated receptor coactivator-1 α (PGC1A). Using adenoviral approaches, we show that acute elevation of PGC1A enhances the fatty acid oxidation pathway and decreases the susceptibility of BC cells to NK92-mediated lysis. Importantly, we identified the involvement of PGC1A and leptin in the regulation of hypoxia inducible factor-1 alpha (HIF1A) expression by tumor cells. We further demonstrate that basal BC cells MDA-MB-231 and BT-20 exhibit an increased PGC1A mRNA level and an enhanced oxidative phosphorylation activity; in comparison with luminal BC cells MCF7 and MDA-361, which are associated with more resistance NK92 lysis. Altogether, our results demonstrate for the first time how leptin could promote tumor resistance to immune attacks. Reagents blocking leptin or PGC1A activity might aid in developing new therapeutic strategies to limit tumor development in obese BC patients." 6232;"[Multiple focal nodular hyperplasia of the liver associated with congenital absence of the portal vein].";"R. ANTY";"Equipe 08, Team 08";16565669;"Gastroenterologie clinique et biologique";"Schmidt S, Saint-Paul MC, Anty R, Bruneton JN, Gugenheim J, Chevallier P";;"Feb 2006";1138752000;;"We report the 32nd case of congenital absence of portal vein in an 18-year-old female adult associated with multiple focal nodular hyperplasia of the liver. The association of various hepatic tumors has been observed in half of the publications about congenital absence of portal vein. Hepatic tumors seem to result from systemic diversion of portal vein flow with a resultant increase of arterial flow causing important vascular and nutritif changes the liver and consequent parenchymal transformation." 6230;"Effects of total enteral nutrition supplemented with a multi-fibre mix on faecal short-chain fatty acids and microbiota.";"R. ANTY";"Equipe 08, Team 08";16253403;"Clinical nutrition (Edinburgh, Scotland)";"Schneider SM, Girard-Pipau F, Anty R, van der Linde EG, Philipsen-Geerling BJ, Knol J, Filippi J, Arab K, Hébuterne X";;"Feb 2006";1138752000;;"Impaired bowel function is frequent in tube-fed patients, and diarrhoea is associated with decreased faecal short-chain fatty acids (SCFAs) concentrations. The aim of this study was to compare the effects of a multi-fibre-enriched formula (15 g/l) and a fibre-free isoenergetic and isonitrogenous formula on faecal SCFAs and microbiota in long-term enteral nutrition (EN) patients." 6228;"Gallbladder motility and gut hormone plasma levels in subjects with and without gallstones.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";15980753;"Gastroenterologie clinique et biologique";"Montet JC, Caroli-Bosc FX, Ferrari P, Piche T, Baize N, Anty R, Montet AM, Rampal P, Tran A";;"May 2005";1114905600;;"Hormonal control of gallbladder motility is still unclear in patients with cholelithiasis. In a case-control study, we determined the characteristics of gallbladder emptying evaluated sonographically and the hormone levels of somatostatin, gastrin, and pancreatic polypeptide, before and after a fatty meal in 10 gallstone patients compared with 20 healthy subjects. Patients with lithiasis had a larger residual volume (median 12,0 ml vs 6,5 ml; P = 0.01) and a lower gallbladder ejection fraction (43% vs 70%, P = 0.02) than healthy subjects. During fasting, plasma pancreatic polypeptide concentrations were significantly higher in lithiasis patients (P < 0.03). In contrast, no differences between the two groups of patients were observed during the post prandial period. Somatostatin and gastrin plasma levels were similar in the two groups. Lastly, the serum bile salt levels were in the normal range and were not different between groups both during fasting and postprandial states. We conclude that large basal plasma concentrations of pancreatic polypeptide, a gut peptide inducing gallbladder relaxation, may constitute a factor facilitating lithogenesis." 6226;"Serum fibrosis markers can detect large oesophageal varices with a high accuracy.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";15716658;"European journal of gastroenterology & hepatology";"Vanbiervliet G, Barjoan-Mariné E, Anty R, Piche T, Hastier P, Rakotoarisoa C, Benzaken S, Rampal P, Tran A";;"Mar 2005";1109635200;;"The aim of this study was to determine the value of serum fibrosis markers for the diagnosis of oesophageal varices in alcoholic patients." 6224;"Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";15577649;"AIDS (London, England)";"Mariné-Barjoan E, Saint-Paul MC, Pradier C, Chaillou S, Anty R, Michiels JF, Sattonnet C, Ouzan D, Dellamonica P, Tran A, ";;"Nov 2004";1099267200;;"The impact of immune reconstitution on liver fibrosis in HIV/hepatitis C virus (HCV) patients is unknown. In this case-control study, we investigated the impact of HIV infection on the severity of liver fibrosis and identified related factors." 6222;"[Is combined treatment with interferon alpha and ribavirin for 3 months enough in selected patients with a genotype 2 or 3 hepatitis C virus?].";"A. TRAN, R. ANTY";"Equipe 08, Team 08";15094682;"Gastroenterologie clinique et biologique";"Anty R, Vanbiervliet G, Benzaken S, Rampal P, Tran A";;"Mar 2004";1078099200;;"Peginterferon plus ribavirin for 24 weeks is the recommended treatment, for previously untreated patients infected by genotype 2 or 3 hepatitis C virus. We report 2 patients with genotype 3 and 2a, with a sustained virological response, after bitherapy with interferon plus ribavirin with 16 and 14 weeks respectively. Thus in selected patients having genotype 2 or 3, and other predictive factors of a sustained virological response, shorter bitherapy could be enough and improve the effectiveness/tolerance ratio." 6220;"[Fulminant hepatitis after a therapeutic dose of acetaminophen in a chronic alcoholic patient].";"R. ANTY";"Equipe 08, Team 08";14990303;"La Revue de medecine interne";"Hyvernat H, Vandenbos F, Anty R, Barel R, Demarquay JF, Saint-Paul MC, Bernardin G";;"Mar 2004";1078099200;; 6218;"[A man with non alcoholic steatohepatitis].";"A. TRAN, R. ANTY";"Equipe 08, Team 08";14586252;"Gastroenterologie clinique et biologique";"Tran A, Anty R";;"Sep Aug 2003";1060387200;; 6216;"Serum C-reactive protein: a non-invasive marker of alcoholic hepatitis.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";17101579;"Scandinavian journal of gastroenterology";"Vanbiervliet G, Le Breton F, Rosenthal-Allieri MA, Gelsi E, Marine-Barjoan E, Anty R, Piche T, Benzaken S, Saint-Paul MC, Huet PM, Tran A";;"Dec 2006";1164931200;;"To determine the diagnostic accuracy of C-reactive protein (CRP) for alcoholic hepatitis in heavy drinkers." 6214;"Glucose intolerance and hypoadiponectinemia are already present in lean patients with chronic hepatitis C infected with genotype non-3 viruses.";"A. TRAN, P. GUAL, R. ANTY";"Equipe 08, Team 08";17625437;"European journal of gastroenterology & hepatology";"Anty R, Gelsi E, Giudicelli J, Mariné-Barjoan E, Gual P, Benzaken S, Saint-Paul MC, Sadoul JL, Huet PM, Tran A";;"Aug 2007";1185926400;;"Steatosis and metabolic abnormalities seem to be frequent and deleterious in chronic hepatitis C. Changes in glucose homeostasis and in adiponectin levels, an adipokine with anti-inflammatory and insulin-sensitive properties, were evaluated in patients with chronic hepatitis C according to steatosis, liver fibrosis and body mass index." 6212;"Predictive factors of bleeding related to post-banding ulcer following endoscopic variceal ligation in cirrhotic patients: a case-control study.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";20412065;"Alimentary pharmacology & therapeutics";"Vanbiervliet G, Giudicelli-Bornard S, Piche T, Berthier F, Gelsi E, Filippi J, Anty R, Arab K, Huet PM, Hebuterne X, Tran A";;"Jul 2010";1277942400;;"Life-threatening bleeding caused by early spontaneous slippage of rubber bands has been described after variceal ligation in cirrhotic patients." 6210;"Inflammation, insulin resistance, lipid disturbances, anthropometrics, and metabolic syndrome in morbidly obese patients: a case control study comparing laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy.";"A. TRAN, A. IANNELLI, R. ANTY";"Equipe 08, Team 08";20932542;Surgery;"Iannelli A, Anty R, Schneck AS, Tran A, Gugenheim J";;"Mar 2011";1298937600;;"Laparoscopic sleeve gastrectomy (LSG) is a common bariatric procedure that has several advantages over Roux-en-Y gastric bypass, but data on the effectiveness of this procedure on metabolic syndrome have rarely been reported." 6208;"Effect of detoxification on liver stiffness assessed by Fibroscan® in alcoholic patients.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";21143253;"Alcoholism, clinical and experimental research";"Gelsi E, Dainese R, Truchi R, Mariné-Barjoan E, Anty R, Autuori M, Burroni S, Vanbiervliet G, Evesque L, Cherikh F, Tran A";;"Mar 2011";1298937600;;"The aims of this study were to determine whether alcohol consumption or cessation influences transient elastography (TE) measurements and whether TE is a useful tool to monitor alcoholic patients." 6206;"A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis.";;;21145828;"Journal of hepatology";"Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, Sogni P, Maynard M, Larrey D, Serfaty L, Bonnefont-Rousselot D, Bastard JP, Rivière M, Spénard J, ";;"May 2011";1304208000;;"Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH." 6204;"Plasma carnitine is associated with fatigue in chronic hepatitis C but not in the irritable bowel syndrome.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";21366633;"Alimentary pharmacology & therapeutics";"Anty R, Marjoux S, Bekri S, DeGalleani L, Dainese R, Gelsi E, Cherikh F, Tran A, Piche T";;"Apr 2011";1301616000;;"Fatigue is an important determinant of altered quality of life in patients affected by chronic hepatitis C or the irritable bowel syndrome (IBS)." 6202;"Unusual evolution of ciprofloxacin-induced hepatitis revealing a possible link with IgG4-associated autoimmune hepatitis.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";21752734;"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver";"Anty R, Hastier P, Saint-Paul MC, Tran A";;"Nov 2011";1320105600;; 6200;"Liver fibrogenesis and metabolic factors.";"R. ANTY";"Equipe 08, Team 08";21742296;"Clinics and research in hepatology and gastroenterology";"Anty R, Lemoine M";;"Jun 2011";1306886400;;"Mechanisms of liver fibrosis are complex and varied. Among them, metabolic factors are particularly important in the development of fibrosis associated with nonalcoholic steatohepatitis (NASH). These factors are some of the ""multiple parallel hits"" responsible for liver damage during NASH. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Major profibrogenic protagonists, such as hepatic stellate cells and Kupffer cells, are activated by insulin resistance, apoptosis and local inflammation. Relations between steatosis, insulin resistance and fibrosis are complex. Initially, simple steatosis may be a way to store deleterious free fatty acid in neutral triglycerides. If the lipid storage threshold is exceeded, steatosis may become associated with lipotoxicity. Similarly, interindividual variations of adipose tissue expandability might explain various phenotypes, ranging from ""metabolically obese patients with normal weight"" to ""metabolically normal morbidly obese patients"". The metabolic abnormalities in subcutaneous and visceral adipose tissue are insulin resistance and low-grade inflammation, which are associated with increased release of free fatty acid flux and changes in adipocytokines production such as leptin, adiponectin and interleukin 6. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the endocannabinoid system might have important roles in liver fibrogenesis and are potential therapeutic targets. Finally, with the development of new molecular tools, gut microbiota has been recently identified for its pleiotropic functions, including metabolism regulation. Better knowledge of these mechanisms should lead to new strategies for the treatment of metabolic factors that play a key role in liver injuries." 6198;"Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";21931380;"The American journal of gastroenterology";"Vivinus-Nébot M, Dainese R, Anty R, Saint-Paul MC, Nano JL, Gonthier N, Marjoux S, Frin-Mathy G, Bernard G, Hébuterne X, Tran A, Theodorou V, Piche T";;"Jan 2012";1325376000;;"Recent evidence suggests a role for increased colonic permeability and mucosal mast cell (MC) mediators on symptoms related to the irritable bowel syndrome (IBS). Whether allergic factors (AFs) are involved in the pathophysiology of IBS is unclear. We addressed the question of the possible influence of an allergic background on IBS symptoms." 6196;"First case report of an acute genotype 3 hepatitis E infected pregnant woman living in South-Eastern France.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";22336086;"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology";"Anty R, Ollier L, Péron JM, Nicand E, Cannavo I, Bongain A, Giordanengo V, Tran A";;"May 2012";1335830400;;"In European countries, epidemiology of hepatitis E virus (HEV) infection is not well known. Although, seroprevalence of HEV Immunoglobulin G reached a few percent in European women, no acute hepatitis E during pregnancy has been described so far. Here, we report a case of an autochthonous HEV genotype 3 infection in a 41-years-old pregnant woman living in a non-endemic country. The acute hepatitis had a spontaneous good outcome for the mother and the child. In non-endemic areas where Hepatitis E infections are emerging, unexplained cytolysis, whatever its level, in a pregnant woman could be investigated for HEV, using biological molecular and serology tools." 6194;"Hepatitis E: are rheumatic patients at risk?";"S. PATOURAUX, R. ANTY";"Equipe 08, Team 08";23280171;"The Journal of rheumatology";"Roux CH, Anty R, Patouraux S, Euller-Ziegler L";;"Jan 2013";1356998400;; 6192;"Antioxidant therapy and drugs interfering with lipid metabolism: could they be effective in NAFLD patients?";"R. ANTY";"Equipe 08, Team 08";23394094;"Current pharmaceutical design";"Musso G, Anty R, Petta S";;"Jan 2013";1356998400;;"This review is part of a special issue dealing with various aspects of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We will focus on promising treatments of NASH with antioxidants and drugs that interfere with lipid metabolism.The other therapies of interest, such as diet, behavioral changes, and insulin sensitizers are presented elsewhere. Oxidative stress is believed to play a key role in the pathogenesis of NASH and other liver diseases. Antioxidants aimed at improving chronic alcoholic or viral liver diseases have been an object of study for some time. However, only a few high quality, randomized, versus placebo-controlled, double-blinded trials have been carried out to assess these drugs. Vitamin E is currently the most widely assessed antioxidant. Several questions need to be answered, including long-term tolerance and efficacy of vitamin E in particular subsets, such as diabetes and NASH-related cirrhosis. Other antioxidants are promising, and should be assessed using the standards of evidence-based medicine. NAFLD frequently coexists with hyperlipidemia and carries an increased risk of cardiovascular disease (CVD). Furthermore, altered lipid metabolism is thought to be central to the pathogenesis of liver injury in NASH. Therefore, lipid-lowering drugs are attractive therapeutic tools in the treatment of NAFLD. Statins have ameliorated surrogate markers of steatosis in several randomized controlled trials, but their impact on liver histology is unknown. They have, however, been found to be the only class of lipid-lowering drugs that reduces cardiovascular risk in NAFLD. Preliminary evidence suggests that ezetimibe, an inhibitor of intestinal and hepatic cholesterol absorption, may improve liver histology, but its impact on the risk of CVD and on clinical outcome remains to be determined. Despite strong experimental evidence supporting the use of omega-3 polyunsaturated fatty acids in NAFLD, the studies published on humans have consisted of small sample sizes and had a number of methodological flaws, including the absence of post-treatment histology. Association of antioxidants and/or lipid-lowering drugs plus other drugs of interest in NASH, such as insulin sensitizers, warrant investigation. However, as promising as these drug treatments may continue to be, they should be associated with diet and modifications in lifestyle. " 6188;"Preoperative 4-week supplementation with omega-3 polyunsaturated fatty acids reduces liver volume and facilitates bariatric surgery in morbidly obese patients.";"A. IANNELLI, R. ANTY";"Equipe 08, Team 08";23686653;"Obesity surgery";"Iannelli A, Martini F, Schneck AS, Ghavami B, Baudin G, Anty R, Gugenheim J";;"Nov 2013";1383264000;;"Non-alcoholic fatty liver disease (NAFLD) is a very common condition among obese patients that may lead to the enlargement of the liver, that in turn impairs the access to the gastro-esophageal junction during laparoscopic bariatric surgery. Omega-3 polyunsaturated fatty acids (Ω-3 PUFAs) supplementation has been shown to reduce nutritional hepatic steatosis. The aim of this study was to assess the effects of a 4-week course of oral Ω-3 PUFAs supplementation on the volume of the liver." 6184;"Evolution of low-grade systemic inflammation, insulin resistance, anthropometrics, resting energy expenditure and metabolic syndrome after bariatric surgery: a comparative study between gastric bypass and sleeve gastrectomy.";"A. TRAN, A. IANNELLI, R. ANTY";"Equipe 08, Team 08";24016714;"Journal of visceral surgery";"Iannelli A, Anty R, Schneck AS, Tran A, Hébuterne X, Gugenheim J";;"Sep 2013";1377993600;;"Laparoscopic sleeve gastrectomy (LSG) for morbid obesity is gaining in popularity as it offers several advantages over laparoscopic Roux-en-Y gastric bypass (LRYGBP), but comparative data between these two procedures have rarely been reported." 6182;"Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial.";"R. ANTY";"Equipe 08, Team 08";24026598;JAMA;"Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, Anty R, Diaz E, Thabut D, Moirand R, Lebrec D, Moreno C, Talbodec N, Paupard T, Naveau S, Silvain C, Pageaux GP, Sobesky R, Canva-Delcambre V, Dharancy S, Salleron J, Dao T";;"Sep 2013";1377993600;;"Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown." 6180;"Sudden severe jaundice with high fever in a young woman.";"A. TRAN, S. PATOURAUX, R. ANTY";"Equipe 08, Team 08";24953202;"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver";"Canivet CM, Anty R, Patouraux S, Tran A";;"Nov 2014";1414800000;; 6178;"TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.";"R. ANTY";"Equipe 08, Team 08";24978903;"Nature communications";"Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, Allison ME, Alexander GJ, Piguet AC, Anty R, Donaldson P, Aithal GP, Francque S, Van Gaal L, Clement K, Ratziu V, Dufour JF, Day CP, Daly AK, Anstee QM";;"Jun 2014";1401580800;;"Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD. " 6176;"Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial.";"R. ANTY";"Equipe 08, Team 08";25463545;"Journal of hepatology";"Thévenot T, Bureau C, Oberti F, Anty R, Louvet A, Plessier A, Rudler M, Heurgué-Berlot A, Rosa I, Talbodec N, Dao T, Ozenne V, Carbonell N, Causse X, Goria O, Minello A, De Ledinghen V, Amathieu R, Barraud H, Nguyen-Khac E, Becker C, Paupard T, Botta-Fridlung D, Abdelli N, Guillemot F, Monnet E, Di Martino V";;"Apr 2015";1427846400;;"Albumin infusion improves renal function and survival in cirrhotic patients with spontaneous bacterial peritonitis (SBP) but its efficacy in other types of infections remains unknown. We investigated this issue through a multicenter randomized controlled trial." 6174;"Severe hyperemesis gravidarum associated with gestational thyrotoxicosis and acute biliary pancreatitis.";"R. ANTY";"Equipe 08, Team 08";25758559;"European journal of obstetrics, gynecology, and reproductive biology";"Chevalier N, Anty R, Gilly O, Paul C, Panaïa-Ferrari P, Brucker-Davis F";;"Apr 2015";1427846400;; 6172;"Predictors of metabolic syndrome persistence 1 year after laparoscopic Roux-en-Y gastric bypass.";"A. IANNELLI, R. ANTY";"Equipe 08, Team 08";25868838;"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery";"Martini F, Anty R, Schneck AS, Casanova V, Iannelli A, Gugenheim J";;"Oct Sep 2015";1441843200;;"Laparoscopic Roux-en-Y gastric bypass (LRYGB) is effective in reversing the metabolic syndrome (MS) in up to 90% of patients." 6170;"Treatment of hepatocellular carcinomas by thermal ablation and hepatic transarterial chemoembolization.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";25981213;"Diagnostic and interventional imaging";"Chevallier P, Baudin G, Anty R, Guibal A, Chassang M, Avril L, Tran A";;"Jun 2015";1433116800;;"Local tumor recurrence after thermal ablation of hepatocellular carcinoma (HCC) can impact on overall survival and are very closely linked to partial treatment of the primary lesion or to potential microvascular invasion or satellite micronodules located close to the main lesion. The diagnosis of these liver metastases close to the primary lesion on CT and MRI is difficult and their incidence, number and spread throughout the liver correlates with diameter of primary tumor. Tumor diameter is currently the key factor to predict whether or not thermal ablation of HCC will be complete or not. It has now been shown for monopolar radiofrequency ablation that this therapy alone is sufficient to effectively treat single HCCs<3cm in diameter provided that liver micrometastases are not present. If the HCC is>3cm in size, multifocal or in the case of tumor recurrence, overall survival and recurrence-free survival results are better if monopolar radiofrequency ablation is combined with hepatic trans-arterial chemoembolization. The timing of this combination of treatments probably influences its effectiveness on tumor and tolerability and remains to be assessed. " 6168;"Ascitic fluid TREM-1 for the diagnosis of spontaneous bacterial peritonitis.";"R. ANTY";"Equipe 08, Team 08";26141143;Gut;"Ichou L, Carbonell N, Rautou PE, Laurans L, Bourcier S, Pichereau C, Baudel JL, Nousbaum JB, Renou C, Anty R, Tankovic J, Maury E, Guidet B, Landraud L, Ait-Oufella H";;"Mar 2016";1456790400;; 6166;"Treatment of autochthonous acute hepatitis E with short-term ribavirin: a multicenter retrospective study.";"R. ANTY";"Equipe 08, Team 08";26179015;"Liver international : official journal of the International Association for the Study of the Liver";"Péron JM, Abravanel F, Guillaume M, Gérolami R, Nana J, Anty R, Pariente A, Renou C, Bureau C, Robic MA, Alric L, Vinel JP, Izopet J, Kamar N";;"Mar 2016";1456790400;;"Hepatitis E virus (HEV) genotypes 3 and 4 cause sporadic cases of infection in developed countries. Being elderly and having an underlying liver disease are the main risk factors for death in this population. Chronic infection has been described in immunocompromised patients. Ribavirin is now the antiviral treatment of choice in solid-organ-transplant recipients with chronic HEV infection. We hypothesized that early short-term treatment of acute HEV infection may be useful for patients with risk factors or undergoing chemotherapy." 6164;"Improvement of Kidney Function Following Bariatric Surgery: Hope or Illusion?";"A. IANNELLI, R. ANTY";"Equipe 08, Team 08";26220237;"Obesity surgery";"Favre G, Schneck AS, Anty R, Esnault VL, Iannelli A";;"Oct 2015";1443657600;; 6162;"MELD Score Kinetics in Decompensated HIV+/HCV+ Patients: A Useful Prognostic Tool (ANRS HC EP 25 PRETHEVIC Cohort Study).";"R. ANTY";"Equipe 08, Team 08";26222860;Medicine;"Gelu-Simeon M, Bayan T, Ostos M, Boufassa F, Teicher E, Steyaert JM, Bertucci I, Anty R, Pageaux GP, Meyer L, Duclos-Vallée JC, ";;"Jul 2015";1435708800;;"To assess prognostic factors for survival and describe Model for End-Stage liver disease (MELD) dynamics in human immunodeficiency virus+/hepatitis C virus+ (HIV+/HCV+) patients after an initial episode of hepatic decompensation.An HIV+/HCV+ cohort of patients experiencing an initial decompensation episode within the year preceding enrollment were followed prospectively. Clinical and biological data were collected every 3 months. Predictors for survival were identified using Kaplan-Meier curves and Cox models. A 2-slope-mixed linear model was used to estimate MELD score changes as a function of survival.Sixty seven patients were included in 32 centers between 2009 and 2012 (72% male; median age: 48 years [interquartile ratio (IQR):45-52], median follow-up: 22.4 months [range: 0.5-65.3]). Overall survival rates were 86%, 78%, and 59% at 6, 12, and 24 months, respectively. Under multivariate analysis, the MELD score at initial decompensation was predictive of survival, adjusted for age, type of decompensation, baseline CD4 counts, and further decompensation during follow-up as a time-dependent variable. The adjusted hazard ratio of death was 1.32 for a score 3 points higher (95% CI: [1.06-1.63], P = 0.012). MELD score kinetics within the 6 months after initial decompensation differed significantly between non-deceased and deceased patients, with a decreased (-0.49/month; P = 0.016), versus a flat (+0.06/month, P = 0.753) mean change in score.MELD is an effective tool to predict survival in HIV+/HCV+ patients with decompensated cirrhosis. A non-decreasing MELD score within 6 months following this initial decompensation episode may benefit from privileged access to liver transplantation in this poor prognosis population." 6160;"De novo hiatal hernia of the gastric tube after sleeve gastrectomy.";"R. ANTY";"Equipe 08, Team 08";26318133;"International journal of surgery case reports";"Amor IB, Debs T, Kassir R, Anty R, Amor VB, Gugenheim J";;"Jan 2015";1420070400;;"Sleeve gastrectomy (SG) is a frequently used surgical procedure for the treatment of morbid obesity. Several complications of SG have been described; however, de novo hiatal hernia of the gastric tube, as a complication of SG, has not been described in the literature." 6158;"Increased Prevalence of Irritable Bowel Syndrome in a Cohort of French Morbidly Obese Patients Candidate for Bariatric Surgery.";"A. TRAN, A. IANNELLI, R. ANTY";"Equipe 08, Team 08";26424705;"Obesity surgery";"Schneck AS, Anty R, Tran A, Hastier A, Amor IB, Gugenheim J, Iannelli A, Piche T";;"07 2016";1467331200;;"Only a few recent reports have suggested a correlation between obesity and irritable bowel syndrome (IBS). We aimed to determine the prevalence and severity of IBS in a prospective cohort of obese patients undergoing bariatric surgery in Nice Hospital (France)." 6156;"Nonalcoholic steatohepatitis cirrhosis and type 1 refractory celiac disease: More than a fortuitous association?";"A. TRAN, S. PATOURAUX, R. ANTY";"Equipe 08, Team 08";26526847;"Clinics and research in hepatology and gastroenterology";"Hastier A, Patouraux S, Canivet CM, Lebeaupin C, Tran A, Anty R";;"Feb 2016";1454284800;; 6154;"Direct-acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge.";"R. ANTY";"Equipe 08, Team 08";26967675;"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology";"De Monte A, Courjon J, Anty R, Cua E, Naqvi A, Mondain V, Cottalorda J, Ollier L, Giordanengo V";;"May 2016";1462060800;;"Use of direct-acting antiviral drugs (DAAs) greatly improves management of adults infected with hepatitis C virus (HCV) whether patients are treatment-naive or unsuccessfully pre-treated. Several inhibitors of viral nonstructural proteins (NS3/4A protease, NS5A and NS5B polymerase) allow a rapid HCV clearance and increase rates of sustained virological response. Both the EASL and AASLD guidelines have recently published up-to-date recommendations for their use, addressing each HCV genotype and particular situations. However, management of patients coinfected with hepatitis B virus (HBV) has been developed by these guidelines with reference to cases of HBV reactivation reported during previous anti-HCV regimens containing interferon known active against both HBV and HCV. In the setting of the interferon-free HCV therapies with DAAs only, the possibility of HBV reactivation during treatment of hepatitis C is raised due to viral interferences in HCV/HBV coinfected persons. Herein, we report a case of early HBV reactivation during DAAs-based anti-HCV treatment (ledipasvir/sofosbuvir) in a patient having a resolved HBV infection and chronically infected with HCV genotype 4 and HIV. Moreover, we review similar recent cases of HBV reactivation in patients infected with HBV and HCV genotype 1 during treatment of hepatitis C by regimen incorporating other combination of DAAs (sofosbuvir/simeprevir or daclatasvir/asunaprevir). Due to the potential risk of early HBV reactivation in HCV/HBV-coinfected patients during interferon-free DAAs-based HCV therapies, altogether these cases highlight the necessity to closely monitor HBV coinfection, regardless its stage (chronic, occult, resolved), whatever HCV genotype or class of DAAs used. " 6152;"Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence - The ANRS CUPILT study.";"R. ANTY";"Equipe 08, Team 08";27262758;"Journal of hepatology";"Coilly A, Fougerou-Leurent C, de Ledinghen V, Houssel-Debry P, Duvoux C, Di Martino V, Radenne S, Kamar N, D'Alteroche L, Leroy V, Canva V, Lebray P, Moreno C, Dumortier J, Silvain C, Besch C, Perre P, Botta-Fridlund D, Anty R, Francoz C, Abergel A, Debette-Gratien M, Conti F, Habersetzer F, Rohel A, Rossignol E, Danjou H, Roque-Afonso AM, Samuel D, Duclos-Vallée JC, Pageaux GP, ";;"10 2016";1475280000;;"HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy." 6150;"Efficacy and safety of boceprevir-based triple therapy in HCV cirrhotic patients awaiting liver transplantation (ANRS HC29 BOCEPRETRANSPLANT).";"R. ANTY";"Equipe 08, Team 08";27554134;"Clinics and research in hepatology and gastroenterology";"Fontaine H, Maynard M, Bouix C, Carrieri MP, Botta-Fridlund D, D'Alteroche L, Conti F, Pageaux GP, Leroy V, Métivier S, Anty R, Durand F, Canva V, Vilotitch A, Lebray P, Alric L, Duvoux C, Petrov-Sanchez V, Beaulieux F, Wellems C, Paul C, Roque-Afonso AM, Roche B, Pradat P, Samuel D, Duclos-Vallée JC, ";;"Feb 2017";1485907200;;"In this French multicentre, open-label study, we analyzed the efficacy, safety and patient-reported outcomes of a boceprevir-based triple therapy in HCV genotype 1 cirrhotic patients awaiting liver transplantation (LT)." 6148;"The Periscreen Strip Is Highly Efficient for the Exclusion of Spontaneous Bacterial Peritonitis in Cirrhotic Outpatients.";"R. ANTY";"Equipe 08, Team 08";27619833;"The American journal of gastroenterology";"Thévenot T, Briot C, Macé V, Lison H, Elkrief L, Heurgué-Berlot A, Bureau C, Jézéquel C, Riachi G, Louvet A, Pauwels A, Ollivier-Hourmand I, Anty R, Carbonell N, Labadie H, Aziz K, Grasset D, Nguyen-Khac E, Kaassis M, Hermann S, Tanné F, Mouillot T, Roux O, Le Thuaut A, Cervoni JP, Cadranel JF, Schnee M, ";;"10 2016";1475280000;;"We aimed to assess the performance of a new strip (Periscreen) for the rapid diagnosis of spontaneous bacterial peritonitis (SBP)." 6146;"A stepwise algorithm using an at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis.";"R. ANTY";"Equipe 08, Team 08";28088581;"Journal of hepatology";"Boursier J, de Ledinghen V, Leroy V, Anty R, Francque S, Salmon D, Lannes A, Bertrais S, Oberti F, Fouchard-Hubert I, Calès P";;"06 2017";1496275200;;"Chronic liver diseases (CLD) are common, and are therefore mainly managed by non-hepatologists. These physicians lack access to the best non-invasive tests of liver fibrosis, and consequently cannot accurately determine the disease severity. Referral to a hepatologist is then needed. We aimed to implement an algorithm, comprising a new first-line test usable by all physicians, for the detection of advanced liver fibrosis in all CLD patients." 6144;"Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";29665081;"Alimentary pharmacology & therapeutics";"Anty R, Favre G, Coilly A, Rossignol E, Houssel-Debry P, Duvoux C, De Ledinghen V, Di Martino V, Leroy V, Radenne S, Kamar N, Canva V, D'Alteroche L, Durand F, Dumortier J, Lebray P, Besch C, Tran A, Canivet CM, Botta-Fridlund D, Montialoux H, Moreno C, Conti F, Silvain C, Perré P, Habersetzer F, Abergel A, Debette-Gratien M, Dharancy S, Esnault VLM, Fougerou-Leurent C, Cagnot C, Diallo A, Veislinger A, Danjou H, Samuel D, Pageaux GP, Duclos-Vallée JC, ";;"06 2018";1527811200;;"In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable." 6142;"The epidemiology of Budd-Chiari syndrome in France.";"R. ANTY";"Equipe 08, Team 08";29803757;"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver";"Ollivier-Hourmand I, Allaire M, Goutte N, Morello R, Chagneau-Derrode C, Goria O, Dumortier J, Cervoni JP, Dharancy S, Ganne-Carrié N, Bureau C, Carbonell N, Abergel A, Nousbaum JB, Anty R, Barraud H, Ripault MP, De Ledinghen V, Minello A, Oberti F, Radenne S, Bendersky N, Farges O, Archambeaud I, Guillygomarc'h A, Ecochard M, Ozenne V, Hilleret MN, Nguyen-Khac E, Dauvois B, Perarnau JM, Lefilliatre P, Raabe JJ, Doffoel M, Becquart JP, Saillard E, Valla D, Dao T, Plessier A, ";;"Sep 2018";1535760000;;"Epidemiological data is lacking on primary Budd-Chiari syndrome (BCS) in France." 6140;"A decompensated cryptogenic cirrhosis? No, a late liver histiocytosis!";"S. PATOURAUX, R. ANTY";"Equipe 08, Team 08";30077466;"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver";"Ouizeman DJ, Patouraux S, Lacour JP, Anty R";;"12 2018";1543622400;; 6138;"Effects of Long-term Norfloxacin Therapy in Patients With Advanced Cirrhosis.";"R. ANTY";"Equipe 08, Team 08";30144431;Gastroenterology;"Moreau R, Elkrief L, Bureau C, Perarnau JM, Thévenot T, Saliba F, Louvet A, Nahon P, Lannes A, Anty R, Hillaire S, Pasquet B, Ozenne V, Rudler M, Ollivier-Hourmand I, Robic MA, d'Alteroche L, Di Martino V, Ripault MP, Pauwels A, Grangé JD, Carbonell N, Bronowicki JP, Payancé A, Rautou PE, Valla D, Gault N, Lebrec D, ";;"12 2018";1543622400;;"There is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis." 6136;"Assessment of Liver Graft Steatosis: Where Do We Stand?";"A. IANNELLI, R. ANTY";"Equipe 08, Team 08";30380197;"Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society";"Cesaretti M, Addeo P, Schiavo L, Anty R, Iannelli A";;"03 2019";1551398400;;"The growing number of patients on waiting lists for liver transplantation and the shortage of organs have forced many centers to adopt extended criteria for graft selection, moving the limit of acceptance for marginal livers. Steatotic grafts that were, in the past, considered strictly unacceptable for transplantation because of the high risk of early nonfunction are now considered as a potential resource for organ implementation. Several methods to diagnose, measure, classify, and stage steatosis exist, but none can be considered qualitatively and quantitatively ""the ideal method"" to date. Clinical, biological, and imaging data can be very helpful to estimate graft steatosis, but histology still remains the gold standard. There is an increasing need for rapid and reliable tools to assess graft steatosis. Herein, we present a comprehensive review of the approaches that are currently used to quantify steatosis in liver grafts." 6134;"Fatal cholestatic hepatitis after a single dose of celecoxib.";"A. TRAN, S. PATOURAUX, R. ANTY";"Equipe 08, Team 08";30449626;"Clinics and research in hepatology and gastroenterology";"Larrey E, Patouraux S, Spreux A, Canivet CM, Piche T, Tran A, Anty R";;"10 2019";1569888000;; 6132;"Bariatric Surgery Significantly Improves the Quality of Sexual Life and Self-esteem in Morbidly Obese Women.";"A. IANNELLI, R. ANTY";"Equipe 08, Team 08";30712172;"Obesity surgery";"Cherick F, Te V, Anty R, Turchi L, Benoit M, Schiavo L, Iannelli A";;"05 2019";1556668800;;"The impact of bariatric surgery (BS) on the sexual functioning of patients is poorly studied. Our aim was to analyze the sexual function, depressive symptoms, and self-esteem of morbidly obese women (MOW) undergoing BS." 6130;"Safety and efficacy of the combination simeprevir-sofosbuvir in HCV genotype 1- and 4-mono-infected patients from the French ANRS CO22 hepather cohort.";"A. TRAN";"Equipe 08, Team 08";30940090;"BMC infectious diseases";"Laurain A, Metivier S, Haour G, Larrey D, Dorival C, Hezode C, Zoulim F, Marcellin P, Bourliere M, Zarski JP, Thabut D, Alric L, Ganne-Carrie N, Cales P, Bronowicki JP, Riachi G, Geist C, Causse X, Abergel A, Chazouilleres O, Mathurin P, Guyader D, Samuel D, Tran A, Loustaud-Ratti V, Petrov-Sanchez V, Diallo A, Luzivika-Nzinga C, Fontaine H, Carrat F, Pol S, ";;"Apr 2019";1554076800;;"Although real-life results of sofosbuvir/simeprevir have been extensively reported from the United States, data from other geographical areas are limited. In the French observational cohort, ANRS CO22 HEPATHER, 9432 patients were given the new oral antivirals from December 2013 to June 30, 2018. We report the results of sofosbuvir/simeprevir in genotypes 1- and 4-infected patients." 6128;"Liver transplantation for bariatric surgery-related liver failure: a systematic review of a rare condition.";"A. IANNELLI, R. ANTY";"Equipe 08, Team 08";31285130;"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery";"Addeo P, Cesaretti M, Anty R, Iannelli A";;"Aug 2019";1564617600;;"Protein malnutrition and bacterial overgrowth occurring after bariatric surgery (BS) might cause severe liver failure (LF) needing liver transplantation (LT)." 6126;"ALBI-based BCLC nomogram: A new or an additional prognostic tool?";"R. ANTY";"Equipe 08, Team 08";32147932;"Liver international : official journal of the International Association for the Study of the Liver";"Adhoute X, Larrey E, Pénaranda G, Anty R";;"07 2020";1593561600;; 6124;"Absence of impact of direct acting antivirals for hepatitis C virus on recurrent hepatocellular carcinoma tumor growth in the AFEF/ANRS CO22 Hepather cohort.";"A. TRAN";"Equipe 08, Team 08";32595103;"Clinics and research in hepatology and gastroenterology";"Vallet-Pichard A, Correas JM, Dorival C, Zoulim F, Tran A, Bourlière M, Calès P, Guyader D, Bronowicki JP, Larrey D, Hezode C, Loustaud-Ratti V, Gournay J, de Ledinghen V, Asselah T, Ganne N, Metivier S, Chazouillères O, Leroy V, Rosa I, Samuel D, Mathurin P, Cagnot C, Fontaine H, Carrat F, Pol S, ";;"Jan 2021";1609459200;;"Although it has now been excluded that direct-acting antivirals (DAA) are associated with a significant risk of hepatocellular carcinoma (HCC) in HCV-infected patients, a possible effect of DAA on tumor growth is still a subject of debate. We performed a blind comparison of the kinetics of HCC recurrence in patients after HCV treatment with or without DAA to evaluate the potential aggressiveness of HCC after DAA treatment." 6122;"Accurate assessment of nonalcoholic fatty liver disease lesions in liver allograft biopsies by a smartphone platform: A proof of concept.";"A. IANNELLI, S. PATOURAUX, R. ANTY";"Equipe 08, Team 08";32608555;"Microscopy research and technique";"Cesaretti M, Gal J, Bouveyron C, Diaspro A, Fontas E, Antonini A, Anty R, Iannelli A, Patouraux S";;"Sep 2020";1598918400;;"Macrovesicular steatosis (MS) is a major risk factor for liver graft failure after transplantation and pathological microscopic examination of a frozen tissue section remains the gold standard for its assessment. However, the latter requires an experienced in-house pathologist for correct and rapid diagnosis as well as specific equipment that is not always available. Smartphones, which are must-have tools for everyone, are very suitable for incorporation into promising technology to generate moveable diagnostic tools as for telepathology. The study aims to compare the microscopic assessment of nonalcoholic fatty liver disease (NAFLD) spectrum in liver allograft biopsies by a smartphone microscopy platform (DIPLE device) to standard light microscopy. Forty-two liver graft biopsies were evaluated in transmitted light, using an iPhone X and the microscopy platform. A significant correlation was reported between the two different approaches for graft MS assessment (Spearman's correlation coefficient: r = .93; p < .001) and for steatohepatitis feature (r = .56; p < .001; r = .45; p < .001). Based on these findings, a smartphone integrated with a cheap microscopy platform can achieve adequate accuracy in the assessment of NAFLD in liver graft and could be used as an alternative to standard light microscopy when the latter is unavailable." 6120;"Prevalence of NASH/NAFLD in people with obesity who are currently classified as metabolically healthy.";"A. IANNELLI, S. PATOURAUX, R. ANTY";"Equipe 08, Team 08";32788075;"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery";"Frey S, Patouraux S, Debs T, Gugenheim J, Anty R, Iannelli A";;"Dec 2020";1606780800;;"While metabolic health in obesity may confer a protective status, recent studies indicate that nonalcoholic fatty liver disease (NAFLD) or even nonalcoholic steatohepatitis (NASH) may exist in this category of individuals. Although cardiovascular and diabetic risks have been well described, the risk of NAFLD and NASH among this population requires further investigation." 6118;"""Six-and-twelve"" score for outcome prediction of hepatocellular carcinoma following transarterial chemoembolization. In-depth analysis from a multicenter French cohort.";"R. ANTY";"Equipe 08, Team 08";32952879;"World journal of hepatology";"Adhoute X, Pénaranda G, Raoul JL, Bronowicki JP, Anty R, Bourlière M";;"Aug 2020";1596240000;;"The ""six-and-twelve"" (6&12) score is a new hepatocellular carcinoma (HCC) prognostic index designed for recommended transarterial chemoembolization (TACE) candidates. Quick and easy to use by the sum of tumor size (cm) and number, this model identifies three groups with different survival time (the sum is ≤ 6; or > 6 but ≤ 12; or > 12); a survival benefit with TACE can be expected for HCC patients with a score not exceeding twelve. Recently, Wang ZW et al showed that the ""6&12"" model was the best system correlated with radiological response after the first TACE. Thus, we wanted to assess its survival prediction ability as well as its prognostic value and compared it to other systems (Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer (HKLC) staging, Albumin-Bilirubin grade, tumor nodularity, infiltrative nature of the tumor, alpha-fetoprotein, Child-Pugh class, and Performance Status score, Cancer of the Liver Italian Program, Model to Estimate Survival for HCC scores, up-to-seven criteria) different from Wang ZW et al study in a multicenter French cohort of HCC including only recommended TACE candidates retrospectively enrolled. As previously demonstrated, we show that the ""6&12"" score can classify survival within this French cohort, with a prognostic value comparable to that of other systems, except HKLC staging. More importantly, the ""6&12"" score simplicity and ability in patients' stratification outperform other systems for a routine clinical practice." 6116;"Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis.";"R. ANTY";"Equipe 08, Team 08";33764590;"Alimentary pharmacology & therapeutics";"Soret PA, Lam L, Carrat F, Smets L, Berg T, Carbone M, Invernizzi P, Leroy V, Trivedi P, Cazzagon N, Weiler-Normann C, Alric L, Rosa-Hezode I, Heurgué A, Cervoni JP, Dumortier J, Potier P, Roux O, Silvain C, Bureau C, Anty R, Larrey D, Levy C, Pares A, Schramm C, Nevens F, Chazouillères O, Corpechot C";;"05 2021";1619827200;;"Obeticholic acid (OCA) and fibrates are second-line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA)." 6114;"Large-scale screening of lipase acid deficiency in at risk population.";"R. ANTY";"Equipe 08, Team 08";33857477;"Clinica chimica acta; international journal of clinical chemistry";"Tebani A, Sudrié-Arnaud B, Boudabous H, Brassier A, Anty R, Snanoudj S, Abergel A, Abi Warde MT, Bardou-Jacquet E, Belbouab R, Blanchet E, Borderon C, Bronowicki JP, Cariou B, Carette C, Dabbas M, Dranguet H, de Ledinghen V, Ferrières J, Guillaume M, Krempf M, Lacaille F, Larrey D, Leroy V, Musikas M, Nguyen-Khac E, Ouzan D, Perarnau JM, Pilon C, Ratzlu V, Thebaut A, Thevenot T, Tragin I, Triolo V, Vergès B, Vergnaud S, Bekri S";;"Aug 2021";1627776000;;"Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD)." 6112;"Severe Protein Malnutrition After Bariatric Surgery and Liver Failure: a Dangerous Sequence.";"A. IANNELLI, R. ANTY";"Equipe 08, Team 08";33860463;"Obesity surgery";"Iannelli A, Petrucciani N, Schiavo L, Anty R";;"08 2021";1627776000;; 6110;"Expected outcomes and patients' selection before chemoembolization-""Six-and-Twelve or Pre-TACE-Predict"" scores may help clinicians: Real-life French cohorts results.";"A. TRAN, R. ANTY";"Equipe 08, Team 08";34222423;"World journal of clinical cases";"Adhoute X, Larrey E, Anty R, Chevallier P, Penaranda G, Tran A, Bronowicki JP, Raoul JL, Castellani P, Perrier H, Bayle O, Monnet O, Pol B, Bourliere M";;"Jun 2021";1622505600;;"Careful selection of hepatocellular carcinoma (HCC) patients prior to chemoembolization treatment is a daily reality, and is even more necessary with new available therapeutic options in HCC." 6108;"Management of diabetes mellitus in patients with cirrhosis: An overview and joint statement.";"R. ANTY";"Equipe 08, Team 08";34363981;"Diabetes & metabolism";"Boursier J, Anty R, Carette C, Cariou B, Castera L, Caussy C, Fontaine H, Garioud A, Gourdy P, Guerci B, Guillaume M, Michot N, Minello A, Ouizeman DJ, Serfaty L, Bonnet F, Vergès B, Petit JM, ";;"09 2021";1630454400;;"Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction." 6106;"Clinical and Economic Impact of Previous Bariatric Surgery on Liver Transplantation: a Nationwide, Population-Based Retrospective Study.";"A. TRAN, A. IANNELLI, R. ANTY";"Equipe 08, Team 08";34499293;"Obesity surgery";"Iannelli A, Bulsei J, Debs T, Tran A, Lazzati A, Gugenheim J, Anty R, Petrucciani N, Fontas E";;"Jan 2022";1640995200;;"The present study aims to determine the impact of previous bariatric surgery (BS) on the length of hospital stay; the incidence of mortality, re-transplantation, and re-hospitalization after LT; and the related economic costs, through the analysis of the French National Health Insurance Information System." 6104;"Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction.";"B. Bailly-Maitre";"Equipe 08, Team 08";11319611;"Cell death and differentiation";"Bailly-Maitre B, de Sousa G, Boulukos K, Gugenheim J, Rahmani R";;"Mar 2001";983404800;;"We examined the effects of dexamethasone (DEX) on the apoptotic process in primary cultures of human and rat hepatocytes. DEX prolonged cell viability, inhibited the development of an apoptotic morphology, and stabilised the expression of procaspase-3 in both human and rat hepatocytes. In addition, the inhibition of apoptosis by DEX was strongly correlated with a decrease of caspase-3-like protease activity. Moreover, DEX treatment increased the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins in human and rat hepatocytes, respectively, whereas the expression of pro-apoptotic proteins Bcl-xS or Bad was not detected or remained unchanged. The bcl-xL transcript is regulated at the transcriptional level and its expression paralleled that of Bcl-xL protein in DEX-treated rat hepatocytes. Taken together, these results indicate that this glucocorticoid exerts a protective role on cell survival and it delays apoptosis of human and rat hepatocytes by modulating caspase-3-like protease activity and bcl-2 and bcl-x gene expression." 6102;"Spontaneous apoptosis in primary cultures of human and rat hepatocytes: molecular mechanisms and regulation by dexamethasone.";"B. Bailly-Maitre";"Equipe 08, Team 08";12181745;"Cell death and differentiation";"Bailly-Maitre B, de Sousa G, Zucchini N, Gugenheim J, Boulukos KE, Rahmani R";;"Sep 2002";1030838400;;"To elucidate the biochemical pathways leading to spontaneous apoptosis in primary cultures of human and rat hepatocytes, we examined the activation of the caspase cascade, the expression of Bcl-2-related-proteins and heat shock proteins. Comparisons were made before and after dexamethasone (DEX) treatment. We show that DEX inhibited spontaneous apoptosis in a dose-dependent manner. DEX increases the expression of anti-apoptotic Bcl-2 and Bcl-x(L) proteins, decreases the expression of pro-apoptotic Bax and inhibits Bad translocation thereby preventing the release of cytochrome c, the activation of caspases, and cell death. Although, the expression of Hsp27 and Hsp70 proteins remained unchanged, the oncogenic protein c-Myc is upregulated upon DEX-treatment. These results indicate that DEX mediates its survival effect against spontaneous apoptosis by acting upstream of the mitochondrial changes. Thus, the mitochondrial apoptotic pathway plays a major role in regulating spontaneous apoptosis in these cells. Blocking this pathway therefore may assist with organ preservation for transplant, drug screening, and other purposes." 6100;"Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity.";"B. Bailly-Maitre";"Equipe 08, Team 08";14749124;"Cancer cell";"Schimmer AD, Welsh K, Pinilla C, Wang Z, Krajewska M, Bonneau MJ, Pedersen IM, Kitada S, Scott FL, Bailly-Maitre B, Glinsky G, Scudiero D, Sausville E, Salvesen G, Nefzi A, Ostresh JM, Houghten RA, Reed JC";;"Jan 2004";1072915200;;"Apoptosis resistance commonly occurs in cancers, preventing activation of Caspase family cell death proteases. XIAP is an endogenous inhibitor of Caspases overexpressed in many cancers. We developed an enzyme derepression assay, based on overcoming XIAP-mediated suppression of Caspase-3, and screened mixture-based combinatorial chemical libraries for compounds that reversed XIAP-mediated inhibition of Caspase-3, identifying a class of polyphenylureas with XIAP-inhibitory activity. These compounds, but not inactive structural analogs, stimulated increases in Caspase activity, directly induced apoptosis of many types of tumor cell lines in culture, and sensitized cancer cells to chemotherapeutic drugs. Active compounds also suppressed growth of established tumors in xenograft models in mice, while displaying little toxicity to normal tissues. These findings validate IAPs as targets for cancer drug discovery." 6098;"Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain.";"B. Bailly-Maitre, JE. Ricci";"Equipe 08, Equipe 03, Team 08";15186778;Cell;"Ricci JE, Muñoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, Scheffler IE, Ellisman MH, Green DR";;"Jun 2004";1086048000;;"Mitochondrial outer membrane permeabilization and cytochrome c release promote caspase activation and execution of apoptosis through cleavage of specific caspase substrates in the cell. Among the first targets of activated caspases are the permeabilized mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmembrane potential (DeltaPsim), decline in ATP levels, production of reactive oxygen species (ROS), and loss of mitochondrial structural integrity. Here, we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as a critical caspase substrate in the mitochondria. Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened. While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed. Therefore, caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis." 6096;"BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress.";"B. Bailly-Maitre";"Equipe 08, Team 08";15304216;"Molecular cell";"Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S, Banares S, Cui J, Digicaylioglu M, Ke N, Kitada S, Monosov E, Thomas M, Kress CL, Babendure JR, Tsien RY, Lipton SA, Reed JC";;"Aug 2004";1091318400;;"Bax inhibitor-1 (BI-1) is an evolutionarily conserved endoplasmic reticulum (ER) protein that suppresses cell death in both animal and plant cells. We characterized mice in which the bi-1 gene was ablated. Cells from BI-1-deficient mice, including fibroblasts, hepatocytes, and neurons, display selective hypersensitivity to apoptosis induced by ER stress agents (thapsigargin, tunicamycin, brefeldin A), but not to stimulators of mitochondrial or TNF/Fas-death receptor apoptosis pathways. Conversely, BI-1 overexpression protects against apoptosis induced by ER stress. BI-1-mediated protection from apoptosis induced by ER stress correlated with inhibition of Bax activation and translocation to mitochondria, preservation of mitochondrial membrane potential, and suppression of caspase activation. BI-1 overexpression also reduces releasable Ca(2+) from the ER. In vivo, bi-1(-/-) mice exhibit increased sensitivity to tissue damage induced by stimuli that trigger ER stress, including stroke and tunicamycin injection. Thus, BI-1 regulates a cell death pathway important for cytopreservation during ER stress." 6094;"Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL.";"B. Bailly-Maitre, JE. Ricci";"Equipe 08, Equipe 03, Team 08";15661735;"The Journal of biological chemistry";"Luciano F, Zhai D, Zhu X, Bailly-Maitre B, Ricci JE, Satterthwait AC, Reed JC";;"Apr 2005";1112313600;;"Humanin (HN) is a recently identified endogenous peptide that protects cells against cytotoxicity induced by various stimuli. Recently, we showed that HN binds to and inhibits Bax, a proapoptotic Bcl-2 family protein, suggesting a mechanism for HN action. In this study, we identified Bim, a Bcl-2 homology 3-only member of the Bcl-2/Bax family, as an additional HN target protein. Using in vitro protein binding, immunoprecipitation, and coimmunolocalization assays, we demonstrated that HN binds directly to the extra long isoform of Bim (BimEL) but not the long (BimL) or short (BimS) isoforms. HN also protects cells against apoptosis induced by BimEL but not BimL and BimS in gene transfection studies. In contrast, mutants of HN which failed to bind BimEL failed to protect from BimEL-induced cell death. Moreover, HN inhibited BimEL-induced release of SMAC and cytochrome c from mitochondria isolated from bax-/-cells, indicating that HN can suppress BimEL independently of its effect on Bax. Finally, we demonstrate that HN prevents BimEL-induced oligomerization of Bak using isolated mitochondria. Taken together, our results indicate that the inhibition of BimEL may contribute to the antiapoptotic properties of the HN peptide." 6092;"Regulation of Bcl-2 and Bcl-xL anti-apoptotic protein expression by nuclear receptor PXR in primary cultures of human and rat hepatocytes.";"B. Bailly-Maitre";"Equipe 08, Team 08";16085054;"Biochimica et biophysica acta";"Zucchini N, de Sousa G, Bailly-Maitre B, Gugenheim J, Bars R, Lemaire G, Rahmani R";;"Aug 2005";1122854400;;"The pregnane X receptor (PXR) plays a major role in the protection of the body by regulating the genes involved in the metabolism and elimination of potentially toxic xeno- and endobiotics. We previously described that PXR activator dexamethasone protects hepatocytes from spontaneous apoptosis. We hypothesise a PXR-dependent co-regulation process between detoxication and programmed cell death. Using primary cultured human and rat hepatocytes, we investigated to determine if PXR is implicated in the regulation of Bcl-2 and Bcl-xL, two crucial apoptosis inhibitors. In the present study we demonstrated that the treatment of primary cultured hepatocytes with PXR agonists increased hepatocyte viability and protects them from staurosporine-induced apoptosis. The anti-apoptotic capacity of PXR activation was correlated with Bcl-2 and Bcl-xL induction at both the transcriptional and protein levels in man and rats, respectively. The inhibition of PXR expression by antisense oligonucleotide abolished PXR activators Bcl-xL induction. Accordingly, PXR overexpression in HepG2 cells led to bcl-2 induction upon clotrimazole treatment and protects cells against Fas-induced apoptosis. Our results demonstrate that PXR expression is required for Bcl-2 and Bcl-xL up-regulation upon PXR activators treatment in human and rat hepatocytes. They also suggest that PXR may protect the liver against chemicals by simultaneously regulating detoxication and the apoptotic pathway." 6090;"Endoplasmic reticulum stress: cell life and death decisions.";"B. Bailly-Maitre";"Equipe 08, Team 08";16200199;"The Journal of clinical investigation";"Xu C, Bailly-Maitre B, Reed JC";;"Oct 2005";1128124800;;"Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes." 6088;"Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury.";"B. Bailly-Maitre, JE. Ricci";"Equipe 08, Equipe 03, Team 08";16478805;"Proceedings of the National Academy of Sciences of the United States of America";"Bailly-Maitre B, Fondevila C, Kaldas F, Droin N, Luciano F, Ricci JE, Croxton R, Krajewska M, Zapata JM, Kupiec-Weglinski JW, Farmer D, Reed JC";;"Feb 2006";1138752000;;"Ischemia-reperfusion (IR) injury induces endoplasmic reticulum (ER) stress and cell death. Bax Inhibitor-1 (BI-1) is an evolutionarily conserved ER protein that suppresses cell death and that is abundantly expressed in both liver and kidney. We explored the role of BI-1 in protection from ER stress and IR injury by using bi-1 knockout mice, employing models of transient hepatic or renal artery occlusion. Compared to wild-type bi-1 mice, bi-1 knockout mice subjected to hepatic IR injury exhibited these characteristics: (i) increased histological injury; (ii) increased serum transaminases, indicative of more hepatocyte death; (iii) increased percentages of TUNEL-positive hepatocytes; (iv) greater elevations in caspase activity; and (v) more activation of ER stress proteins inositol-requiring enzyme 1 and activating transcription factor 6 and greater increases in expression of ER stress proteins C/EBP homologous protein and spliced XBP-1 protein. Moreover, hepatic IR injury induced elevations in bi-1 mRNA in wild-type liver, suggesting a need for bi-1 gene induction to limit tissue injury. Similar sensitization of kidney to ER stress and IR injury was observed in bi-1(-/-) mice. We conclude that bi-1 provides endogenous protection of liver and kidney from ER stress and IR injury. Analysis of components of the bi-1-dependent pathway for protection from IR injury may therefore reveal new strategies for organ preservation." 6086;"HBXIP, cellular target of hepatitis B virus oncoprotein, is a regulator of centrosome dynamics and cytokinesis.";"B. Bailly-Maitre";"Equipe 08, Team 08";16982752;"Cancer research";"Fujii R, Zhu C, Wen Y, Marusawa H, Bailly-Maitre B, Matsuzawa S, Zhang H, Kim Y, Bennett CF, Jiang W, Reed JC";;"Sep 2006";1157068800;;"Hepatitis B virus accounts for more than 1 million cancer deaths annually, but the mechanism by which this virus promotes hepatocellular carcinoma remains unclear. The hepatitis B virus genome encodes an oncoprotein, HBx, which binds various cellular proteins including HBXIP. We show here that HBXIP is a regulator of centrosome duplication, required for bipolar spindle formation in HeLa human carcinoma cells and primary mouse embryonic fibroblast cells. We found that most cells deficient in HBXIP arrest in prometaphase with monopolar spindles whereas HBXIP overexpression causes tripolar or multipolar spindles due to excessive centrosome replication. Additionally, a defect in cytokinesis was seen in HBXIP-deficient HeLa cells, with most cells failing to complete division and succumbing eventually to apoptosis. Expression of viral HBx in HeLa cells mimicked the effects of HBXIP overexpression, causing excessive centrosome replication, resulting in tripolar and multipolar spindles and defective cytokinesis. Immunolocalization and fluorescent protein tagging experiments showed that HBXIP associates with microtubules of dividing cells and colocalizes with HBx on centrosomes. Thus, viral HBx and its cellular target HBXIP regulate centrosome dynamics and cytokinesis affecting genetic stability. In vivo experiments using antisense oligonucleotides targeting HBXIP in a mouse model of liver regeneration showed a requirement for HBXIP for growth and survival of replicating hepatocytes. Thus, HBXIP is a critical regulator of hepatocyte cell growth in vivo, making it a strong candidate for explaining the tumorigenic actions of viral HBx." 6084;"Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma.";"B. Bailly-Maitre";"Equipe 08, Team 08";17227826;Blood;"Luciano F, Krajewska M, Ortiz-Rubio P, Krajewski S, Zhai D, Faustin B, Bruey JM, Bailly-Maitre B, Lichtenstein A, Kolluri SK, Satterthwait AC, Zhang XK, Reed JC";;"May 2007";1177977600;;"Defects in apoptosis mechanisms play important roles in malignancy and autoimmunity. Orphan nuclear receptor Nur77/TR3 has been demonstrated to bind antiapoptotic protein Bcl-2 and convert it from a cytoprotective to a cytodestructive protein, representing a phenotypic conversion mechanism. Of the 6 antiapoptotic human Bcl-2 family members, we found that Nur77/TR3 binds strongest to Bcl-B, showing selective reactivity with Bcl-B, Bcl-2, and Bfl-1 but not Bcl-X(L), Mcl-1, or Bcl-W. Nur77 converts the phenotype of Bcl-B from antiapoptotic to proapoptotic. Bcl-B is prominently expressed in plasma cells and multiple myeloma. Endogenous Bcl-B associates with endogenous Nur77 in RPMI 8226 myeloma cells, where RNA interference experiments demonstrated dependence on Bcl-B for Nur77-induced apoptosis. Furthermore, a Nur77-mimicking peptide killed RPMI 8226 myeloma cells through a Bcl-B-dependent mechanism. Because Bcl-B is abundantly expressed in plasma cells and some myelomas, these findings raise the possibility of exploiting the Nur77/Bcl-B mechanism for apoptosis for eradication of autoimmune plasma cells or myeloma." 6082;"Mice lacking bi-1 gene show accelerated liver regeneration.";"B. Bailly-Maitre";"Equipe 08, Team 08";17308082;"Cancer research";"Bailly-Maitre B, Bard-Chapeau E, Luciano F, Droin N, Bruey JM, Faustin B, Kress C, Zapata JM, Reed JC";;"Feb 2007";1170288000;;"The liver has enormous regenerative capacity such that, after partial hepatectomy, hepatocytes rapidly replicate to restore liver mass, thus providing a context for studying in vivo mechanisms of cell growth regulation. Bax inhibitor-1 (BI-1) is an evolutionarily conserved endoplasmic reticulum (ER) protein that suppresses cell death. Interestingly, the BI-1 protein has been shown to regulate Ca(2+) handling by the ER similar to antiapoptotic Bcl-2 family proteins. Effects on cell cycle entry by Bcl-2 family proteins have been described, prompting us to explore whether bi-1-deficient mice display alterations in the in vivo regulation of cell cycle entry using a model of liver regeneration. Accordingly, we compared bi-1(+/+) and bi-1(-/-) mice subjected to partial hepatectomy with respect to the kinetics of liver regeneration and molecular events associated with hepatocyte proliferation. We found that bi-1 deficiency accelerates liver regeneration after partial hepatectomy. Regenerating hepatocytes in bi-1(-/-) mice enter cell cycle faster, as documented by more rapid incorporation of deoxynucleotides, associated with earlier increases in cyclin D1, cyclin D3, cyclin-dependent kinase (Cdk) 2, and Cdk4 protein levels, more rapid hyperphosphorylation of retinoblastoma protein, and faster degradation of p27(Kip1). Dephosphorylation and nuclear translocation of nuclear factor of activated T cells 1 (NFAT1), a substrate of the Ca(2+)-sensitive phosphatase calcineurin, were also accelerated following partial hepatectomy in BI-1-deficient hepatocytes. These findings therefore reveal additional similarities between BI-1 and Bcl-2 family proteins, showing a role for BI-1 in regulating cell proliferation in vivo, in addition to its previously described actions as a regulator of cell survival." 6080;"Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation.";"B. Bailly-Maitre";"Equipe 08, Team 08";17349957;"Molecular cell";"Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC";;"Mar 2007";1172707200;;"Interleukin (IL)-1beta maturation is accomplished by caspase-1-mediated proteolysis, an essential element of innate immunity. NLRs constitute a recently recognized family of caspase-1-activating proteins, which contain a nucleotide-binding oligomerization domain and leucine-rich repeat (LRR) domains and which assemble into multiprotein complexes to create caspase-1-activating platforms called ""inflammasomes."" Using purified recombinant proteins, we have reconstituted the NALP1 inflammasome and have characterized the requirements for inflammasome assembly and caspase-1 activation. Oligomerization of NALP1 and activation of caspase-1 occur via a two-step mechanism, requiring microbial product, muramyl-dipeptide, a component of peptidoglycan, followed by ribonucleoside triphosphates. Caspase-1 activation by NALP1 does not require but is enhanced by adaptor protein ASC. The findings provide the biochemical basis for understanding how inflammasome assembly and function are regulated, and shed light on NALP1 as a direct sensor of bacterial components in host defense against pathogens." 6078;"Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1.";"B. Bailly-Maitre";"Equipe 08, Team 08";17418785;Cell;"Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, Matsuzawa S, Terskikh AV, Faustin B, Reed JC";;"Apr 2007";1175385600;;"Caspases are intracellular proteases that cleave substrates involved in apoptosis or inflammation. In C. elegans, a paradigm for caspase regulation exists in which caspase CED-3 is activated by nucleotide-binding protein CED-4, which is suppressed by Bcl-2-family protein CED-9. We have identified a mammalian analog of this caspase-regulatory system in the NLR-family protein NALP1, a nucleotide-dependent activator of cytokine-processing protease caspase-1, which responds to bacterial ligand muramyl-dipeptide (MDP). Antiapoptotic proteins Bcl-2 and Bcl-X(L) bind and suppress NALP1, reducing caspase-1 activation and interleukin-1beta (IL-1beta) production. When exposed to MDP, Bcl-2-deficient macrophages exhibit more caspase-1 processing and IL-1beta production, whereas Bcl-2-overexpressing macrophages demonstrate less caspase-1 processing and IL-1beta production. The findings reveal an interaction of host defense and apoptosis machinery." 6076;"Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death.";"B. Bailly-Maitre";"Equipe 08, Team 08";19001090;"Molecular and cellular biology";"Princen F, Bard E, Sheikh F, Zhang SS, Wang J, Zago WM, Wu D, Trelles RD, Bailly-Maitre B, Kahn CR, Chen Y, Reed JC, Tong GG, Mercola M, Chen J, Feng GS";;"Jan 2009";1230768000;;"The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-zeta/lambda and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones." 6074;"Hepatic Bax inhibitor-1 inhibits IRE1alpha and protects from obesity-associated insulin resistance and glucose intolerance.";"B. Bailly-Maitre";"Equipe 08, Team 08";19996103;"The Journal of biological chemistry";"Bailly-Maitre B, Belgardt BF, Jordan SD, Coornaert B, von Freyend MJ, Kleinridders A, Mauer J, Cuddy M, Kress CL, Willmes D, Essig M, Hampel B, Protzer U, Reed JC, Brüning JC";;"Feb 2010";1264982400;;"The unfolded protein response (UPR) or endoplasmic reticulum (ER) stress response is a physiological process enabling cells to cope with altered protein synthesis demands. However, under conditions of obesity, prolonged activation of the UPR has been shown to have deteriorating effects on different metabolic pathways. Here we identify Bax inhibitor-1 (BI-1), an evolutionary conserved ER-membrane protein, as a novel modulator of the obesity-associated alteration of the UPR. BI-1 partially inhibits the UPR by interacting with IRE1alpha and inhibiting IRE1alpha endonuclease activity as seen on the splicing of the transcription factor Xbp-1. Because we observed a down-regulation of BI-1 expression in liver and muscle of genetically obese ob/ob and db/db mice as well as in mice with diet-induced obesity in vivo, we investigated the effect of restoring BI-1 expression on metabolic processes in these mice. Importantly, BI-1 overexpression by adenoviral gene transfer dramatically improved glucose metabolism in both standard diet-fed mice as well as in mice with diet-induced obesity and, critically, reversed hyperglycemia in db/db mice. This improvement in whole body glucose metabolism and insulin sensitivity was due to dramatically reduced gluconeogenesis as shown by reduction of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression. Taken together, these results identify BI-1 as a critical regulator of ER stress responses in the development of obesity-associated insulin resistance and provide proof of concept evidence that gene transfer-mediated elevations in hepatic BI-1 may represent a promising approach for the treatment of type 2 diabetes." 6072;"Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis.";"B. Bailly-Maitre";"Equipe 08, Team 08";21575863;"Cancer cell";"Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, Fang DD, Han T, Bailly-Maitre B, Poli V, Varki NM, Wang H, Feng GS";;"May 2011";1304208000;;"The human gene Ptpn11, which encodes the tyrosine phosphatase Shp2, may act as a proto-oncogene because dominantly activating mutations have been detected in several types of leukemia. Herein we report a tumor-suppressor function of Shp2. Hepatocyte-specific deletion of Shp2 promotes inflammatory signaling through the Stat3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and development of tumors in aged mice. Furthermore, Shp2 ablation dramatically enhanced diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) development, which was abolished by concurrent deletion of Shp2 and Stat3 in hepatocytes. Decreased Shp2 expression was detected in a subfraction of human HCC specimens. Thus, in contrast to the leukemogenic effect of dominant-active mutants, Ptpn11/Shp2 has a tumor-suppressor function in liver." 6070;"L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.";"B. Bailly-Maitre, JF. PEYRON, J. BENADIBA, M. NEBOUT, V. Imbert";"Team 04, Equipe 04, Team 08";25482130;Leukemia;"Rosilio C, Nebout M, Imbert V, Griessinger E, Neffati Z, Benadiba J, Hagenbeek T, Spits H, Reverso J, Ambrosetti D, Michiels JF, Bailly-Maitre B, Endou H, Wempe MF, Peyron JF";;"Jun 2015";1433116800;;"The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability. " 6068;"Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.";"B. Bailly-Maitre";"Equipe 08, Team 08";26923166;"Brain research";"Mollereau B, Rzechorzek NM, Roussel BD, Sedru M, Van den Brink DM, Bailly-Maitre B, Palladino F, Medinas DB, Domingos PM, Hunot S, Chandran S, Birman S, Baron T, Vivien D, Duarte CB, Ryoo HD, Steller H, Urano F, Chevet E, Kroemer G, Ciechanover A, Calabrese EJ, Kaufman RJ, Hetz C";;"10 2016";1475280000;;"In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress." 6066;"Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis.";"B. Bailly-Maitre";"Equipe 08, Team 08";27247426;"Bioscience reports";"Robert S, Gicquel T, Victoni T, Valença S, Barreto E, Bailly-Maître B, Boichot E, Lagente V";;"08 2016";1470009600;;"Fibrosis is a basic connective tissue lesion defined by the increase in the fibrillar extracellular matrix (ECM) components in tissue or organ. Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turn-over of ECM and so they are suggested to be important in tissue remodelling observed during fibrogenic process associated with chronic inflammation. Tissue remodelling is the result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of ECM components markedly controlled by the MMPs/TIMP imbalance. We previously showed an association of the differences in collagen deposition in the lungs of bleomycin-treated mice with a reduced molar pro-MMP-9/TIMP-1 ratio. Using the carbon tetrachloride (CCl4) preclinical model of liver fibrosis in mice, we observed a significant increase in collagen deposition with increased expression and release of tissue inhibitors of metalloproteinase (TIMP)-1 both at 24 h and 3 weeks later. This suggests an early altered regulation of matrix turnover involved in the development of fibrosis. We also demonstrated an activation of NLRP3-inflammasome pathway associated with the IL-1R/MyD88 signalling in the development of experimental fibrosis both in lung and liver. This was also associated with an increased expression of purinergic receptors mainly P2X7 Finally, these observations emphasize those effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of tissue remodelling and fibrosis." 6064;"BCL-B (BCL2L10) is overexpressed in patients suffering from multiple myeloma (MM) and drives an MM-like disease in transgenic mice.";"A. Jacquel, B. Bailly-Maitre, G. Robert, J. GILLERON, M. Deckert, P. Auberger, S. Marchetti, T. Cluzeau";;27455953;"The Journal of experimental medicine";"Hamouda MA, Jacquel A, Robert G, Puissant A, Richez V, Cassel R, Fenouille N, Roulland S, Gilleron J, Griessinger E, Dubois A, Bailly-Maitre B, Goncalves D, Mallavialle A, Colosetti P, Marchetti S, Amiot M, Gomez-Bougie P, Rochet N, Deckert M, Avet-Loiseau H, Hofman P, Karsenti JM, Jeandel PY, Blin-Wakkach C, Nadel B, Cluzeau T, Anderson KC, Fuzibet JG, Auberger P, Luciano F";;"08 2016";1470009600;;"Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that Eµ-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease. Indeed, with age, Eµ-bcl-b transgenic mice develop the characteristic features of human MM, including bone malignant plasma cell infiltration, a monoclonal immunoglobulin peak, immunoglobulin deposit in renal tubules, and highly characteristic bone lytic lesions. In addition, the tumors are serially transplantable in irradiated wild-type mice, underlying the tumoral origin of the disease. Eµ-bcl-b plasmocytes show increased expression of a panel of genes known to be dysregulated in human MM pathogenesis. Treatment of Eµ-bcl-b mice with drugs currently used to treat patients such as melphalan and VELCADE efficiently kills malignant plasmocytes in vivo. Finally, we find that Bcl-B is overexpressed in plasmocytes from MM patients but neither in MGUS patients nor in healthy individuals, suggesting that Bcl-B may drive MM. These findings suggest that Bcl-B could be an important factor in MM disease and pinpoint Eµ-bcl-b mice as a pertinent model to validate new therapies in MM." 6062;"Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α.";"B. Bailly-Maitre";"Equipe 08, Team 08";29351844;"Molecular cell";"Sepulveda D, Rojas-Rivera D, Rodríguez DA, Groenendyk J, Köhler A, Lebeaupin C, Ito S, Urra H, Carreras-Sureda A, Hazari Y, Vasseur-Cognet M, Ali MMU, Chevet E, Campos G, Godoy P, Vaisar T, Bailly-Maitre B, Nagata K, Michalak M, Sierralta J, Hetz C";;"01 2018";1514764800;;"Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to engage an adaptive UPR." 6060;"Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease.";"B. Bailly-Maitre";"Equipe 08, Team 08";29940269;"Journal of hepatology";"Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B";;"Oct 2018";1538352000;;"The global epidemic of obesity has been accompanied by a rising burden of non-alcoholic fatty liver disease (NAFLD), with manifestations ranging from simple steatosis to non-alcoholic steatohepatitis, potentially developing into hepatocellular carcinoma. Although much attention has focused on NAFLD, its pathogenesis remains largely obscure. The hallmark of NAFLD is the hepatic accumulation of lipids, which subsequently leads to cellular stress and hepatic injury, eventually resulting in chronic liver disease. Abnormal lipid accumulation often coincides with insulin resistance in steatotic livers and is associated with perturbed endoplasmic reticulum (ER) proteostasis in hepatocytes. In response to chronic ER stress, an adaptive signalling pathway known as the unfolded protein response is triggered to restore ER proteostasis. However, the unfolded protein response can cause inflammation, inflammasome activation and, in the case of non-resolvable ER stress, the death of hepatocytes. Experimental data suggest that the unfolded protein response influences hepatic tumour development, aggressiveness and response to treatment, offering novel therapeutic avenues. Herein, we provide an overview of the evidence linking ER stress to NAFLD and discuss possible points of intervention." 6058;"BAX inhibitor-1: between stress and survival.";"B. Bailly-Maitre";"Equipe 08, Team 08";31841271;"The FEBS journal";"Lebeaupin C, Blanc M, Vallée D, Keller H, Bailly-Maitre B";;"05 2020";1588291200;;"Cellular gatekeepers are essential to maintain order within a cell and anticipate signals of stress to promote survival. BCL2 associated X, apoptosis regulator (BAX) inhibitor-1 (BI-1), also named transmembrane BAX inhibitor motif containing-6, is a highly conserved endoplasmic reticulum (ER) transmembrane protein. Originally identified as an inhibitor of BAX-induced apoptosis, its pro-survival properties have been expanded to include functions targeted against ER stress, calcium imbalance, reactive oxygen species accumulation, and metabolic dysregulation. Nevertheless, the structural biology and biochemical mechanism of action of BI-1 are still under debate. BI-1 has been implicated in several diseases, including chronic liver disease, diabetes, ischemia/reperfusion injury, neurodegeneration, and cancer. While most studies have demonstrated a beneficial role for BI-1 in the ubiquitous maintenance of cellular homeostasis, its expression in cancer cells seems most often to contribute to tumorigenesis and metastasis. Here, we summarize what is known about BI-1 and encourage future studies on BI-1's contribution to cellular life and death decisions to advocate its potential as a target for drug development and other therapeutic strategies." 6056;"[Endoplasmic reticulum stress response and pathogenesis of non-alcoholic steatohepatitis].";"B. Bailly-Maitre";"Equipe 08, Team 08";32129747;"Medecine sciences : M/S";"Vallée D, Blanc M, Lebeaupin C, Bailly-Maitre B";;"Feb 2020";1580515200;;"The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. Non-alcoholic fatty liver disease (NAFLD) is currently affecting 20-30% of the general population and 75-100% of obese individuals. NAFLD ranges from simple steatosis to damaging non-alcoholic steatohepatitis (NASH), potentially developing into hepatocellular carcinoma. No efficient pharmacological treatment is yet available. During obesity, the hepatic ER stress response can arise from extracellular stress (lipids, glucose, cytokines) and from intracellular stress including lipid buildup in the hepatocyte (steatosis), a hallmark of NAFLD. The chronic activation of the hepatic ER stress response may be a crucial event in the steatosis-NASH transition, triggering cell death, inflammation and accelerating metabolic disorders. We discuss these aspects and we propose that targeting the ER stress response could be effective in treating NAFLD." 6054;"Monocytes control natural killer cell differentiation to effector phenotypes.";"C. LUCI";"Equipe 08, Team 08";21389319;Blood;"Soderquest K, Powell N, Luci C, van Rooijen N, Hidalgo A, Geissmann F, Walzer T, Lord GM, Martín-Fontecha A";;"Apr 2011";1301616000;;"Natural killer (NK) cells play a major role in immunologic surveillance of cancer. Whether NK-cell subsets have specific roles during antitumor responses and what the signals are that drive their terminal maturation remain unclear. Using an in vivo model of tumor immunity, we show here that CD11b(hi)CD27(low) NK cells migrate to the tumor site to reject major histocompatibility complex class I negative tumors, a response that is severely impaired in Txb21(-/-) mice. The phenotypical analysis of Txb21-deficient mice shows that, in the absence of Txb21, NK-cell differentiation is arrested specifically at the CD11b(hi)CD27(hi) stage, resulting in the complete absence of terminally differentiated CD11b(hi)CD27(low) NK cells. Adoptive transfer experiments and radiation bone marrow chimera reveal that a Txb21(+/+) environment rescues the CD11b(hi)CD27(hi) to CD11b(hi)CD27(low) transition of Txb21(-/-) NK cells. Furthermore, in vivo depletion of myeloid cells and in vitro coculture experiments demonstrate that spleen monocytes mediate the terminal differentiation of peripheral NK cells in a Txb21- and IL-15Rα-dependent manner. Together, these data reveal a novel, unrecognized role for Txb21 expression in monocytes in promoting NK-cell development and help appreciate how various NK-cell subsets are generated and participate in antitumor immunity." 6052;"Natural killer cells and T cells induce different types of skin reactions during recall responses to haptens.";"C. LUCI";"Equipe 08, Team 08";21968602;"European journal of immunology";"Rouzaire P, Luci C, Blasco E, Bienvenu J, Walzer T, Nicolas JF, Hennino A";;"Jan 2012";1325376000;;"The role of T cells in contact hypersensitivity (CHS) to haptens has been well described. However, recent reports demonstrated that CHS-like reactions to experimental haptens could be induced in mice deficient in T cells and B cells, as a result of adaptive-like features of NK cells. Here, we compared hapten-specific inflammatory reactions induced by memory T cells or NK cells. Classical CHS protocols were applied to WT or T- and B-cell deficient mice. Adoptive transfers of hapten-specific T cells and NK cells were also performed. Liver NK cells from hapten-primed mice induced specific recall responses to haptens upon transfer in CD3ε-deficient mice, thus confirming the existence of ""memory"" NK cells in the liver. We investigated the nature of the inflammation generated in these transfer conditions and found that hapten-induced skin inflammation mediated by CD8(+) T cells or ""memory"" NK cells are different. Indeed, ear swelling induced by memory NK cells was transient and not associated with cellular infiltrate and inflammation markers, characteristic for T-cell-mediated responses. Thus, NK cells and T cells mediate distinct forms of skin inflammation. NK cell-mediated pathogenesis does not rely on cellular infiltrate and could be involved in atypical forms of adverse drug reactions." 6050;"CD8 T cells are essential for the effects of enriched environment on hippocampus-dependent behavior, hippocampal neurogenesis and synaptic plasticity.";"C. LUCI";"Equipe 08, Team 08";29175168;"Brain, behavior, and immunity";"Zarif H, Nicolas S, Guyot M, Hosseiny S, Lazzari A, Canali MM, Cazareth J, Brau F, Golzné V, Dourneau E, Maillaut M, Luci C, Paquet A, Lebrigand K, Arguel MJ, Daoudlarian D, Heurteaux C, Glaichenhaus N, Chabry J, Guyon A, Petit-Paitel A";;"03 2018";1519862400;;"Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4 T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8 T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8 T cells. In addition, we show that spleen CD8 T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFα release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8 CD44 CD62L and CD62L T cells repartition 4) transcriptomic signature as revealed by RNA sequencing. CD8 T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8 T cells are essential mediators of beneficial EE effects on brain plasticity and cognition. Additionally, we propose that EE differentially primes CD8 T cells leading to behavioral improvement." 6038;"In vivo adjuvant-induced mobilization and maturation of gut dendritic cells after oral administration of cholera toxin.";"C. LUCI";"Equipe 08, Team 08";15470054;"Journal of immunology (Baltimore, Md. : 1950)";"Anjuère F, Luci C, Lebens M, Rousseau D, Hervouet C, Milon G, Holmgren J, Ardavin C, Czerkinsky C";;"Oct 2004";1096588800;;"Although dendritic cells (DCs) regulate immune responses, they exhibit functional heterogeneity depending on their anatomical location. We examined the functional properties of intestinal DCs after oral administration of cholera toxin (CT), the most potent mucosal adjuvant. Two CD11c+ DC subsets were identified both in Peyer's patches and mesenteric lymph nodes (MLN) based on the expression of CD8alpha (CD8+ and CD8- DCs, respectively). A third subset of CD11c+CD8int was found exclusively in MLN. Feeding mice with CT induced a rapid and transient mobilization of a new CD11c+CD8- DC subset near the intestinal epithelium. This recruitment was associated with an increased production of the chemokine CCL20 in the small intestine and was followed by a massive accumulation of CD8int DCs in MLN. MLN DCs from CT-treated mice were more potent activators of naive T cells than DCs from control mice and induced a Th2 response. This increase in immunostimulating properties was accounted for by CD8int and CD8- DCs, whereas CD8+ DCs remained insensitive to CT treatment. Consistently, the CD8int and CD8- subsets expressed higher levels of costimulatory molecules than CD8+ and corresponding control DCs. Adoptive transfer experiments showed that these two DC subsets, unlike CD8+ DCs, were able to present Ags orally coadministered with CT in an immunostimulating manner. The ability of CT to mobilize immature DCs in the intestinal epithelium and to promote their emigration and differentiation in draining lymph nodes may explain the exceptional adjuvant properties of this toxin on mucosal immune responses." 6036;"Imprinting of BALB/c mice with low Leishmania infantum parasite dose markedly protects spleen against high-dose challenge.";"C. LUCI";"Equipe 08, Team 08";16157427;Vaccine;"Ferrua B, Luci C, Le Fichoux Y, Paul A, Marty P";;"Jan 2006";1136073600;;"In this study, we investigated in the BALB/c model, the dose-dependent protective potential of previous infection with Leishmania infantum parasites, against a high-dose challenge and showed for the first time that low-dose imprinting conferred substantial spleen resistance. Mice were immunized for 1 month or 5 months by IV route with parasite inocula ranging from 10(4) to 10(7) and from 10(3) to 10(5), respectively, and challenged for 1 month with 3 x 10(7) parasites. Liver protection was directly proportional to the parasite dose used for infection and reached 90-95% whereas, only low doses (< or =10(5)) protected spleen. Maximal spleen resistance (80%) was reached in mice infected for 5 months with 10(5) parasites. In most cases, protection was accompanied in spleen, by restored in vitro responses to Leishmania antigens. Analysis of anti L. infantum isotype responses and in vitro antigen-induced cytokine production, indicated that the acquired protection was irrespective of a Th1/Th2 imbalance." 6034;"Dendritic cell-mediated induction of mucosal cytotoxic responses following intravaginal immunization with the nontoxic B subunit of cholera toxin.";"C. LUCI";"Equipe 08, Team 08";16493030;"Journal of immunology (Baltimore, Md. : 1950)";"Luci C, Hervouet C, Rousseau D, Holmgren J, Czerkinsky C, Anjuère F";;"Mar 2006";1141171200;;"The use of the nontoxic B subunit of cholera toxin (CTB) as mucosal adjuvant and carrier-delivery system for inducing secretory Ab responses has been documented previously with different soluble Ags. In this study, we have evaluated this approach for inducing CTL responses against a prototype Ag, OVA, in the female genital mucosa. We report here the ability of an immunogen comprised of CTB conjugated to OVA (CTB-OVA) given by intravaginal (ivag) route to induce genital OVA-specific CTLs in mice. Using adoptive transfer models, we demonstrate that ivag application of CTB-OVA activates OVA-specific IFN-gamma-producing CD4 and CD8 T cells in draining lymph nodes (DLN). Moreover, ivag CTB induces an expansion of IFN-gamma-secreting CD8+ T cells in DLN and genital mucosa and promotes Ab responses to OVA. In contrast, ivag administration of OVA alone or coadministered with CTB failed to induce such responses. Importantly, we demonstrate that ivag CTB-OVA generates OVA-specific CTLs in DLN and the genital mucosa. Furthermore, genital CD11b+ CD11c+ dendritic cells (DCs), but not CD8+ CD11c+ or CD11c- APCs, present MHC class I epitopes acquired after ivag CTB-OVA, suggesting a critical role of this DC subset in the priming of genital CTLs. Inhibition studies indicate that the presentation of OVA MHC class I epitopes by DCs conditioned with CTB-OVA involves a proteasome-dependent and chloroquine-sensitive mechanism. These results demonstrate that CTB is an efficient adjuvant-delivery system for DC-mediated induction of genital CTL responses and may have implications for the design of vaccines against sexually transmitted infections." 6032;"Transepithelial immunomodulation by cholera toxin and non-toxic derivatives.";"C. LUCI";"Equipe 08, Team 08";16823930;Vaccine;"Anjuère F, Luci C, Hervouet C, Rousseau D, Czerkinsky C";;"Apr 2006";1143849600;;"Comparative analyses of murine dendritic cells (DC) isolated from the skin and from the intestinal mucosa after exposure to cholera toxin and its non-toxic B subunit disclose striking differences regarding the migratory and functional behaviour of these cells. The nature of the epithelial microenvironment, especially locally produced cytokines and chemokines, appears to influence the functional ability of skin and mucosal DCs to convey immunogenic as opposed to tolerogenic signals and hence to regulate immune responsiveness at skin and at mucosal sites." 6030;"The trafficking of natural killer cells.";"C. LUCI";"Equipe 08, Team 08";17979846;"Immunological reviews";"Grégoire C, Chasson L, Luci C, Tomasello E, Geissmann F, Vivier E, Walzer T";;"Dec 2007";1196467200;;"Natural killer (NK) cells are large granular lymphocytes of the innate immune system that participate in the early control of microbial infections and cancer. NK cells can induce the death of autologous cells undergoing various forms of stress, recognizing and providing non-microbial 'danger' signals to the immune system. NK cells are widely distributed in lymphoid and non-lymphoid organs. NK cell precursors originate from the bone marrow and go through a complex maturation process that leads to the acquisition of their effector functions, to changes in their expression of integrins and chemotactic receptors, and to their redistribution from the bone marrow and lymph nodes to blood, spleen, liver, and lung. Here, we describe the tissue localization of NK cells, using NKp46 as an NK cell marker, and review the current knowledge on the mechanisms that govern their trafficking in humans and in mice." 6028;"Sublingual immunization induces broad-based systemic and mucosal immune responses in mice.";"C. LUCI";"Equipe 08, Team 08";17996991;Vaccine;"Cuburu N, Kweon MN, Song JH, Hervouet C, Luci C, Sun JB, Hofman P, Holmgren J, Anjuère F, Czerkinsky C";;"Dec 2007";1196467200;;"The potential of sublingual (s.l.) delivery of vaccine was examined in mice. We show the existence of a dense network of dendritic cells (DCs) in the s.l. epithelium and a rapid and transient increase in the frequency of s.l. DCs after topical application of cholera toxin (CT) adjuvant under the tongue. S.l. immunization with ovalbumin and CT induced vigorous systemic and mucosal antibody responses. Such treatment promoted mixed Th1 and Th2 cytokine responses and induced cytotoxic CD8(+) T cells in lung tissues and in systemic lymphoid organs. S.l. immunization was comparable to intranasal immunization and was superior to oral immunization regarding the magnitude and anatomic dissemination of the induced immune responses. S.l. administration of live influenza virus at a dose lethal by the nasal route was well tolerated and did not redirect virus to the olfactory bulb. These features underscore the potential of the s.l. mucosa to serve as an alternative vaccine delivery route." 6026;"Natural killer cells: detectors of stress.";"C. LUCI";"Equipe 08, Team 08";18595768;"The international journal of biochemistry & cell biology";"Luci C, Tomasello E";;"Jan 2008";1199145600;;"Natural killer (NK) cells are a key component of the innate immune system, as they are able to detect microbe-infected cells, tumors as well as allogeneic cells, without specific sensitization. NK cell effector functions (cytotoxicity, cytokine secretion) are regulated by a wide array of inhibitory and activating receptors. MHC class I molecules are the ligands of most inhibitory receptors, while activating receptors recognize either pathogen-encoded molecules, or self-proteins whose expression is up-regulated upon microbial infection or tumor development. Upon integration of these negative and positive signals, Natural Killer cells can discriminate between healthy ""self"" (tolerance) and autologous cells undergoing different types of cellular stress or allogeneic cells (immunosurveillance). The knowledge of the different mechanisms of target cell recognition is thus crucial to dissect NK cell involvement in homeostatic and disease conditions as well as to develop novel alternative therapeutic approaches based on NK cell manipulation." 6024;"Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.";"C. LUCI";"Equipe 08, Team 08";19029904;"Nature immunology";"Luci C, Reynders A, Ivanov II, Cognet C, Chiche L, Chasson L, Hardwigsen J, Anguiano E, Banchereau J, Chaussabel D, Dalod M, Littman DR, Vivier E, Tomasello E";;"Jan 2009";1230768000;;"NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes. Unlike RORgammat- lamina propria and dermis natural killer cells, gut RORgammat+NKp46+ cells produced interleukin 22. Our data show that lymphoid tissue-inducer cells and natural killer cells shared unanticipated similarities and emphasize the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair." 6022;"Langerhans cells prime IL-17-producing T cells and dampen genital cytotoxic responses following mucosal immunization.";"C. LUCI";"Equipe 08, Team 08";20351191;"Journal of immunology (Baltimore, Md. : 1950)";"Hervouet C, Luci C, Rol N, Rousseau D, Kissenpfennig A, Malissen B, Czerkinsky C, Anjuère F";;"May 2010";1272672000;;"Langerhans cells (LCs) are dendritic cells (DCs) localized in stratified epithelia, such as those overlaying skin, buccal mucosa, and vagina. The contribution of LCs to the promotion or control of immunity initiated at epithelial sites remains debated. We report in this paper that an immunogen comprising OVA linked to the B subunit of cholera toxin, used as delivery vector, was efficient to generate CTLs after vaginal immunization. Using Lang-EGFP mice, we evaluated the contribution of distinct DC subsets to the generation of CD4 and CD8 T cell responses. We demonstrate that the vaginal epithelium, unlike the skin epidermis, includes a minor population of LCs and a major subset of langerin(-) DCs. Intravaginally administered Ag is taken up by LCs and langerin(-) DCs and carried up to draining lymph nodes, where both subsets prime CD8 T cells, unlike blood-derived DCs, although with distinct capabilities. LCs prime CD8 T cells with a cytokine profile dominated by IL-17, whereas Lang(-) DCs induce IFN-gamma-producing T cells. Using Lang-DTR-EGFP mice to ensure a transient ablation of LCs, we found that these cells not only are dispensable for the generation of genital CTL responses but also downregulate these responses, by a mechanism that may involve IL-10 and IL-17 cytokines. This finding has implications for the development of mucosal vaccines and immunotherapeutic strategies designed for the targeting of DCs." 6020;"Sublingual immunization with an HIV subunit vaccine induces antibodies and cytotoxic T cells in the mouse female genital tract.";"C. LUCI";"Equipe 08, Team 08";20600505;Vaccine;"Hervouet C, Luci C, Cuburu N, Cremel M, Bekri S, Vimeux L, Marañon C, Czerkinsky C, Hosmalin A, Anjuère F";;"Aug 2010";1280620800;;"A vaccine against heterosexual transmission by human immunodeficiency virus (HIV) should generate cytotoxic and antibody responses in the female genital tract and in extra-genital organs. We report that sublingual immunization with HIV-1 gp41 and a reverse transcriptase polypeptide coupled to the cholera toxin B subunit (CTB) induced gp41-specific IgA antibodies and antibody-secreting cells, as well as reverse transcriptase-specific CD8 T cells in the genital mucosa, contrary to intradermal immunization. Conjugation of the reverse transcriptase peptide to CTB favored its cross-presentation by human dendritic cells to a T cell line from an HIV(+) patient. Sublingual vaccination could represent a promising vaccine strategy against heterosexual transmission of HIV-1." 6018;"Inflammatory blood monocytes contribute to tumor development and represent a privileged target to improve host immunosurveillance.";"C. LUCI";"Equipe 08, Team 08";21078911;"Journal of immunology (Baltimore, Md. : 1950)";"Augier S, Ciucci T, Luci C, Carle GF, Blin-Wakkach C, Wakkach A";;"Dec 2010";1291161600;;"Progressing tumors in humans and mice are frequently infiltrated by a highly heterogeneous population of inflammatory myeloid cells that contribute to tumor growth. Among these cells, inflammatory Gr-1(+) monocytes display a high developmental plasticity in response to specific microenvironmental signals, leading to diverse immune functions. These observations raise the question of the immune mechanisms by which inflammatory monocytes may contribute to tumor development. In this study, we found that adoptive transfer of normal inflammatory Gr-1(+) monocytes in tumor-bearing mice promotes tumor growth. In this tumoral environment, these monocytes can differentiate into tolerogenic dendritic cells (DCs) that produce IL-10 and potently induce regulatory T cell responses in vivo. Moreover, diverting the differentiation of Gr-1(+) monocytes into tolerogenic DCs by forced expression of IL-10 soluble receptor and IL-3 in tumor cells improves host immunosurveillance by reducing the regulatory T cell frequency and by inducing immunogenic DCs in the tumor. As a consequence, tumor growth is strongly reduced. Our findings indicate that Gr-1(+) monocytes represent a valuable target for innovative immunotherapeutic strategies against cancer." 6016;"IFN-λs and BDCA3+/CD8α+ dendritic cells: towards the design of novel vaccine adjuvants?";"C. LUCI";"Equipe 08, Team 08";21332265;"Expert review of vaccines";"Luci C, Anjuère F";;"Feb 2011";1296518400;;"IFN-λs are related to type I interferons but their receptor has a more cell-restricted pattern of expression. Consequently, one can expect that IFN-λs have antiviral and anti-tumoral activities as well as immunomodulatory properties with less adverse side-effects than type I interferons. However, their roles in physiopathology and immunoregulation remain to be fully elucidated. The study under evaluation identifies that murine CD8α(+) dendritic cells and their recently described human equivalent, BDCA3(+) dendritic cells, are the major producers of IFN-λs in response to dsRNA poly I:C. This study illustrates a new function for a DC subset conserved between species. These findings may impact the development of vaccine or therapeutic strategies based on DC targeting." 6014;"Mechanisms of NK cell activation: CD4(+) T cells enter the scene.";"C. LUCI";"Equipe 08, Team 08";21861183;"Cellular and molecular life sciences : CMLS";"Bihl F, Germain C, Luci C, Braud VM";;"Nov 2011";1320105600;;"Natural killer (NK) cells are innate lymphocytes involved in immunosurveillance through their cytotoxic activity and their capacity to secrete inflammatory cytokines. NK cell activation is necessary to initiate effector functions and results from a complex series of molecular and cellular events. We review here the signals that trigger NK cells and discuss recent findings showing that, besides antigen-presenting cells, T cells can play a central role in the initiation of NK cell activation in lymph nodes." 6012;"Mapping of NKp46(+) Cells in Healthy Human Lymphoid and Non-Lymphoid Tissues.";"C. LUCI";"Equipe 08, Team 08";23181063;"Frontiers in immunology";"Tomasello E, Yessaad N, Gregoire E, Hudspeth K, Luci C, Mavilio D, Hardwigsen J, Vivier E";;"Jan 2012";1325376000;;"Understanding Natural Killer (NK) cell anatomical distribution is key to dissect the role of these unconventional lymphocytes in physiological and disease conditions. In mouse, NK cells have been detected in various lymphoid and non-lymphoid organs, while in humans the current knowledge of NK cell distribution at steady state is mainly restricted to lymphoid tissues. The translation to humans of findings obtained in mice is facilitated by the identification of NK cell markers conserved between these two species. The Natural Cytotoxicity Receptor (NCR) NKp46 is a marker of the NK cell lineage evolutionary conserved in mammals. In mice, NKp46 is also present on rare T cell subsets and on a subset of gut Innate Lymphoid Cells (ILCs) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) transcription factor. Here, we documented the distribution and the phenotype of human NKp46(+) cells in lymphoid and non-lymphoid tissues isolated from healthy donors. Human NKp46(+) cells were found in splenic red pulp, in lymph nodes, in lungs, and gut lamina propria, thus mirroring mouse NKp46(+) cell distribution. We also identified a novel cell subset of CD56(dim)NKp46(low) cells that includes RORγt(+) ILCs with a lineage(-)CD94(-)CD117(bright)CD127(bright) phenotype. The use of NKp46 thus contributes to establish the basis for analyzing quantitative and qualitative changes of NK cell and ILC subsets in human diseases." 6010;"Escherichia coli α-hemolysin counteracts the anti-virulence innate immune response triggered by the Rho GTPase activating toxin CNF1 during bacteremia.";"A. Jacquel, C. LUCI, G. MICHEL, P. Auberger, S. Marchetti";"Equipe 02, Equipe 08, Equipe 06, Team 08";25781937;"PLoS pathogens";"Diabate M, Munro P, Garcia E, Jacquel A, Michel G, Obba S, Goncalves D, Luci C, Marchetti S, Demon D, Degos C, Bechah Y, Mege JL, Lamkanfi M, Auberger P, Gorvel JP, Stuart LM, Landraud L, Lemichez E, Boyer L";;"Mar 2015";1425168000;;"The detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1β signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1β antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1β and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the α-hemolysin toxin inhibits IL-1β secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia. " 6008;"NKp46+ Innate Lymphoid Cells Dampen Vaginal CD8 T Cell Responses following Local Immunization with a Cholera Toxin-Based Vaccine.";"C. LUCI";"Equipe 08, Team 08";26630176;"PloS one";"Luci C, Bekri S, Bihl F, Pini J, Bourdely P, Nouhen K, Malgogne A, Walzer T, Braud VM, Anjuère F";;"Jan 2015";1420070400;;"Innate and adaptive immune cells work in concert to generate efficient protection at mucosal surface. Vaginal mucosa is an epithelial tissue that contains innate and adaptive immune effector cells. Our previous studies demonstrated that vaginal administration of Cholera toxin -based vaccines generate antigen-specific CD8 T cells through the stimulation of local dendritic cells (DC). Innate lymphoid cells (ILC) are a group of lymphocytes localized in epithelial tissues that have important immune functions against pathogens and in tissue homeostasis. Their contribution to vaccine-induced mucosal T cell responses is an important issue for the design of protective vaccines. We report here that the vaginal mucosa contains a heterogeneous population of NKp46+ ILC that includes conventional NK cells and ILC1-like cells. We show that vaginal NKp46+ ILC dampen vaccine-induced CD8 T cell responses generated after local immunization. Indeed, in vivo depletion of NKp46+ ILC with anti-NK1.1 antibody or NKG2D blockade increases the magnitude of vaginal OVA-specific CD8 T cells. Furthermore, such treatments also increase the number of DC in the vagina. NKG2D ligands being expressed by vaginal DC but not by CD8 T cells, these results support that NKp46+ ILC limit mucosal CD8 T cell responses indirectly through the NKG2D-dependent elimination of vaginal DC. Our data reveal an unappreciated role of NKp46+ ILC in the regulation of mucosal CD8 T cell responses. " 6006;"Sublingual Priming with a HIV gp41-Based Subunit Vaccine Elicits Mucosal Antibodies and Persistent B Memory Responses in Non-Human Primates.";"C. LUCI";"Equipe 08, Team 08";28203239;"Frontiers in immunology";"Bekri S, Bourdely P, Luci C, Dereuddre-Bosquet N, Su B, Martinon F, Braud VM, Luque I, Mateo PL, Crespillo S, Conejero-Lara F, Moog C, Le Grand R, Anjuère F";;"Jan 2017";1483228800;;"Persistent B cell responses in mucosal tissues are crucial to control infection against sexually transmitted pathogens like human immunodeficiency virus 1 (HIV-1). The genital tract is a major site of infection by HIV. Sublingual (SL) immunization in mice was previously shown to generate HIV-specific B cell immunity that disseminates to the genital tract. We report here the immunogenicity in female cynomolgus macaques of a SL vaccine based on a modified gp41 polypeptide coupled to the cholera toxin B subunit designed to expose hidden epitopes and to improve mucosal retention. Combined SL/intramuscular (IM) immunization with such mucoadhesive gp41-based vaccine elicited mucosal HIV-specific IgG and IgA antibodies more efficiently than IM immunization alone. This strategy increased the number and duration of gp41-specific IgA secreting cells. Importantly, combined immunization improved the generation of functional antibodies 3 months after vaccination as detected in HIV-neutralizing assays. Therefore, SL immunization represents a promising vaccine strategy to block HIV-1 transmission." 6002;"Tumor-Associated Neutrophils Dampen Adaptive Immunity and Promote Cutaneous Squamous Cell Carcinoma Development.";"C. LUCI";"Equipe 08, Team 08";32664318;Cancers;"Khou S, Popa A, Luci C, Bihl F, Meghraoui-Kheddar A, Bourdely P, Salavagione E, Cosson E, Rubod A, Cazareth J, Barbry P, Mari B, Rezzonico R, Anjuère F, Braud VM";;"Jul 2020";1593561600;;"Cutaneous squamous cell carcinoma (cSCC) development has been linked to immune dysfunctions but the mechanisms are still unclear. Here, we report a progressive infiltration of tumor-associated neutrophils (TANs) in precancerous and established cSCC lesions from chemically induced skin carcinogenesis. Comparative in-depth gene expression analyses identified a predominant protumor gene expression signature of TANs in lesions compared to their respective surrounding skin. In addition, in vivo depletion of neutrophils delayed tumor growth and significantly increased the frequency of proliferating IFN-γ (interferon-γ)-producing CD8+ T cells. Mechanisms that limited antitumor responses involved high arginase activity, production of reactive oxygen species (ROS) and nitrite (NO), and the expression of programmed death-ligand 1 (PD-L1) on TAN, concomitantly with an induction of PD-1 on CD8 T cells, which correlated with tumor size. Our data highlight the relevance of targeting neutrophils and PD-L1-PD-1 (programmed death-1) interaction in the treatment of cSCC." 6000;"Cutaneous Squamous Cell Carcinoma Development Is Associated with a Temporal Infiltration of ILC1 and NK Cells with Immune Dysfunctions.";"C. LUCI";"Equipe 08, Team 08";33831432;"The Journal of investigative dermatology";"Luci C, Bihl F, Bourdely P, Khou S, Popa A, Meghraoui-Kheddar A, Vermeulen O, Elaldi R, Poissonnet G, Sudaka A, Bozec A, Bekri S, Cazareth J, Ponzio G, Barbry P, Rezzonico R, Mari B, Braud VM, Anjuère F";;"10 2021";1633046400;;"NK cells and tissue-resident innate lymphoid cells (ILCs) are innate effectors found in the skin. To investigate their temporal dynamics and specific functions throughout the development of cutaneous squamous cell carcinoma (cSCC), we combined transcriptomic and immunophenotyping analyses in mouse and human cSCCs. We identified an infiltration of NK cells and ILC1s as well as the presence of a few ILC3s. Adoptive transfer of NK cells in NK cell‒ and ILC-deficient Nfil3 mice revealed a role for NK cells in early control of cSCC. During tumor progression, we identified a population skewing with the infiltration of atypical ILC1 secreting inflammatory cytokines but reduced levels of IFN-γ at the papilloma stage. NK cells and ILC1s were functionally impaired, with reduced cytotoxicity and IFN-γ secretion associated with the downregulation of activating receptors. They also showed a high degree of heterogeneity in mouse and human cSCCs with the expression of several markers of exhaustion, including TIGIT on NK cells and PD-1 and TIM-3 on ILC1s. Our data show an enrichment in inflammatory ILC1 at the precancerous stage together with impaired antitumor functions in NK cells and ILC1 that could contribute to the development of cSCC and thus suggest that future immunotherapies should take both ILC populations into account." 5998;"A conformational change in the beta-subunit of the insulin-like growth factor I receptor identified by antipeptide antibodies.";"P. GUAL";"Equipe 08, Team 08";7588274;Endocrinology;"Gual P, Baron V, Alengrin F, Van Obberghen E";;"Dec 1995";817776000;;"Insulin-like growth factor I (IGF-I) binding to its receptor results in receptor autophosphorylation and phosphorylation of several cellular substrates. The mechanism by which binding of the ligand to the extracellular receptor domain activates the intracellular kinase remains to be defined. Using polyclonal antibodies against four regions of the IGF-I receptor, we searched for putative conformational changes occurring in purified receptors. We studied the ability of the antipeptide antibodies to immunoprecipitate the native, ligand-occupied, or autophosphorylated IGF-I receptor. We found that the antipeptide antibody directed to the sequence 985-998 of the kinase domain immunoprecipitated the phosphorylated receptor, but not the native or the ligand-occupied receptor. By contrast, the antibody against the sequence 950-957 of the juxtamembrane domain immunoprecipitated the three receptor forms. The difference between phosphorylated receptors and unphosphorylated receptors was not observed in Western blot experiments, indicating that the conformational modification of the receptors is not detected upon unfolding. These data demonstrate that the IGF-I receptor undergoes an autophosphorylation-induced conformational change detectable in the kinase domain. Our work provides evidence that conformational changes induced by autophosphorylation may be a common activation mechanism for tyrosine kinase receptors." 5996;"Insulin receptor-induced phosphorylation of cellular and synthetic substrates is regulated by the receptor beta-subunit C-terminus.";"P. GUAL";"Equipe 08, Team 08";8754769;Endocrinology;"Gual P, Baron V, Alengrin F, Mothe I, Van Obberghen E";;"Aug 1996";838857600;;"The transmembrane beta-subunits of the insulin receptor possess hormone-sensitive tyrosine kinase activity. To study the role of the C-terminus domain, a rabbit antipeptide antibody directed to the 1294-1317 domain was produced. The antipeptide antibody inhibited the receptor-induced phosphorylation of poly (Glu, Tyr) and synthetic peptides corresponding to the receptor autophosphorylation sites. In contrast, the same antibody did not inhibit receptor autophosphorylation. The kinetic parameters of the poly(Glu, Tyr) phosphorylation reaction indicated that the antibody interfered with the receptor enzymatic site. Concerning the insulin receptor cellular substrates, the anti-(1294-1317) antibody inhibited Src homology/collagen and IRS-1 phosphorylation. The extent of inhibition was 52% for Src homology/collagen phosphorylation and 30% for IRS-1 phosphorylation. From our data, we conclude that a similar regulation of insulin receptor-induced phosphorylation of artificial and cellular insulin receptor substrates can be generated at the level of the receptor beta-subunit C-terminus." 5994;"Role of the insulin receptor C-terminal acidic domain in the modulation of the receptor kinase by polybasic effectors.";"P. GUAL";"Equipe 08, Team 08";8898905;"European journal of biochemistry";"Baron V, Gual P, Alengrin F, Van Obberghen E";;"Oct 1996";844128000;;"Basic polymers such as polylysine have been found to activate insulin receptor autophosphorylation and kinase activity toward substrates. It was suggested that acidic receptor domains may be involved in the interaction of the receptor with these basic effectors. In a previous study, we have shown that the receptor acid-rich C-terminal sequence, including residues 1270-1280, is involved in the regulation of the receptor kinase activity. Moreover, this domain may be the site of interaction with histone, which is a modulator of the receptor kinase. In this study, we investigated whether the insulin receptor domain comprising amino acids 1270-1280 is involved in the interaction with polybasic effectors. We used anti-peptide serum directed to this sequence, and basic activators such as polylysine, polyarginine and protamine sulfate. Our antibodies inhibit polylysine-induced receptor autophosphorylation, whereas they have no effect on receptor phosphorylation stimulated by concanavalin A which is a non-basic activator of the insulin receptor. Polylysine-induced receptor aggregation was blocked by the antibodies (Fab fragments or whole Ig), indicating that competition occurs between the antibody and polylysine at the level of their binding site to the receptor. Finally, we observed a direct interaction of the 125I-peptide corresponding to receptor sequence 1270-1280 with the basic polymers in dot-blot experiments. Interestingly, the peptide did not bind spermine, a basic molecule which is not an activator of the insulin receptor kinase. Our data indicate that the insulin receptor C-terminal acidic domain including residues 1270-1280 is involved in the interaction of polylysine and other polybasic molecules with the receptor. Since this receptor region has been implicated in the regulation of the receptor kinase activity, we propose that interaction of basic effectors with this domain may be responsible for their activating properties." 5992;"Interaction of Janus kinases JAK-1 and JAK-2 with the insulin receptor and the insulin-like growth factor-1 receptor.";"P. GUAL";"Equipe 08, Team 08";9492017;Endocrinology;"Gual P, Baron V, Lequoy V, Van Obberghen E";;"Mar 1998";888710400;;"Insulin and insulin-like growth factor-1 (IGF-1) treatment of cells overexpressing the insulin receptor or the IGF-1 receptor promotes phosphorylation and activation of Janus kinases JAK-1 and JAK-2 but not of TYK-2. With insulin, we observed maximal phosphorylation of JAK-1 within 2 min (5.2 +/- 0.6-fold) and maximal phosphorylation of JAK-2 within 10 min (2.4 +/- 0.6-fold). In cells incubated with IGF-1, we found maximal phosphorylation of JAK-2 within 2 min (1.9 +/- 0.2-fold) and of JAK-1 within 5 min (4.5 +/- 0.4-fold). The JAKs from insulin- or IGF-1-stimulated cells were activated, as shown by their autophosphorylation in vitro. Moreover, they were able to phosphorylate in vitro native insulin receptor substrate (IRS)-1 and a fragment of IRS-2 (GST-IRS-2591-786). Comparison of 32P-peptide maps of IRS-1 phosphorylated in vitro by the insulin receptor vs. JAK-1 showed the occurrence of different phosphopeptides, suggesting that different sites are likely to be phosphorylated by the two kinases. Finally, coprecipitation of receptors and JAK-1 was seen, and phosphorylation of both receptors was found to be necessary for receptor binding to JAK-1. Two domains of JAK- 1 are involved in the formation of the complex between receptor and JAK-1, i.e. the N-terminal portion containing JH7 and JH6 domains, and the C-terminal kinase domain (JH1 domain). Taking our data together, we conclude that: 1) insulin and IGF-1 lead to phosphorylation and activation of JAK-1 and JAK-2 in intact cells; 2) phosphorylation of IRS-I by JAK-1 seems to occur on sites different from those phosphorylated by the insulin receptor; 3) JAK-1 interacts directly with phosphorylated insulin and IGF-1 receptors; and 4) the JH7-JH6 and JH1 domains of JAK-1 are responsible for the interaction with insulin and IGF-1 receptors." 5990;"MET(PRC) mutations in the Ron receptor result in upregulation of tyrosine kinase activity and acquisition of oncogenic potential.";"P. GUAL";"Equipe 08, Team 08";10528237;"Journal of cellular physiology";"Williams TA, Longati P, Pugliese L, Gual P, Bardelli A, Michieli P";;"Dec 1999";944006400;;"Ron and Met are structurally related receptor tyrosine kinases that elicit a complex biological response leading to invasive growth. Naturally occurring point mutations activate the Met kinase in papillary renal carcinomas (MET(PRC) mutations). By site-directed mutagenesis, we generated homologous amino acid substitutions in the Ron kinase domain and analyzed the biochemical and biological properties of the mutant receptors. Among the mutations studied, D(1232)H and M(1254)T displayed transforming activity in NIH3T3 cells, inducing focus formation and anchorage-independent growth. The D(1232)H and M(1254)T substitutions resulted in increased Ron autophosphorylation both in vivo and in vitro and constitutive binding to intracellular signal transducers. Both mutations yielded a dramatic increase in catalytic efficiency, indicating a direct correlation between kinase activity and oncogenic potential. Molecular modeling of the Ron D(1232)H mutation suggests that this single amino acid substitution favors the transition of the kinase from the inactive to the active state. These data demonstrate that point mutations can confer transforming activity to the Ron receptor and show that RON is a potential oncogene." 5988;"Different point mutations in the met oncogene elicit distinct biological properties.";"P. GUAL";"Equipe 08, Team 08";10657996;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Giordano S, Maffe A, Williams TA, Artigiani S, Gual P, Bardelli A, Basilico C, Michieli P, Comoglio PM";;"Feb 2000";949363200;;"The MET proto-oncogene, encoding the tyrosine kinase receptor for HGF, controls genetic programs leading to cell growth, invasiveness, and protection from apoptosis. Recently, MET mutations have been identified in hereditary and sporadic forms of papillary renal carcinoma (PRC). Introduction of different naturally occurring mutations into the MET cDNA results in the acquisition of distinct biochemical and biological properties of transfected cells. Some mutations result in a high increase in tyrosine kinase activity and confer transforming ability in focus forming assays. These mutants hyperactivate the Ras signaling pathway. Other mutations are devoid of transforming potential but are effective in inducing protection from apoptosis and sustaining anchorage-independent growth. These Met(PRC) receptors interact more efficiently with the intracellular transducer Pi3Kinase. The reported results show that MET(PRC) mutations can be responsible for malignant transformation through different mechanisms, either by increasing the growth ability of cells or by protecting cells from apoptosis and allowing accumulation of other genetic lesions.-Giordano, S., Maffe, A., Williams, T. A., Artigiani, S., Gual, P., Bardelli, A., Basilico, C., Michieli, P., Comoglio, P. M. Different point mutations in the met oncogene elicit distinct biological properties." 5984;"Cross-talk between the proto-oncogenes Met and Ron.";"P. GUAL";"Equipe 08, Team 08";10871856;Oncogene;"Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM";;"Jun 2000";959817600;;"Scatter Factors control a complex genetic program known as 'invasive growth'. HGF (Scatter factor 1) and MSP (Scatter Factor 2) bind to tyrosine kinase receptors encoded by the proto-oncogenes MET and RON. Using the appropriate 'kinase inactive' mutant receptors, we show that ligand-induced activation of Met results in transphosphorylation of Ron, and vice versa. Transphosphorylation is direct, as it occurs in Met or Ron receptors lacking the docking sites for signal transducers. Phosphate groups are transferred to the tyrosine phosphorylation sites responsible both for kinase up-regulation (Met: Y1234/Y1235 and Ron: Y1238/Y1239) and for generation of signal transducer docking sites (Met: Y1349/Y1356 and Ron Y1353/Y1360). The transphosphorylation specifically takes place for the receptor subfamily, as it is not observed between Met or Ron and ErbB1, ErbB2 or TrkA. Cross-linking experiments show that non-covalent Met-Ron complexes are present on the cell surface, before ligand-induced dimerization. Co-expression of a kinase inactive Ron receptor with naturally-occurring oncogenic Met mutants suppresses the transforming phenotype, suggesting a dominant negative role for the inefficient kinase partner. These data show that, while specific for their ligands, scatter factor receptors cross-talk and cooperate in intracellular signaling." 5982;"Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling.";"P. GUAL";"Equipe 08, Team 08";11313945;Oncogene;"Gual P, Giordano S, Anguissola S, Parker PJ, Comoglio PM";;"Jan 2001";978307200;;"Signal transduction by HGF receptor, the tyrosine kinase encoded by the MET oncogene, switches on a genetic program called 'invasive growth' inducing epithelial cell dissociation, migration, growth, and ultimately leading to differentiation into branched tubular structures. Sustained tyrosine phosphorylation of the downstream adaptor protein Gab1 is required for the HGF response. Here we show that serine/threonine phosphorylation of Gab1 provides a control mechanism for negative regulation. Treatment with okadaic acid, a potent inhibitor of the serine/threonine protein phosphatases PP1 and PP2A, was followed by activation of a number of serine/threonine kinases, hyper-phosphorylation in serine and threonine of Gab1 and severe inhibition of the HGF-induced biological responses. Under these conditions, Gab1 was found to be concomitantly hypo-phosphorylated in tyrosine, and thus endowed with reduced ability to recruit SH2 containing signal transducers such as PI3 kinase. Among the serine-threonine kinases activated by PP1 and PP2A inhibition, we found that PKC-alpha and PKC-beta1 are required for negative regulation of Gab1. These data provide a novel negative mechanism for the HGF receptor signaling pathways and highlight a potentially useful target for inhibitors of invasive growth." 5980;"Differential requirement of the last C-terminal tail of Met receptor for cell transformation and invasiveness.";"P. GUAL";"Equipe 08, Team 08";11571647;Oncogene;"Gual P, Giordano S, Anguissola S, Comoglio PM";;"Sep 2001";999302400;;"Biological responses to Hepatocyte Growth Factor are mediated by the tyrosine kinase receptor encoded by the Met oncogene. Under physiological conditions, Met triggers a multi-step genetic program called 'invasive growth' including cell-dissociation, invasion of extracellular matrices and growth. When constitutively activated, Met can induce cell transformation and metastasis. Phosphorylation of two docking tyrosines in the receptor tail is essential for all biological responses. To investigate the role of the C-terminal part of Met, we have generated mutants lacking either the last 26 or 47 amino acids. As expected, mutants lacking the docking sites fail to mediate cell transformation and invasion. Interestingly, while Met Delta26 can mediate invasion, its transforming ability is severely impaired. Moreover, the lack of the last 26 amino acids strongly reduces Met ability to phosphorylate substrates in vitro and in vivo. These data indicate that the last 26 amino acids are required to confer the kinase its full enzymatic activity, which is critical for cell transformation but dispensable for invasive properties. Finally, we also show that up-regulation of Met enzymatic activity by insertion of a point mutation in the kinase domain (M1250T) overcomes the regulatory role played by the last 26 amino acids of the tail. It is concluded that the C-terminal domain of Met is crucial not only for recruitment of transducers but also for regulation of receptor enzymatic activity." 5978;"The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, Type 2 diabetes, and NASH.";"P. GUAL";"Equipe 08, Team 08";16790033;"The American journal of gastroenterology";"Anty R, Bekri S, Luciani N, Saint-Paul MC, Dahman M, Iannelli A, Amor IB, Staccini-Myx A, Huet PM, Gugenheim J, Sadoul JL, Le Marchand-Brustel Y, Tran A, Gual P";;"Aug 2006";1154390400;;"C-Reactive Protein (CRP), a nonspecific marker of inflammation that is moderately elevated in obesity, metabolic syndrome (MS), and type 2 diabetes, has been proposed as a surrogate marker of nonalcoholic steatohepatitis (NASH). Its clinical usefulness in the diagnosis of NASH was evaluated in severely obese patients without or with MS, diabetes, and NASH and the potential roles of the liver and of the adipose tissue in CRP production were characterized." 5976;"Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH.";"P. GUAL";"Equipe 08, Team 08";16952548;Gastroenterology;"Bekri S, Gual P, Anty R, Luciani N, Dahman M, Ramesh B, Iannelli A, Staccini-Myx A, Casanova D, Ben Amor I, Saint-Paul MC, Huet PM, Sadoul JL, Gugenheim J, Srai SK, Tran A, Le Marchand-Brustel Y";;"Sep 2006";1157068800;;"Hepcidin is an acute-phase response peptide. We have investigated the possible involvement of hepcidin in massive obesity, a state of chronic low-grade inflammation. Three groups of severely obese patients with or without diabetes or nonalcoholic steatohepatitis were investigated." 5974;"[Metabolic fatty liver diseases: hepatic consequences of the metabolic syndrome].";"P. GUAL";"Equipe 08, Team 08";18176372;"Gastroenterologie clinique et biologique";"Anty R, Gual P, Huet PM, Marchand-Brustel YL, Tran A";;"Dec 2007";1196467200;;"Metabolic fatty liver diseases (Non Alcoholic Fatty Liver Diseases-NAFLD) are liver abnormalities (steatosis and steatohépatitis) commonly related to visceral obesity and to the metabolic syndrome. The pathogenesis of metabolic fatty liver diseases is most probably linked to the adipose tissue insulin resistance with a very high free fatty acids release, an abnormal secretion of factors produced by the adipose tissue (adipokines) and a low grade of chronic inflammation. The link between metabolic fatty liver diseases and the metabolic syndrome is further supported by epidemiological studies, as well as the frequently encountered cardio-vascular complications in both diseases. Changes in lifestyle with dietary restriction and increased physical activity are mandatory and similar for both conditions. Drugs such as thiazolidinediones, known to reduce insulin resistance and inflammation, still need further evaluation." 5972;"HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon.";"P. GUAL";"Equipe 08, Team 08";18214854;"International journal of cancer";"Italiano A, Bianchini L, Keslair F, Bonnafous S, Cardot-Leccia N, Coindre JM, Dumollard JM, Hofman P, Leroux A, Mainguené C, Peyrottes I, Ranchere-Vince D, Terrier P, Tran A, Gual P, Pedeutour F";;"May 2008";1209600000;;"Data concerning the fine structure of the 12q13-15 amplicon which contains MDM2 and CDK4 in well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS) are scarce. We investigated a series of 38 WDLPS/DDLPS using fluorescence in situ hybridization analysis with 17 probes encompassing the 12q13-15 region. In addition, using quantitative RT-PCR we studied the expression of MDM2, CDK4, DDIT3 (CHOP/GADD153), DYRK2, HMGA2, TSPAN31 and YEATS4 (GAS41) in 11 cases. We showed that CDK4 (12q14.1) belonged to a distinct amplicon than MDM2 (12q15). There was no continuity in the amplified sequences between MDM2 and CDK4. Moreover, while MDM2 was amplified and overexpressed in all cases, CDK4 was not amplified or overexpressed in 13% of cases. The centromeric border of the CDK4 amplicon was located immediately downstream the 5' end of DDIT3, a gene known for being involved in myxoid liposarcoma translocations. DDIT3 was amplified in 3 cases and overexpressed in 9 cases. The overexpression of DDIT3 was correlated to the CDK4 amplification and not to its own amplification status. This suggested that the CDK4 amplicon, as well as the overexpression of DDIT3, might be generated by the disruption of a fragile region in 5' DDIT3. HMGA2 was always amplified and rearranged indicating that it plays a central role in WDLPS/DDLPS. HMGA2 rearrangement frequently resulted in a loss of the 3' end region that is a binding site for let-7. We also found a frequent amplification and overexpression of YEATS4, an oncogene that inactivates P53, suggesting that YEATS4 might play an important role together with MDM2 in WDLPS/DDLPS oncogenesis." 5970;"Bariatric surgery can correct iron depletion in morbidly obese women: a link with chronic inflammation.";"P. GUAL";"Equipe 08, Team 08";18330662;"Obesity surgery";"Anty R, Dahman M, Iannelli A, Gual P, Staccini-Myx A, Amor IB, Luciani N, Saint-Paul MC, Huet PM, Sadoul JL, Srai SK, Unwin R, Gugenheim J, Le Marchand-Brustel Y, Tran A, Bekri S";;"Jun 2008";1212278400;;"Obesity is associated with a chronic and low-grade inflammation which may cause hypoferremia as seen in patients with chronic inflammatory diseases. The aim of the present study was to investigate the relationship between iron status and markers of inflammation in morbidly obese women and the effect of bariatric surgery." 5968;"Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity.";"P. GUAL";"Equipe 08, Team 08";18952835;Diabetes;"Bertola A, Deveaux V, Bonnafous S, Rousseau D, Anty R, Wakkach A, Dahman M, Tordjman J, Clément K, McQuaid SE, Frayn KN, Huet PM, Gugenheim J, Lotersztajn S, Le Marchand-Brustel Y, Tran A, Gual P";;"Jan 2009";1230768000;;"Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis." 5966;"Impact of laparoscopic Roux-en-Y gastric bypass on metabolic syndrome, inflammation, and insulin resistance in super versus morbidly obese women.";"P. GUAL";"Equipe 08, Team 08";19018603;"Obesity surgery";"Iannelli A, Anty R, Piche T, Dahman M, Gual P, Tran A, Gugenheim J";;"May 2009";1241136000;;"Although Roux-en-Y gastric bypass (RYGBP) is one of the preferred bariatric procedures in obese individuals, the efficacy of this procedure in the setting of super-obesity [body mass index (BMI) >/=50] is unclear. The aim of this study was to compare the efficacy of laparoscopic (L) RYGBP to reverse metabolic syndrome, inflammation, and insulin resistance in super-obese women compared to morbidly obese women." 5964;"Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis.";"P. GUAL";"Equipe 08, Team 08";19513120;"PloS one";"Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S, Nhieu JT, Belot MP, Zimmer A, Even P, Cani PD, Knauf C, Burcelin R, Bertola A, Le Marchand-Brustel Y, Gual P, Mallat A, Lotersztajn S";;"Jun 2009";1243814400;;"Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver." 5962;"Rab4b is a small GTPase involved in the control of the glucose transporter GLUT4 localization in adipocyte.";"M. Cormont, P. GUAL";"Equipe 07, Equipe 08, Team 08";19590752;"PloS one";"Kaddai V, Gonzalez T, Keslair F, Grémeaux T, Bonnafous S, Gugenheim J, Tran A, Gual P, Le Marchand-Brustel Y, Cormont M";;"Apr 2009";1238544000;;"Endosomal small GTPases of the Rab family, among them Rab4a, play an essential role in the control of the glucose transporter GLUT4 trafficking, which is essential for insulin-mediated glucose uptake. We found that adipocytes also expressed Rab4b and we observed a consistent decrease in the expression of Rab4b mRNA in human and mice adipose tissue in obese diabetic states. These results led us to study this poorly characterized Rab member and its potential role in glucose transport." 5960;"Liquid chromatography-mass spectrometry-based parallel metabolic profiling of human and mouse model serum reveals putative biomarkers associated with the progression of nonalcoholic fatty liver disease.";"P. GUAL";"Equipe 08, Team 08";20684516;"Journal of proteome research";"Barr J, Vázquez-Chantada M, Alonso C, Pérez-Cormenzana M, Mayo R, Galán A, Caballería J, Martín-Duce A, Tran A, Wagner C, Luka Z, Lu SC, Castro A, Le Marchand-Brustel Y, Martínez-Chantar ML, Veyrie N, Clément K, Tordjman J, Gual P, Mato JM";;"Sep 2010";1283299200;;"Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in most western countries. Current NAFLD diagnosis methods (e.g., liver biopsy analysis or imaging techniques) are poorly suited as tests for such a prevalent condition, from both a clinical and financial point of view. The present work aims to demonstrate the potential utility of serum metabolic profiling in defining phenotypic biomarkers that could be useful in NAFLD management. A parallel animal model/human NAFLD exploratory metabolomics approach was employed, using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) to analyze 42 serum samples collected from nondiabetic, morbidly obese, biopsy-proven NAFLD patients, and 17 animals belonging to the glycine N-methyltransferase knockout (GNMT-KO) NAFLD mouse model. Multivariate statistical analysis of the data revealed a series of common biomarkers that were significantly altered in the NAFLD (GNMT-KO) subjects in comparison to their normal liver counterparts (WT). Many of the compounds observed could be associated with biochemical perturbations associated with liver dysfunction (e.g., reduced Creatine) and inflammation (e.g., eicosanoid signaling). This differential metabolic phenotyping approach may have a future role as a supplement for clinical decision making in NAFLD and in the adaption to more individualized treatment protocols." 5958;"Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients.";"P. GUAL";"Equipe 08, Team 08";21042596;"PloS one";"Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, Iannelli A, Gugenheim J, Barr J, Mato JM, Le Marchand-Brustel Y, Tran A, Gual P";;"Oct 2010";1285891200;;"Obesity modulates inflammation and activation of immune pathways which can lead to liver complications. We aimed at identifying expression patterns of inflammatory and immune response genes specifically associated with obesity and NASH in the liver of morbidly obese patients." 5956;"A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients.";"P. GUAL";"Equipe 08, Team 08";21050233;"Alimentary pharmacology & therapeutics";"Anty R, Iannelli A, Patouraux S, Bonnafous S, Lavallard VJ, Senni-Buratti M, Amor IB, Staccini-Myx A, Saint-Paul MC, Berthier F, Huet PM, Le Marchand-Brustel Y, Gugenheim J, Gual P, Tran A";;"Dec 2010";1291161600;;"Non-invasive approaches are useful to differentiate simple steatosis from non-alcoholic steatohepatitis (NASH) in obese and morbidly obese patients." 5954;"C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients.";"P. GUAL";"Equipe 08, Team 08";21238518;"Journal of hepatology";"Zimmermann E, Anty R, Tordjman J, Verrijken A, Gual P, Tran A, Iannelli A, Gugenheim J, Bedossa P, Francque S, Le Marchand-Brustel Y, Clement K, Van Gaal L, Sørensen TIA, Jess T";;"Sep 2011";1314835200;;"Non-alcoholic fatty liver disease (NAFLD) is a major hepatic consequence of obesity. It has been suggested that the high sensitivity C-reactive protein (hs-CRP) is an obesity-independent surrogate marker of severity of NAFLD, especially development of non-alcoholic steato-hepatitis (NASH), but this remains controversial. We aimed to investigate whether associations between various features of NAFLD and hs-CRP are independent of body mass index (BMI) in its broad range among obese patients." 5952;"Hemojuvelin: a new link between obesity and iron homeostasis.";"M. Cormont, P. GUAL";"Equipe 07, Equipe 08, Team 08";21311510;"Obesity (Silver Spring, Md.)";"Luciani N, Brasse-Lagnel C, Poli M, Anty R, Lesueur C, Cormont M, Laquerriere A, Folope V, LeMarchand-Brustel Y, Gugenheim J, Gual P, Tran A, Bekri S";;"Aug 2011";1312156800;;"The adipose tissue may play an active role in systemic iron regulation and this role may be determinant in obese patients. Indeed, we reported previously that hepcidin, the iron-regulatory hormone, is expressed in adipose tissue and its messenger RNA (mRNA) expression is increased in adipose tissue of morbidly obese patients. The objectives of this study were to characterize the status of hemojuvelin (HJV), another iron-regulatory protein, within the adipose tissue of morbidly obese patients. Since cell-associated HJV acts as a coreceptor of bone morphogenetic protein (BMP) to enhance hepcidin expression in liver cells, we investigated the possible involvement of this pathway in adipose tissue in regulating hepcidin expression. HJV expression was studied in adipose tissue of morbidly obese patients. Soluble HJV blood concentrations were assessed. Hepcidin regulation through BMP pathway was investigated in cultured adipocytes. HJV was expressed both at mRNA and protein levels in adipose tissue. Moreover, its mRNA expression was highly increased in adipose tissue of obese patients and correlated with mRNA hepcidin expression levels. Interestingly, HJV expressed by adipose tissue may be effective since cultured adipocytes increased their hepcidin expression when challenged with BMP2 through Smad effectors. In addition, blood concentrations of soluble HJV were significantly increased. In conclusion, adipose tissue may influence iron homeostasis in obese patients by expressing major iron-regulatory proteins and the BMP signaling pathway could be involved in regulating hepcidin expression in this tissue." 5950;"Serum markers of hepatocyte death and apoptosis are non invasive biomarkers of severe fibrosis in patients with alcoholic liver disease.";"P. GUAL";"Equipe 08, Team 08";21445263;"PloS one";"Lavallard VJ, Bonnafous S, Patouraux S, Saint-Paul MC, Rousseau D, Anty R, Le Marchand-Brustel Y, Tran A, Gual P";;"Mar 2011";1298937600;;"Quantification of hepatocyte death is useful to evaluate the progression of alcoholic liver diseases. Our aims were to quantify and correlate the circulating levels of Cytokeratin 18 (CK18) and its caspases-generated fragment to disease severity in heavy alcoholics." 5948;"Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.";"P. GUAL";"Equipe 08, Team 08";22364559;"Journal of proteome research";"Barr J, Caballería J, Martínez-Arranz I, Domínguez-Díez A, Alonso C, Muntané J, Pérez-Cormenzana M, García-Monzón C, Mayo R, Martín-Duce A, Romero-Gómez M, Lo Iacono O, Tordjman J, Andrade RJ, Pérez-Carreras M, Le Marchand-Brustel Y, Tran A, Fernández-Escalante C, Arévalo E, García-Unzueta M, Clement K, Crespo J, Gual P, Gómez-Fleitas M, Martínez-Chantar ML, Castro A, Lu SC, Vázquez-Chantada M, Mato JM";;"Apr 2012";1333238400;;"Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention." 5946;"The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease.";"P. GUAL";"Equipe 08, Team 08";22530059;"PloS one";"Patouraux S, Bonnafous S, Voican CS, Anty R, Saint-Paul MC, Rosenthal-Allieri MA, Agostini H, Njike M, Barri-Ova N, Naveau S, Le Marchand-Brustel Y, Veillon P, Calès P, Perlemuter G, Tran A, Gual P";;"Jan 2012";1325376000;;"Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis." 5944;"Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients.";"P. GUAL";"Equipe 08, Team 08";22596049;Diabetes;"Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, Blin-Wakkach C, Anty R, Iannelli A, Gugenheim J, Tran A, Bouloumié A, Gual P, Wakkach A";;"Sep 2012";1346457600;;"T-cell regulation in adipose tissue provides a link between inflammation and insulin resistance. Because of alterations in adipose tissue T-cell composition in obesity, we aimed to identify the antigen-presenting cells in adipose tissue of obese mice and patients with insulin resistance. Dendritic cells (DCs) and T cells were studied in mice and in two cohorts of obese patients. In lean mice, only CD11c(+) DCs were detected in adipose tissue. Adoptive transfer of naive CD4(+) T cells in Rag1(-/-) mice led to a predominant Th1 response in adipose tissue. In contrast, during obesity DCs (human CD11c(+)CD1c(+) and mouse CD11c(high)F4/80(low)) accumulated in adipose tissue. CD11c(high)F4/80(low) DCs from obese mice induced Th17 differentiation. In patients, the presence of CD11c(+)CD1c(+) DCs correlated with the BMI and with an elevation in Th17 cells. In addition, these DCs led to ex vivo Th17 differentiation. CD1c gene expression further correlated with homeostatic model assessment-insulin resistance in the subcutaneous adipose tissue of obese patients. We show for the first time the presence and accumulation of specific DCs in adipose tissue in mouse and human obesity. These DCs were functional and could be important regulators of adipose tissue inflammation by regulating the switch toward Th17 cell responses in obesity-associated insulin resistance." 5942;"Regular coffee but not espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery.";"P. GUAL";"Equipe 08, Team 08";22820478;"Journal of hepatology";"Anty R, Marjoux S, Iannelli A, Patouraux S, Schneck AS, Bonnafous S, Gire C, Amzolini A, Ben-Amor I, Saint-Paul MC, Mariné-Barjoan E, Pariente A, Gugenheim J, Gual P, Tran A";;"Nov 2012";1351728000;;"The aim of this study was to determine the influence of coffee and other caffeinated drinks on liver fibrosis of severely obese European patients." 5940;"Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease.";"P. GUAL";"Equipe 08, Team 08";22961556;"Hepatology (Baltimore, Md.)";"Vazquez-Chantada M, Gonzalez-Lahera A, Martinez-Arranz I, Garcia-Monzon C, Regueiro MM, Garcia-Rodriguez JL, Schlangen KA, Mendibil I, Rodriguez-Ezpeleta N, Lozano JJ, Banasik K, Justesen JM, Joergensen T, Witte DR, Lauritzen T, Hansen T, Pedersen O, Veyrie N, Clement K, Tordjman J, Tran A, Le Marchand-Brustel Y, Buque X, Aspichueta P, Echevarria-Uraga JJ, Martin-Duce A, Caballeria J, Gual P, Castro A, Mato JM, Martinez-Chantar ML, Aransay AM";;"Feb 2013";1359676800;;"Susceptibility to develop nonalcoholic fatty liver disease (NAFLD) has genetic bases, but the associated variants are uncertain. The aim of the present study was to identify genetic variants that could help to prognose and further understand the genetics and development of NAFLD. Allele frequencies of 3,072 single-nucleotide polymorphisms (SNPs) in 92 genes were characterized in 69 NAFLD patients and 217 healthy individuals. The markers that showed significant allele-frequency differences in the pilot groups were subsequently studied in 451 NAFLD patients and 304 healthy controls. Besides this, 4,414 type 2 diabetes mellitus (T2DM) cases and 4,567 controls were genotyped. Liver expression of the associated gene was measured and the effect of its potential role was studied by silencing the gene in vitro. Whole genome expression, oxidative stress (OS), and the consequences of oleic acid (OA)-enriched medium on lipid accumulation in siSLC2A1-THLE2 cells were studied by gene-expression analysis, dihydroethidium staining, BODIPY, and quantification of intracellular triglyceride content, respectively. Several SNPs of SLC2A1 (solute carrier family 2 [facilitated glucose transporter] member 1) showed association with NAFLD, but not with T2DM, being the haplotype containing the minor allele of SLC2A1 sequence related to the susceptibility to develop NAFLD. Gene-expression analysis demonstrated a significant down-regulation of SLC2A1 in NAFLD livers. Enrichment functional analyses of transcriptome profiles drove us to demonstrate that in vitro silencing of SLC2A1 induces an increased OS activity and a higher lipid accumulation under OA treatment." 5938;"Autophagy, signaling and obesity.";"P. GUAL";"Equipe 08, Team 08";22982482;"Pharmacological research";"Lavallard VJ, Meijer AJ, Codogno P, Gual P";;"Dec 2012";1354320000;;"Autophagy is a cellular pathway crucial for development, differentiation, survival and homeostasis. Autophagy can provide protection against aging and a number of pathologies such as cancer, neurodegeneration, cardiac disease and infection. Recent studies have reported new functions of autophagy in the regulation of cellular processes such as lipid metabolism and insulin sensitivity. Important links between the regulation of autophagy and obesity including food intake, adipose tissue development, β cell function, insulin sensitivity and hepatic steatosis exist. This review will provide insight into the current understanding of autophagy, its regulation, and its role in the complications associated with obesity." 5936;"Non-alcoholic steatohepatitis in morbidly obese patients.";"P. GUAL";"Equipe 08, Team 08";23347840;"Clinics and research in hepatology and gastroenterology";"Tran A, Gual P";;"Feb 2013";1359676800;;"The hepatic complications of morbid obesity range from steatosis to steatohepatitis (Non-alcoholic steatohepatitis [NASH]), fibrosis, cirrhosis and finally hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to a liver showing steatosis and then steatohepatitis are complex, including, per se, insulin-resistance, iron accumulation, oxidative stress and hepatocyte death. An imbalance in anti- and pro-inflammatory factors may be the trigger. These factors can originate from intra- or extrahepatic sites, particularly the adipose tissue and the gut. This review will provide insight into the current diagnosis and understanding of hepatic inflammation including non-invasive markers of NASH (markers of hepatocyte death), intrahepatic mechanisms (regulation of the immune and inflammatory response, hepatocellular iron deposition, hepatocyte death) and extrahepatic factors (from adipose tissue and gut) in morbidly obese patients." 5934;"M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.";"P. GUAL";"Equipe 08, Team 08";23832548;"Hepatology (Baltimore, Md.)";"Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, Lotersztajn S, Pavoine C";;"Jan 2014";1388534400;;"Alcoholic and nonalcoholic fatty liver disease (ALD and NAFLD) are the predominant causes of liver-related mortality in Western countries. We have shown that limiting classical (M1) Kupffer cell (KC) polarization reduces alcohol-induced liver injury. Herein, we investigated whether favoring alternatively activated M2 KCs may protect against ALD and NAFLD. Ongoing alcohol drinkers and morbidly obese patients, with minimal hepatic injury and steatosis, displayed higher hepatic expression of M2 genes, as compared to patients with more severe liver lesions; individuals with limited liver lesions showed negligible hepatocyte apoptosis but significant macrophage apoptosis. Experiments in mouse models of ALD or NAFLD further showed that BALB/c or resveratrol-treated mice fed alcohol or a high-fat diet displayed preponderant M2 KC polarization, M1 KC apoptosis, and resistance to hepatocyte steatosis and apoptosis, as compared to control C57BL6/J mice. In vitro experiments in isolated KC, peritoneal, and Raw264.7 macrophages demonstrated that M1 macrophage apoptosis was promoted by conditioned medium from macrophages polarized into an M2 phenotype by either interleukin (IL)4, resveratrol, or adiponectin. Mechanistically, IL10 released from M2 cells promoted M1 death, and anti-IL10 antibodies blunted the proapoptic effects of M2-conditioned media. IL10 secreted by M2 KCs promoted selective M1 death by a mechanism involving activation of arginase in high inducible nitric oxide synthase-expressing M1 KCs. In alcohol-exposed mice, neutralization of IL10 impaired M1 apoptosis." 5932;"Body composition, anthropometrics, energy expenditure, systemic inflammation, in premenopausal women 1 year after laparoscopic Roux-en-Y gastric bypass.";"P. GUAL";"Equipe 08, Team 08";24013471;"Surgical endoscopy";"Iannelli A, Martini F, Rodolphe A, Schneck AS, Gual P, Tran A, Hébuterne X, Gugenheim J";;"Feb 2014";1391212800;;"Laparoscopic Roux-en-Y gastric bypass (LRYGBP) is currently the most common bariatric procedure and results in a substantial weight loss and recovery from obesity-related comorbidities, both of which are maintained in the long term. However, besides the desired loss of fat mass, LRYGBP is also followed by the loss of fat-free mass (FFM). We aimed to determine the factors associated with the loss of ≥20 % of the initial FFM 1 year after LRYGBP in a prospective series of 115 Caucasian, premenopausal women." 5930;"Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice.";"P. GUAL";"Equipe 08, Team 08";24048522;"Science translational medicine";"Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, Patouraux S, Tran A, Gual P, Le Marchand-Brustel Y, Gennero I, Gouze E";;"Sep 2013";1377993600;;"Achondroplasia is a rare genetic disease characterized by abnormal bone development, resulting in short stature. It is caused by a single point mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3), which leads to prolonged activation upon ligand binding. To prevent excessive intracellular signaling and rescue the symptoms of achondroplasia, we have developed a recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3), which acts as a decoy receptor and prevents FGF from binding to mutant FGFR3. sFGFR3 was injected subcutaneously to newborn Fgfr3(ach/+) mice-the mouse model of achondroplasia-twice per week throughout the growth period during 3 weeks. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, with a dose-dependent enhancement of skeletal growth in Fgfr3(ach/+) mice. This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity. These results describe a new approach for restoring bone growth and suggest that sFGFR3 could be a potential therapy for children with achondroplasia and related disorders. " 5928;"Effects of sleeve gastrectomy in high fat diet-induced obese mice: respective role of reduced caloric intake, white adipose tissue inflammation and changes in adipose tissue and ectopic fat depots.";"P. GUAL";"Equipe 08, Team 08";24196540;"Surgical endoscopy";"Schneck AS, Iannelli A, Patouraux S, Rousseau D, Bonnafous S, Bailly-Maitre B, Le Thuc O, Rovere C, Panaia-Ferrari P, Anty R, Tran A, Gual P, Gugenheim J";;"Feb 2014";1391212800;;"Sleeve gastrectomy (SG) has become a popular bariatric procedure. The mechanisms responsible for weight loss and improvement of metabolic disturbances have still not been completely elucidated. We investigated the effect of SG on body weight, adipose tissue depots, glucose tolerance, and liver steatosis independent of reduced caloric intake in high-fat-diet-induced obese mice." 5926;"Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice.";"P. GUAL";"Equipe 08, Team 08";24810044;"Cell death & disease";"Patouraux S, Rousseau D, Rubio A, Bonnafous S, Lavallard VJ, Lauron J, Saint-Paul MC, Bailly-Maitre B, Tran A, Crenesse D, Gual P";;"May 2014";1398902400;;"Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn(-/-) mice compared with wild-type (Wt) mice after I-R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn(-/-) mice versus Wt mice after I-R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn(-/-) mice versus Wt mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages." 5924;"Low Levels of 25-Hydroxy Vitamin D are Independently Associated with the Risk of Bacterial Infection in Cirrhotic Patients.";"P. GUAL";"Equipe 08, Team 08";24871371;"Clinical and translational gastroenterology";"Anty R, Tonohouan M, Ferrari-Panaia P, Piche T, Pariente A, Anstee QM, Gual P, Tran A";;"May 2014";1398902400;;"Low levels of vitamin D are associated with a higher mortality in cirrhotic patients, but the role of this deficiency is still unknown. The purpose of this study was to assess the levels of vitamin D in cirrhotic patients with and without bacterial infection." 5922;"Prophylaxis of bacterial infections in cirrhosis: is an optimal 25-OH vitamin D level required?";"P. GUAL";"Equipe 08, Team 08";25020157;"Journal of hepatology";"Anty R, Anstee QM, Gual P, Tran A";;"Oct 2014";1412121600;; 5920;"Autophagy and non-alcoholic fatty liver disease.";"P. GUAL";"Equipe 08, Team 08";25295245;"BioMed research international";"Lavallard VJ, Gual P";;"Jan 2014";1388534400;;"Autophagy, or cellular self-digestion, is a catabolic process that targets cell constituents including damaged organelles, unfolded proteins, and intracellular pathogens to lysosomes for degradation. Autophagy is crucial for development, differentiation, survival, and homeostasis. Important links between the regulation of autophagy and liver complications associated with obesity, non-alcoholic fatty liver disease (NAFLD), have been reported. The spectrum of these hepatic abnormalities extends from isolated steatosis to non-alcoholic steatohepatitis (NASH), steatofibrosis, which sometimes leads to cirrhosis, and hepatocellular carcinoma. NAFLD is one of the three main causes of cirrhosis and increases the risk of liver-related death and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to steatosis and then more severe disease are complex and still unclear. The regulation of the autophagic flux, a dynamic response, and the knowledge of the role of autophagy in specific cells including hepatocytes, hepatic stellate cells, immune cells, and hepatic cancer cells have been extensively studied these last years. This review will provide insight into the current understanding of autophagy and its role in the evolution of the hepatic complications associated with obesity, from steatosis to hepatocellular carcinoma. " 5918;"Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation.";"P. GUAL";"Equipe 08, Team 08";25540417;"Proceedings of the National Academy of Sciences of the United States of America";"Patel MN, Bernard WG, Milev NB, Cawthorn WP, Figg N, Hart D, Prieur X, Virtue S, Hegyi K, Bonnafous S, Bailly-Maitre B, Chu Y, Griffin JL, Mallat Z, Considine RV, Tran A, Gual P, Takeuchi O, Akira S, Vidal-Puig A, Bennett MR, Sethi JK";;"Jan 2015";1420070400;;"Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: to limit inflammasome priming and metaflammation. " 5916;"Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1.";"P. GUAL";"Equipe 08, Team 08";25828351;"EMBO molecular medicine";"Seillier M, Pouyet L, N'Guessan P, Nollet M, Capo F, Guillaumond F, Peyta L, Dumas JF, Varrault A, Bertrand G, Bonnafous S, Tran A, Meur G, Marchetti P, Ravier MA, Dalle S, Gual P, Muller D, Rutter GA, Servais S, Iovanna JL, Carrier A";;"Jun 2015";1433116800;;"The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research. " 5914;"Severe Vitamin D Deficiency May be an Additional Cofactor for the Occurrence of Alcoholic Steatohepatitis.";"P. GUAL";"Equipe 08, Team 08";25941109;"Alcoholism, clinical and experimental research";"Anty R, Canivet CM, Patouraux S, Ferrari-Panaia P, Saint-Paul MC, Huet PM, Lebeaupin C, Iannelli A, Gual P, Tran A";;"Jun 2015";1433116800;;"Among its pleiotropic effects, vitamin D may protect the liver from fibrosis and/or inflammation. However, the impact of vitamin D on liver pathology in hepatitis C remains unclear, and very few studies including alcoholic patients with liver pathologies have been performed. Here we compared the levels of 25-OH vitamin D in the blood of alcoholic patients with the occurrence of alcoholic steatohepatitis (ASH) or bridging fibrosis." 5912;"The promyelocytic leukemia protein is upregulated in conditions of obesity and liver steatosis.";"P. GUAL";"Equipe 08, Team 08";25999785;"International journal of biological sciences";"Carracedo A, Rousseau D, Douris N, Fernández-Ruiz S, Martín-Martín N, Weiss D, Webster K, Adams AC, Vazquez-Chantada M, Martinez-Chantar ML, Anty R, Tran A, Maratos-Flier E, Gual P, Pandolfi PP";;"Jan 2015";1420070400;; 5908;"Immunoglobulin G4-associated autoimmune hepatitis may be found in Western countries.";"P. GUAL";"Equipe 08, Team 08";26553036;"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver";"Canivet CM, Anty R, Patouraux S, Saint-Paul MC, Lebeaupin C, Gual P, Duclos-Vallee JC, Tran A";;"Mar 2016";1456790400;;"Immunoglobulin G4-related disease is a multi-systemic autoimmune disease. The sole involvement of the liver has been recently reported in Japanese patients and named ""immunoglobulin G4-associated autoimmune hepatitis""." 5906;"Therapeutic potential of nicotinamide adenine dinucleotide for nonalcoholic fatty liver disease.";"P. GUAL";"Equipe 08, Team 08";26661503;"Hepatology (Baltimore, Md.)";"Gual P, Postic C";;"Apr 2016";1459468800;; 5904;"Severe Vitamin D Deficiency Is Not Associated with Liver Damage in Morbidly Obese Patients.";"P. GUAL";"Equipe 08, Team 08";26787197;"Obesity surgery";"Anty R, Hastier A, Canivet CM, Patouraux S, Schneck AS, Ferrari-Panaia P, Ben-Amor I, Saint-Paul MC, Gugenheim J, Gual P, Iannelli A, Tran A";;"09 2016";1472688000;;"A deficiency in vitamin D could be deleterious during chronic liver diseases. However, contradictory data have been published in patients with non-alcoholic fatty liver disease. The aim of the study was to compare the blood level of 25 hydroxy vitamin D (25-OH vitamin D) with the severity of liver lesions, in a large cohort of morbidly obese patients." 5898;"Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis.";"P. GUAL, R. ANTY, S. PATOURAUX, A. TRAN, A. IANNELLI";"Equipe 08, Team 08";27594839;"Frontiers in physiology";"Schneck AS, Anty R, Patouraux S, Bonnafous S, Rousseau D, Lebeaupin C, Bailly-Maitre B, Sans A, Tran A, Gugenheim J, Iannelli A, Gual P";;"Jan 2016";1451606400;;"The long-term effects of bariatric surgery on non-alcoholic steatohepatitis (NASH), focusing on liver injury and hepatocyte apoptosis, are not well-established. We here performed a longitudinal study with paired liver biopsies of nine morbidly obese women (median BMI: 42 [38.7; 45.1] kg/m(2)) with NASH with a median follow-up of 55 [44; 75] months after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. LRYGB surgery was associated with significant weight loss (median BMI loss -13.7 [-16.4; -9.5] kg/m(2)), improved hepatic steatosis in all patients (55.5% with total resolution), and resolution of hepatic inflammation and hepatocyte ballooning in 100 and 88.8% of cases, respectively. Alanine aminotransferase levels dropped to normal values while hepatic activated cleaved caspase-3 levels strongly decreased after a median follow-up of 55 months. Hepatocyte apoptosis, as evaluated by serum caspase-generated keratin-18 fragment, improved within the first year following LRYGB and these improvements persisted for at least 55 months. LRYGB in morbidly obese patients with NASH is thus associated with a long-lasting beneficial impact on hepatic steatohepatitis and hepatocyte death. " 5896;"Autophagy in chronic liver diseases: the two faces of Janus.";"P. GUAL";"Equipe 08, Team 08";27903585;"American journal of physiology. Cell physiology";"Gual P, Gilgenkrantz H, Lotersztajn S";;"Mar 2017";1488326400;;"Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the leading causes of cirrhosis and increase the risk of hepatocellular carcinoma and liver-related death. ALD and NAFLD share common pathogenic features extending from isolated steatosis to steatohepatitis and steatofibrosis, which can progress to cirrhosis and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of NAFLD and ALD are complex and still unclear. Important links between the regulation of autophagy (macroautophagy and chaperone-mediated autophagy) and chronic liver diseases have been reported. Autophagy may protect against steatosis and progression to steatohepatitis by limiting hepatocyte injury and reducing M1 polarization, as well as promoting liver regeneration. Its role in fibrosis and hepatocarcinogenesis is more complex. It has pro- and antifibrogenic properties depending on the hepatic cell type concerned, and beneficial and deleterious effects on hepatocarcinogenesis at initiating and late phases, respectively. This review summarizes the latest advances on the role of autophagy in different stages of fatty liver disease progression and describes its divergent and cell-specific effects during chronic liver injury." 5894;"CD44 is a key player in non-alcoholic steatohepatitis.";"C. LUCI, P. GUAL, S. PATOURAUX, A. IANNELLI, A. TRAN, R. ANTY";"Equipe 08, Team 08";28323124;"Journal of hepatology";"Patouraux S, Rousseau D, Bonnafous S, Lebeaupin C, Luci C, Canivet CM, Schneck AS, Bertola A, Saint-Paul MC, Iannelli A, Gugenheim J, Anty R, Tran A, Bailly-Maitre B, Gual P";;"08 2017";1501545600;;"Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression." 5892;"[Autophagy in chronic liver diseases: a friend rather than a foe?]";"P. GUAL";"Equipe 08, Team 08";28367811;"Medecine sciences : M/S";"Gual P, Gilgenkrantz H, Lotersztajn S";;"Mar 2017";1488326400;;"Within recycling damaged cell components, autophagy maintains cell homeostasis. Thus, it has been anticipated that autophagy would play an essential role in the pathogenesis of chronic liver diseases. Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most prevalent chronic liver diseases in Western countries, sharing common histopathologic features and a common disease progression. In this review, we discuss the role of autophagy at different stages of NAFLD and ALD as well as in liver regeneration and hepatocarcinogenesis." 5890;"Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients.";"P. GUAL, A. TRAN";"Equipe 08, Team 08";28436449;"Scientific reports";"Chiappini F, Coilly A, Kadar H, Gual P, Tran A, Desterke C, Samuel D, Duclos-Vallée JC, Touboul D, Bertrand-Michel J, Brunelle A, Guettier C, Le Naour F";;"04 2017";1491004800;;"Nonalcoholic steatohepatitis (NASH) is a condition which can progress to cirrhosis and hepatocellular carcinoma. Markers for NASH diagnosis are still lacking. We performed a comprehensive lipidomic analysis on human liver biopsies including normal liver, nonalcoholic fatty liver and NASH. Random forests-based machine learning approach allowed characterizing a signature of 32 lipids discriminating NASH with 100% sensitivity and specificity. Furthermore, we validated this signature in an independent group of NASH patients. Then, metabolism dysregulations were investigated in both patients and murine models. Alterations of elongase and desaturase activities were observed along the fatty acid synthesis pathway. The decreased activity of the desaturase FADS1 appeared as a bottleneck, leading upstream to an accumulation of fatty acids and downstream to a deficiency of long-chain fatty acids resulting to impaired phospholipid synthesis. In NASH, mass spectrometry imaging on tissue section revealed the spreading into the hepatic parenchyma of selectively accumulated fatty acids. Such lipids constituted a highly toxic mixture to human hepatocytes. In conclusion, this study characterized a specific and sensitive lipid signature of NASH and positioned FADS1 as a significant player in accumulating toxic lipids during NASH progression." 5888;"Baseline Anthropometric and Metabolic Parameters Correlate with Weight Loss in Women 1-Year After Laparoscopic Roux-En-Y Gastric Bypass.";"P. GUAL, R. ANTY, A. TRAN, A. IANNELLI";"Equipe 08, Team 08";28550439;"Obesity surgery";"Sans A, Bailly L, Anty R, Sielezenef I, Gugenheim J, Tran A, Gual P, Iannelli A";;"11 2017";1509494400;;"In this study, we explored in a prospective cohort of morbidly obese women undergoing laparoscopic Roux-en-Y gastric bypass (LRYGP) correlations between baseline anthropometrics, metabolic parameters, resting energy expenditure (REE), body composition, and 1-year % excess body mass index loss (%EBMIL). We also investigated risk factors for insufficient %EBMIL." 5886;"Determinants associated with the correction of glomerular hyper-filtration one year after bariatric surgery.";"P. GUAL, R. ANTY, A. TRAN, A. IANNELLI";"Equipe 08, Team 08";28869167;"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery";"Favre G, Anty R, Canivet C, Clément G, Ben-Amor I, Tran A, Gugenheim J, Gual P, Esnault VLM, Iannelli A";;"Oct 2017";1506816000;;"Increased adipokine production and hyperfiltration may explain the links between obesity and chronic kidney disease. Indeed, hyperfiltration may precede a subsequent accelerated decline of kidney function in these patients. Glomerular filtration rate decreases after bariatric surgery in young obese patients with hyperfiltration." 5884;"Non-invasive Evaluation of NAFLD with Indocyanine Green Clearance Test: a Preliminary Study in Morbidly Obese Patients Undergoing Bariatric Surgery.";"P. GUAL, R. ANTY, S. PATOURAUX, A. TRAN, A. IANNELLI";"Equipe 08, Team 08";28875438;"Obesity surgery";"Danin PE, Anty R, Patouraux S, Raucoules-Aimé M, Gugenheim J, Tran A, Gual P, Iannelli A";;"03 2018";1519862400;;"Overweight and obesity dramatically increased in the last years. Hepatic complication of obesity, integrated in the term of non-alcoholic fatty liver disease (NAFLD), is a spectrum of abnormality ranging from steatosis to non-alcoholic steatohepatitis (NASH), potentially leading to cirrhosis. Liver biopsy remains the gold standard to evaluate the stage of NAFLD; however, the procedure is invasive. The indocyanine green (ICG) clearance test is performed since years to assess hepatic function before partial hepatectomy, or after liver transplantation. This study was designed to detect liver complications with the ICG clearance test in a population of obese patients scheduled for bariatric surgery." 5880;"Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production.";"P. GUAL";"Equipe 08, Team 08";29500246;Circulation;"Sawaki D, Czibik G, Pini M, Ternacle J, Suffee N, Mercedes R, Marcelin G, Surenaud M, Marcos E, Gual P, Clément K, Hue S, Adnot S, Hatem SN, Tsuchimochi I, Yoshimitsu T, Hénégar C, Derumeaux G";;"08 2018";1533081600;;"Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown." 5878;"Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.";"P. GUAL, R. ANTY, S. PATOURAUX, A. TRAN";"Equipe 08, Team 08";29577364;"Alimentary pharmacology & therapeutics";"Boursier J, Anty R, Vonghia L, Moal V, Vanwolleghem T, Canivet CM, Michalak S, Bonnafous S, Michielsen P, Oberti F, Iannelli A, Van Gaal L, Patouraux S, Blanchet O, Verrijken A, Gual P, Rousselet MC, Driessen A, Hunault G, Bertrais S, Tran A, Calès P, Francque S";;"05 2018";1525132800;;"The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) (""fibrotic NASH"") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved." 5876;"Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia.";"P. GUAL, A. TRAN";"Equipe 08, Team 08";29652901;"PloS one";"Saint-Laurent C, Garcia S, Sarrazy V, Dumas K, Authier F, Sore S, Tran A, Gual P, Gennero I, Salles JP, Gouze E";;"Jan 2018";1514764800;;"Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication." 5874;"The Differential Expression of Cide Family Members is Associated with Nafld Progression from Steatosis to Steatohepatitis.";"C. LUCI, P. GUAL, S. PATOURAUX, R. ANTY, A. TRAN, A. IANNELLI";"Equipe 08, Team 08";31097771;"Scientific reports";"Sans A, Bonnafous S, Rousseau D, Patouraux S, Canivet CM, Leclere PS, Tran-Van-Nhieu J, Luci C, Bailly-Maitre B, Xu X, Lee AH, Minehira K, Anty R, Tran A, Iannelli A, Gual P";;"05 2019";1556668800;;"Improved understanding of the molecular mechanisms responsible for the progression from a ""non-pathogenic"" steatotic state to Non-Alcoholic Steatohepatitis is an important clinical requirement. The cell death-inducing DFF45 like effector (CIDE) family members (A, B and FSP27) regulate hepatic lipid homeostasis by controlling lipid droplet growth and/or VLDL production. However, CIDE proteins, particularly FSP27, have a dual role in that they also regulate cell death. We here report that the hepatic expression of CIDEA and FSP27 (α/β) was similarly upregulated in a dietary mouse model of obesity-mediated hepatic steatosis. In contrast, CIDEA expression decreased, but FSP27-β expression strongly increased in a dietary mouse model of steatohepatitis. The inverse expression pattern of CIDEA and FSP27β was amplified with the increasing severity of the liver inflammation and injury. In obese patients, the hepatic CIDEC2 (human homologue of mouse FSP27β) expression strongly correlated with the NAFLD activity score and liver injury. The hepatic expression of CIDEA tended to increase with obesity, but decreased with NAFLD severity. In hepatic cell lines, the downregulation of FSP27β resulted in the fractionation of lipid droplets, whereas its overexpression decreased the expression of the anti-apoptotic BCL2 marker. This, in turn, sensitized cells to apoptosis in response to TNF α and saturated fatty acid. Considered together, our animal, human and in vitro studies indicate that differential expression of FSP27β/CIDEC2 and CIDEA is related to NAFLD progression and liver injury." 5872;"Natural Killer Cells and Type 1 Innate Lymphoid Cells Are New Actors in Non-alcoholic Fatty Liver Disease.";"C. LUCI, P. GUAL";"Equipe 08, Team 08";31191550;"Frontiers in immunology";"Luci C, Vieira E, Perchet T, Gual P, Golub R";;"Jan 2019";1546300800;;"Obesity and associated liver diseases (Non Alcoholic Fatty Liver Disease, NAFLD) are a major public health problem with increasing incidence in Western countries (25% of the affected population). These complications develop from a fatty liver (steatosis) to an inflammatory state (steatohepatitis) evolving toward fibrosis and hepatocellular carcinoma. Lipid accumulation in the liver contributes to hepatocyte cell death and promotes liver injury. Local immune cells are activated either by Danger Associated Molecular Patterns (DAMPS) released by dead hepatocytes or by bacterial products (PAMPS) reaching the liver due to increased intestinal permeability. The resulting low-grade inflammatory state promotes the progression of liver complications toward more severe grades. Innate lymphoid cells (ILC) are an heterogeneous family of five subsets including circulating Natural Killer (NK) cells, ILC1, ILC2, ILC3, and lymphocytes tissue-inducer cells (LTi). NK cells and tissue-resident ILCs, mainly located at epithelial surfaces, are prompt to rapidly react to environmental changes to mount appropriate immune responses. Recent works have demonstrated the interplay between ILCs subsets and the environment within metabolic active organs such as liver, adipose tissue and gut during diet-induced obesity leading or not to hepatic abnormalities. Here, we provide an overview of the newly roles of NK cells and ILC1 in metabolism focusing on their contribution to the development of NAFLD. We also discuss recent studies that demonstrate the ability of these two subsets to influence tissue-specific metabolism and how their function and homeostasis are affected during metabolic disorders." 5870;"Pharmacological treatments of the ""Fibrotic-NASH"": Towards a delivery on time?";"P. GUAL";"Equipe 08, Team 08";31300372;"Clinics and research in hepatology and gastroenterology";"Gual P";;"11 2019";1572566400;; 5868;"[Pathogenesis of non-alcoholic fatty liver disease].";"P. GUAL, R. ANTY";"Equipe 08, Team 08";31767252;"Presse medicale (Paris, France : 1983)";"Anty R, Gual P";;"Dec 2019";1575158400;;"Non-Alcoholic Fatty Liver Disease (NAFLD) is a complex chronic disease resulting from an interaction between genetic and environmental factors. The phenotype and pathophysiology of NAFLD is heterogeneous. NAFLD is a continuum of histological lesions of the liver from steatosis, Non-Alcoholic SteatoHepatitis (NASH), NASH with fibrosis, cirrhosis to hepatocellular carcinoma. The pathophysiology encompasses a dysfunction in fatty tissue (sub-cutaneous and visceral) associated with insulin-resistance and metabolic inflammation. NAFLD is a ""multi-systemic"" disease. Reciprocal and aggravating interactions exist between NAFLD, cardiovascular anomalies and diabetes. The understanding of the mechanisms responsible for NAFLD allows the identification of potential novel therapeutic targets." 5866;"Hepatic FNDC5 is a potential local protective factor against Non-Alcoholic Fatty Liver.";"C. LUCI, P. GUAL, S. PATOURAUX, A. IANNELLI, A. TRAN, R. ANTY";"Equipe 08, Team 08";32001301;"Biochimica et biophysica acta. Molecular basis of disease";"Canivet CM, Bonnafous S, Rousseau D, Leclere PS, Lacas-Gervais S, Patouraux S, Sans A, Luci C, Bailly-Maitre B, Iannelli A, Tran A, Anty R, Gual P";;"05 2020";1588291200;;"The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK, a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5-silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N-acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death." 5864;"The mid-infrared spectroscopy: A novel non-invasive diagnostic tool for NASH diagnosis in severe obesity.";"P. GUAL, R. ANTY, S. PATOURAUX, A. IANNELLI, A. TRAN";"Equipe 08, Team 08";32039387;"JHEP reports : innovation in hepatology";"Anty R, Morvan M, Le Corvec M, Canivet CM, Patouraux S, Gugenheim J, Bonnafous S, Bailly-Maitre B, Sire O, Tariel H, Bernard J, Piche T, Loréal O, Aron-Wisnewsky J, Clément K, Tran A, Iannelli A, Gual P";;"Nov 2019";1572566400;;"There is an urgent medical need to develop non-invasive tests for non-alcoholic steatohepatitis (NASH). This study evaluates the diagnostic performance of an innovative model based on mid-infrared (MIR) spectroscopy for the diagnosis of NASH." 5862;"Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.";"P. GUAL, S. Marchetti, T. Strub";"Equipe 08, Equipe 01, Team 08";32337074;"Cell death discovery";"Bellini L, Strub T, Habel N, Pandiani C, Marchetti S, Martel A, Baillif S, Bailly-Maitre B, Gual P, Ballotti R, Bertolotto C";;"Jan 2020";1577836800;;"To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma." 5860;"No association between binge eating disorder and severity of non-alcoholic fatty liver disease in severely obese patients.";"P. GUAL, S. PATOURAUX, A. TRAN, A. IANNELLI, R. ANTY";"Equipe 08, Team 08";32514465;"JGH open : an open access journal of gastroenterology and hepatology";"Canivet CM, Perney P, Cherick F, Orlowski M, Patouraux S, Bailly-Maitre B, Tran A, Iannelli A, Gual P, Anty R";;"Jun 2020";1590969600;;"The main aim of this study was to evaluate if the binge eating disorders (BEDs) related to obesity were associated with the severity of non-alcoholic fatty liver disease (NAFLD)." 5858;"MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice.";"C. LUCI, P. GUAL, S. PATOURAUX, A. TRAN";"Equipe 08, Team 08";32699233;"Scientific reports";"Leclère PS, Rousseau D, Patouraux S, Guérin S, Bonnafous S, Gréchez-Cassiau A, Ruberto AA, Luci C, Subramaniam M, Tran A, Delaunay F, Gual P, Teboul M";;"07 2020";1593561600;;"A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor." 5856;"Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies.";"C. LUCI, P. GUAL, R. ANTY";"Equipe 08, Team 08";33384662;"Frontiers in endocrinology";"Luci C, Bourinet M, Leclère PS, Anty R, Gual P";;"Jan 2020";1577836800;;"Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed." 5854;"Plasmatic osteopontin and vascular access dysfunction in hemodialysis patients: a cross-sectional, case-control study (The OSMOSIS Study).";"N. Mazure, P. GUAL";"Equipe 05, Equipe 08, Team 08";34468976;"Journal of nephrology";"Contenti J, Durand M, Vido S, Declemy S, Raffort J, Carboni J, Bonnet S, Koelsch C, Hassen-Khodja R, Gual P, Mazure NM, Sadaghianloo N";;"Sep 2021";1630454400;;"Despite close follow-up of patients with native arteriovenous fistulas (AVFs), up to 10% experience thrombosis each year. The OSMOSIS Study (Osteopontin as a Marker of Stenosis) tested the hypothesis that the systemic osteopontin level, a pro-inflammatory mediator related to vascular remodelling and intimal hyperplasia, increases in AVF stenosis, and may be used in clinical surveillance." 5852;"Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem.";"P. GUAL, R. ANTY";"Equipe 08, Team 08";34944730;Biomedicines;"Le Garf S, Nègre V, Anty R, Gual P";;"Dec 2021";1638316800;;"Metabolic-associated fatty liver disease (MAFLD), previously called nonalcoholic fatty liver diseases (NAFLD), is one of the most important causes of chronic liver disease worldwide and will likely become the leading cause of end-stage liver disease in the decades ahead. MAFLD covers a continuum of liver diseases from fatty liver to nonalcoholic steatohepatitis (NASH), liver fibrosis/cirrhosis and hepatocellular cancer. Importantly, the growing incidence of overweight and obesity in childhood, 4% in 1975 to 18% in 2016, with persisting obesity complications into adulthood, is likely to be harmful by increasing the incidence of severe MAFLD at an earlier age. Currently, MAFLD is the leading form of chronic liver disease in children and adolescents, with a global prevalence of 3 to 10%, pointing out that early diagnosis is therefore crucial. In this review, we highlight the current knowledge concerning the epidemiology, risk factors and potential pathogenic mechanisms, as well as diagnostic and therapeutic approaches, of pediatric MAFLD." 5836;"Modulation of caspase-independent cell death leads to resensitization of imatinib mesylate-resistant cells.";"A. Jacquel, JE. Ricci, P. Auberger";"Equipe 02, Team 02, Equipe 03";19318579;"Cancer research";"Lavallard VJ, Pradelli LA, Paul A, Bénéteau M, Jacquel A, Auberger P, Ricci JE";;"Apr 2009";1238544000;;"Imatinib mesylate is widely used for the treatment of patients with chronic myelogenous leukemia (CML). This compound is very efficient in killing Bcr-Abl-positive cells in a caspase-dependent manner. Nevertheless, several lines of evidence indicated that caspase-mediated cell death (i.e., apoptosis) is not the only type of death induced by imatinib. The goal of our study was to evaluate the importance of the newly described caspase-independent cell death (CID) in Bcr-Abl-positive cells. We established in several CML cell lines that imatinib, in conjunction with apoptosis, also induced CID. CID was shown to be as efficient as apoptosis in preventing CML cell proliferation and survival. We next investigated the potential implication of a recently identified mechanism used by cancer cells to escape CID through overexpression of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We showed here, in several CML cell lines, that GAPDH overexpression was sufficient to induce protection from CID. Furthermore, imatinib-resistant Bcr-Abl-positive cell lines were found to spontaneously overexpress GAPDH. Finally, we showed that a GAPDH partial knockdown, using specific short hairpin RNAs, was sufficient to resensitize those resistant cells to imatinib-induced cell death. Taken together, our results indicate that CID is an important effector of imatinib-mediated cell death. We also established that GAPDH overexpression can be found in imatinib-resistant Bcr-Abl-positive cells and that its down-regulation can resensitize those resistant cells to imatinib-induced death. Therefore, drugs able to modulate GAPDH administered together with imatinib could find some therapeutic benefits in CML patients." 5834;"Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs.";"JE. Ricci";"Equipe 03";19544560;"International journal of cancer";"Pradelli E, Karimdjee-Soilihi B, Michiels JF, Ricci JE, Millet MA, Vandenbos F, Sullivan TJ, Collins TL, Johnson MG, Medina JC, Kleinerman ES, Schmid-Alliana A, Schmid-Antomarchi H";;"Dec 2009";1259625600;;"Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The experimental design involved the use of the CXCR3 antagonist, AMG487 and 2 murine models of osteosarcoma lung metastases. After tail vein injection of osteosarcoma cells, mice that were systematically treated with AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of osteosarcoma cells in vitro with AMG487 led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their ligands intervene in the initial dissemination of the osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit tumor metastasis without adversely affecting antitumoral host response." 5832;"The caspase-cleaved form of LYN mediates a psoriasis-like inflammatory syndrome in mice.";"JE. Ricci, M. Deckert, P. Auberger, S. Marchetti";"Equipe 03, Equipe 11, Team 11, Equipe 02, Team 02, Team 03";19590497;"The EMBO journal";"Marchetti S, Gamas P, Belhacène N, Grosso S, Pradelli LA, Colosetti P, Johansen C, Iversen L, Deckert M, Luciano F, Hofman P, Ortonne N, Khemis A, Mari B, Ortonne JP, Ricci JE, Auberger P";;"Aug 2009";1249084800;;"We showed previously that Lyn is a substrate for caspases, a family of cysteine proteases, involved in the regulation of apoptosis and inflammation. Here, we report that expression of the caspase-cleaved form of Lyn (LynDeltaN), in mice, mediates a chronic inflammatory syndrome resembling human psoriasis. Genetic ablation of TNF receptor 1 in a LynDeltaN background rescues a normal phenotype, indicating that LynDeltaN mice phenotype is TNF-alpha-dependent. The predominant role of T cells in the disease occurring in LynDeltaN mice was highlighted by the distinct improvement of LynDeltaN mice phenotype in a Rag1-deficient background. Using pan-genomic profiling, we also established that LynDeltaN mice show an increased expression of STAT-3 and inhibitory members of the NFkappaB pathway. Accordingly, LynDeltaN alters NFkappaB activity underlying a link between inhibition of NFkappaB and LynDeltaN mice phenotype. Finally, analysis of Lyn expression in human skin biopsies of psoriatic patients led to the detection of Lyn cleavage product whose expression correlates with the activation of caspase 1. Our data identify a new role for Lyn as a regulator of psoriasis through its cleavage by caspases." 5830;"Novel roles for GAPDH in cell death and carcinogenesis.";"JE. Ricci";"Equipe 03";19779498;"Cell death and differentiation";"Colell A, Green DR, Ricci JE";;"Dec 2009";1259625600;;"Growing evidence points to the fact that glucose metabolism has a central role in carcinogenesis. Among the enzymes controlling this energy production pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest. Initially identified as a glycolytic enzyme and considered as a housekeeping gene, this enzyme is actually tightly regulated and is involved in numerous cellular functions. Particularly intriguing are recent reports describing GAPDH as a regulator of cell death. However, its role in cell death is unclear; whereas some studies point toward a proapoptotic function, others describe a protective role and suggest its participation in tumor progression. In this study, we highlight recent findings and discuss potential mechanisms through which cells regulate GAPDH to fulfill its diverse functions to influence cell fate." 5828;"Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation.";"JE. Ricci, P. Auberger, S. Marchetti";"Equipe 03, Equipe 02, Team 02, Team 03";19966861;Oncogene;"Pradelli LA, Bénéteau M, Chauvin C, Jacquin MA, Marchetti S, Muñoz-Pinedo C, Auberger P, Pende M, Ricci JE";;"Mar 2010";1267401600;;"Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers." 5826;"Mitochondrial control of caspase-dependent and -independent cell death.";"JE. Ricci";"Equipe 03";20151314;"Cellular and molecular life sciences : CMLS";"Pradelli LA, Bénéteau M, Ricci JE";;"May 2010";1272672000;;"Mitochondria control whether a cell lives or dies. The role mitochondria play in deciding the fate of a cell was first identified in the mid-1990s, because mitochondria-enriched fractions were found to be necessary for activation of death proteases, the caspases, in a cell-free model of apoptotic cell death. Mitochondrial involvement in apoptosis was subsequently shown to be regulated by Bcl-2, a protein that was known to contribute to cancer in specific circumstances. The important role of mitochondria in promoting caspase activation has therefore been a major focus of apoptosis research; however, it is also clear that mitochondria contribute to cell death by caspase-independent mechanisms. In this review, we will highlight recent findings and discuss the mechanism underlying the mitochondrial control of apoptosis and caspase-independent cell death." 5824;"Glucose deprivation induces an atypical form of apoptosis mediated by caspase-8 in Bax-, Bak-deficient cells.";"JE. Ricci";"Equipe 03";20203689;"Cell death and differentiation";"Caro-Maldonado A, Tait SW, Ramírez-Peinado S, Ricci JE, Fabregat I, Green DR, Muñoz-Pinedo C";;"Aug 2010";1280620800;;"Apoptosis induced by most stimuli proceeds through the mitochondrial pathway. One such stimulus is nutrient deprivation. In this study we studied death induced by glucose deprivation in cells deficient in Bax and Bak. These cells cannot undergo mitochondrial outer membrane permeabilization (MOMP) during apoptosis, but they undergo necrosis when treated with MOMP-dependent apoptotic stimuli. We find in these cells that glucose deprivation, rather than inducing necrosis, triggered apoptosis. Cell death required caspase activation as inhibition of caspases with peptidic inhibitors prevented death. Glucose deprivation-induced death displayed many hallmarks of apoptosis, such as caspase cleavage and activity, phosphatidyl-serine exposure and cleavage of caspase substrates. Neither overexpression of Bcl-xL nor knockdown of caspase-9 prevented death. However, transient or stable knockdown of caspase-8 or overexpression of CrmA inhibited apoptosis. Cell death was not inhibited by preventing death receptor-ligand interactions, by overexpression of c-FLIP or by knockdown of RIPK1. Glucose deprivation induced apoptosis in the human tumor cell line HeLa, which was prevented by knockdown of caspase-8. Thus, we have found that glucose deprivation can induce a death receptor-independent, caspase-8-driven apoptosis, which is engaged to kill cells that cannot undergo MOMP." 5822;"miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity.";"JE. Ricci, N. Mazure";"Equipe 03, Equipe 05, Team 05";20885442;"Cell death and differentiation";"Puisségur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, Maurin T, Lebrigand K, Cardinaud B, Hofman V, Fourre S, Magnone V, Ricci JE, Pouysségur J, Gounon P, Hofman P, Barbry P, Mari B";;"Mar 2011";1298937600;;"Following the identification of a set of hypoxia-regulated microRNAs (miRNAs), recent studies have highlighted the importance of miR-210 and of its transcriptional regulation by the transcription factor hypoxia-inducible factor-1 (HIF-1). We report here that miR-210 is overexpressed at late stages of non-small cell lung cancer. Expression of miR-210 in lung adenocarcinoma A549 cells caused an alteration of cell viability associated with induction of caspase-3/7 activity. miR-210 induced a loss of mitochondrial membrane potential and the apparition of an aberrant mitochondrial phenotype. The expression profiling of cells overexpressing miR-210 revealed a specific signature characterized by enrichment for transcripts related to 'cell death' and 'mitochondrial dysfunction', including several subunits of the electron transport chain (ETC) complexes I and II. The transcript coding for one of these ETC components, SDHD, subunit D of succinate dehydrogenase complex (SDH), was validated as a bona fide miR-210 target. Moreover, SDHD knockdown mimicked miR-210-mediated mitochondrial alterations. Finally, miR-210-dependent targeting of SDHD was able to activate HIF-1, in line with previous studies linking loss-of-function SDH mutations to HIF-1 activation. miR-210 can thus regulate mitochondrial function by targeting key ETC component genes with important consequences on cell metabolism, survival and modulation of HIF-1 activity. These observations help explain contradictory data regarding miR-210 expression and its putative function in solid tumors." 5820;"Glycolysis inhibition targets Mcl-1 to restore sensitivity of lymphoma cells to ABT-737-induced apoptosis.";"JE. Ricci";"Equipe 03";22076465;Leukemia;"Meynet O, Bénéteau M, Jacquin MA, Pradelli LA, Cornille A, Carles M, Ricci JE";;"May 2012";1335830400;; 5818;"Cancer metabolism: current perspectives and future directions.";"JE. Ricci";"Equipe 03";22237205;"Cell death & disease";"Muñoz-Pinedo C, El Mjiyad N, Ricci JE";;"Jan 2012";1325376000;;"Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how 'metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer's 'Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells." 5816;"PPARγ contributes to PKM2 and HK2 expression in fatty liver.";"JE. Ricci";"Equipe 03";22334075;"Nature communications";"Panasyuk G, Espeillac C, Chauvin C, Pradelli LA, Horie Y, Suzuki A, Annicotte JS, Fajas L, Foretz M, Verdeguer F, Pontoglio M, Ferré P, Scoazec JY, Birnbaum MJ, Ricci JE, Pende M";;"Feb 2012";1328054400;;"Rapidly proliferating cells promote glycolysis in aerobic conditions, to increase growth rate. Expression of specific glycolytic enzymes, namely pyruvate kinase M2 and hexokinase 2, concurs to this metabolic adaptation, as their kinetics and intracellular localization favour biosynthetic processes required for cell proliferation. Intracellular factors regulating their selective expression remain largely unknown. Here we show that the peroxisome proliferator-activated receptor gamma transcription factor and nuclear hormone receptor contributes to selective pyruvate kinase M2 and hexokinase 2 gene expression in PTEN-null fatty liver. Peroxisome proliferator-activated receptor gamma expression, liver steatosis, shift to aerobic glycolysis and tumorigenesis are under the control of the Akt2 kinase in PTEN-null mouse livers. Peroxisome proliferator-activated receptor gamma binds to hexokinase 2 and pyruvate kinase M promoters to activate transcription. In vivo rescue of peroxisome proliferator-activated receptor gamma activity causes liver steatosis, hypertrophy and hyperplasia. Our data suggest that therapies with the insulin-sensitizing agents and peroxisome proliferator-activated receptor gamma agonists, thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis." 5814;"The human MSH5 (MutSHomolog 5) protein localizes to mitochondria and protects the mitochondrial genome from oxidative damage.";"JE. Ricci";"Equipe 03";22917773;Mitochondrion;"Bannwarth S, Figueroa A, Fragaki K, Destroismaisons L, Lacas-Gervais S, Lespinasse F, Vandenbos F, Pradelli LA, Ricci JE, Rötig A, Michiels JF, Vande Velde C, Paquis-Flucklinger V";;"Nov 2012";1351728000;;"MutS homologs play a central role in maintaining genetic stability. We show that MSH5 (MutSHomolog 5) is localized into the mitochondria of germ and somatic cells. This protein binds to mtDNA and interacts with the Twinkle helicase and the DNA polymerase gamma. hMSH5 stimulates mtDNA repair in response to DNA damage induced by oxidative stress. Furthermore, we observed a subsarcolemmal accumulation of hMSH5 in COX negative muscle fibers of patients presenting a mitochondrial myopathy. We report a novel localization for hMSH5 suggesting that this protein may have functions other than those known in meiotic recombination." 5812;"Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.";"JE. Ricci";"Equipe 03";22990144;"European journal of human genetics : EJHG";"Fragaki K, Ait-El-Mkadem S, Chaussenot A, Gire C, Mengual R, Bonesso L, Bénéteau M, Ricci JE, Desquiret-Dumas V, Procaccio V, Rötig A, Paquis-Flucklinger V";;"May 2013";1367366400;;"We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases." 5810;"Severe thymic atrophy in a mouse model of skin inflammation accounts for impaired TNFR1 signaling.";"A. Jacquel, JE. Ricci, P. Auberger, S. Marchetti";"Equipe 02, Team 02, Equipe 03, Team 03";23071785;"PloS one";"Belhacéne N, Gamas P, Gonçalvès D, Jacquin M, Beneteau M, Jacquel A, Colosetti P, Ricci JE, Wakkach A, Auberger P, Marchetti S";;"Jan 2012";1325376000;;"Transgenic mice expressing the caspase-cleaved form of the tyrosine kinase Lyn (LynΔN) develop a TNFα-dependent skin disease that accurately recapitulates human psoriasis. Participation of lymphocytes in this disease was confirmed by backcrossing LynΔN mice on a Rag-1 deficient background. The present study was therefore conducted to analyze whether modification of lymphocyte homeostasis does occur and participate in the phenotype of LynΔN mice. We show here that LynΔN mice consistently exhibit thymic atrophy that correlates with both a net decrease in the CD4+/CD8+ Double Positive (DP) and an increase in Single Positive (SP) thymocyte sub-populations, but also display an increase of splenic mature B cell. Interestingly, a normal immune phenotype was rescued in a TNFR1 deficient background. Finally, none of these immune alterations was detected in newborn mice before the onset of inflammation. Therefore, we conclude that chronic inflammation can induce thymic atrophy and perturb spleen homeostasis in LynΔN mice through the increased production of TNFα, LTß and TNFR1 signaling." 5808;"Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response.";"JE. Ricci, J. Chiche, S. Marchetti";"Equipe 03, Team 03";23169636;"Proceedings of the National Academy of Sciences of the United States of America";"Bénéteau M, Zunino B, Jacquin MA, Meynet O, Chiche J, Pradelli LA, Marchetti S, Cornille A, Carles M, Ricci JE";;"Dec 2012";1354320000;;"Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice. We then established that only cotreated cells induced an efficient tumor-specific T-cell activation ex vivo and that tumor antigen-specific T cells could only be isolated from cotreated animals. In addition, only when mice were immunized with cotreated dead tumor cells could they be protected (vaccinated) from a subsequent challenge using the same tumor in viable form. Finally, we demonstrated that this effect was at least partially mediated through ERp57/calreticulin exposure on the plasma membrane. These data identify that the targeting of glycolysis can convert conventional tolerogenic cancer cell death stimuli into immunogenic ones, thus creating new strategies for immunogenic chemotherapy." 5806;"Tumor hypoxia and metabolism -- towards novel anticancer approaches.";"JE. Ricci, J. Chiche";"Equipe 03, Team 03";23597945;"Annales d'endocrinologie";"Chiche J, Ricci JE, Pouysségur J";;"May 2013";1367366400;;"The transcription factor hypoxia-inducible factor-1 (HIF-1) facilitates the induction of enzymes necessary for regulation of biological processes required for cell survival and the acquisition of an aggressive and invasive phenotype, such as regulation of the intracellular pH (pHi), anaerobic glycolysis, angiogenesis, migration/invasion... In this presentation, we will highlight some of the HIF-1-induced gene products - carbonic anhydrases IX and XII (CAs) and monocarboxylate transporters (MCTs) - which regulate the pHi by controlling export of metabolically-generated acids (carbonic and lactic acids). We reported that targeting these pHi-regulated processes through inhibition of either HIF-1-induced CAIX/CAXII or HIF-1-induced MCT4, MCT1 or Basigin/EMMPRIN/CD147 chaperone of MCTs, severely restricts glycolysis-generated ATP levels and tumor growth. In addition, we demonstrated that the Myc/HIF-1-targeted glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzing a key step producing the NADH cofactor, activates the Akt pathway, thereby upregulating expression of the anti-apoptotic Bcl-xL. As a consequence, high expression of GAPDH contributes to tumor aggressiveness, in particular in the context Myc-driven B lymphomas. We propose that membrane-bound carbonic anhydrases (CAIX, CAXII), monocarboxylate transporters/chaperon Basigin (Myc-induced MCT1 and HIF-induced-MCT4) and GAPDH that are associated with exacerbated tumor metabolism, represent new potential targets for anticancer therapy." 5804;"GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death.";"JE. Ricci, J. Chiche, S. Marchetti";"Equipe 03, Team 03";23645209;"Cell death and differentiation";"Jacquin MA, Chiche J, Zunino B, Bénéteau M, Meynet O, Pradelli LA, Marchetti S, Cornille A, Carles M, Ricci JE";;"Aug 2013";1375315200;;"Increased glucose catabolism and resistance to cell death are hallmarks of cancers, but the link between them remains elusive. Remarkably, under conditions where caspases are inhibited, the process of cell death is delayed but rarely blocked, leading to the occurrence of caspase-independent cell death (CICD). Escape from CICD is particularly relevant in the context of cancer as apoptosis inhibition only is often not sufficient to allow oncogenic transformation. While most glycolytic enzymes are overexpressed in tumors, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest as it can allow cells to recover from CICD. Here, we show that GAPDH, but no other glycolytic enzymes tested, when overexpressed could bind to active Akt and limit its dephosphorylation. Active Akt prevents FoxO nuclear localization, which precludes Bcl-6 expression and leads to Bcl-xL overexpression. The GAPDH-dependent Bcl-xL overexpression is able to protect a subset of mitochondria from permeabilization that are required for cellular survival from CICD. Thus, our work suggests that GAPDH overexpression could induce Bcl-xL overexpression and protect cells from CICD-induced chemotherapy through preservation of intact mitochondria that may facilitate tumor survival and chemotherapeutic resistance. " 5802;"TNFα-induced lysosomal membrane permeability is downstream of MOMP and triggered by caspase-mediated NDUFS1 cleavage and ROS formation.";"JE. Ricci";"Equipe 03";23788428;"Journal of cell science";"Huai J, Vögtle FN, Jöckel L, Li Y, Kiefer T, Ricci JE, Borner C";;"Sep 2013";1377993600;;"When NF-κB activation or protein synthesis is inhibited, tumor necrosis factor alpha (TNFα) can induce apoptosis through Bax- and Bak-mediated mitochondrial outer membrane permeabilization (MOMP) leading to caspase-3 activation. Additionally, previous studies have implicated lysosomal membrane permeability (LMP) and formation of reactive oxygen species (ROS) as early steps of TNFα-induced apoptosis. However, how these two events connect to MOMP and caspase-3 activation has been largely debated. Here, we present the novel finding that LMP induced by the addition of TNFα plus cycloheximide (CHX), the release of lysosomal cathepsins and ROS formation do not occur upstream but downstream of MOMP and require the caspase-3-mediated cleavage of the p75 NDUFS1 subunit of respiratory complex I. Both a caspase non-cleavable p75 mutant and the mitochondrially localized antioxidant MitoQ prevent LMP mediated by TNFα plus CHX and partially interfere with apoptosis induction. Moreover, LMP is completely blocked in cells deficient in both Bax and Bak, Apaf-1, caspase-9 or both caspase-3 and -7. Thus, after MOMP, active caspase-3 exerts a feedback action on complex I to produce ROS. ROS then provoke LMP, cathepsin release and further caspase activation to amplify TNFα apoptosis signaling. " 5800;"Heat-shock response increases lung injury caused by Pseudomonas aeruginosa via an interleukin-10-dependent mechanism in mice.";"JE. Ricci";"Equipe 03";24667831;Anesthesiology;"Carles M, Wagener BM, Lafargue M, Roux J, Iles K, Liu D, Rodriguez CA, Anjum N, Zmijewski J, Ricci JE, Pittet JF";;"Jun 2014";1401580800;;"The heat-shock response (HSR) protects from insults, such as ischemia-reperfusion injury, by inhibiting signaling pathways activated by sterile inflammation. However, the mechanisms by which the HSR activation would modulate lung damage and host response to a bacterial lung infection remain unknown." 5798;"Caloric restriction and cancer: molecular mechanisms and clinical implications.";"JE. Ricci";"Equipe 03";24916302;"Trends in molecular medicine";"Meynet O, Ricci JE";;"Aug 2014";1406851200;;"Caloric restriction (CR) is currently the most robust environmental intervention known to increase healthy life and prolong lifespan in several models, from yeast to mice. Although the protective effect of CR on the incidence of cancer is well established, its impact on tumor cell responses to chemotherapeutic treatment is currently being investigated. Interestingly, the molecular mechanisms required to extend lifespan upon reduced food intake are being evaluated, and these mechanisms may offer new opportunities for therapeutic intervention. In addition, new findings suggest a beneficial effect of CR in enhancing the efficiency of tumor cell killing by chemotherapeutic drugs and inducing an anticancer immune response. " 5796;"Glucose metabolism is inhibited by caspases upon the induction of apoptosis.";"JE. Ricci, S. Marchetti";"Equipe 03, Team 03";25188516;"Cell death & disease";"Pradelli LA, Villa E, Zunino B, Marchetti S, Ricci JE";;"Sep 2014";1409529600;;"Rapidly proliferating cells, such as cancer cells, have adopted aerobic glycolysis rather than oxidative phosphorylation to supply their energy demand; this phenomenon is known as 'the Warburg effect'. It is now widely accepted that during apoptosis the loss of energy production, orchestrated by caspases, contributes to the dismantling of the dying cell. However, how this loss of energy production occurs is still only partially known. In the present work, we established that during apoptosis the level of cellular ATP decreased in a caspase-dependent manner. We demonstrated that this decrease in ATP content was independent of any caspase modification of glucose uptake, ATP consumption or reactive oxygen species production but was dependent on a caspase-dependent inhibition of glycolysis. We found that the activity of the two glycolysis-limiting enzymes, phosphofructokinase and pyruvate kinase, were affected by caspases, whereas the activity of phosphoglycerate kinase was not, suggesting specificity of the effect. Finally, using a metabolomic analysis, we observed that caspases led to a decrease in several key metabolites, including phosphoserine, which is a major regulator of pyruvate kinase muscle isozyme activity. Thus, we have established that during apoptosis, caspases can shut down the main energy production pathway in cancer cells, leading to the impairment in the activity of the two enzymes controlling limiting steps of glycolysis. " 5794;"Hyperthermic intraperitoneal chemotherapy leads to an anticancer immune response via exposure of cell surface heat shock protein 90.";"JE. Ricci, J. Chiche";"Equipe 03, Team 03";25867070;Oncogene;"Zunino B, Rubio-Patiño C, Villa E, Meynet O, Proics E, Cornille A, Pommier S, Mondragón L, Chiche J, Bereder JM, Carles M, Ricci JE";;"Jan 2016";1451606400;;"The occurrence of peritoneal carcinomatosis is a major cause of treatment failure in colorectal cancer and is considered incurable. However, new therapeutic approaches have been proposed, including cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Although HIPEC has been effective in selected patients, it is not known how HIPEC prolongs a patient's lifespan. Here, we have demonstrated that HIPEC-treated tumor cells induce the activation of tumor-specific T cells and lead to vaccination against tumor cells in mice. We have established that this effect results from the HIPEC-mediated exposure of heat shock protein (HSP) 90 at the plasma membrane. Inhibition or blocking of HSP90, but not HSP70, prevented the HIPEC-mediated antitumoral vaccination. Our work raises the possibility that the HIPEC procedure not only kills tumor cells but also induces an efficient anticancer immune response, therefore opening new opportunities for cancer treatment. " 5792;"Consensus guidelines for the detection of immunogenic cell death.";"JE. Ricci";"Equipe 03";25941621;Oncoimmunology;"Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, Apetoh L, Aranda F, Barnaba V, Bloy N, Bracci L, Breckpot K, Brough D, Buqué A, Castro MG, Cirone M, Colombo MI, Cremer I, Demaria S, Dini L, Eliopoulos AG, Faggioni A, Formenti SC, Fučíková J, Gabriele L, Gaipl US, Galon J, Garg A, Ghiringhelli F, Giese NA, Guo ZS, Hemminki A, Herrmann M, Hodge JW, Holdenrieder S, Honeychurch J, Hu HM, Huang X, Illidge TM, Kono K, Korbelik M, Krysko DV, Loi S, Lowenstein PR, Lugli E, Ma Y, Madeo F, Manfredi AA, Martins I, Mavilio D, Menger L, Merendino N, Michaud M, Mignot G, Mossman KL, Multhoff G, Oehler R, Palombo F, Panaretakis T, Pol J, Proietti E, Ricci JE, Riganti C, Rovere-Querini P, Rubartelli A, Sistigu A, Smyth MJ, Sonnemann J, Spisek R, Stagg J, Sukkurwala AQ, Tartour E, Thorburn A, Thorne SH, Vandenabeele P, Velotti F, Workenhe ST, Yang H, Zong WX, Zitvogel L, Kroemer G, Galluzzi L";;"Oct 2014";1412121600;;"Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named ""immunogenic cell death"" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine." 5790;"NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis.";"JE. Ricci, S. Marchetti";"Equipe 03, Team 03";26045047;"Cell death and differentiation";"Boutaffala L, Bertrand MJ, Remouchamps C, Seleznik G, Reisinger F, Janas M, Bénézech C, Fernandes MT, Marchetti S, Mair F, Ganeff C, Hupalowska A, Ricci JE, Becher B, Piette J, Knolle P, Caamano J, Vandenabeele P, Heikenwalder M, Dejardin E";;"Dec 2015";1448928000;;"NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex. In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway. " 5788;"How does metabolism affect cell death in cancer?";"JE. Ricci";"Equipe 03";26498911;"The FEBS journal";"Villa E, Ricci JE";;"07 2016";1467331200;;"In cancer research, identifying a specificity of tumor cells compared with 'normal' proliferating cells for targeted therapy is often considered the Holy Grail for researchers and clinicians. Although diverse in origin, most cancer cells share characteristics including the ability to escape cell death mechanisms and the utilization of different methods of energy production. In the current paradigm, aerobic glycolysis is considered the central metabolic characteristic of cancer cells (Warburg effect). However, recent data indicate that cancer cells also show significant changes in other metabolic pathways. Indeed, it was recently suggested that Kreb's cycle, pentose phosphate pathway intermediates, and essential and nonessential amino acids have key roles. Renewed interest in the fact that cancer cells have to reprogram their metabolism in order to proliferate or resist treatment must take into consideration the ability of tumor cells to adapt their metabolism to the local microenvironment (low oxygen, low nutrients). This variety of metabolic sources might be either a strength, resulting in infinite possibilities for adaptation and increased ability to resist chemotherapy-induced death, or a weakness that could be targeted to kill cancer cells. Here, we discuss recent insights showing how energetic metabolism may regulate cell death and how this might be relevant for cancer treatment." 5786;"Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death.";"JE. Ricci";"Equipe 03";26635802;"Frontiers in immunology";"Garg AD, Galluzzi L, Apetoh L, Baert T, Birge RB, Bravo-San Pedro JM, Breckpot K, Brough D, Chaurio R, Cirone M, Coosemans A, Coulie PG, De Ruysscher D, Dini L, de Witte P, Dudek-Peric AM, Faggioni A, Fucikova J, Gaipl US, Golab J, Gougeon ML, Hamblin MR, Hemminki A, Herrmann M, Hodge JW, Kepp O, Kroemer G, Krysko DV, Land WG, Madeo F, Manfredi AA, Mattarollo SR, Maueroder C, Merendino N, Multhoff G, Pabst T, Ricci JE, Riganti C, Romano E, Rufo N, Smyth MJ, Sonnemann J, Spisek R, Stagg J, Vacchelli E, Vandenabeele P, Vandenberk L, Van den Eynde BJ, Van Gool S, Velotti F, Zitvogel L, Agostinis P";;"Jan 2015";1420070400;;"The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called ""damage-associated molecular patterns"" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation. " 5784;"CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.";"JE. Ricci";"Equipe 03";26666268;"EMBO molecular medicine";"Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M, Ortega-Vila B, Fragaki K, Lespinasse F, Pinero-Martos E, Augé G, Moore D, Burté F, Lacas-Gervais S, Kageyama Y, Itoh K, Yu-Wai-Man P, Sesaki H, Ricci JE, Vives-Bauza C, Paquis-Flucklinger V";;"Jan 2016";1451606400;;"CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the ""mitochondrial contact site and cristae organizing system"" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release. " 5782;"Inactivation of Pif1 helicase causes a mitochondrial myopathy in mice.";"JE. Ricci";"Equipe 03";26923168;Mitochondrion;"Bannwarth S, Berg-Alonso L, Augé G, Fragaki K, Kolesar JE, Lespinasse F, Lacas-Gervais S, Burel-Vandenbos F, Villa E, Belmonte F, Michiels JF, Ricci JE, Gherardi R, Harrington L, Kaufman BA, Paquis-Flucklinger V";;"09 2016";1472688000;;"Mutations in genes coding for mitochondrial helicases such as TWINKLE and DNA2 are involved in mitochondrial myopathies with mtDNA instability in both human and mouse. We show that inactivation of Pif1, a third member of the mitochondrial helicase family, causes a similar phenotype in mouse. pif1-/- animals develop a mitochondrial myopathy with respiratory chain deficiency. Pif1 inactivation is responsible for a deficiency to repair oxidative stress-induced mtDNA damage in mouse embryonic fibroblasts that is improved by complementation with mitochondrial isoform mPif1(67). These results open new perspectives for the exploration of patients with mtDNA instability disorders." 5780;"Hyperthermic intra-peritoneal chemotherapy and anticancer immune response.";"JE. Ricci";"Equipe 03";26942072;Oncoimmunology;"Zunino B, Ricci JE";;"Jan 2016";1451606400;;"Peritoneal carcinomatosis (PC) is a metastatic disease of primary tumors localized in the abdomen. Although this disease is considered a terminal condition, recent treatments combining surgery with heated intra-peritoneal chemotherapy (HIPEC) significantly increase patient survival. We have determined that the protective effect of HIPEC is partially linked to the induction of an efficient anticancer immune response." 5778;"Differentiation inducing factor 3 mediates its anti-leukemic effect through ROS-dependent DRP1-mediated mitochondrial fission and induction of caspase-independent cell death.";"A. Jacquel, G. Robert, JE. Ricci, P. Auberger, S. Marchetti, T. Cluzeau";"Equipe 02, Team 02, Equipe 03, Team 03";27027430;Oncotarget;"Dubois A, Ginet C, Furstoss N, Belaid A, Hamouda MA, El Manaa W, Cluzeau T, Marchetti S, Ricci JE, Jacquel A, Luciano F, Driowya M, Benhida R, Auberger P, Robert G";;"May 2016";1462060800;;"Differentiation-inducing factor (DIF) defines a group of chlorinated hexaphenones that orchestrate stalk-cell differentiation in the slime mold Dictyostelium discoideum (DD). DIF-1 and 3 have also been reported to have tumor inhibiting properties; however, the mechanisms that underlie the effects of these compounds remain poorly defined. Herein, we show that DIF-3 rapidly triggers Ca2+ release and a loss of mitochondrial membrane potential (MMP) in the absence of cytochrome c and Smac release and without caspase activation. Consistently with these findings, we also detected no evidence of apoptosis in cells treated with DIF-3 but instead found that this compound induced autophagy. In addition, DIF-3 promoted mitochondrial fission in K562 and HeLa cells, as assessed by electron and confocal microscopy analysis. Importantly, DIF-3 mediated the phosphorylation and redistribution of dynamin-related protein 1 (DRP1) from the cytoplasmic to the microsomal fraction of K562 cells. Pharmacological inhibition or siRNA silencing of DRP1 not only inhibited mitochondrial fission but also protected K562 cells from DIF-3-mediated cell death. Furthermore, DIF-3 potently inhibited the growth of imatinib-sensitive and imatinib-resistant K562 cells. It also inhibited tumor formation in athymic mice engrafted with an imatinib-resistant CML cell line. Finally, DIF-3 exhibited a clear selectivity toward CD34+ leukemic cells from CML patients, compared with CD34- cells. In conclusion, we show that the potent anti-leukemic effect of DIF-3 is mediated through the induction of mitochondrial fission and caspase-independent cell death. Our findings may have important therapeutic implications, especially in the treatment of tumors that exhibit defects in apoptosis regulation. " 5776;"Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics.";"E. Verhoeyen, F. BOST, JE. Ricci, J. Chiche";"Team 03, Equipe 03";27689327;Oncotarget;"Rubio-Patiño C, Bossowski JP, Villa E, Mondragón L, Zunino B, Proïcs E, Chiche J, Bost F, Verhoeyen E, Ricci JE";;"11 2016";1477958400;;"Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food. Indeed, feeding lymphoma-bearing mice with a diet having 25% less carbohydrates was sufficient to decrease Mcl-1 expression by 50% in lymphoma cells. We showed that a low CHO diet resulted in AMPK activation and mTOR inhibition leading to eukaryotic elongation factor 2 (eEF2) inhibition, blocking protein translation elongation. Strikingly, a low CHO diet was sufficient to sensitize Myc-driven lymphoma-bearing mice to ABT-737-induced cell death in vivo. Thus reducing carbohydrate intake may represent a safe way to decrease Mcl-1 expression and to sensitize tumor cells to anti-cancer therapeutics." 5774;"Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency.";"JE. Ricci";"Equipe 03";28846096;"Nature cell biology";"Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proïcs E, Rubio-Patiño C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H, Albert ML, Milling S, Oberst A, Ricci JE, Ryan KM, Blyth K, Tait SWG";;"Sep 2017";1504224000;;"Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies." 5772;"Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells.";"E. Verhoeyen, JE. Ricci, J. Chiche, S. Marchetti";"Team 03, Equipe 03";28930681;"Cell reports";"Villa E, Proïcs E, Rubio-Patiño C, Obba S, Zunino B, Bossowski JP, Rozier RM, Chiche J, Mondragón L, Riley JS, Marchetti S, Verhoeyen E, Tait SWG, Ricci JE";;"Sep 2017";1504224000;;"Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance." 5770;"Regulation of tumor-stroma interactions by the unfolded protein response.";"JE. Ricci";"Equipe 03";29239107;"The FEBS journal";"Obacz J, Avril T, Rubio-Patiño C, Bossowski JP, Igbaria A, Ricci JE, Chevet E";;"01 2019";1546300800;;"The unfolded protein response (UPR) is a conserved adaptive pathway that helps cells cope with the protein misfolding burden within the endoplasmic reticulum (ER). Imbalance between protein folding demand and capacity in the ER leads to a situation called ER stress that is often observed in highly proliferative and secretory tumor cells. As such, activation of the UPR signaling has emerged as a key adaptive mechanism promoting cancer progression. It is becoming widely acknowledged that, in addition to its intrinsic effect on tumor biology, the UPR can also regulate tumor microenvironment. In this review, we discuss how the UPR coordinates the crosstalk between tumor and stromal cells, such as endothelial cells, normal parenchymal cells, and immune cells. In addition, we further describe the involvement of ER stress signaling in the response to current treatments as well as its impact on antitumor immunity mainly driven by immunogenic cell death. Finally, in this context, we discuss the relevance of targeting ER stress/UPR signaling as a potential anticancer approach." 5768;"The oncogenic tyrosine kinase Lyn impairs the pro-apoptotic function of Bim.";"A. Jacquel, G. Robert, JE. Ricci, P. Auberger, S. Marchetti";"Equipe 02, Team 02, Equipe 03, Team 03";29391601;Oncogene;"Aira LE, Villa E, Colosetti P, Gamas P, Signetti L, Obba S, Proics E, Gautier F, Bailly-Maitre B, Jacquel A, Robert G, Luciano F, Juin PP, Ricci JE, Auberger P, Marchetti S";;"04 2018";1522540800;;"Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptotic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim. In the present study, we show that Bim is phosphorylated onto tyrosine residues 92 and 161 by Lyn, which results in an inhibition of its pro-apoptotic function. Mechanistically, we show that Lyn-dependent tyrosine phosphorylation of Bim increases its interaction with anti-apoptotic members such as Bcl-xL, therefore limiting mitochondrial outer membrane permeabilization and subsequent apoptosis. Collectively, our data uncover one molecular mechanism through which the oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptotic pathway, which may contribute to the transformation and/or the chemotherapeutic resistance of cancer cells." 5764;"Reshaping the Immune Tumor Microenvironment Through IRE1 Signaling.";"JE. Ricci";"Equipe 03";29804923;"Trends in molecular medicine";"Rubio-Patiño C, Bossowski JP, Chevet E, Ricci JE";;"07 2018";1530403200;;"The ability of a tumor cell to cope with environmental and intracellular stress depends on its capacity to activate appropriate adaptive pathways. As such, the endoplasmic reticulum (ER) adjusts the adaptive capacity of tumor cells by engaging the unfolded protein response (UPR). The UPR maintains the functionality of the secretory pathway, thereby allowing tumor cells to shape their microenvironment, thus likely determining the nature of the tumor immune response. Consequently, this makes the UPR very relevant in the context of cancer therapeutics. We focus here on inositol-requiring enzyme 1α (IRE1) and compile novel molecular mechanisms demonstrating that tumoral UPR controls the tumor microenvironment (TME) and the immune response, therefore opening potential novel therapeutic avenues." 5762;"Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases.";"JE. Ricci";"Equipe 03";30092269;"Neurobiology of disease";"Genin EC, Bannwarth S, Lespinasse F, Ortega-Vila B, Fragaki K, Itoh K, Villa E, Lacas-Gervais S, Jokela M, Auranen M, Ylikallio E, Mauri-Crouzet A, Tyynismaa H, Vihola A, Augé G, Cochaud C, Sesaki H, Ricci JE, Udd B, Vives-Bauza C, Paquis-Flucklinger V";;"11 2018";1541030400;;"Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10 mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10 allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10 allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease." 5760;"No Parkin Zone: Mitophagy without Parkin.";"JE. Ricci, S. Marchetti";"Equipe 03, Team 03";30115557;"Trends in cell biology";"Villa E, Marchetti S, Ricci JE";;"11 2018";1541030400;;"Mitochondria are essential highly dynamic organelles that provide the necessary energy for a variety of different processes, such as survival, proliferation, and migration. In order to maintain an intact mitochondrial network, cells have developed quality control systems that allow the removal of damaged or superfluous mitochondria by selective mitochondrial autophagy called mitophagy. Although the parkin/PINK1 axis is often considered the main regulator of mitophagy, a growing body of evidence has shown that this pathway is not unique and that mitophagy can still be functional in the absence of parkin. Here, we will review recent literature describing parkin-independent mitophagy and its role in various physiopathological conditions, therefore representing potential new targets to treat diseases affected by dysregulated mitophagy." 5758;"Metabolic Reprogramming of Non-Hodgkin's B-Cell Lymphomas and Potential Therapeutic Strategies.";"JE. Ricci, J. Chiche";"Equipe 03, Team 03";30564554;"Frontiers in oncology";"Ricci JE, Chiche J";;"Jan 2018";1514764800;;"Metabolism is a wide and general term that refers to any intracellular pathways the cell utilizes in order to satisfy its energetic demand and to support cell viability and/or division. Along with phenotypic changes, all mammalian cells including immune cells modulate their metabolic program in order to reach their effector functions. Exacerbated metabolism and metabolic flexibility are also hallmarks of tumor initiation and of tumor cell progression in a complex tumor microenvironment. Metabolic reprogramming is mainly directed by the serine/threonine kinase mTOR (mammalian target of rapamycin). mTOR exists in two structurally and functionally distinct complexes, mTORC1 and mTORC2 that coordinate environmental signals and metabolic/anabolic pathways to provide macromolecules and energy needed for survival and growth. Activation of mTORC1 is required during development, differentiation and activation of immune cells. Aberrant and persistent activation of mTORC1 is often observed in malignant B cells such as Non-Hodgkin's (NH) B-cell lymphomas. Here, we review recent insights on cell metabolism and on basic mechanisms of mTORC1 regulation and metabolic functions. We highlight the distinct mechanisms driving mTORC1 activation in the three most-common types of NH B-cell lymphomas (Diffuse Large B Cell Lymphomas, Follicular Lymphomas, and Mantle Cell Lymphomas), for which the first generation of mTORC1 inhibitors (rapalogs) have been extensively evaluated in preclinical and clinical settings. Finally, we discuss the reasons for limited clinical success of this therapy and focus on potential therapeutic strategies targeting metabolic pathways, upstream and downstream of mTORC1, that can be combined to rapalogs in order to improve patient's outcome." 5754;"GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors.";"E. Verhoeyen, JE. Ricci, J. Chiche, S. Marchetti";"Team 03, Equipe 03";30827861;"Cell metabolism";"Chiche J, Reverso-Meinietti J, Mouchotte A, Rubio-Patiño C, Mhaidly R, Villa E, Bossowski JP, Proics E, Grima-Reyes M, Paquet A, Fragaki K, Marchetti S, Briere J, Ambrosetti D, Michiels JF, Molina TJ, Copie-Bergman C, Lehmann-Che J, Peyrottes I, Peyrade F, de Kerviler E, Taillan B, Garnier G, Verhoeyen E, Paquis-Flucklinger V, Shintu L, Delwail V, Delpech-Debiais C, Delarue R, Bosly A, Petrella T, Brisou G, Nadel B, Barbry P, Mounier N, Thieblemont C, Ricci JE";;"06 2019";1559347200;;"Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH B cells and improve GAPDH B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH B cell lymphomas. Ultimately, we selected four GAPDH DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors." 5752;"Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10 mouse.";"JE. Ricci";"Equipe 03";30874923;"Acta neuropathologica";"Genin EC, Madji Hounoum B, Bannwarth S, Fragaki K, Lacas-Gervais S, Mauri-Crouzet A, Lespinasse F, Neveu J, Ropert B, Augé G, Cochaud C, Lefebvre-Omar C, Bigou S, Chiot A, Mochel F, Boillée S, Lobsiger CS, Bohl D, Ricci JE, Paquis-Flucklinger V";;"07 2019";1561939200;;"Recently, we provided genetic basis showing that mitochondrial dysfunction can trigger motor neuron degeneration, through identification of CHCHD10 encoding a mitochondrial protein. We reported patients, carrying the p.Ser59Leu heterozygous mutation in CHCHD10, from a large family with a mitochondrial myopathy associated with motor neuron disease (MND). Rapidly, our group and others reported CHCHD10 mutations in amyotrophic lateral sclerosis (ALS), frontotemporal dementia-ALS and other neurodegenerative diseases. Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family. Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy. CHCHD10 mice also displayed neuromuscular junction (NMJ) and motor neuron degeneration with hyper-fragmentation of the motor end plate and moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease. At this stage, we observed TDP-43 cytoplasmic aggregates in spinal neurons. We also showed that motor neurons differentiated from human iPSC carrying the p.Ser59Leu mutation were much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells. These data confirm that mitochondrial deficiency associated with CHCHD10 mutations can be at the origin of MND. CHCHD10 is highly expressed in the NMJ post-synaptic part. Importantly, the fragmentation of the motor end plate was associated with abnormal CHCHD10 expression that was also observed closed to NMJs which were morphologically normal. Furthermore, we found OXPHOS deficiency in muscle of CHCHD10 mice at 3 months of age in the absence of neuron loss in spinal cord. Our data show that the pathological effects of the p.Ser59Leu mutation target muscle prior to NMJ and motor neurons. They likely lead to OXPHOS deficiency, loss of cristae junctions and destabilization of internal membrane structure within mitochondria at motor end plate of NMJ, impairing neurotransmission. These data are in favor with a key role for muscle in MND associated with CHCHD10 mutations." 5750;"Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells.";"JE. Ricci, S. Marchetti";"Equipe 03, Team 03";32312819;"Proceedings of the National Academy of Sciences of the United States of America";"Püschel F, Favaro F, Redondo-Pedraza J, Lucendo E, Iurlaro R, Marchetti S, Majem B, Eldering E, Nadal E, Ricci JE, Chevet E, Muñoz-Pinedo C";;"05 2020";1588291200;;"Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation." 5748;"New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP.";"E. Verhoeyen, JE. Ricci";"Equipe 03, Team 03";32796826;Oncogenesis;"Mhaidly R, Krug A, Gaulard P, Lemonnier F, Ricci JE, Verhoeyen E";;"Aug 2020";1596240000;;"Mouse models are essential to study and comprehend normal and malignant hematopoiesis. The ideal preclinical model should mimic closely the human malignancy. This means that these mice should recapitulate the clinical behavior of the human diseases such as cancer and therapeutic responses with high reproducibility. In addition, the genetic mutational status, the cell phenotype, the microenvironment of the tumor and the time until tumor development occurs, should be mimicked in a preclinical model. This has been particularly challenging for human angioimmunoblastic lymphoma (AITL), one of the most prominent forms of peripheral T-cell lymphomas. A complex network of interactions between AITL tumor cells and the various cells of the tumor microenvironment has impeded the study of AITL pathogenesis in vitro. Very recently, new mouse models that recapitulate faithfully the major features of human AITL disease have been developed. Here, we provide a summary of the pathology, the transcriptional profile and genetic and immune-phenotypic features of human AITL. In addition, we give an overview of preclinical models that recapitulate more or less faithfully human AITL characteristics and pathology. These recently engineered mouse models were essential in the evaluation of novel therapeutic agents for possible treatment of AITL, a malignancy in urgent need of new treatment options." 5746;"The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway.";"JE. Ricci";"Equipe 03";33288741;"Cell death & disease";"Villa E, Paul R, Meynet O, Volturo S, Pinna G, Ricci JE";;"12 2020";1606780800;;"Escape from cell death is a key event in cancer establishment/progression. While apoptosis is often considered as the main cell death pathway, upon caspase inhibition, cell death is rather delayed than blocked leading to caspase-independent cell death (CICD). Although described for years, CICD's underlying mechanism remains to be identified. Here, we performed a genome-wide siRNA lethality screening and identified the RING-Type E3 Ubiquitin Transferase (UBR2) as a specific regulator of CICD. Strikingly, UBR2 downregulation sensitized cells towards CICD while its overexpression was protective. We established that UBR2-dependent protection from CICD was mediated by the MAPK/Erk pathway. We then observed that UBR2 is overexpressed in several cancers, especially in breast cancers and contributes to CICD resistance. Therefore, our work defines UBR2 as a novel regulator of CICD, found overexpressed in cancer cells, suggesting that its targeting may represent an innovative way to kill tumor cells." 5744;"Pharmacological preconditioning protects from ischemia/reperfusion-induced apoptosis by modulating Bcl-xL expression through a ROS-dependent mechanism.";"E. Verhoeyen, JE. Ricci, J. Chiche, S. Marchetti";"Team 03, Equipe 03";33340237;"The FEBS journal";"Rozier R, Paul R, Madji Hounoum B, Villa E, Mhaidly R, Chiche J, Verhoeyen E, Marchetti S, Vandenberghe A, Raucoules M, Carles M, Ricci JE";;"06 2021";1622505600;;"Myocardial ischemia/reperfusion (I/R) injury is a frequent perioperative threat, with numerous strategies developed to limit and/or prevent it. One interesting axis of research is the anesthetic preconditioning (APc) agent's hypothesis (such as sevoflurane, SEV). However, APc's mode of action is still poorly understood and volatile anesthetics used as preconditioning agents are often not well suited in clinical practice. Here, in vitro using H9C2 cells lines (in myeloblast state or differentiated toward cardiomyocytes) and in vivo in mice, we identified that SEV-induced APc is mediated by a mild induction of reactive oxygen species (ROS) that activates Akt and induces the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL), therefore protecting cardiomyocytes from I/R-induced death. Furthermore, we extended these results to human cardiomyocytes (derived from induced pluripotent stem - IPS - cells). Importantly, we demonstrated that this protective signaling pathway induced by SEV could be stimulated using the antidiabetic agent metformin (MET), suggesting the preconditioning properties of MET. Altogether, our study identified a signaling pathway allowing APc of cardiac injuries as well as a rational for the use of MET as a pharmacological preconditioning agent to prevent I/R injuries." 5740;"Physiological impact of in vivo stable isotope tracing on cancer metabolism.";"JE. Ricci, J. Chiche";"Equipe 03, Team 03";34256164;"Molecular metabolism";"Grima-Reyes M, Martinez-Turtos A, Abramovich I, Gottlieb E, Chiche J, Ricci JE";;"11 2021";1635724800;;"There is growing interest in the analysis of tumor metabolism to identify cancer-specific metabolic vulnerabilities and therapeutic targets. Finding of such candidate metabolic pathways mainly relies on the highly sensitive identification and quantitation of numerous metabolites and metabolic fluxes using metabolomics and isotope tracing analyses. However, nutritional requirements and metabolic routes used by cancer cells cultivated in vitro do not always reflect the metabolic demands of malignant cells within the tumor milieu. Therefore, to understand how the metabolism of tumor cells in its physiological environment differs from that of normal cells, these analyses must be performed in vivo." 5738;"EVT-701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti-tumor activity in models of solid cancers.";"JE. Ricci, J. Chiche";"Equipe 03, Team 03";34478236;"Pharmacology research & perspectives";"Luna Yolba R, Visentin V, Hervé C, Chiche J, Ricci JE, Méneyrol J, Paillasse MR, Alet N";;"10 2021";1633046400;;"Targeting the first protein complex of the mitochondrial electron transport chain (MC1) in cancer has become an attractive therapeutic approach in the recent years, given the metabolic vulnerabilities of cancer cells. The anticancer effect exerted by the pleiotropic drug metformin and the associated reduction in hypoxia-inducible factor 1α (HIF-1α) levels putatively mediated by MC1 inhibition led to the development of HIF-1α inhibitors, such as BAY87-2243, with a more specific MC1 targeting. However, the development of BAY87-2243 was stopped early in phase 1 due to dose-independent emesis and thus there is still no clinical proof of concept for the approach. Given the importance of mitochondrial metabolism during cancer progression, there is still a strong therapeutic need to develop specific and safe MC1 inhibitors. We recently reported the synthesis of compounds with a novel chemotype and potent action on HIF-1α degradation and MC1 inhibition. We describe here the selectivity, safety profile and anti-cancer activity in solid tumors of lead compound EVT-701. In addition, using murine models of lung cancer and of Non-Hodgkin's B cell lymphoma we demonstrated that EVT-701 reduced tumor growth and lymph node invasion when used as a single agent therapy. LKB1 deficiency in lung cancer was identified as a potential indicator of accrued sensitivity to EVT-701, allowing stratification and selection of patients in clinical trials. Altogether these results support further evaluation of EVT-701 alone or in combination in preclinical models and eventually in patients." 5736;"The prohibitin-binding compound fluorizoline inhibits mitophagy in cancer cells.";"JE. Ricci, S. Marchetti";"Equipe 03, Team 03";34580273;Oncogenesis;"Núñez-Vázquez S, Saura-Esteller J, Sánchez-Vera I, Guilbaud E, Cosialls AM, Pons G, Ricci JE, Iglesias-Serret D, Marchetti S, Gil J";;"Sep 2021";1630454400;;"Fluorizoline is a prohibitin-binding compound that triggers apoptosis in several cell lines from murine and human origin, as well as in primary cells from hematologic malignancies by inducing the integrated stress response and ER stress. Recently, it was described that PHB (Prohibitin) 1 and 2 are crucial mitophagy receptors involved in mediating the autophagic degradation of mitochondria. We measured mitophagy in HeLa cells expressing Parkin and in A549, a lung cancer cell line that can undergo mitophagy in a Parkin-independent manner, and we demonstrated that both fluorizoline and rocaglamide A, another PHB-binding molecule, inhibit CCCP- and OA-induced mitophagy. Moreover, we demonstrated that PHBs are mediating Parkin-dependent mitophagy. In conclusion, besides being a potent pro-apoptotic compound, we present fluorizoline as a promising new mitophagy modulator that could be used as anticancer agent." 5659;"Liver Transcriptome Dynamics During Hibernation Are Shaped by a Shifting Balance Between Transcription and RNA Stability.";"J. Jager";"Equipe 07, Team 07";34093224;"Frontiers in physiology";"Gillen AE, Fu R, Riemondy KA, Jager J, Fang B, Lazar MA, Martin SL";;"Jan 2021";1609459200;;"Hibernators dramatically lower metabolism to save energy while fasting for months. Prolonged fasting challenges metabolic homeostasis, yet small-bodied hibernators emerge each spring ready to resume all aspects of active life, including immediate reproduction. The liver is the body's metabolic hub, processing and detoxifying macromolecules to provide essential fuels to brain, muscle and other organs throughout the body. Here we quantify changes in liver gene expression across several distinct physiological states of hibernation in 13-lined ground squirrels, using RNA-seq to measure the steady-state transcriptome and GRO-seq to measure transcription for the first time in a hibernator. Our data capture key timepoints in both the seasonal and torpor-arousal cycles of hibernation. Strong positive correlation between transcription and the transcriptome indicates that transcriptional control dominates the known seasonal reprogramming of metabolic gene expression in liver for hibernation. During the torpor-arousal cycle, however, discordance develops between transcription and the steady-state transcriptome by at least two mechanisms: 1) although not transcribed during torpor, some transcripts are unusually stable across the torpor bout; and 2) unexpectedly, on some genes, our data suggest continuing, slow elongation with a failure to terminate transcription across the torpor bout. While the steady-state RNAs corresponding to these read through transcripts did not increase during torpor, they did increase shortly after rewarming despite their simultaneously low transcription. Both of these mechanisms would assure the immediate availability of functional transcripts upon rewarming. Integration of transcriptional, post-transcriptional and RNA stability control mechanisms, all demonstrated in these data, likely initiate a serial gene expression program across the short euthermic period that restores the tissue and prepares the animal for the next bout of torpor." 5657;"Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity.";"J. Jager";"Equipe 07, Team 07";34425095;Gastroenterology;"Azzimato V, Chen P, Barreby E, Morgantini C, Levi L, Vankova A, Jager J, Sulen A, Diotallevi M, Shen JX, Miller A, Ellis E, Rydén M, Näslund E, Thorell A, Lauschke VM, Channon KM, Crabtree MJ, Haschemi A, Craige SM, Mori M, Spallotta F, Aouadi M";;"12 2021";1638316800;;"Oxidative stress plays a key role in the development of metabolic complications associated with obesity, including insulin resistance and the most common chronic liver disease worldwide, nonalcoholic fatty liver disease. We have recently discovered that the microRNA miR-144 regulates protein levels of the master mediator of the antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2). On miR-144 silencing, the expression of NRF2 target genes was significantly upregulated, suggesting that miR-144 controls NRF2 at the level of both protein expression and activity. Here we explored a mechanism whereby hepatic miR-144 inhibited NRF2 activity upon obesity via the regulation of the tricarboxylic acid (TCA) metabolite, fumarate, a potent activator of NRF2." 5655;"Identification of adipocytes as target cells for Leishmania infantum parasites.";"G. MICHEL, J. Jager";"Equipe 06, Team 06, Equipe 07, Team 07";34711872;"Scientific reports";"Schwing A, Pisani DF, Pomares C, Majoor A, Lacas-Gervais S, Jager J, Lemichez E, Marty P, Boyer L, Michel G";;"Oct 2021";1633046400;;"Leishmania infantum is the causative agent of visceral leishmaniasis transmitted by the bite of female sand flies. According to the WHO, the estimated annual incidence of leishmaniasis is one million new cases, resulting in 30,000 deaths per year. The recommended drugs for treating leishmaniasis include Amphotericin B. But over the course of the years, several cases of relapses have been documented. These relapses cast doubt on the efficiency of actual treatments and raise the question of potential persistence sites. Indeed, Leishmania has the ability to persist in humans for long periods of time and even after successful treatment. Several potential persistence sites have already been identified and named as safe targets. As adipose tissue has been proposed as a sanctuary of persistence for several pathogens, we investigated whether Leishmania infantum could be found in this tissue. We demonstrated both in cell cultures and in vivo that Leishmania infantum was able to infect adipocytes. Altogether our results suggest adipocytes as a 'safe target' for Leishmania infantum parasites." 5537;"[Recombinant activated factor VII in paediatric practice. Universal hemostatic agent?].";"J. BENADIBA";"Equipe 04, Team 04";20598867;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Monpoux F, Chambost H, Haouy S, Benadiba J, Sirvent N";;"Aug 2010";1280620800;;"NovoSeven (eptacog alfa [activated]) is a concentrate of recombinant activated factor VII currently indicated in 3 types of situation: (1) hemorrhagic syndromes in patients with acquired haemophilia or constitutional A or B haemophilia with inhibitor; (2) Glanzmann thrombasthenia in patients with ineffective platelet transfusion due to alloimmunization; (3) constitutional factor VII deficiency. NovoSeven is also used, off label, in a very large number of bleeding conditions or bleeding risk especially in adult's trauma; abdominal, cardiac or chest surgery; gastroenterology; gynaecology and obstetrics or haematology. In these situations and sometimes in the context of randomized trials, against placebo studies, a large number of publications are reported, with variable scientific value according to evidence-based proofs. Studies conducted in children are far fewer and most of them did not achieve a high-level of evidence. However, we wanted to write a synthesis of the paediatric experience reported in the literature. Whereas it is important to build on work done in adults published data, the conclusions drawn from them are not perfectly applicable in paediatric practice. This bibliographical work is not an accurate guide of recommendations but should allow everyone to get an idea of situations where the use of this drug should or might be considered." 5535;"[Activated partial thromboplastin time prolongation in paediatrics. Retrospective monocentric study at the Nice University Hospital].";"J. BENADIBA";"Equipe 04, Team 04";20822861;Pathologie-biologie;"Benadiba J, Monpoux F, Appert-Flory A, Fischer F, Sirvent N";;"Dec 2011";1322697600;;"The study of hemostasis often arises in paediatrics. Evidence of activated partial thromboplastin time (aPTT) prolongation sometime due to the presence of a circulating anticoagulant (antiphospholipid syndrome [APS]) may be embarrassing for the physician." 5533;"Health status and quality of life of long-term survivors of childhood acute leukemia: the impact of central nervous system irradiation.";"J. BENADIBA, M. POIREE";"Equipe 04, Team 04";24936742;"Journal of pediatric hematology/oncology";"Benadiba J, Michel G, Auquier P, Chastagner P, Kanold J, Poirée M, Plantaz D, Padovani L, Berbis J, Barlogis V, Contet A, Chambost H, Sirvent N";;"Mar 2015";1425168000;;"We evaluated the impact of central nervous system irradiation (CNSI) on long-term health status and quality of life (QoL) of childhood lymphoblastic leukemia survivors included in the French L.E.A. (Childhood and Adolescent Leukemia) multicentric cohort. QoL was self-reported in adults and assessed by parents in children and adolescents, using adapted questionnaires. From 2004 to 2009, 630 nongrafted patients were assessed after 11.8±6.3 years from diagnosis. Patients receiving CNSI (18.6%) or chemotherapy alone (81.4%) were compared. The risk of having long-term physical effects was increased with CNSI (odds ratio=3.3; 95% confidence interval, 1.8-5.9), especially regarding growth failure, second tumor, cataract, and overweight. QoL did not differ significantly according to the treatment received, despite a tendency toward lower scores with CNSI in children and adolescents (summary score 63.6±13.3 vs. 71.7±12.4, P=0.14). Compared with French norms, adult survivors had an impaired QoL, especially in mental domains (mental composite score 45.2±9.8 vs. 47.9±2.1, P<0.001). In pediatric survivors, QoL was not impaired and even tended to be higher than population norms (summary score 71.7±12.4 vs. 70.0±4.2, P=0.054), mainly in social and relational domains. In conclusion, QoL seems to be impaired by the trauma of a life-threatening illness in childhood, as well as by the treatment received." 5531;"Pharmacokinetics-adapted Busulfan-based myeloablative conditioning before unrelated umbilical cord blood transplantation for myeloid malignancies in children.";"J. BENADIBA";"Equipe 04, Team 04";29608607;"PloS one";"Benadiba J, Ansari M, Krajinovic M, Vachon MF, Duval M, Teira P, Cellot S, Bittencourt H";;"Jan 2018";1514764800;;"Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT." 5529;"Thrombopoietin receptor agonists as an emergency treatment for severe newly diagnosed immune thrombocytopenia in children.";"J. BENADIBA";"Equipe 04, Team 04";33410895;Blood;"Nolla M, Aladjidi N, Leblanc T, Fernandes H, Ducassou S, Fahd M, Barlogis V, Michel M, Blouin P, Jeziorski E, Benadiba J, Pondarre C, Leverger G, Pasquet M";;"01 2021";1609459200;; 5527;"Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.";"J. BENADIBA";"Equipe 04, Team 04";33440924;Haematologica;"Pincez T, Fernandes H, Leblanc T, Michel G, Barlogis V, Bertrand Y, Neven B, Chahla WA, Pasquet M, Guitton C, Marie-Cardine A, Pellier I, Armari-Alla C, Benadiba J, Blouin P, Jeziorski E, Millot F, Paillard C, Thomas C, Cheikh N, Bayart S, Fouyssac F, Piguet C, Deparis M, Briandet C, Dore E, Picard C, Rieux-Laucat F, Landman-Parker J, Leverger G, Aladjidi N";;"Jan 2021";1609459200;;"Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IMs). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 (6.8-50.0) years and the median follow-up period was 11.3 (5.1-38.0) years. At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio, 1.4; 95% confidence interval, 1.15-1.60; p = 0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 (1.7-31.5) years, and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup." 5525;"Effect of Child Position on Pain Experience During Lumbar Puncture: A Prospective Pilot Study.";"J. BENADIBA, M. POIREE";"Equipe 04, Team 04";34224519;"Journal of pediatric hematology/oncology";"Chavanes P, Benadiba J, Caci H, Poirée M";;"Jul 2021";1625097600;;"This study aimed to evaluate the impact of patient's position on pain and anxiety during lumbar puncture (LP)." 5522;"Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia.";"M. POIREE";"Team 04, Equipe 04";21278355;Blood;"Oudin C, Simeoni MC, Sirvent N, Contet A, Begu-Le Coroller A, Bordigoni P, Curtillet C, Poirée M, Thuret I, Play B, Massot MC, Chastagner P, Chambost H, Auquier P, Michel G";;"Apr 2011";1301616000;;"We evaluate the prevalence and risk factors of the metabolic syndrome (MS) in young adults surviving childhood leukemia. During the years 2007 to 2008, assessment of MS was proposed to all adults included in the Leucémie de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of leukemia survivors. Among 220 eligible patients, 184 (83.6%) had complete evaluation. Median age at evaluation and follow-up duration were 21.2 and 15.4 years. Overall prevalence of MS was 9.2% (95% confidence interval, 5.5-14.4). There was no association of MS with sex, age at diagnosis, leukemia subtype, steroid therapy, and central nervous system irradiation. Patients were stratified according to 4 therapeutic modalities: chemotherapy alone (n = 97), chemotherapy and central nervous system irradiation (n = 27), hematopoietic stem cell transplantation (HSCT) without (n = 17) or with (n = 43) total body irradiation (TBI). MS occurred in 5.2%, 11.1%, 5.9%, and 18.6% of them, respectively. The higher risk observed in the HSCT-TBI group was significant in univariate and in multivariate analysis (odds ratio [OR] = 3.9, P = .03). HSCT with TBI was associated with a higher rate of hypertriglyceridemia (OR = 4.5, P = .004), low level of high-density lipoprotein cholesterol (OR = 2.5, P = .02), and elevated fasting glucose (OR = 6.1, P = .04) So, TBI is a major risk factor for MS. Further studies are warranted to explain this feature." 5520;"ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.";"M. POIREE";"Team 04, Equipe 04";22071890;"European journal of human genetics : EJHG";"Bourdeaut F, Ferrand S, Brugières L, Hilbert M, Ribeiro A, Lacroix L, Bénard J, Combaret V, Michon J, Valteau-Couanet D, Isidor B, Rialland X, Poirée M, Defachelles AS, Peuchmaur M, Schleiermacher G, Pierron G, Gauthier-Villars M, Janoueix-Lerosey I, Delattre O, ";;"Mar 2012";1330560000;;"Neuroblastic tumours may occur in a predisposition context. Two main genes are involved: PHOX2B, observed in familial cases and frequently associated with other neurocristopathies (Ondine's and Hirschsprung's disease); and ALK, mostly in familial tumours. We have assessed the frequency of mutations of these two genes in patients with a presumable higher risk of predisposition. We sequenced both genes in 26 perinatal cases (prebirth and <1 month of age, among which 10 were multifocal), 16 multifocal postnatal (>1 month) cases, 3 pairs of affected relatives and 8 patients with multiple malignancies. The whole coding sequences of the two genes were analysed in tumour and/or constitutional DNAs. We found three ALK germline mutations, all in a context of multifocal tumours. Two mutations (T1151R and R1192P) were inherited and shared by several unaffected patients, thus illustrating an incomplete penetrance. Younger age at tumour onset did not seem to offer a relevant selection criterion for ALK analyses. Conversely, multifocal tumours might be the most to benefit from the genetic screening. Finally, no PHOX2B germline mutation was found in this series. In conclusion, ALK deleterious mutations are rare events in patients with a high probability of predisposition. Other predisposing genes remain to be discovered." 5516;"Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood.";"M. POIREE";"Team 04, Equipe 04";23645686;Haematologica;"Girard P, Auquier P, Barlogis V, Contet A, Poiree M, Demeocq F, Berbis J, Herrmann I, Villes V, Sirvent N, Kanold J, Chastagner P, Chambost H, Plantaz D, Michel G";;"Jul 2013";1372636800;;"Corticosteroid can induce osteonecrosis in children with leukemia. Few studies have been designed to assess the influence of a wide range of cumulative steroid dose on this side effect. Prevalence, risk factors of symptomatic osteonecrosis and its impact on adults' Quality of Life were assessed in 943 patients enrolled in the French ""Leucémies de l'Enfant et de l'Adolescent"" (LEA) cohort of childhood leukemia survivors. During each medical visit, data on previous osteonecrosis diagnosis were retrospectively collected. Patients without a history but with suggestive symptoms were investigated with magnetic resonance imaging. The total steroid dose in equivalent of prednisone was calculated for each patient and its effect on osteonecrosis occurrence was studied in multivariate models. Cumulative incidence was 1.4% after chemotherapy alone versus 6.8% after transplantation (P<0.001). A higher cumulative steroid dose, age over ten years at diagnosis, and treatment with transplantation significantly increased the risk of osteonecrosis. A higher post-transplant steroid dose and age over ten years at time of transplantation were significant factors in the transplanted group. With patients grouped according to steroid dose quartile, cumulative incidence of osteonecrosis reached 3.8% in the chemotherapy group for a dose beyond 5835 mg/m(2) and 23.8% after transplantation for a post-transplant dose higher than 2055 mg/m(2). Mean physical composite score of Quality of Life was 44.3 in patients with osteonecrosis versus 54.8% in patients without (P<0.001). We conclude that total and post-transplant cumulative steroid dose may predict the risk of osteonecrosis, a rare late effect with a strong negative impact on physical domains of Quality of Life." 5514;"Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study.";"M. POIREE";"Team 04, Equipe 04";24116693;"British journal of haematology";"Alloin AL, Barlogis V, Auquier P, Contet A, Poiree M, Demeocq F, Herrmann I, Villes V, Bertrand Y, Plantaz D, Kanold J, Chastagner P, Chambost H, Sirvent N, Michel G";;"Jan 2014";1388534400;;"Corticosteroid and central nervous system (CNS) irradiation can induce cataract in childhood lymphoblastic leukaemia survivors. Few prospective studies with systematic ophthalmological evaluation have been published. Cataract was prospectively assessed by serial slip lamp tests in 517 patients. All had acute lymphoblastic leukaemia, all had been treated by chemotherapy with or without CNS irradiation, and none had received haematopoietic stem cell transplantation. Median ages at last evaluation and follow-up duration from leukaemia diagnosis were 16·8 and 10·9 years, respectively. Cataract was observed in 21/517 patients (4·1%). Cumulative incidence was 4·5 ± 1·2% at 15 years and reached 26 ± 8·1% at 25 years. CNS irradiation was the only risk factor: prevalence was 11·1% in patients who had received irradiation and 2·8% in those who did not. We did not detect any steroid dose effect: cumulative dose was 5133 and 5190 mg/m(2) in patients with and without cataract, respectively. Cataract occurrence did not significantly impact quality of life. We conclude that, in the range of steroid dose reported here, the cataract risk proves very low 15 years after treatment without CNS irradiation but an even more prolonged follow-up is required because of potential very late occurrence." 5512;"Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study.";"M. POIREE";"Team 04, Equipe 04";25284463;"British journal of haematology";"Horwitz M, Auquier P, Barlogis V, Contet A, Poiree M, Kanold J, Bertrand Y, Plantaz D, Galambrun C, Berbis J, Villes V, Chastagner P, Sirvent N, Oudin C, Michel G";;"Feb 2015";1422748800;;"Cataract was prospectively assessed by serial slip lamp tests in 271 patients included in the Leucémie Enfants Adolescents (LEA) programme, the French cohort of childhood leukaemia survivors. All had received haematopoietic stem cell transplantation (HSCT) after total body irradiation (TBI, n = 201) or busulfan-based (n = 70) myeloablative conditioning regimen. TBI was fractionated in all but six patients. The mean duration of follow-up from HSCT was 10·3 years. Cataract was observed in 113/271 patients (41·7%); 9/113 (8·1%) needed surgery. Cumulative incidence after TBI increased over time from 30% at 5 years to 70·8% and 78% at 15 and 20 years, respectively, without any plateau thereafter. The 15-year cumulative incidence was 12·5% in the Busulfan group. A higher cumulative steroid dose appeared to be a cofactor of TBI for cataract risk, in both univariate and multivariate Cox analysis. In the multivariate analysis, cataract had an impact in two quality of life domains: 'the role limitation due to physical problems' and 'the role limitation due to emotional problems'. These data suggest that with increasing follow-up, nearly all patients who receive TBI, even when fractionated, will suffer from cataract that can impact on their quality of life and that high cumulative steroid dose is a cofactor." 5510;"Late cardiomyopathy in childhood acute myeloid leukemia survivors: a study from the L.E.A. program.";"M. POIREE";"Team 04, Equipe 04";25616572;Haematologica;"Barlogis V, Auquier P, Bertrand Y, Chastagner P, Plantaz D, Poiree M, Kanold J, Berbis J, Oudin C, Vercasson C, Allouche M, Tabone MD, Thouvenin-Doulet S, Saumet L, Chambost H, Baruchel A, Leverger G, Michel G";;"May 2015";1430438400;; 5508;"[Long term follow-up after chilhood cancer].";"M. POIREE";"Team 04, Equipe 04";25638871;"La Revue du praticien";"Plantaz D, Tabone MD, Berger C, Poirée M, Ducassou S, Michel G";;"Nov 2014";1414800000;;"Five year survival rates among childhood cancer rose to 80%. Relapses are rare after five years of remission. Long term follow-up should also detect treatment related late adverse effects. Repeated cardiac evaluations are necessary, due to cumulative dose dependent cardiotoxicity of anthracycline. Endocrinological disorders and problems of fertility are mainly related to radiotherapy or high dose chemotherapy. Bone mineral density can be altered. Cognitive function, academic level and social outcome of irradiated patients and patients treated for cerebral tumors should be closely assessed and helped. Second neoplasms related to previous treatments may occur. One of the major on going treatment objective is to preserve the quality of life of cured patients, and to improve their information in the framework of a shared-care model involving the general practionner, the adult medicine specialists and the oncologic pediatric centre." 5506;"Late thyroid complications in survivors of childhood acute leukemia. An L.E.A. study.";"M. POIREE";"Team 04, Equipe 04";26969082;Haematologica;"Oudin C, Auquier P, Bertrand Y, Chastagner P, Kanold J, Poirée M, Thouvenin S, Ducassou S, Plantaz D, Tabone MD, Dalle JH, Gandemer V, Lutz P, Sirvent A, Villes V, Barlogis V, Baruchel A, Leverger G, Berbis J, Michel G";;"06 2016";1464739200;;"Thyroid complications are known side effects of irradiation. However, the risk of such complications in childhood acute leukemia survivors who received either central nervous system irradiation or hematopoietic stem cell transplantation is less described. We prospectively evaluated the incidence and risk factors for thyroid dysfunction and tumors in survivors of childhood acute myeloid or lymphoid leukemia. A total of 588 patients were evaluated for thyroid function, and 502 individuals were assessed for thyroid tumors (median follow-up duration: 12.6 and 12.5 years, respectively). The cumulative incidence of hypothyroidism was 17.3% (95% CI: 14.1-21.1) and 24.6% (95% CI: 20.4-29.6) at 10 and 20 years from leukemia diagnosis, respectively. Patients who received total body irradiation (with or without prior central nervous system irradiation) were at higher risk of hypothyroidism (adjusted HR: 2.87; P=0.04 and 2.79, P=0.01, respectively) as compared with transplanted patients who never received any irradiation. Patients transplanted without total body irradiation who received central nervous system irradiation were also at higher risk (adjusted HR: 3.39; P=0.02). Patients irradiated or transplanted at older than 10 years of age had a lower risk (adjusted HR: 0.61; P=0.02). Thyroid malignancy was found in 26 patients (5.2%). Among them, two patients had never received any type of irradiation: alkylating agents could also promote thyroid cancer. The cumulative incidence of thyroid malignancy was 9.6% (95% CI: 6.0-15.0) at 20 years. Women were at higher risk than men (adjusted HR: 4.74; P=0.002). In conclusion, thyroid complications are frequent among patients who undergo transplantation after total body irradiation and those who received prior central nervous system irradiation. Close monitoring is thus warranted for these patients. Clinicaltrials.gov identifier: NCT 01756599." 5504;"The Impact of Donor Type on Long-Term Health Status and Quality of Life after Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Leukemia: A Leucémie de l'Enfant et de L'Adolescent Study.";"M. POIREE";"Team 04, Equipe 04";27522039;"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation";"Visentin S, Auquier P, Bertrand Y, Baruchel A, Tabone MD, Pochon C, Jubert C, Poirée M, Gandemer V, Sirvent A, Bonneau J, Paillard C, Freycon C, Kanold J, Villes V, Berbis J, Oudin C, Galambrun C, Pellier I, Plat G, Chambost H, Leverger G, Dalle JH, Michel G";;"11 2016";1477958400;;"We compared the long-term impact of donor type (sibling donor [SD] versus matched unrelated donor [MUD] or umbilical cord blood [UCB]) on late side effects and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic stem cell transplantation. We included 314 patients who underwent transplantation from 1997 to 2012 and were enrolled in the multicenter French Leucémie de l'Enfant et de L'Adolescent (""Leukemia in Children and Adolescents"") cohort. More than one-third of the patients were adults at last visit; mean follow-up duration was 6.2 years. At least 1 late effect was observed in 284 of 314 patients (90.4%). The average number of adverse late effects was 2.1 ± .1, 2.4 ± .2, and 2.4 ± .2 after SD, MUD, and UCB transplantation, respectively. In a multivariate analysis, considering the SD group as the reference, we did not detect an impact of donor type for most sequelae, with the exception of increased risk of major growth failure after MUD transplantation (odds ratio [OR], 2.42) and elevated risk of osteonecrosis after UCB transplantation (OR, 4.15). The adults and children's parents reported comparable QoL among the 3 groups. Adult patient QoL scores were lower than age- and sex-matched French reference scores for almost all dimensions. We conclude that although these patients are heavily burdened by long-term complications, donor type had a very limited impact on their long-term health status and QoL." 5502;"Prolonged standard native asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951.";"M. POIREE, PS. ROHRLICH";"Team 04, Equipe 04";28751566;Haematologica;"Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poirée M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cavé H, Rohrlich P, Bertrand Y, Benoit Y, ";;"10 2017";1506816000;;"Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) standard (short-asparaginase) native asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native asparaginase were switched to equivalent doses of or pegylated asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; =0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; =0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; =0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2% 14.4%) and late intensification (22.6% 15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30% 21%). Prolonged native asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy." 5500;"Adolescence and Socioeconomic Factors: Key Factors in the Long-Term Impact of Leukemia on Scholastic Performance-A LEA Study.";"M. POIREE";"Team 04, Equipe 04";30442413;"The Journal of pediatrics";"Bonneau J, Berbis J, Michel G, Vercasson C, Bertrand Y, Ansoborlo S, Dalle JH, Baruchel A, Tabone MD, Paillard C, Contet A, Poirée M, Sirvent N, Thouvenin S, Kanold J, Freycon C, Saultier P, Auquier P, Gandemer V";;"02 2019";1548979200;;"To evaluate the association between medical and social environmental factors and the risk of repeating a grade in childhood leukemia survivors." 5498;"EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome.";"M. POIREE";"Team 04, Equipe 04";31151987;Blood;"Tan S, Kermasson L, Hoslin A, Jaako P, Faille A, Acevedo-Arozena A, Lengline E, Ranta D, Poirée M, Fenneteau O, Ducou le Pointe H, Fumagalli S, Beaupain B, Nitschké P, Bôle-Feysot C, de Villartay JP, Bellanné-Chantelot C, Donadieu J, Kannengiesser C, Warren AJ, Revy P";;"07 2019";1561939200;;"Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation." 5496;"Disorder of sex development with germ cell tumors: Which is uncovered first?";"M. POIREE";"Team 04, Equipe 04";32020769;"Pediatric blood & cancer";"Faure-Conter C, Orbach D, Fresneau B, Verité C, Bonneau J, Thebaud E, Poirée M, Thouvenin S, Pluchart C, Mure PY, Dijoud F, Morel Y";;"04 2020";1585699200;;"Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of DSD discovery." 5494;"Quality of life in parents of childhood leukemia survivors. A French Childhood Cancer Survivor Study for Leukemia study.";"M. POIREE";"Team 04, Equipe 04";32798263;"Pediatric blood & cancer";"Vercasson C, Auquier P, Michel G, Bertrand Y, Ansoborlo S, Tabone MD, Leverger G, Gandemer V, Baruchel A, Contet A, Dalle JH, Paillard C, Poirée M, Thouvenin-Doulet S, Sirvent N, Kanold J, Freycon C, Hamidou Z, Berbis J";;"10 2020";1601510400;;"Our objectives were to assess the quality of life (QoL) of parents of childhood leukemia survivors compared with population norms and to identify the determinants of parents' long-term QoL." 5492;"Impact of COVID-19 on cancer care: A survey from the French Society of Pediatric Oncology (SFCE).";"M. POIREE";"Team 04, Equipe 04";32893961;"Pediatric blood & cancer";"Rouger-Gaudichon J, Gariazzo L, Thébault E, Brethon B, Fenwarth L, Gambart M, Alimi A, Réguerre Y, Piguet C, Jubert C, Gouache E, Thébaud E, Plantaz D, Paillard C, Raimbault S, Haouy S, Schneider P, Phulpin A, Mallebranche C, Dubrasquet M, de Berranger E, Devoldere C, Laithier V, Poirée M, Thouvenin S, Carausu L, Dupraz C, Bouttefroy S, André N, Gandemer V";;"01 2021";1609459200;; 5490;"Tolerance induction to deferasirox in a child with transfusion-dependent beta thalassemia.";"M. POIREE";"Team 04, Equipe 04";33250331;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Pondrom M, Monpoux F, Rocher F, Gastaut N, Bailly-Piccini C, Poirée M";;"Nov 2020";1606694400;;"Beta thalassemias are autosomal recessive hemoglobin disorders related to a defect in the beta-globin chain production. Most of the major forms of beta-thalassemia are transfusion dependent leading to iron overload. Today, three iron chelators are available in France. We report the case of a patient suffering from β major transfusion-dependent thalassemia who presented with severe skin reactions to deferoxamine and deferasirox as well as with agranulocytosis after deferiprone administration. The patient benefited from successful tolerance induction to deferasirox. With the increasing number of children suffering from iron overload, we believe that our protocol can be useful to pediatric hematology teams confronted with multiple iron chelator reactions." 5488;"Invasive Fungal Infections in Immunocompromised Children: Novel Insight Following a National Study.";"M. POIREE";"Team 04, Equipe 04";33991540;"The Journal of pediatrics";"Olivier-Gougenheim L, Rama N, Dupont D, Saultier P, Leverger G, AbouChahla W, Paillard C, Gandemer V, Theron A, Freycon C, Pluchart C, Blouin P, Pellier I, Thouvenin-Doulet S, Desplantes C, Ducassou S, Oudot C, Rouger-Gaudichon J, Cheikh N, Poiree M, Schneider P, Plat G, Contet A, Rialland F, Gouache E, Brethon B, Bertrand Y, Domenech C";;"Sep 2021";1630454400;;"To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT)." 5483;"Four-color flow cytometry bypasses limitations of IG/TCR polymerase chain reaction for minimal residual disease detection in certain subsets of children with acute lymphoblastic leukemia.";"PS. ROHRLICH";"Equipe 04, Team 04";16266899;Haematologica;"Robillard N, Cavé H, Méchinaud F, Guidal C, Garnache-Ottou F, Rohrlich PS, Avet-Loiseau H, Garand R";;"Nov 2005";1130803200;;"Competitive immunoglobulin/T-cell receptor polymerase-chain reaction (PCR) analysis with fluorescent detection is a rapid, cheap and reproducible method for quantifying minimal residual disease (MRD), which is well adapted to the recognition of high-risk childhood acute lymphoblastic leukemia (ALL). We aimed at defining whether flow cytometry (FC) techniques can bypass limitations of PCR for MRD determination." 5481;"[HFE, a MHC class Ib molecule that regulates iron metabolism].";"PS. ROHRLICH";"Equipe 04, Team 04";16386215;"Medecine sciences : M/S";"Rohrlich PS, Kanellopoulos J, Lemonnier FA";;"Jan 2006";1136073600;; 5475;"Comparative analysis of the CD8(+) T cell repertoires of H-2 class I wild-type/HLA-A2.1 and H-2 class I knockout/HLA-A2.1 transgenic mice.";"PS. ROHRLICH";"Equipe 04, Team 04";12147629;"International immunology";"Firat H, Cochet M, Rohrlich PS, Garcia-Pons F, Darche S, Danos O, Lemonnier FA, Langlade-Demoyen P";;"Aug 2002";1028160000;;"HHD transgenic mice which express HLA-A2.1 monochain molecules in a H-2 class I(-) context have an improved capacity to develop HLA-A2.1-restricted cytotoxic T lymphocyte (CTL) responses as compared with classical A2.1/K(b) transgenic mice, which express heterodimeric HLA-A2.1 molecules in a H-2 class I wild-type context. A detailed TCR analysis of HLA-A2.1-restricted CD8(+) T cells educated and mobilized in both strains of mice was undertaken. Focusing on TCR beta chains, comparative PCR analysis of naive and immune CD8(+) T cell repertoires were performed. In spite of lower cell surface expression of HLA class I molecules and lower overall number of CD8(+) T cells, HHD mice educate a qualitatively normally diversified CD8(+) T cell repertoire and mobilize a larger variety of CD8(+) T cells in response to HLA-A2.1-restricted antigens compared with A2.1/K(b) mice. These observations provide the molecular bases accounting for the fact that HHD mice represent the most versatile animal model currently available for preclinical studies of HLA-A2.1-restricted CTL responses." 5476;"Heparin stimulates fibroblasts growth induced by platelet derived growth factor.";"PS. ROHRLICH";"Equipe 04, Team 04";3135121;"Cell biology international reports";"Dupuy E, Rohrlich PS, Tobelem G";;"Jan 1988";567993600;;"We have demonstrated that 125I unfractionated heparin binds to cultured human skin fibroblasts with a Kd of 1.16 10(-8) M and is internalized partly. A low molecular weight heparin fraction (PK 10169) competed (50%) with 125I unfractionated heparin, but to a lesser extent than cold unfractionated heparin (90%). When the cell proliferation was induced by pure PDGF, heparin markedly potentiated the fibroblast growth. Similar stimulation was observed when the growth was induced by FGF or EGF. Low molecular weight heparin enhanced the fibroblast proliferation induced by PDGF but to a lesser extent than unfractionated heparin. Chondroitin sulfate has no effect. PDGF did not modify the heparin binding on fibroblast cultures either at 4 degrees C or 37 degrees C and did not alter the process of heparin internalization. PDGF binding to the cultured fibroblast (Kd 10.1 +/- 3.4 10(-10) M) was not modified by the presence of heparin when studied at 4 degrees C or 37 degrees C." 5473;"Tmevpg1, a candidate gene for the control of Theiler's virus persistence, could be implicated in the regulation of gamma interferon.";"PS. ROHRLICH";"Equipe 04, Team 04";12719555;"Journal of virology";"Vigneau S, Rohrlich PS, Brahic M, Bureau JF";;"May 2003";1051747200;;"The Tmevp3 locus controls the load of Theiler's virus RNA during persistent infection of the mouse central nervous system (CNS). We identified a candidate gene at this locus, Tmevpg1, by using a positional cloning approach. Tmevpg1 and its human ortholog, TMEVPG1, are expressed in the immune system and encode what appears to be a noncoding RNA. They are located in a cluster of cytokine genes that includes the genes for gamma interferon and one or two homolog of interleukin-10. We now report that Tmevpg1 is expressed in CNS-infiltrating immune cells of resistant B10.S mice, but not in those of susceptible SJL/J mice, following inoculation with Theiler's virus. The pattern of expression of Tmevpg1 is the same in B10.S mice and in SJL/J mice congenic for the resistant B10.S haplotype of Tmevp3. Nineteen polymorphisms were identified when the Tmevpg1 genes of B10.S and SJL/J mice were compared. Interestingly, Tmevpg1 is down regulated after in vitro stimulation of murine CD4(+) or CD8(+) splenocytes, whereas Ifng is up regulated. Similar patterns of expression of TMEVPG1 and IFNG were observed in human NK cells and CD4(+) and CD8(+) T lymphocytes. Therefore, Tmevpg1 is a strong candidate gene for the Tmevp3 locus and may be involved in the control of Ifng gene expression." 5471;"HLA-B*0702 transgenic, H-2KbDb double-knockout mice: phenotypical and functional characterization in response to influenza virus.";"PS. ROHRLICH";"Equipe 04, Team 04";12750360;"International immunology";"Rohrlich PS, Cardinaud S, Firat H, Lamari M, Briand P, Escriou N, Lemonnier FA";;"Jun 2003";1054425600;;"HLA-B*0702 transgenic mice (expressing a chimeric heavy chain with a murine alpha 3 domain: HLA-B7(m alpha 3)) in which the H-2K(b) and H-2D(b) class I-a (Cl I-a(-/-)) genes have been inactivated were compared with H-2K(b)D(b) Cl I-a(+/+) positive controls. Expression of the HLA-B7(m alpha 3) molecules resulted in a 3- to 4-fold increase in peripheral CD8(+) T lymphocyte numbers compared to H-2 Cl I-a(-/-) knockout mice. These cells show a diversified TCR repertoire. Following influenza infection, a significant improvement in HLA-B0702-restricted cytotoxic T lymphocyte (CTL) responses was observed in HLA-B7(m alpha 3), H-2 Cl I-a(-/-) compared to HLA-B7(m alpha 3), H-2 Cl I-a(+/+) mice. The CTL response of infected HLA-B7(m alpha 3), H-2 Cl I-a(-/-) mice was directed against the nucleoprotein (NP) 418-426 epitope in which mutations have accumulated. Whereas all NP 418-426 variant peptides induced a CTL response, cross-reactivity to the variants was affected. These NP mutations could have been selected over time in humans for the virus to escape HLA-B0702-restricted CTL responses since a similar response was seen in humans with, as in mice, altered cross-recognition of the NP 418-426 variants. These animals may prove a suitable model to study HLA-B0702-restricted CTL responses." 5469;"Identification of cryptic MHC I-restricted epitopes encoded by HIV-1 alternative reading frames.";"PS. ROHRLICH";"Equipe 04, Team 04";15078897;"The Journal of experimental medicine";"Cardinaud S, Moris A, Février M, Rohrlich PS, Weiss L, Langlade-Demoyen P, Lemonnier FA, Schwartz O, Habel A";;"Apr 2004";1080777600;;"Human immunodeficiency virus (HIV) 1 major histocompatibility complex (MHC) I-restricted epitopes are widely believed to be derived from viral proteins encoded by primary open reading frames. However, the HIV-1 genome contains alternative reading frames (ARFs) potentially encoding small polypeptides. We have identified a panel of epitopes encoded by ARFs within the gag, pol, and env genes. The corresponding epitopic peptides were immunogenic in mice humanized for MHC-I molecules. In addition, cytotoxic T lymphocytes recognizing these epitopes were found in HIV-infected patients. These results reveal the existence of atypical mechanisms of HIV-1 epitope generation. They indicate that the repertoire of epitopes recognized by the cellular anti-HIV-1 immune response is broader than initially thought. This should be taken into account when designing vaccine strategies aimed at activating these responses." 5467;"Peripheral T-cell expansion and low infection rate after reduced-intensity conditioning and allogeneic blood stem cell transplantation.";"PS. ROHRLICH";"Equipe 04, Team 04";15765116;"Bone marrow transplantation";"Larosa F, Marmier C, Robinet E, Ferrand C, Saas P, Deconinck E, Bulabois CE, Rohrlich PS, Ledu K, Helias P, Tiberghien P, Cahn JY";;"May 2005";1114905600;;"Peripheral blood stem cell transplantation after reduced-intensity conditioning (RIC-PBSCT) regimen is an alternative to conventional regimens with less immediate toxicity. Since immune recovery is of crucial importance for the control of infections, we retrospectively studied the recovery of T-, B- and NK cell subsets in 20 consecutive patients undergoing RIC-PBSCT. We also studied the thymic output using T-cell receptor excision circle assay. Engraftment was rapid and few infectious complications were seen: three early (before 2.5 months) cases of asymptomatic cytomegalovirus reactivation, two late Gram-negative bacterial infections and no fungal infection. While CD4+ T-cell reconstitution was slow, CD8+ T-cell counts were close to normal values at 4 months. Median CD19+ B-cell counts reached normal values at 11 months. Rapid CD56+ NK cell reconstitution was noticed as early as 1.5 months. Low T-cell receptor excision circle numbers and preponderance of memory-type subsets among T cells further suggested that CD8+ T-cell reconstitution resulted predominantly from peripheral expansion and that thymic-dependent reconstitution was severely impaired. In conclusion, large peripheral T-cell expansion may compensate for late thymic-dependent lymphopoiesis, and may, with other factors such as NK and B-cell reconstitution and careful antiinfectious prophylaxis, help limit the incidence of severe infections after RIC-PBSCT." 5465;"Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function.";"PS. ROHRLICH";"Equipe 04, Team 04";16123136;"Proceedings of the National Academy of Sciences of the United States of America";"Rohrlich PS, Fazilleau N, Ginhoux F, Firat H, Michel F, Cochet M, Laham N, Roth MP, Pascolo S, Nato F, Coppin H, Charneau P, Danos O, Acuto O, Ehrlich R, Kanellopoulos J, Lemonnier FA";;"Sep 2005";1125532800;;"Crystallographic analysis of human Hfe has documented an overall structure similar to classical (class Ia) MHC molecules with a peptide binding groove deprived of ligand. Thus, to address the question of whether alphabeta T cells could recognize MHC molecules independently of bound ligands, we studied human and mouse Hfe interactions with T lymphocytes. We provide formal evidence of direct cytolytic recognition of human Hfe by mouse alphabeta T cell receptors (TCR) in HLA-A*0201 transgenic mice and that this interaction results in ZAP-70 phosphorylation. Furthermore, direct recognition of mouse Hfe molecules by cytotoxic T lymphocytes (CTLs) was demonstrated in DBA/2 Hfe knockout mice. These CTLs express predominantly two T cell antigen receptor alpha variable gene segments (AV6.1 and AV6.6). Interestingly, in wild-type mice we identified a subset of CD8+ T cells positively selected by Hfe that expresses the AV6.1/AV6.6 gene segments. T cell antigen receptor recognition of MHC molecules independently of bound ligand has potential general implications in alloreactivity and identifies in the Hfe case a cognitive link supporting the concept that the immune system could be involved in the control of iron metabolism." 5463;"[Involvement of thyroid gland at non-Hodgkin lymphoma initial diagnosis: 2 pediatric cases].";"PS. ROHRLICH";"Equipe 04, Team 04";16271453;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Frache S, Peter MO, Laithier V, Bertrand AM, Thiriez G, Menget A, Kantelip B, Yakouben K, Plouvier E, Rohrlich PS";;"Jan 2006";1136073600;;"Extranodal thyroid lymphomatous involvement is rare in childhood. We report here 2 children, 1 with vertical transmission-acquired human immunodeficiency virus (HIV), presenting with lymphomatous infiltration of the thyroid gland at diagnosis. One child had infra-clinical endocrine impairment and both responded well to chemotherapy. Although the cases are too scarce to be affirmative, thyroid gland involvement doesn't seem to alter the good prognosis of childhood Burkitt's lymphoma. The third child's cancer in frequency is Non-Hodgkin Lymphomas. Presenting as the initial AIDS event in 1 patient, this case report also highlights the need to systematically propose antiretroviral therapy in vertically HIV infected children." 5461;"[Superior mesenteric artery syndrome: a cause of vomiting in children. Report of 3 cases].";"PS. ROHRLICH";"Equipe 04, Team 04";16359849;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Galli G, Aubert D, Rohrlich P, Kamdem AF, Bawab F, Sarlieve P";;"Feb 2006";1138752000;;"Duodenal obstruction by Superior Mesenteric Artery (SMA) is a misdiagnosed vomiting syndrome in children. Several factors are involved, including rapid weight loss, rapid statural growth without weight augmentation. Diagnosis is suspected when an improvement is achieved by ventral decubitus and it is confirmed by plain films of the abdomen, GI study with barium and echography, measuring the aortomesenteric angle (inferior to 25-30 degrees ). Patients must at first be treated conservatively. Surgery is indicated for occlusive episodes with unsuccessful conservative therapy. The authors report 3 cases with different clinical presentation. However, all the patients presented important weight loss and vomiting." 5457;"Natural killer cells prevent CD28-mediated Foxp3 transcription in CD4+CD25- T lymphocytes.";"PS. ROHRLICH";"Equipe 04, Team 04";17309822;"Experimental hematology";"Brillard E, Pallandre JR, Chalmers D, Ryffel B, Radlovic A, Seilles E, Rohrlich PS, Pivot X, Tiberghien P, Saas P, Borg C";;"Mar 2007";1172707200;;"CD4(+)CD25(+) regulatory T lymphocytes (Treg) have been initially shown to prevent organ-specific autoimmunity. It is now accepted that Treg homeostasis depends in part on the peripheral conversion of naïve CD4(+)CD25(-) T cells. This conversion implicates acquisition of the Treg-specific markers, forkhead winged helix protein 3 (Foxp3), after CD28 costimulation. Because natural killer cells (NK) are critical for efficient cytotoxic T-cell priming and TH1 polarization, we investigated their role in Foxp3 induction in CD4(+) T lymphocytes." 5458;"Optimized vaccination regimen linked to exhaustive screening approaches identifies 2 novel HLA-B7 restricted epitopes within hepatitis C virus NS3 protein.";"PS. ROHRLICH";"Equipe 04, Team 04";16859951;"Microbes and infection";"Martin P, Parroche P, Pajot A, Chatel L, Barreto C, Touat L, Dubois V, Rohrlich PS, Bain C, Trépo C, Negro F, Inchauspé G, Fournillier A";;"Aug 2006";1154390400;;"Broad immune responses, in particular specific for the NS3 protein and mediated by both CD8+ and CD4+T lymphocytes, are thought to play a critical role in the control of hepatitis C virus (HCV) infection. In this study, we searched for novel HLA-B*0702 NS3 restricted epitopes following an optimized NS3NS4 immunization protocol in transgenic mice expressing HLA-B*0702 molecule. Combining predicted and overlapping peptides, we identified two novel epitopes, WPA10 (aa 1111-1120) and LSP10 (aa 1153-1162), which triggered significant IFN-gamma-producing T cell frequencies and high CTL responses. Both epitopes were shown to be immunogenic when used as synthetic peptides to immunize mice. The relevance of these epitopes to humans was demonstrated, as both were able in vitro to recall specific IFN-gamma and IL10-producing cells from peripheral blood mononuclear cells of HCV infected patients. Such epitopes enlarge the pool of NS3-specific CD8+T cell epitopes available to perform immunomonitoring of HCV infection and to develop vaccines." 5455;"Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation: implications in graft-versus-host disease and antitumor immunity.";"PS. ROHRLICH";"Equipe 04, Team 04";18025205;"Journal of immunology (Baltimore, Md. : 1950)";"Pallandre JR, Brillard E, Créhange G, Radlovic A, Remy-Martin JP, Saas P, Rohrlich PS, Pivot X, Ling X, Tiberghien P, Borg C";;"Dec 2007";1196467200;;"Immunological tolerance is maintained by specialized subsets of T cells including CD4(+)CD25(+)FOXP3(+) regulatory cells (Treg). Previous studies established that Treg thymic differentiation or peripheral conversion depend on CD28 and Lck signaling. Moreover, foxp3 gene transfer in murine CD4(+)CD25(-) T lymphocytes results in the acquisition of suppressive functions. However, molecular pathways leading to FOXP3 expression remain to be described. In this study, we investigated the molecular events driving FOXP3 expression. We demonstrated that CD28 activation in CD4(+)CD25(-) T lymphocytes leads to STAT3 Tyr(705) phosphorylation in an Lck-dependent manner. STAT3 neutralization during naive peripheral CD4(+)CD25(-) T cell conversion into Treg through costimulation with TCR/CD28 and TGF-beta1, decreased FOXP3 expression, prevented the acquisition of suppressive functions and restored the ability of the converted lymphocytes to produce IL-2 and IFN-gamma. Furthermore, we observed that STAT3 ablation using small interfering RNA strategies inhibited FOXP3 expression and suppressive functions among naturally differentiated CD4(+)CD25(+) T lymphocytes, suggesting a direct role of STAT3 in Treg phenotype and function maintenance. CD4(+)CD25(+) T lymphocytes transduced with specific STAT3 small interfering RNA were devoid of suppressive functions and failed to control the occurrence of acute graft-vs-host disease. Finally, STAT3 inhibition in CD4(+) lymphocytes enhanced the anti-tumor immunity conferred by a lymphocyte adoptive transfer. In summary, our findings determine that STAT3 is critical in the molecular pathway required for FOXP3 expression. STAT3 modulation should be taken into account when assessing how regulatory T cells contribute to inflammatory diseases and tumor immunosurveillance." 5453;"Adjuvant corticosteroid therapy for chronic disseminated candidiasis.";"PS. ROHRLICH";"Equipe 04, Team 04";18230039;"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America";"Legrand F, Lecuit M, Dupont B, Bellaton E, Huerre M, Rohrlich PS, Lortholary O";;"Mar 2008";1204329600;;"Chronic disseminated candidiasis (CDC) is typically observed during neutrophil recovery in patients with acute leukemia and requires protracted antifungal therapy." 5451;"Dendritic cell and natural killer cell cross-talk: a pivotal role of CX3CL1 in NK cytoskeleton organization and activation.";"PS. ROHRLICH";"Equipe 04, Team 04";18682600;Blood;"Pallandre JR, Krzewski K, Bedel R, Ryffel B, Caignard A, Rohrlich PS, Pivot X, Tiberghien P, Zitvogel L, Strominger JL, Borg C";;"Dec 2008";1228089600;;"Initial molecular events leading to natural killer lymphocyte (NK) and dendritic cell (DC) interactions are largely unknown. Here, the role of CX3CL1 (fractalkine), a chemokine expressed on mature dendritic cells (mDCs) has been investigated. We show that CX3CL1 promotes NK activation by mDCs. After blocking of CX3CL1 by antibody, no activation occurred but major histocompatibility complex (MHC) class I neutralization restored DC-mediated NK activation, suggesting an interaction between CX3CL1 signaling and the functioning of inhibitory KIR. Then the YTS NK cell line, in which the inhibitory receptor KIR2DL1 had been introduced, was used. The presence of KIR2DL1 did not decrease YTS activation by HLA-Cw4 DC when CX3CL1 was functional. In contrast, CX3CL1 neutralization led to killer cell immunoglobulin-like receptor (KIR) phosphorylation and SHP-1 recruitment in YTS(KIR2DL1) cultured with HLA-Cw4 mDCs. Moreover, CX3CL1 neutralization promoted dispersion of lipid rafts and the formation of a multiprotein complex required for cytoskeletal rearrangements in YTS NK cells. These findings point to a pivotal role of CX3CL1 in the activation of resting NK cells by mature DCs." 5449;"[Familial infantile myofibromatosis].";"PS. ROHRLICH";"Equipe 04, Team 04";19361702;"Annales de dermatologie et de venereologie";"Puzenat E, Marioli S, Algros MP, Faivre B, Fotso A, Humbert P, Rohrlich PS, Aubin F";;"Apr 2009";1238544000;;"Infantile myofibromatosis (IM) is the most common fibrous disorder of infancy and childhood. It is characterized by congenital tumours of the skin, striated muscle, bones and viscera. Most cases are sporadic and few familial cases have been reported." 5447;"Design of a HIV-1-derived HLA-B07.02-restricted polyepitope construct.";"PS. ROHRLICH";"Equipe 04, Team 04";19644347;"AIDS (London, England)";"Cardinaud S, Bouziat R, Rohrlich PS, Tourdot S, Weiss L, Langlade-Demoyen P, Burgevin A, Fiorentino S, van Endert P, Lemonnier FA";;"Sep 2009";1251763200;;"To design a vaccine construct containing various but conserved HIV-1-derived epitopes and generating broad CD8 T cell responses." 5445;"Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance.";"PS. ROHRLICH";"Equipe 04, Team 04";20089966;Blood;"Henry C, Deschamps M, Rohrlich PS, Pallandre JR, Rémy-Martin JP, Callanan M, Traverse-Glehen A, GrandClément C, Garnache-Ottou F, Gressin R, Deconinck E, Salles G, Robinet E, Tiberghien P, Borg C, Ferrand C";;"Mar 2010";1267401600;;"Human CD20 is a B-cell lineage-specific marker expressed by normal and leukemic B cells from the pre-B to the plasma-cell stages and is a target for rituximab (RTX) immunotherapy. A CD20 reverse transcriptase-polymerase chain reaction (PCR) on B-cell lines cDNA yielded a short PCR product (DeltaCD20) corresponding to a spliced mRNA transcript linking the exon 3 and exon 7 ends. We established here that this novel, alternatively spliced CD20 transcript is expressed and detectable at various levels in leukemic B cells, lymphoma B cells, in vivo tonsil- or in vitro CD40L-activated B cells, and Epstein-Barr virus (EBV)-transformed B cells, but not in resting CD19(+)- or CD20(+)-sorted B cells from peripheral blood or bone marrow of healthy donors. The truncated CD20 sequence is within the reading frame, codes a protein of 130 amino acids ( approximately 15-17 kDa) lacking large parts of the 4 transmembrane segments, suggesting that DeltaCD20 is a nonanchored membrane protein. We demonstrated the translation into a DeltaCD20 protein which is associated with the membrane CD20 protein and showed its involvement in RTX resistance. Study of patient samples before and after RTX resistance or escape confirms our in vitro findings." 5441;"Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets.";"PS. ROHRLICH";"Equipe 04, Team 04";20644117;Blood;"Hislop AD, Palendira U, Leese AM, Arkwright PD, Rohrlich PS, Tangye SG, Gaspar HB, Lankester AC, Moretta A, Rickinson AB";;"Oct 2010";1285891200;;"X-linked lymphoproliferative disease (XLP) is a condition associated with mutations in the signaling lymphocytic activation molecule (SLAM)-associated protein (SAP; SH2D1A). SAP functions as an adaptor, binding to and recruiting signaling molecules to SLAM family receptors expressed on T and natural killer cells. XLP is associated with extreme sensitivity to primary Epstein-Barr virus (EBV) infection, often leading to a lethal infectious mononucleosis. To investigate EBV-specific immunity in XLP patients, we studied 5 individuals who had survived EBV infection and found CD8(+) T-cell responses numerically comparable with healthy donors. However, further investigation of in vitro-derived CD8(+) T-cell clones established from 2 of these donors showed they efficiently recognized SLAM ligand-negative target cells expressing EBV antigens, but showed impaired recognition of EBV-transformed, SLAM ligand-positive, lymphoblastoid cell lines (LCLs). Importantly, LCL recognition was restored when interactions between the SLAM receptors CD244 and natural killer-, T-, and B-cell antigen (NTBA) and their ligands on LCLs were blocked. We propose that XLP patients' particular sensitivity to EBV, and not to other viruses, reflects at least in part EBV's strict tropism for B lymphocytes and the often inability of the CD8(+) T-cell response to contain the primary infection of SLAM ligand-expressing target cells." 5439;"Early immune reconstitution and efficient graft vs tumor effect after unrelated partially matched double cord blood transplantation in refractory 8p11 syndrome.";"PS. ROHRLICH";"Equipe 04, Team 04";20661237;"Bone marrow transplantation";"Larosa F, Maddens S, Legrand F, Pouthier F, Ferrand C, Saas P, Hayette S, Chabod J, Tiberghien P, Rohrlich PS, Deconinck E";;"Apr 2011";1301616000;; 5437;"Diagnosis and treatment of digestive cryptosporidiosis in allogeneic haematopoietic stem cell transplant recipients: a prospective single centre study.";"PS. ROHRLICH";"Equipe 04, Team 04";20729925;"Bone marrow transplantation";"Legrand F, Grenouillet F, Larosa F, Dalle F, Saas P, Millon L, Deconinck E, Rohrlich PS";;"Jun 2011";1306886400;;"Digestive cryptosporidiosis (DC) can mimic GVHD after allogeneic haematopoietic stem cell transplantation (HSCT), thus requiring a reduction of immunosuppressive drugs and a specific therapy, whereas GVHD requires an intensification of immunosuppression. We systematically searched for cryptosporidiosis by light microscopy, immunochromatography and PCR in HSCT recipients who presented with at least one episode of diarrhoea. Of 115 consecutive patients allografted between July 2006 and November 2008, we analysed stools in 52 of 56 patients meeting these criteria. We identified Cryptosporidium parvum in 5 of the 52 patients (9.6%) at a median of 503 days (range 20-790) after HSCT. In those five patients, the median CD4+ cell and B lymphocyte counts were 60/mm3 (0-234) and 0/mm3 (0-96), respectively. Two patients died of invasive fungal infections. In the other three patients, diarrhoea disappeared after a median of 5 weeks following onset of bitherapy with azithromycine and nitazoxanide; they were still alive 433, 380 and 1179 days after the DC diagnosis. DC is probably under diagnosed after HSCT because it is difficult to detect during the asymptomatic phase. Early bitherapy and reduction of immunosuppression seem efficacious. In our series, DC has a seasonal pattern and is promoted by profound T lymphopenia." 5435;"Computerized physician order entry of injectable antineoplastic drugs: an epidemiologic study of prescribing medication errors.";"PS. ROHRLICH";"Equipe 04, Team 04";20829102;"International journal of medical informatics";"Nerich V, Limat S, Demarchi M, Borg C, Rohrlich PS, Deconinck E, Westeel V, Villanueva C, Woronoff-Lemsi MC, Pivot X";;"Oct 2010";1285891200;;"In the context of CPOE of standardized antineoplastic drugs, the objectives of the present study were to determine the incidence of prescribing medication errors (PME) and to analyse PME related to antineoplastic treatment in university teaching hospitals." 5433;"Dendritic cell-specific antigen delivery by coronavirus vaccine vectors induces long-lasting protective antiviral and antitumor immunity.";"PS. ROHRLICH";"Equipe 04, Team 04";20844609;mBio;"Cervantes-Barragan L, Züst R, Maier R, Sierro S, Janda J, Levy F, Speiser D, Romero P, Rohrlich PS, Ludewig B, Thiel V";;"Sep 2010";1283299200;;"Efficient vaccination against infectious agents and tumors depends on specific antigen targeting to dendritic cells (DCs). We report here that biosafe coronavirus-based vaccine vectors facilitate delivery of multiple antigens and immunostimulatory cytokines to professional antigen-presenting cells in vitro and in vivo. Vaccine vectors based on heavily attenuated murine coronavirus genomes were generated to express epitopes from the lymphocytic choriomeningitis virus glycoprotein, or human Melan-A, in combination with the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). These vectors selectively targeted DCs in vitro and in vivo resulting in vector-mediated antigen expression and efficient maturation of DCs. Single application of only low vector doses elicited strong and long-lasting cytotoxic T-cell responses, providing protective antiviral and antitumor immunity. Furthermore, human DCs transduced with Melan-A-recombinant human coronavirus 229E efficiently activated tumor-specific CD8(+) T cells. Taken together, this novel vaccine platform is well suited to deliver antigens and immunostimulatory cytokines to DCs and to initiate and maintain protective immunity." 5431;"Successful mobilization and engraftment of PBSCs derived from donor cord blood cells after a previous allogeneic RIC single unrelated cord blood transplantation.";"PS. ROHRLICH";"Equipe 04, Team 04";21757631;Blood;"Larosa F, Deconinck E, Helias P, Fontan J, Heczko M, Brion A, Ledu K, Delaby P, Vuiller J, Ferrand C, Saas P, Pouthier F, Dormoy A, Chabod J, Malugani C, Rohrlich PS, Legrand F";;"Jul 2011";1309478400;; 5429;"CD304 is preferentially expressed on a subset of B-lineage acute lymphoblastic leukemia and represents a novel marker for minimal residual disease detection by flow cytometry.";"PS. ROHRLICH";"Equipe 04, Team 04";22052678;"Cytometry. Part A : the journal of the International Society for Analytical Cytology";"Solly F, Angelot F, Garand R, Ferrand C, Seillès E, Schillinger F, Decobecq A, Billot M, Larosa F, Plouvier E, Deconinck E, Legrand F, Saas P, Rohrlich PS, Garnache-Ottou F";;"Jan 2012";1325376000;;"Minimal residual disease (MRD) has emerged as a major prognostic factor for monitoring patients with B-lineage acute lymphoblastic leukemia (B-ALL). The quantification of MRD by flow cytometry (FC) is based on the identification of a leukemia-associated phenotype (LAP). Because phenotypic switch is common during treatment, multiple LAPs must be available and used for MRD detection over time. We evaluated the potential usefulness of CD304 as a new marker for monitoring MRD. CD304 was expressed in 48% of B-ALL (24/50) with discriminative fluorescence intensity compared with CD304-negative normal B-cell precursors (n = 15). The sensitivity of CD304-based MRD detection reached 10(-4), as with some of established LAPs. The stability of CD304 expression evaluated during therapy and at relapse confirms the usefulness of this marker for MRD quantification. Finally, CD304 was repeatedly expressed in patients with TEL-AML1 gene rearrangement, which warrants further investigation on its potential relevance as a prognosis marker or therapeutic target." 5427;"Systematic donor blood qualification by flow cytometry would have been able to avoid CLL-type MBL transmission after unrelated hematopoietic stem cell transplantation.";"PS. ROHRLICH";"Equipe 04, Team 04";22168404;"European journal of haematology";"Ferrand C, Garnache-Ottou F, Collonge-Rame MA, Larosa F, Blanc M, Behar C, Giannoli C, Garnier F, Tiberghien P, Deconinck E, Rohrlich PS";;"Mar 2012";1330560000;;"The current screening for eligibility of unrelated volunteer marrow donors comprises a complete clinical check-up, a blood CBC and serum protein immunoelectrophoresis. This allows to eliminate acute leukemias, myeloproliferative and myelodysplastic disorders, myelomas and MGUS. To date, the risk of transmission of chronic lymphocytic leukemia (CLL) disease is only evaluated by the clinical evaluation and CBC. We report here the case of a CLL-type MBL disease occurring in a 12-year-old boy after unrelated BMT. Deep biological investigations, as Immunophenotyping, cytogenetic and molecular biology allow us to determine the donor origin of the CLL clone. In 2010, 14.2% donor (105/737) for unrelated hematopoietic stem cell transplantation were over 45y. It is currently estimated (USA) that 1 in 210 men and women will be diagnosed with CLL during their lifetime. Given the long asymptomatic phase of CLL, this raises the case for a detection strategy analog to that used for MGUS and myeloma through serum protein electrophoresis. This case-report, to our knowledge, of a CLL-type MBL unrelated donor-to-recipient transmission through BMT raises ethical and practical questions, such as the proper information about disease transmission risk. The cost-effectiveness of a systematic peripheral blood Immunophenotyping in donors elder than 40y at time of stem cell donation should be evaluated." 5425;"Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis.";"PS. ROHRLICH";"Equipe 04, Team 04";22531912;"European journal of immunology";"Boucherma R, Kridane-Miledi H, Vives FL, Vauchy C, Borg C, Kleinclauss F, Fiette L, Tiberghien P, Lemonnier FA, Rohrlich PS, Huetz F";;"Apr 2012";1333238400;;"HFE, an MHC class Ib molecule that controls iron metabolism, can be directly targeted by cytotoxic TCR αβ T lymphocytes. Transgenic DBA/2 mice expressing, in a Rag 2 KO context, an αβ TCR that directly recognizes mouse HFE (mHFE) were created to further explore the interface of HFE with the immune system. TCR-transgenic mHfe WT mice deleted mHFE-reactive T cells in the thymus, but a fraction of reprogrammed cells were able to escape deletion. In contrast, TCR-transgenic mice deprived of mHFE molecules (mHfe KO mice) or expressing a C282→Y mutated mHFE molecule - the most frequent mutation associated with human hereditary hemochromatosis - positively selected mHFE-reactive CD8(+) T lymphocytes and were not tolerant toward mHFE. By engrafting these mice with DBA/2 WT (mHFE(+)) skin, it was established, as suspected on the basis of similar engraftments performed on DBA/2 mHfe KO mice, that mHFE behaves as an autonomous skin-associated histocompatibility antigen, even for mHFE-C282→Y mutated mice. By contrast, infusion of DBA/2 mHFE(+) mice with naïve mHFE-reactive transgenic CD8(+) T lymphocytes did not induce GVHD. Thus, tolerance toward HFE in mHfe WT mice can be acquired at either thymic or peripheral levels but is disrupted in mice reproducing human familial hemochromatosis." 5423;"Economic impact of prescribing error prevention with computerized physician order entry of injectable antineoplastic drugs.";"PS. ROHRLICH";"Equipe 04, Team 04";22623276;"Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners";"Nerich V, Borg C, Villanueva C, Thiery-Vuillemin A, Helias P, Rohrlich PS, Demarchi M, Pivot X, Limat S";;"Mar 2013";1362096000;;"A cost-benefit analysis was carried out to determine the potential economic costs and benefits of pharmaceutical analysis in preventing prescribing errors for full standardized injectable antineoplastic drugs computerized physician order entry, in a pharmaceutical unit (University teaching hospital), compared with theoretical setting with no pharmaceutical analysis. The viewpoint is that of the payer or the French national Public Health Insurance system, and is limited to hospital cost (only direct medical costs related to net cost and net benefit. A decision analysis model was performed to compare two strategies: with pharmaceutical analysis (± pharmacy intervention) and without pharmaceutical analysis." 5421;"Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.";"PS. ROHRLICH";"Equipe 04, Team 04";23009155;"Orphanet journal of rare diseases";"Beaussant Cohen S, Fenneteau O, Plouvier E, Rohrlich PS, Daltroff G, Plantier I, Dupuy A, Kerob D, Beaupain B, Bordigoni P, Fouyssac F, Delezoide AL, Devouassoux G, Nicolas JF, Bensaid P, Bertrand Y, Balabanian K, Chantelot CB, Bachelerie F, Donadieu J";;"Sep 2012";1346457600;;"WHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors." 5419;"Opposing Mcl-1, the GALIG proapoptotic gene is upregulated as neutrophils die and underexpressed in Acute Myeloid Leukemia cells.";"PS. ROHRLICH";"Equipe 04, Team 04";23711389;"Molecular immunology";"Mollet L, Robinet P, Dubois M, Aurouet A, Normand T, Charpentier S, Sureau A, Grandclement C, Garnache-Ottou F, Deconinck E, Brulé F, Rohrlich PS, Legrand A";;"Nov 2013";1383264000;;"GALIG gene expression induces apoptosis in cultured cells through a pathway still under investigation. It is highly expressed in leukocytes but weakly detectable in bone marrow, suggesting a role in the myeloid lineage homeostasis. We show here that GALIG-induced cell death is counteracted by the overexpression of MCL-1, a pro-survival member of the Bcl2 family. Moreover, during spontaneous neutrophil apoptosis, a substantial increase in GALIG gene expression is observed: GALIG still opposes MCL-1. Finally, in bone marrow and peripheral blood cells from patients with Acute Myeloid Leukemia type 2, the level of GALIG transcripts is massively down-regulated when compared to their normal counterparts, while MCL-1 is expressed to the same extent. These data suggest that GALIG could be a key player in the cell death pathway involved in leukocytes homeostasis and myeloid malignancies." 5417;"[Development of psychological and intellectual performance in transplanted sickle cell disease patients: a prospective study from pretransplant period to 5 years after HSCT].";"PS. ROHRLICH";"Equipe 04, Team 04";23769628;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Bockenmeyer J, Chamboredon E, Missud F, Benkerrou M, Holvoët L, Ithier G, Lescoeur B, Yakouben K, Ouachée-Chardin M, Rohrlich PS, Duval M, Baruchel A, Dalle JH";;"Jul 2013";1372636800;;"Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD). Cerebral vasculopathy was the principal indication for transplantation. These children could present impaired neuropsychological development related to different causes, hence the value of exploring their intellectual capacities before and after transplantation." 5413;"Impact on long-term OS of conditioning regimen in allogeneic BMT for children with AML in first CR: TBI+CY versus BU+CY: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire.";"PS. ROHRLICH";"Equipe 04, Team 04";24317131;"Bone marrow transplantation";"de Berranger E, Cousien A, Petit A, Peffault de Latour R, Galambrun C, Bertrand Y, Salmon A, Rialland F, Rohrlich PS, Vannier JP, Lutz P, Yakouben K, Duhamel A, Bruno B, Michel G, Dalle JH";;"Mar 2014";1393632000;;"Allogeneic hematopoietic SCT (HSCT) appears to be an efficient tool to cure high-risk AML in first CR but the choice between BU-based or TBI-based conditioning regimens still remains controversial. In order to analyze the impact of conditioning regimen on long-term survival, we conducted a retrospective analysis from French registry data including all consecutive patients under 18 years old (n=226) from 1980 to 2004 transplanted for AML in CR1 from sibling (n=142) or matched unrelated donors and given either TBI-1200 cGy and CY 120 mg/kg (TBI-Cy, n=84) or BU 16 mg/kg and CY 200 mg/kg (BuCy200, n=142). Patient subgroups were comparable for all criteria except for median age at diagnosis and HSCT and for donor type. Both 5-year OS and disease-free survival (DFS) were significantly better in BuCy200 group (P=0.02 and 0.005, respectively). In multivariate analysis, both HLA matching and BuCy200 appeared as good prognostic factors for treatment-related mortality and DFS. Grade 2-4 acute GvHD and chronic GvHD rates were statistically higher in TBI-Cy group than in Bu-Cy200 one with a RR at 2 (P=0.002). In total, Bu-Cy200 conditioning regimen gives better outcome compared with TBI-Cy irrespective of the stem cell source and the donor type." 5414;"[Social connection: a report of the SFGM-TC on the maintaining social and family connections during Hematopoietic Stem Cell Transplantation].";"PS. ROHRLICH";"Equipe 04, Team 04";24011958;Pathologie-biologie;"Rohrlich PS, Kerautret K, Bancillon N, Vauzelle K, Bertrand-Letort M, Ruiz M, Schmitt S, Samy JP, Guiraud M, Yakoub-Agha I, ";;"Aug 2013";1375315200;;"To set up the minimal conditions necessary to ensure that the social and familial network of the patient is preserved during the hospital stay for allogeneic hematopoïetic stem cell transplantation." 5411;"Malignancy and thrombotic microangiopathy or atypical haemolytic and uraemic syndrome?";"PS. ROHRLICH";"Equipe 04, Team 04";24749807;"British journal of haematology";"Favre GA, Touzot M, Fremeaux-Bacchi V, Hyvernat H, Gueffet JP, Rohrlich PS, Queyrel V, Esnault V, Fakhouri F";;"Sep 2014";1409529600;; 5409;"Diagnosis and management of nocardiosis after bone marrow stem cell transplantation in adults: lack of lymphocyte recovery as a major contributing factor.";"PS. ROHRLICH";"Equipe 04, Team 04";24875455;Pathologie-biologie;"Mansi L, Daguindau E, Saas P, Pouthier F, Ferrand C, Dormoy A, Patry I, Garnache F, Rohrlich PS, Deconinck E, Larosa F";;"Jun 2014";1401580800;;"Hematopoietic cell transplantation (HCT) is a curative treatment for hematological malignancies. This therapeutic approach is associated with a profound immune deficiency and an increased rate of opportunistic infections. Nocardiosis is a rare bacterial infection occurring mainly in patients with deficient cell-mediated immunity, such as AIDS patients or transplant recipients. Diagnosis of nocardiosis can be challenging, as signs and symptoms are non-specific. Routine prophylaxis with trimethoprin/sulfamethoxazole (TMP/SMZ) does not prevent the risk of infection. Between May 2001 and December 2009, five cases of nocardiosis were diagnosed from the 366 allogeneic HCT recipients in our centre. Four patients developed a disseminated nocardiosis within the first year after HCT. The fifth patient presented a localized cutaneous nocardiosis. In disseminated cases, median total CD4+ T-cells were below 100 cells/μL. Naive CD4+ CD45RA+/RO- T-cells were almost undetectable. CD8(+) T-cells and NK cells were below the normal range and CD19+ B-cell reconstitution was completely deficient. In a localized case, we observed a lack of naive thymic emigrants CD4+ CD45RA+/RO- T-cells." 5407;"[Managing late-effects after allogeneic stem cell transplantation in children: recommendations from the SFGM-TC].";"PS. ROHRLICH";"Equipe 04, Team 04";24973860;Pathologie-biologie;"de Berranger E, Michel G, Fahd M, Gandemer V, Jubert C, Marie-Cardine A, Pochon C, Rohrlich PS, Sirvent A, Cartigny M, Deschildre A, Yakoub-Agha I, ";;"Aug 2014";1406851200;;"In this report, we address the issue of late-effects after allogeneic stem cell transplantation in children. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille." 5405;"Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.";"PS. ROHRLICH";"Equipe 04, Team 04";25310094;"PloS one";"Seyed N, Taheri T, Vauchy C, Dosset M, Godet Y, Eslamifar A, Sharifi I, Adotevi O, Borg C, Rohrlich PS, Rafati S";;"Jan 2014";1388534400;;"There are several reports demonstrating the role of CD8 T cells against Leishmania species. Therefore peptide vaccine might represent an effective approach to control the infection. We developed a rational polytope-DNA construct encoding immunogenic HLA-A2 restricted peptides and validated the processing and presentation of encoded epitopes in a preclinical mouse model humanized for the MHC-class-I and II." 5403;"Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in non-Hodgkin lymphoma.";"PS. ROHRLICH";"Equipe 04, Team 04";25388916;"Journal of hematology & oncology";"Guenat D, Quentin S, Rizzari C, Lundin C, Coliva T, Edery P, Fryssira H, Bermont L, Ferrand C, Soulier J, Borg C, Rohrlich PS";;"Nov 2014";1414800000;;"Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated." 5401;"CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes.";"PS. ROHRLICH";"Equipe 04, Team 04";25449106;"International journal of cancer";"Vauchy C, Gamonet C, Ferrand C, Daguindau E, Galaine J, Beziaud L, Chauchet A, Henry Dunand CJ, Deschamps M, Rohrlich PS, Borg C, Adotevi O, Godet Y";;"Jul 2015";1435708800;;"Cancer-specific splice variants gain significant interest as they generate neo-antigens that could be targeted by immune cells. CD20, a membrane antigen broadly expressed in mature B cells and in B cell lymphomas, is subject to an alternative splicing named D393-CD20 leading to loss of membrane expression of the spliced isoform. D393-CD20 expression is detectable in transformed B cells and upregulated in various lymphoma B cells. In this study, we show that D393-CD20 is translated in malignant B cells and that D393-CD20 specific CD4 T cells producing IFN-γ are present in B-cell lymphoma patients. Then, we have investigated whether the 20mer D393-CD20 peptide spanning the splicing site might be targeted by the immune system and we have shown that D393-CD20-specific CD4 Th1 clones could directly recognize malignant B cell lines and kill autologous lymphoma B cells indicating that D393-CD20-derived epitopes are naturally processed and presented on tumor cells. Finally, D393-CD20 peptide-based vaccination induced specific CD8 and CD4 T cell responses in HLA-humanized transgenic mice suggesting the presentation of D393-CD20 derived peptides on both HLA Class-I and -II. These findings support further investigations on the potential use of D393-CD20 directed specific immunotherapy in B cell malignancies." 5399;"Management of Myelodysplastic Syndrome Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: A Study by the French Society of Bone Marrow Transplantation and Cell Therapies.";"PS. ROHRLICH";"Equipe 04, Team 04";26256942;"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation";"Guièze R, Damaj G, Pereira B, Robin M, Chevallier P, Michallet M, Vigouroux S, Beguin Y, Blaise D, El Cheikh J, Roos-Weil D, Thiebaut A, Rohrlich PS, Huynh A, Cornillon J, Contentin N, Suarez F, Lioure B, Mohty M, Maillard N, Clement L, François S, Guillerm G, Yakoub-Agha I";;"Feb 2016";1454284800;;"To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT." 5397;"Different outcome of T cell acute lymphoblastic leukemia with translocation t(11;14) treated in two consecutive children leukemia group EORTC trials.";"PS. ROHRLICH";"Equipe 04, Team 04";26455579;"Annals of hematology";"Simon P, Suciu S, Clappier E, Cave H, Sirvent N, Plat G, Thyss A, Mechinaud F, Costa VM, Ferster A, Lutz P, Mazingue F, Plantaz D, Plouvier E, Bertrand Y, Benoit Y, Dastugue N, Rohrlich PS, ";;"Jan 2016";1451606400;;"Acute lymphoblastic leukemia of T cell lineage (T-ALL) is an aggressive malignant disease which accounts for 15 % of childhood ALL. T(11;14) is the more frequent chromosomal abnormality in childhood T-ALL, but its prognostic value remained controversial. Our aim was to analyze the outcome of childhood T-ALL with t(11;14) to know if the presence of this translocation is associated with a poor prognosis. We conducted a retrospective study from a series of 20 patients with t(11;14), treated in two consecutive trials from the European Organization for Research and Treatment of Cancer Children Leukemia Group over a 19-year period from 1989 to 2008. There were no significant differences between the 2 consecutive groups of patients with t(11;14) regarding the clinical and biological features at diagnosis. Among 19 patients who reached complete remission, 9 patients relapsed. We noticed 7 deaths all relapse- or failure-related. In the 58881 study, a presence of t(11;14) was associated with a poor outcome with an event-free survival at 5 years at 22.2 % versus 65.1 % for the non-t(11;14) T-ALL (p = 0.0004). In the more recent protocol, the outcome of T-ALL with t(11;14) reached that of non-t(11;14) T-ALL with an event-free survival at 5 years at 65.5 versus 74.9 % (p = 0.93). The presence of t(11;14) appeared as a poor prognostic feature in the 58881 trial whereas this abnormality no longer affected the outcome in the 58951 study. This difference is probably explained by the more intensive chemotherapy in the latest trial." 5395;"DOCK8 Mutation Syndrome: A Diagnostic Challenge for Dermatologists.";"PS. ROHRLICH";"Equipe 04, Team 04";26573532;"Acta dermato-venereologica";"Moreau J, Beaussant-Cohen S, Aubin F, Rohrlich PS, Puzenat E";;"11 2016";1477958400;; 5393;"Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study.";"PS. ROHRLICH";"Equipe 04, Team 04";26689746;"American journal of hematology";"Loschi M, Porcher R, Barraco F, Terriou L, Mohty M, de Guibert S, Mahe B, Lemal R, Dumas PY, Etienne G, Jardin F, Royer B, Bordessoule D, Rohrlich PS, Fornecker LM, Salanoubat C, Maury S, Cahn JY, Vincent L, Sene T, Rigaudeau S, Nguyen S, Lepretre AC, Mary JY, Corront B, Socie G, Peffault de Latour R";;"Jun 2016";1464739200;;"Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (>2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1-10]) as compared to the historical cohort (27% [20-34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution." 5391;"Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the EBMT.";"PS. ROHRLICH";"Equipe 04, Team 04";27229716;Haematologica;"Paviglianiti A, Xavier E, Ruggeri A, Ceballos P, Deconinck E, Cornelissen JJ, Nguyen-Quoc S, Maillard N, Sanz G, Rohrlich PS, Garderet L, Volt F, Rocha V, Kroeger N, Gluckman E, Fegueux N, Mohty M";;"09 2016";1472688000;;"Although allogeneic stem cell transplantation is not a standard therapy for multiple myeloma, some patients can benefit from this intense therapy. There are few reports on outcomes after umbilical cord blood transplantation in multiple myeloma, and investigation of this procedure is warranted. We retrospectively analyzed 95 patients, 85 with multiple myeloma and 10 with plasma cell leukemia, receiving single or double umbilical cord blood transplantation from 2001 to 2013. Median follow up was 41 months. The majority of patients received a reduced intensity conditioning. The cumulative incidence of neutrophil engraftment was 97%±3% at 60 days, and that of 100-day acute graft-versus-host disease grade II-IV was 41%±5%. Chronic graft-versus-host disease at two years was 22%±4%. Relapse and non-relapse mortality was 47%±5% and 29%±5% at three years, respectively. Three-year progression-free survival and overall survival were 24%±5% and 40%±5%, respectively. Anti-thymocyte globulin was associated with decreased incidence of acute graft-versus-host disease, higher non-relapse mortality, decreased overall and progression-free survival. Patients with high cytogenetic risk had higher relapse, and worse overall and progression-free survival. In conclusion, umbilical cord blood transplantation is feasible for multiple myeloma patients." 5389;"[Assessment and management of post-transplant iron overload: Guidelines of the Francophone Society of Marrow Transplantation and Cellular Therapy (SFGM-TC)].";"PS. ROHRLICH";"Equipe 04, Team 04";27842863;"Bulletin du cancer";"Jaspers A, Bouhya S, Belaiche S, Chevallier P, Hermet E, Hospital-Gustems C, Michallet M, Rialland F, Samsonova O, Sirvent A, Yakoub-Agha I, Rohrlich PS, Beguin Y";;"Nov 2016";1477958400;;"To harmonize clinical practice in hematopoietic stem cell transplantation, the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the sixth annual series of workshops which brought together practitioners from all member centers and took place in September 2015 in Lille. The main aim of this session was to describe the impact, evaluation and treatment of post-transplant iron overload." 5387;"Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience.";"PS. ROHRLICH";"Equipe 04, Team 04";27941778;"Bone marrow transplantation";"Alloin AL, Leverger G, Dalle JH, Galambrun C, Bertrand Y, Baruchel A, Auvrignon A, Gandemer V, Ragu C, Loundou A, Bilhou-Nabera C, Lafage-Pochitaloff M, Dastugue N, Nelken B, Jubert C, Rialland F, Plat G, Pochon C, Vannier JP, Rohrlich PS, Kanold J, Lutz P, Sirvent A, Oudin C, Cuccuini W, Michel G";;"Apr 2017";1491004800;;"We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved." 5385;"Can a reduced-intensity conditioning regimen cure blastic plasmacytoid dendritic cell neoplasm?";"PS. ROHRLICH";"Equipe 04, Team 04";27986653;Blood;"Leclerc M, Peffault de Latour R, Michallet M, Blaise D, Chevallier P, Rohrlich PS, Turlure P, Nguyen S, Jardin F, Yakoub-Agha I, Maury S, ";;"03 2017";1488326400;; 5383;"Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma.";"PS. ROHRLICH";"Equipe 04, Team 04";28073785;Blood;"Merryman RW, Kim HT, Zinzani PL, Carlo-Stella C, Ansell SM, Perales MA, Avigdor A, Halwani AS, Houot R, Marchand T, Dhedin N, Lescaut W, Thiebaut-Bertrand A, François S, Stamatoullas-Bastard A, Rohrlich PS, Labussière Wallet H, Castagna L, Santoro A, Bachanova V, Bresler SC, Srivastava A, Kim H, Pesek E, Chammas M, Reynolds C, Ho VT, Antin JH, Ritz J, Soiffer RJ, Armand P";;"03 2017";1488326400;;"Anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are being increasingly tested in patients with advanced lymphoma. Following treatment, many of those patients are likely to be candidates for allogeneic hematopoietic stem cell transplant (HSCT). However, the safety and efficacy of HSCT may be affected by prior PD-1 blockade. We conducted an international retrospective analysis of 39 patients with lymphoma who received prior treatment with a PD-1 inhibitor, at a median time of 62 days (7-260) before HSCT. After a median follow-up of 12 months, the 1-year cumulative incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) were 44% and 23%, respectively, whereas the 1-year incidence of chronic GVHD was 41%. There were 4 treatment-related deaths (1 from hepatic sinusoidal obstruction syndrome, 3 from early acute GVHD). In addition, 7 patients developed a noninfectious febrile syndrome shortly after transplant requiring prolonged courses of steroids. One-year overall and progression-free survival rates were 89% (95% confidence interval [CI], 74-96) and 76% (95% CI, 56-87), respectively. One-year cumulative incidences of relapse and nonrelapse mortality were 14% (95% CI, 4-29) and 11% (95% CI, 3-23), respectively. Circulating lymphocyte subsets were analyzed in 17 patients. Compared with controls, patients previously treated with PD-1 blockade had significantly decreased PD-1 T cells and decreased ratios of T-regulatory cells to conventional CD4 and CD8 T cells. In conclusion, HSCT after PD-1 blockade appears feasible with a low rate of relapse. However, there may be an increased risk of early immune toxicity, which could reflect long-lasting immune alterations triggered by prior PD-1 blockade." 5381;"DNA damage response defect in Williams-Beuren syndrome.";"PS. ROHRLICH";"Equipe 04, Team 04";28098859;"International journal of molecular medicine";"Guenat D, Merla G, Deconinck E, Borg C, Rohrlich PS";;"Mar 2017";1488326400;;"Williams-Beuren syndrome (WBS, no. OMIM 194050) is a rare multisystem genetic disorder caused by a microdeletion on chromosome 7q11.23 and characterized by cardiovascular malformations, mental retardation, and a specific facial dysmorphism. Recently, we reported that a series of non‑Hodgkin's lymphoma occurs in children with WBS and thus hypothesized that a predisposition to cancer may be associated with this genetic disorder. The aim of the present study was to ascertain the role played by three genes hemizygously deleted in WBS (RFC2, GTF2I and BAZ1B) in DNA damage response pathways. Cell proliferation, cell cycle analysis, γ‑H2A.X induction, and expression of DNA damage response proteins were investigated upon exposure to genotoxic treatments in WBS patient‑derived primary fibroblasts and in the 293T cell line treated with specific siRNAs targeting RFC2, GTF2I and BAZ1B. An impaired hydroxyurea‑induced phosphorylation of CHK1 was observed in the WBS cells. However, this defective DNA damage response was not associated with an increased sensitivity to genotoxic agents. In addition, depletion of RFC2, GTF2I and BAZ1B using specific siRNAs did not have a significant impact on the DNA damage response in 293T cells. Our results highlight that the ATR‑dependent DNA damage response is impaired in WBS patient cells but is also dispensable for viability when these cells undergo a genotoxic stress. The mechanism by which the ATR pathway is impaired in WBS warrants elucidation through further investigation." 5379;"Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).";"PS. ROHRLICH";"Team 04, Equipe 04";28112748;"Bone marrow transplantation";"Roux C, Tifratene K, Socié G, Galambrun C, Bertrand Y, Rialland F, Jubert C, Pochon C, Paillard C, Sirvent A, Nelken B, Vannier JP, Freycon C, Beguin Y, Raus N, Yakoub-Agha I, Mohty M, Dalle JH, Michel G, Pradier C, Peffault de Latour R, Rohrlich PS";;"May 2017";1493596800;;"Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML." 5377;"Extracorporeal photopheresis for GVHD prophylaxis after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation: a prospective multicenter phase 2 study.";"PS. ROHRLICH";"Equipe 04, Team 04";28587506;"Leukemia & lymphoma";"Michallet M, Sobh M, Garban F, Bulabois CE, Yakoub-Agha I, Coiteux V, Dulery R, Rohrlich PS, Legrand F, Clement L, Praire A, Detrait M, Barraco F, Nicolini FE, Hequet O";;"02 2018";1517443200;;"We performed a prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic Extracorporeal Photopheresis (ECP) in adult patients with hematological malignancies early after RIC allo-HSCT on day 21 twice per week during the first two weeks and then once per week for the next four weeks for a total of eight ECP courses. A total of 20 patients were included; 10 were males, median age was 60 years. All patients engrafted, 17 (85%) received the total eight ECP courses. There were no adverse effects related to ECP. Seven patients developed acute graft-versus-host disease (GVHD), with 15% grade ≥ II cumulative incidence at day 100. The cumulative incidence of chronic GVHD at 2 years was 22%. The 2 years probability of overall survival (OS) and progression-free survival (PFS) were 84 and 74%, respectively. This study shows encouraging results with low acute and chronic GVHD incidence and no interference with graft-versus-leukemia (GVL) effect." 5375;"Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia: results of the EORTC CLG 58881 and 58951 trials.";"M. POIREE, PS. ROHRLICH";"Team 04, Equipe 04";29064485;Leukemia;"Piette C, Suciu S, Clappier E, Bertrand Y, Drunat S, Girard S, Yakouben K, Plat G, Dastugue N, Mazingue F, Grardel N, van Roy N, Uyttebroeck A, Costa V, Minckes O, Sirvent N, Simon P, Lutz P, Ferster A, Pluchart C, Poirée M, Freycon C, Dresse MF, Millot F, Chantrain C, van der Werff Ten Bosch J, Norga K, Gilotay C, Rohrlich PS, Benoit Y, Cavé H";;"01 2018";1514764800;; 5373;"[Management of the chronic graft versus host disease: Guidelines from the Francophone society of bone marrow transplantation and cellular therapies (SFGM-TC)].";"PS. ROHRLICH";"Equipe 04, Team 04";29174321;"Bulletin du cancer";"Magro L, Forcade E, Giraud C, Granata A, Parquet N, Rohrlich PS, Terriou L, Yakoub-Agha I, Beguin Y";;"Dec 2017";1512086400;;"The Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2016 in Lille, France. The objective of our workshop is to discuss chronic graft versus host disease and to provide recommendations for the indications and treatment of this condition." 5371;"Acute Myeloid Leukemia With Central Nervous System Involvement in Children: Experience From the French Protocol Analysis ELAM02.";"PS. ROHRLICH";"Equipe 04, Team 04";29189507;"Journal of pediatric hematology/oncology";"Felix A, Leblanc T, Petit A, Nelkem B, Bertrand Y, Gandemer V, Sirvent A, Paillard C, Schmitt C, Rohrlich PS, Fenneteau O, Ragu C, Michel G, Auvrignon A, Baruchel A, Leverger G";;"01 2018";1514764800;;"Central nervous system (CNS) involvement at diagnosis of pediatric acute myeloid leukemia (AML) is not considered as an independent prognostic factor. This study describes the prognostic value of pediatric AML with CNS involvement at diagnosis. Pediatric patients were treated for de novo AML in the French multicenter trial ELAM02. Lumbar puncture was carried out in the first week, and the treatment was adapted to the CNS status. No patient received CNS radiotherapy. The patients were classified into 2 groups: CNS+ and CNS-. Of the 438 patients, 16% (n=70) had CNS involvement at diagnosis, and 29% showed clinical signs. The patients with CNS disease were younger (40% were below 2 y old), had a higher white blood cell count (median of 45 vs. 13 G/L), and had M4 and M5 morphologies. The complete remission rate was similar at 92.8% for CNS+ and 88.5% for CNS-. There was no significant difference between the CNS+ and the CNS- group in overall survival (76% and 71%, respectively) and event-free survival (57% and 52%, respectively). Regarding the occurrence of first relapse, the CNS+ group had a higher combined relapse rate of 26.1% compared with 10% for the CNS- group. The results indicate that CNS involvement at diagnosis of pediatric AML is not an independent prognostic factor. Triple intrathecal chemotherapy combined with high-dose intravenous cytarabine should be the first-line treatment for CNS disease." 5369;"Hematopoietic stem cell transplantation for patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a retrospective study of 21 patients from SFGM-TC centers.";"PS. ROHRLICH";"Equipe 04, Team 04";29269526;Haematologica;"Vallet N, de Fontbrune FS, Loschi M, Desmier D, Villate A, Barraco F, Chevallier P, Terriou L, Yakoub-Agha I, Ruggeri A, Mohty M, Maillard N, Rohrlich PS, Ceballos P, Nguyen S, Poiré X, Guillerm G, Tabrizi R, Farhi J, Devillier R, Rubio MT, Socié G, de Latour RP, ";;"03 2018";1519862400;; 5367;"Chronic graft-versus-host disease features in double unit cord blood transplantation according to National Institutes of Health 2005 cGVHD Consensus criteria.";"PS. ROHRLICH";"Equipe 04, Team 04";29330402;"Bone marrow transplantation";"Hayashi H, Ruggeri A, Volt F, Cornelissen JJ, Socié G, Sengeloev H, Michallet M, Karakasis D, Petersen E, Cahn JY, Veelken H, Mercier M, Rohrlich PS, Rafii H, Kenzey C, Xavier E, Duarte RF, Basak GW, Rocha V, Gluckman E, ";;"04 2018";1522540800;; 5365;"Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin's lymphoma undergoing allogeneic haematopoietic cell transplantation-a study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.";"PS. ROHRLICH";"Equipe 04, Team 04";29330405;"Bone marrow transplantation";"Gauthier J, Poiré X, Gac AC, Leclerc M, Guillaume T, Chalandon Y, Nguyen S, Forcade E, Régny C, Bay JO, Bazarbachi A, Rohrlich PS, Huynh A, Farhi J, Marchand T, Malfuson JV, Pilorge S, Labussière-Wallet H, Renard C, Fornecker LM, Detrait M, Duléry R, Delage J, Ménard AL, Charbonnier A, Nelken B, Jubert C, Suarez F, de la Tour RP, Beguin Y, Schoemans H, Blaise D, Yakoub-Agha I";;"04 2018";1522540800;;"The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N  =  61) or MRD (N  =  90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR  =  2.95, P   < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR  =  1.74, P  =  0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR  =  0.52, P  =  0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD." 5363;"Cord Blood Unit Dominance Analysis and Effect of the Winning Unit on Outcomes after Double-Unit Umbilical Cord Blood Transplantation in Adults with Acute Leukemia: A Retrospective Study on Behalf of Eurocord, the Cord Blood Committee of Cellular Therapy, Immunobiology Working Party, and the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.";"PS. ROHRLICH";"Equipe 04, Team 04";29477777;"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation";"Tozatto-Maio K, Giannotti F, Labopin M, Ruggeri A, Volt F, Paviglianiti A, Kenzey C, Hayashi H, Cornelissen J, Michallet M, Karakasis D, Deconinck E, Rohrlich PS, de la Tour RP, Blaise D, Petersen E, D'Aveni M, Sengeloev H, Lamy T, Russell NH, Forcade E, Craddock CF, Nagler A, Gluckman E, Rocha V";;"08 2018";1533081600;;"Usually, after double umbilical cord blood transplantation (DUCBT), only 1 of the transplanted units persists in the long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analyzed 347 patients with acute leukemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were ≥5/6 HLA matched to the recipient and 59% were ≤4/6. Multivariate analysis indicated that ≤4/6 HLA-matched W-CBUs led to lower leukemia-free survival (44% versus 56%; hazard ratio [HR], 1.5; P = .032) and overall survival (49% versus 62%; HR, 1.5; P = .028), increased nonrelapse mortality (26% versus 18%; HR, 1.9; P = .027), and acute graft-versus-host disease (46% versus 35%; HR, 1.7; P = .013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated." 5361;"STAT3 Gain of Function: A New Kid on the Block in Interstitial Lung Diseases.";"PS. ROHRLICH";"Equipe 04, Team 04";29590538;"American journal of respiratory and critical care medicine";"Fabre A, Marchal S, Forbes LR, Vogel TP, Barlogis V, Triolo V, Rohrlich PS, Bérard E, Frankel D, Ambrosetti D, Soler C, Hoflack M, Baque M, Bosdure E, Baravalle M, Carsin A, Dubus JC, Giovannini-Chami L";;"Mar 2018";1522281600;; 5359;"Late effects after hematopoietic stem cell transplantation for β-thalassemia major: the French national experience.";"M. POIREE, PS. ROHRLICH";"Team 04, Equipe 04";29599204;Haematologica;"Rahal I, Galambrun C, Bertrand Y, Garnier N, Paillard C, Frange P, Pondarré C, Dalle JH, de Latour RP, Michallet M, Steschenko D, Moshous D, Lutz P, Stephan JL, Rohrlich PS, Yakoub-Agha I, Bernaudin F, Piguet C, Aladjidi N, Badens C, Berger C, Socié G, Dumesnil C, Castex MP, Poirée M, Lambilliotte A, Thomas C, Simon P, Auquier P, Michel G, Loundou A, Agouti I, Thuret I";;"07 2018";1530403200;;"In this retrospective study, we evaluate long-term complications in nearly all β-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia." 5357;"An effective modestly intensive re-induction regimen with bortezomib in relapsed or refractory paediatric acute lymphoblastic leukaemia.";"PS. ROHRLICH";"Equipe 04, Team 04";29676440;"British journal of haematology";"Kaspers GJL, Niewerth D, Wilhelm BAJ, Scholte-van Houtem P, Lopez-Yurda M, Berkhof J, Cloos J, de Haas V, Mathôt RA, Attarbaschi A, Baruchel A, de Bont ES, Fagioli F, Rössig C, Klingebiel T, De Moerloose B, Nelken B, Palumbo G, Reinhardt D, Rohrlich PS, Simon P, von Stackelberg A, Zwaan CM";;"05 2018";1525132800;;"This trial explored the efficacy of re-induction chemotherapy including bortezomib in paediatric relapsed/refractory acute lymphoblastic leukaemia. Patients were randomized 1:1 to bortezomib (1.3 mg/m /dose) administered early or late to a dexamethasone and vincristine backbone. Both groups did not differ regarding peripheral blast count on day 8, the primary endpoint. After cycle 1, 8 of 25 (32%) patients achieved complete remission with incomplete blood count recovery, 7 (28%) a partial remission and 10 had treatment failure. Most common grade 3-4 toxicities were febrile neutropenia (31%) and pain (17%). Bortezomib was safely combined with vincristine. Bortezomib rarely penetrated the cerebrospinal fluid." 5355;"The cells are ambiguous, not the message.";"PS. ROHRLICH";"Equipe 04, Team 04";30026299;Blood;"Rohrlich PS";;"07 2018";1530403200;; 5353;"Scoring System Based on Post-Transplant Complications in Patients after Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome: A Study from the SFGM-TC.";"PS. ROHRLICH";"Equipe 04, Team 04";30206045;"Current research in translational medicine";"Caulier A, Drumez E, Gauthier J, Robin M, Blaise D, Beguin Y, Michallet M, Chevallier P, Bay JO, Vigouroux S, Desbrosses Y, Cornillon J, Nguyen S, Dauriac C, de Latour RP, Lioure B, Rohrlich PS, Carré M, Bourhis JH, Huynh A, Suarez F, Garnier F, Duhamel A, Yakoub-Agha I";;"02 2019";1548979200;;"We developed a prognostic scoring system to evaluate the prognosis of myelodysplastic syndrome (MDS) patients surviving more than 100 days allogeneic hematopoietic cell transplantation after (allo-HCT)." 5351;"Lymphoproliferative disease in patients with Wiskott-Aldrich syndrome: Analysis of the French Registry of Primary Immunodeficiencies.";"PS. ROHRLICH";"Equipe 04, Team 04";30796981;"The Journal of allergy and clinical immunology";"Cheminant M, Mahlaoui N, Desconclois C, Canioni D, Ysebaert L, Dupré L, Vasconcelos Z, Malphettes M, Moshous D, Neven B, Rohrlich PS, Bernard M, Bertrand Y, Fischer A, Suarez F";;"06 2019";1559347200;; 5349;"Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review.";"PS. ROHRLICH";"Equipe 04, Team 04";30825606;"The journal of allergy and clinical immunology. In practice";"Fabre A, Marchal S, Barlogis V, Mari B, Barbry P, Rohrlich PS, Forbes LR, Vogel TP, Giovannini-Chami L";;"Aug Jul 2019";1562544000;;"Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) germline mutations have been recently described. A comprehensive overview of this early-onset multiorgan autoimmune and lymphoproliferative disease has not yet been compiled." 5347;"Comparison of Dynamic International Prognostic Scoring System and MYelofibrosis SECondary to PV and ET Prognostic Model for Prediction of Outcome in Polycythemia Vera and Essential Thrombocythemia Myelofibrosis after Allogeneic Stem Cell Transplantation.";"PS. ROHRLICH";"Equipe 04, Team 04";30930192;"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation";"Gagelmann N, Eikema DJ, de Wreede LC, Koster L, Wolschke C, Arnold R, Kanz L, McQuaker G, Marchand T, Socié G, Bourhis JH, Mohty M, Cornelissen JJ, Chevallier P, Bernasconi P, Stelljes M, Rohrlich PS, Fanin R, Finke J, Maertens J, Blaise D, Itälä-Remes M, Labussière-Wallet H, Robin M, McLornan D, Chalandon Y, Yakoub-Agha I, Kröger N, ";;"06 2019";1559347200;;"We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification." 5345;"Outcomes of Salvage Haploidentical Transplant with Post-Transplant Cyclophosphamide for Rescuing Graft Failure Patients: a Report on Behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.";"PS. ROHRLICH";"Equipe 04, Team 04";31129355;"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation";"Prata PH, Resche-Rigon M, Blaise D, Socié G, Rohrlich PS, Milpied N, Turlure P, Nguyen S, Sirvent A, Bulabois CE, Berceanu A, Charbonnier A, Chevallier P, Bay JO, Neven B, Jubert C, Mohty M, Rubio MT, Peffault de Latour R";;"09 2019";1567296000;;"Prognosis of patients with graft failure is dismal, and retransplantation is the sole option for long-term survival. To address the interest of haploidentical transplantation as a salvage option in this context, we analyzed data from 24 patients with graft failure or loss retransplanted with a haploidentical donor who received post-transplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis (GVHD). Fludarabine-based reduced-intensity conditioning was used in 23 patients and the Baltimore regimen in 14 patients. The median delay between previous and salvage transplantation for graft failure was 63 days (range, 39 to 98). In addition to PTCy, all patients received cyclosporine, and 22 patients also received mycophenolate mofetil for GVHD prophylaxis. With a median follow-up of 353 days (range, 16 to 2010), 1-year overall survival (OS) was 56% (95% confidence interval, 38% to 81%). Transplant complications accounted for 80% of deaths. The cumulative incidence of neutrophil engraftment at day +30 was 79%. Cumulative incidence of grades II to IV acute GVHD at day 100 was 14%, and 1-year cumulative incidence of chronic GVHD was 31%. One-year cumulative incidence of relapse was 13%. Stem cell source did not impact on engraftment, GVHD, relapse, or OS. Salvage haploidentical transplant with PTCy for rescuing graft failure patients leads to an acceptable 1-year OS and might be a valid option in this poor situation." 5343;"Hepatitis E and Allogeneic Hematopoietic Stem Cell Transplantation: A French Nationwide SFGM-TC Retrospective Study.";"PS. ROHRLICH";"Equipe 04, Team 04";31284515;Viruses;"Xhaard A, Roque-Afonso AM, Mallet V, Ribaud P, Nguyen-Quoc S, Rohrlich PS, Tabrizi R, Konopacki J, Lissandre S, Abravanel F, Latour RP, Huynh A";;"07 2019";1561939200;;"Usually self-limited, hepatitis E virus (HEV) infection may evolve to chronicity and cirrhosis in immunosuppressed patients. HEV infection has been described in solid-organ transplantation and hematology patients, but for allogeneic hematopoietic stem cell transplant (alloHSCT) recipients, only small cohorts are available. This retrospective nationwide multi-center series aimed to describe HEV diagnostic practices in alloHSCT French centers, and the course of infection in the context of alloHSCT. Twenty-nine out of 37 centers participated. HEV search in case of liver function tests (LFT) abnormalities was never performed in 24% of centers, occasionally in 55%, and systematically in 21%. Twenty-five cases of active HEV infection were diagnosed in seven centers, all because of LFT abnormalities, by blood nucleic acid testing. HEV infection was diagnosed in three patients before alloHSCT; HEV infection did not influence transplantation planning, and resolved spontaneously before or after alloHSCT. Twenty-two patients were diagnosed a median of 283 days after alloHSCT. Nine patients (41%) had spontaneous viral clearance, mostly after immunosuppressive treatment decrease. Thirteen patients (59%) received ribavirin, with sustained viral clearance in 11/12 evaluable patients. We observed three HEV recurrences but no HEV-related death or liver failure, nor evolution to cirrhosis." 5341;"A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.";"PS. ROHRLICH";"Equipe 04, Team 04";31401750;"Journal of clinical immunology";"Coignard-Biehler H, Mahlaoui N, Pilmis B, Barlogis V, Brosselin P, De Vergnes N, Debré M, Malphettes M, Frange P, Catherinot E, Pellier I, Durieu I, Perlat A, Royer B, Le Quellec A, Jeziorski E, Fischer A, Lortholary O, , Aaron L, Adoue D, Aguilar C, Aladjidi N, Alcais A, Amoura Z, Arlet P, Armari-Alla C, Bader-Meunier B, Bayart S, Bertrand Y, Bienvenu B, Blanche S, Bodet D, Bonnotte B, Borie R, Boutard P, Briandet C, Brion JP, Brouard J, Cohen-Beaussant S, Costes L, Couderc LJ, Cougoul P, Courteille V, de Saint Basile G, Devoldere C, Deville A, Donadieu J, Dore E, Dulieu F, Edan C, Entz-Werle N, Fieschi C, Forestier A, Fouyssac F, Gajdos V, Galicier L, Gandemer V, Gardembas M, Gaud C, Guillerm G, Hachulla E, Hamidou M, Hermine O, Hoarau C, Humbert S, Jaccard A, Jacquot S, Jais JP, Jaussaud R, Jeandel PY, Kebaili K, Korganow AS, Lambotte O, Lanternier F, Larroche C, Lascaux AS, Le Moigne E, Le Moing V, Lebranchu Y, Lecuit M, Lefevre G, Lemal R, Te VLT, Marie-Cardine A, Silva NM, Masseau A, Massot C, Mazingue F, Merlin E, Michel G, Millot F, Monlibert B, Monpoux F, Moshous D, Mouthon L, Munzer M, Neven B, Nove-Josserand R, Oksenhendler E, Ouachée-Chardin M, Oudot C, Pagnier A, Pasquali JL, Pasquet M, Perel Y, Picard C, Piguet C, Plantaz D, Provot J, Quartier P, Rieux-Laucat F, Roblot P, Roger PM, Rohrlich PS, Rubie H, Salle V, Sarrot-Reynauld F, Servettaz A, Stephan JL, Schleinitz N, Suarez F, Swiader L, Taque S, Thomas C, Tournilhac O, Thumerelle C, Tron F, Vannier JP, Viallard JF";;"10 2019";1569888000;;"Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying ""at-risk"" patient profiles." 5339;"Long-term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study.";"M. POIREE, PS. ROHRLICH";"Team 04, Equipe 04";31837008;"British journal of haematology";"Piette C, Suciu S, Bertrand Y, Uyttebroeck A, Vandecruys E, Plat G, Paillard C, Pluchart C, Sirvent N, Maurus R, Poirée M, Simon P, Ferster A, Hoyoux C, Mazingue F, Paulus R, Freycon C, Thomas C, Philippet P, Gilotay C, van der Werff Ten Bosch J, Rohrlich PS, Benoit Y";;"04 2020";1585699200;;"We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983-1989). Median follow-up was 20 years (range 4-32 years). The 25-year disease-free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25-year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28-1·79]; test of non-inferiority: P = 0·01} was not increased without CRT. The 25-year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25-year event-free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57-1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53-1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL." 5337;"How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?";"PS. ROHRLICH";"Equipe 04, Team 04";31869411;"Blood advances";"Garnache-Ottou F, Vidal C, Biichlé S, Renosi F, Poret E, Pagadoy M, Desmarets M, Roggy A, Seilles E, Soret L, Schillinger F, Puyraimond S, Petrella T, Preudhomme C, Roumier C, MacIntyre EA, Harrivel V, Desbrosses Y, Gruson B, Geneviève F, Thepot S, Drebit Y, Leguay T, Gros FX, Lechevalier N, Saussoy P, Salaun V, Cornet E, Benseddik Z, Veyrat-Masson R, Wagner-Ballon O, Salanoubat C, Maynadié M, Guy J, Caillot D, Jacob MC, Cahn JY, Gressin R, Rose J, Quesnel B, Guerin E, Trimoreau F, Feuillard J, Gourin MP, Plesa A, Baseggio L, Arnoux I, Vey N, Blaise D, Lacroix R, Arnoulet C, Benet B, Dorvaux V, Bret C, Drenou B, Debliquis A, Latger-Cannard V, Bonmati C, Bene MC, Peterlin P, Ticchioni M, Rohrlich PS, Arnaud A, Wickenhauser S, Bardet V, Brechignac S, Papoular B, Raggueneau V, Vargaftig J, Letestu R, Lusina D, Braun T, Foissaud V, Tamburini J, Bennani H, Freynet N, Cordonnier C, Le Garff-Tavernier M, Jacques N, Maloum K, Roos-Weil D, Bouscary D, Asnafi V, Lhermitte L, Suarez F, Lengline E, Féger F, Battipaglia G, Mohty M, Bouyer S, Ghoual O, Dindinaud E, Basle C, Puyade M, Lafon C, Fest T, Roussel M, Cahu X, Bera E, Daliphard S, Jardin F, Campos L, Solly F, Guyotat D, Galoisy AC, Eischen A, Mayeur-Rousse C, Guffroy B, Recher C, Loosveld M, Garnier A, Barlogis V, Rosenthal MA, Brun S, Contentin N, Maury S, Callanan M, Lefebvre C, Maillard N, Okamba P, Ferrand C, Adotevi O, Saas P, Angelot-Delettre F, Binda D, Deconinck E";;"12 2019";1575158400;;"Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure." 5333;"Evaluation of bladder stimulation as a non-invasive technique for urine collection to diagnose urinary tract infection in infants under 6 months: a randomized multicenter study (""EE-Sti.Ve.N"").";"PS. ROHRLICH";"Equipe 04, Team 04";31881992;Trials;"Demonchy D, Ciais C, Fontas E, Berard E, Bréaud J, Rohrlich PS, Dubos F, Fortier C, Desmontils J, Hérisse AL, Donzeau D, Haas H, Tran A";;"Dec 2019";1575158400;;"Febrile urinary tract infection (UTI) is common in infants and needs to be diagnosed quickly. However, the symptoms are non-specific, and diagnosis can only be confirmed after high quality urinalysis. The American Academy of Pediatrics recommends suprapubic aspiration (1-9% contamination) and urinary catheterization (8-14% contamination) for urine collection but both these procedures are invasive. Recent studies have shown a new non-invasive method of collecting urine, bladder stimulation, to be quick and safe. However, few data about bacterial contamination rates have been published for this technique. We hypothesize that the contamination rate of urine collection by bladder stimulation to diagnose febrile UTI in infants under 6 months is equivalent to that of urinary catheterization." 5331;"COVID-19 and acute lymphoblastic leukemias of children and adolescents: First recommendations of the Leukemia committee of the French Society for the fight against Cancers and Leukemias in children and adolescents (SFCE).";"PS. ROHRLICH";"Equipe 04, Team 04";32387061;"Bulletin du cancer";"Baruchel A, Bertrand Y, Boissel N, Brethon B, Ducassou S, Gandemer V, Halfon-Domenech C, Leblanc T, Leverger G, Michel G, Petit A, Ray-Lunven AF, Rohrlich PS, Schneider P, Sirvent N, Strullu M, ";;"Jun 2020";1590969600;;"Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19." 5329;"Impact of detectable measurable residual disease on umbilical cord blood transplantation.";"PS. ROHRLICH";"Equipe 04, Team 04";32449964;"American journal of hematology";"Baron F, Labopin M, Ruggeri A, Sierra J, Robinson S, Labussière-Wallet H, Potter M, Ribera JM, Deconinck E, Rambaldi A, Rohrlich PS, de Revel T, Gluckman E, Nagler A, Mohty M";;"09 2020";1598918400;;"The impact of measurable residual disease (MRD) on cord blood transplantation (CBT) outcomes has remained debated. To address this issue, we assessed the impact of measurable MRD at CBT on outcomes in large cohort of patients with acute leukemia. Inclusion criteria included adult patients with acute myeloid (AML) or acute lymphoblastic leukemia (ALL), CBT as first allo-HCT in first or second complete remission (CR) at transplantation, and known MRD status at the time of CBT. Data from 506 patients were included in the analysis. Among them, 317 patients had AML and 189 had ALL. Positive MRD was reported in 169 (33%) patients while the remaining 337 patients were MRD negative at CBT. At 2 years, relapse incidence was 18% in patients with MRD negativity vs 33% in those with MRD positivity at transplantation (P < .001). Two-year leukemia-free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, vs 38% (P < .001) and 48% (P = .004), respectively, in those with MRD positivity. There was no interaction between the impact of MRD on OS and LFS and diagnosis (ie, ALL vs AML), single or double CBT, and reduced-intensity or myeloablative conditioning. On multivariate analysis, MRD positivity was associated with a higher risk of relapse (HR = 1.8, P = .003), comparable non-relapse mortality (P = .44), worse LFS (HR = 1.4, P = .008) and a trend towards worse OS (HR = 1.3, P = .065). In conclusion, these data suggest that novel strategies that are aiming to achieve MRD negativity at CBT are needed for leukemic patients with positive MRD pre-CBT." 5327;"Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.";"PS. ROHRLICH";"Equipe 04, Team 04";32562208;"Journal of clinical immunology";"Lhomme F, Peyrard T, Babinet J, Abou-Chahla W, Durieu I, Moshous D, Neven B, Rohrlich PS, Albinni S, Amiranoff D, Dumont MD, Lortholary O, Héritier S, Marguet C, Suarez F, Fischer A, Blanche S, Hermine O, Mahlaoui N";;"07 2020";1593561600;;"X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype." 5323;"Pediatric randomized trial EORTC CLG 58951: Outcome for adolescent population with acute lymphoblastic leukemia.";"PS. ROHRLICH";"Equipe 04, Team 04";32809224;"Hematological oncology";"Olivier-Gougenheim L, Arfeuille C, Suciu S, Sirvent N, Plat G, Ferster A, de Moerloose B, Domenech C, Uyttebroeck A, Rohrlich PS, Cavé H, Bertrand Y";;"Dec 2020";1606780800;;"Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B-lineage and 27 had T-lineage ALL. The 8-year event-free survival (EFS) and OS for the B-cell precursor ALL cases were 72.3% (59.4%-81.7%) and 80.8% (67.4%-89.1%), respectively. For the T-lineage, the 8-year EFS and OS were 57.4% (36.1%-74.0%) and 59.0% (36.1%-76.2%), respectively. ""B-other"" ALL, defined as BCP-ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents ""B-other"" genetic abnormalities in ALL is critical to improve the outcome of this population." 5312;"Brown adipose tissue in lean and obese mice. Insulin-receptor binding and tyrosine kinase activity.";"JF. Tanti";"Equipe 07, Team 07";3530852;Diabetes;"Tanti JF, Grémeaux T, Brandenburg D, Van Obberghen E, Le Marchand-Brustel Y";;"Nov 1986";531187200;;"Insulin-receptor binding and tyrosine kinase activity have been studied in brown adipose tissue from lean and obese mice. Brown adipose tissue carries functional insulin receptors comparable with those of conventional insulin target tissues. The alpha-subunit (Mr, 130,000) was labeled with photoreactive insulin; the beta-subunit (Mr, 95,000) was phosphorylated in a cell-free system, and its level of phosphorylation was increased in a dose-dependent manner by insulin. Two types of obese mice, mice rendered obese by gold thioglucose injection (GTG obese) and genetically obese ob/ob mice, were used. Insulin-receptor number was decreased by 60-70% in obese mice, when expressed per milligram of plasma membrane protein or per microgram of glycoprotein, whereas only a 30-40% diminution was observed in skeletal muscle, indicating that insulin receptors from brown adipose tissue are greatly affected by the downregulation process. Insulin-stimulated autophosphorylation of the insulin-receptor beta-subunit was decreased by 60-70% in preparations of obese mice compared with lean mice in direct proportion to the diminished level of insulin-receptor number. Similarly, the ability of receptors to catalyze the phosphorylation of a synthetic substrate (copolymer glutamate-tyrosine) was reduced. These results suggest that the decrease in insulin-receptor number and in associated tyrosine kinase activity could explain the insulin-resistant glucose uptake and the alteration in diet-induced thermogenesis described in obese animals." 5310;"Polymyxin B selectively inhibits insulin effects on transport in isolated muscle.";"JF. Tanti";"Equipe 07, Team 07";3030125;"The American journal of physiology";"Grémeaux T, Tanti JF, Van Obberghen E, Le Marchand-Brustel Y";;"Feb 1987";539136000;;"Polymyxin B (PMB), a cyclic decapeptide antibiotic, inhibits the hypoglycemic effect of insulin in vivo. To elucidate the mechanism of PMB action, we have studied its effect in vitro on insulin-stimulated pathways in the mouse skeletal muscle. PMB, added to the incubation mixture, specifically inhibited insulin-stimulated 2-deoxyglucose transport and alpha-aminoisobutyric acid uptake in the isolated soleus muscle but did not affect the basal rates of transport (measured in the absence of insulin). PMB did not alter insulin binding and hexokinase activity. PMB effect was observed at all deoxyglucose concentrations tested, and PMB was also able to inhibit vanadate-stimulated glucose transport. By contrast, insulin activation of glycogen synthase was not prevented by PMB. Basal and maximally insulin-stimulated insulin receptor tyrosine kinase activity, tested in a cell-free system, was similar for both autophosphorylation and phosphorylation of exogenous substrates in the absence or in the presence of PMB. Furthermore, the insulin sensitivity of the kinase was increased in the presence of PMB. Our results suggest that the anti-insulin effect of PMB observed in vivo is due to an inhibition of insulin-stimulated glucose transport in the skeletal muscle perhaps through a specific blockade of the insulin-induced translocation of the glucose carriers." 5308;"Effect of cyclic AMP-dependent protein kinase on insulin receptor tyrosine kinase activity.";"JF. Tanti";"Equipe 07, Team 07";2822014;"The Biochemical journal";"Tanti JF, Grémeaux T, Rochet N, Van Obberghen E, Le Marchand-Brustel Y";;"Jul 1987";552096000;;"To explain the insulin resistance induced by catecholamines, we studied the tyrosine kinase activity of insulin receptors in a state characterized by elevated noradrenaline concentrations in vivo, i.e. cold-acclimation. Insulin receptors were partially purified from brown adipose tissue of 3-week- or 48 h-cold-acclimated mice. Insulin-stimulated receptor autophosphorylation and tyrosine kinase activity of insulin receptors prepared from cold-acclimated mice were decreased. Since the effect of noradrenaline is mediated by cyclic AMP and cyclic AMP-dependent protein kinase, we tested the effect of the purified catalytic subunit of this enzyme on insulin receptors purified by wheat-germ agglutinin chromatography. The catalytic subunit had no effect on basal phosphorylation, but completely inhibited the insulin-stimulated receptor phosphorylation. Similarly, receptor kinase activity towards exogenous substrates such as histone or a tyrosine-containing copolymer was abolished. This inhibitory effect was observed with receptors prepared from brown adipose tissue, isolated hepatocytes and skeletal muscle. The same results were obtained on epidermal-growth-factor receptors. Further, the catalytic subunit exerted a comparable effect on the phosphorylation of highly purified insulin receptors. To explain this inhibition, we were able to rule out the following phenomena: a change in insulin binding, a change in the Km of the enzyme for ATP, activation of a phosphatase activity present in the insulin-receptor preparation, depletion of ATP, and phosphorylation of a serine residue of the receptor. These results suggest that the alteration in the insulin-receptor tyrosine kinase activity induced by cyclic AMP-dependent protein kinase could contribute to the insulin resistance produced by catecholamines." 5306;"Effect of a thermogenic agent, BRL 26830A, on insulin receptors in obese mice.";"JF. Tanti";"Equipe 07, Team 07";2841863;"The American journal of physiology";"Rochet N, Tanti JF, Grémeaux T, Van Obberghen E, Le Marchand-Brustel Y";;"Aug 1988";586396800;;"The effect of a new type of antidiabetic agent, BRL 26830A, has been tested in obese mice. Since this drug increases thermogenesis, insulin receptor binding and kinase activity were studied in brown adipose tissue and skeletal muscle of mice made obese by gold thioglucose. At 1 mg.kg-1.day-1, a 3-wk treatment normalized the glycemia and increased the uncoupling protein content of brown adipose tissue. The insulin receptor number and its associated kinase activity increased only in brown adipose tissue. At 2 mg.kg-1.day-1, additional effects, i.e., a 20% reduction in body weight and a normalization of insulin receptor number both in brown adipose tissue and in skeletal muscle, were observed. All those results were obtained even though hyperinsulinemia was not corrected. At the higher drug dosage, insulin receptor kinase activity evolved in direct proportion to the receptor number in brown adipose tissue. By contrast, in skeletal muscle, the receptor kinase activity toward exogenous substrates increased more than the receptor number, suggesting that the alteration of insulin receptor kinase activity previously reported in skeletal muscle of obese mice was partly reversed by BRL 26830A. None of these parameters was modified by the drug in lean mice. These results show that, even without affecting obesity, BRL 26830A improves insulin resistance in obese mice, probably through its effect on insulin receptors. This action prevails in brown adipose tissue, supporting the idea that this tissue plays an important role in glucose homeostasis. Thermogenic drugs could thus be powerful agents for the treatment of noninsulin-dependent diabetics." 5304;"[Mechanisms of insulin resistance].";"JF. Tanti";"Equipe 07, Team 07";2668611;"Journees annuelles de diabetologie de l'Hotel-Dieu";"Le Marchand-Brustel Y, Tanti JF, Rochet N, Grémeaux T, Van Obberghen E";;"Jan 1989";599616000;; 5302;"Insulin-stimulated glucose transport in muscle. Evidence for a protein-kinase-C-dependent component which is unaltered in insulin-resistant mice.";"JF. Tanti";"Equipe 07, Team 07";2649084;"The Biochemical journal";"Tanti JF, Rochet N, Grémeaux T, Van Obberghen E, Le Marchand-Brustel Y";;"Feb 1989";602294400;;"The aim of our work was to investigate a possible role of protein kinase C (PKC) in insulin-stimulated glucose uptake in mouse skeletal muscle, and to search for a defect in PKC activation in insulin resistance found in obesity. In isolated soleus muscle of lean mice, insulin (100 nM) and 12-O-tetradecanoylphorbol 13-acetate (TPA) (1 microM) acutely stimulated glucose uptake 3- and 2-fold respectively. The effects of insulin and TPA were not additive. When PKC activity was down-regulated by long-term (24 h) TPA pretreatment, before measurement of glucose transport, the TPA effect was abolished, but in addition insulin-stimulated glucose transport returned to basal values. Furthermore, polymyxin B, which inhibits PKC in muscle extracts, prevented insulin-stimulated glucose uptake in muscle. In muscle of obese insulin-resistant mice, glucose uptake evoked by insulin was decreased, whereas the TPA effect, expressed as a fold increase, was unaltered. Thus both agents stimulated glucose transport to the same extent. Furthermore, no difference was observed when PKC activation by TPA was measured in muscle from lean and obese mice. These results suggest that: (1) PKC is involved in the insulin effect on glucose transport in muscle; (2) PKC activation explains only part of the insulin stimulation of glucose transport; (3) the defect in insulin response in obese mice does not appear to be due to an alteration in the PKC-dependent component of glucose transport. We propose that insulin stimulation of glucose uptake occurs by a sequential two-step mechanism, with first translocation of transporters to the plasma membrane, which is PKC dependent, and second, activation of the glucose transporters. In obesity only the activation step was decreased, whereas the translocation step was unaltered." 5300;"Functional labeling of insulin receptor subunits in live cells. Alpha 2 beta 2 species is the major autophosphorylated form.";"JF. Tanti";"Equipe 07, Team 07";2687278;"The Journal of biological chemistry";"Le Marchand-Brustel Y, Ballotti R, Grémeaux T, Tanti JF, Brandenburg D, Van Obberghen E";;"Dec 1989";628473600;;"Both receptor subunits were functionally labeled in order to provide methods allowing, in live cells and in broken cell systems, concomitant evaluation of the insulin receptor dual function, hormone binding, and kinase activity. In cell-free systems, insulin receptors were labeled on their alpha-subunit with 125I-photoreactive insulin, and on their beta-subunit by autophosphorylation. Thereafter, phosphorylated receptors were separated from the complete set of receptors by means of anti-phosphotyrosine antibodies. Using this approach, a subpopulation of receptors was found which had bound insulin, but which were not phosphorylated. Under nonreducing conditions, receptors appeared in three oligomeric species identified as alpha 2 beta 2, alpha 2 beta, and alpha 2. Mainly the alpha 2 beta 2 receptor species was found to be phosphorylated while insulin was bound to alpha 2 beta 2, alpha 2 beta, and alpha 2 forms. In live cells, biosynthetic labeling of insulin receptors was used. Receptors were first labeled with [35S]methionine. Subsequently, the addition of insulin led to receptor autophosphorylation by virtue of the endogenous ATP pool. The total amount of [35S]methionine-labeled receptors was precipitated with antireceptor antibodies, whereas with anti-phosphotyrosine antibodies, only the phosphorylated receptors were isolated. Using this approach we made the two following key findings: (1) Both receptor species, alpha 2 beta 2 and alpha 2 beta, are present in live cells and in comparable amounts. This indicates that the alpha 2 beta form is not a degradation product of the alpha 2 beta 2 form artificially generated during receptor preparation. (2) The alpha 2 beta 2 species is the prevalently autophosphorylated form." 5298;"Autoantibodies to the insulin receptor are infrequent findings in type 1 (insulin-dependent) diabetes mellitus of recent onset.";"JF. Tanti";"Equipe 07, Team 07";2205528;Diabetologia;"Rochet N, Sadoul JL, Ferrua B, Kubar J, Tanti JF, Bougnères P, Vialettes B, Van Obberghen E, Le Marchand-Brustel Y, Freychet P";;"Jul 1990";646790400;;"To determine whether autoantibodies to the insulin receptor may represent markers of Type 1 (insulin-dependent) diabetes, the prevalence of such antibodies was investigated in sera of 60 newly diagnosed untreated Type 1 diabetic patients. A sensitive assay, based on enzyme linked immunosorbent assay has been set up which detects antibodies to the insulin receptor irrespective of their potentially inhibiting effect on insulin binding. Moreover, this method allows easy determination of the immunoglobulin class involved in the anti-receptor activity. Among the 60 sera examined, only one was found to contain anti-insulin receptor autoantibodies (IgG class). In view of our data, we conclude that autoantibodies to the insulin receptor are infrequent findings in Type 1 diabetes of recent onset." 5296;"Glucose transporter in insulin sensitive tissues of lean and obese mice. Effect of the thermogenic agent BRL 26830A.";"JF. Tanti";"Equipe 07, Team 07";2249621;Endocrinology;"Le Marchand-Brustel Y, Olichon-Berthe C, Grémeaux T, Tanti JF, Rochet N, Van Obberghen E";;"Dec 1990";660009600;;"Glucose transport is decreased in skeletal muscle and adipose tissues of obese, hyperglycemic, insulin-resistant animals. Here we have characterized the glucose transporter(s) in muscle and adipose tissues from normal and obese mice, and we have studied the effect of a treatment with the thermogenic agent BRL 26830A. Glucose transporters were examined in crude tissue membrane fractions (microsomal + plasma membranes) by Western blot analysis using antipeptide antibodies specific for the erythroid (Glut 1) or muscle/fat (Glut 4) glucose transporters. In these insulin sensitive tissues, only Glut 4 was detected. In membranes from obese animals, the Glut 4 number was decreased by 40% +/- 4% in brown adipose tissue (mean +/- SEM of 9 preparations, P less than 0.001), whether the results were expressed per total tissue or per mg of protein. By contrast, Glut 4 number was unchanged in skeletal muscle. In white adipose tissue of obese animals, Glut 4 number per total fat pad was increased. However, due to the enlarged fat pad size, Glut 4 content was diminished when expressed per mg of white adipose tissue membrane protein in obese compared to lean animals. After a 18 day-treatment with BRL 26830A (1 or 2 mg/kg.day), glycemia of obese mice, which was slightly elevated compared to lean animals, was normalized, while insulinemia remained markedly above control values. In brown adipose tissue, the total number of Glut 4 returned to normal at 1 mg of the drug, or increased by 63% +/- 14% at 2 mg. Since membrane protein content was increased by the treatment, when results were expressed per mg of membrane protein, Glut 4 was similar in lean and BRL 26830A (1 or 2 mg) treated obese mice. BRL 26830A treatment did not modify Glut 4 in skeletal muscle, and it increased Glut 4 number in white adipose tissue in a dose-dependent manner. In conclusion, in obese mice, the glucose transporter number was reduced mainly in brown adipose tissue, a defect which could contribute to the hyperglycemic syndrome. Treatment with the thermogenic agent BRL 26830A normalized in parallel glycemia and glucose transporter number in brown adipose tissue, suggesting that this tissue could play a role in glucose homeostasis in rodents." 5294;"Effects of okadaic acid, an inhibitor of protein phosphatases-1 and -2A, on glucose transport and metabolism in skeletal muscle.";"JF. Tanti";"Equipe 07, Team 07";1846612;"The Journal of biological chemistry";"Tanti JF, Grémeaux T, Van Obberghen E, Le Marchand-Brustel Y";;"Feb 1991";665366400;;"The effect of okadaic acid, an inhibitor of protein phosphatases-1 and -2A, was studied on glucose transport and metabolism in soleus muscles isolated from lean and insulin-resistant obese mice. In muscles from lean mice, the uptake of 2-deoxyglucose, an index of glucose transport and phosphorylation, was increased by okadaic acid in a concentration-dependent manner. At 5 microM, okadaic acid was as efficient as a maximally effective insulin concentration. Glucose metabolism (glycolysis and glycogen synthesis) was also measured. Whereas glycolysis was stimulated by okadaic acid, glycogen synthesis was unchanged. When okadaic acid and insulin were added together in the incubation medium, the rates of glucose transport, glycolysis, and glycogen synthesis were similar to those obtained with insulin alone, whether maximal or submaximal insulin concentrations were used. Furthermore, okadaic acid did not activate the kinase activity of the insulin receptor studied in an acellular system or in intact muscles. These results indicate that a step in the insulin-induced stimulation of muscle glucose transport involves a serine/threonine phosphorylation event that is regulated by protein phosphatases-1 and/or -2A. In muscles of insulin-resistant obese mice, the absolute values of deoxyglucose uptake stimulated by okadaic acid were lower than in muscles from lean mice. However, the okadaic acid effect, expressed as a fold stimulation, was normal. These observations suggest that in the insulin-resistant state linked to obesity, the serine/threonine phosphorylation event is likely occurring normally, but a defect at the level of the glucose transporter itself would prevent a normal response to insulin or okadaic acid." 5292;"Subcellular distribution of low molecular weight guanosine triphosphate-binding proteins in adipocytes: colocalization with the glucose transporter Glut 4.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";1954910;Endocrinology;"Cormont M, Tanti JF, Grémeaux T, Van Obberghen E, Le Marchand-Brustel Y";;"Dec 1991";691545600;;"Insulin stimulation of glucose transport involves the translocation of vesicles containing the glucose transporter Glut 4 to the plasma membrane. Since low mol wt GTP-binding proteins (LMW-GTP-binding proteins) have been implicated in the regulation of vesicular trafficking, we have analyzed these proteins in adipocytes. Isolated adipocytes were incubated in the absence or presence of insulin before separation of plasma membranes (PM) and low density microsomes (LDM). [alpha-32P]GTP binding to proteins transferred to nitrocellulose after sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed specific and distinct subsets of proteins in the PM and LDM; those proteins were more abundant in PM than in LDM. [alpha-32P]GTP binding to these proteins was specific for the guanylnucleotides, since it was competed for by GTP and guanosine 5'-O-(3-thiotriphosphate), but not by ATP or adenosine 5'-O-(3-thiotriphosphate). The LMW-GTP-binding proteins were tightly associated with the membranes, as treatment with 1.5 M KCl did not modify this association. The distribution of the LMW-GTP-binding proteins in the fractions and their affinity for guanylnucleotides were the same in control and insulin-treated adipocytes. When the presence of Gi alpha subunits was looked for with a specific antibody, Gi alpha 1 and Gi alpha 2 were found almost exclusively in PM. By contrast, the same antibody revealed the presence of a 100 kDa band in the LDM. Insulin treatment of adipocytes did not modify the amounts of those G-proteins in PM or LDM fractions, although it promoted the translocation of Glut 4 proteins from LDM to PM. LDM fractions contain a specific subset of vesicles markedly enriched in Glut 4 molecules. When those vesicles were isolated from the total LDM fraction by immunoadsorption on highly specific antibodies to Glut 4 protein, LMW-GTP-binding proteins were found in the immune pellet. Those proteins were absent when immunoprecipitation was performed after solubilization of the vesicles with 1% Triton X-100. Our results strongly suggest that the vesicles containing the Glut 4 protein also contained LMW-GTP-binding proteins and indicate that these GTP-binding proteins could play a role in the exocytosis of the Glut 4-containing vesicles." 5290;"Polymyxin B inhibits insulin-induced glucose transporter and IGF II receptor translocation in isolated adipocytes.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";1321040;"European journal of biochemistry";"Cormont M, Gremeaux T, Tanti JF, Van Obberghen E, Le Marchand-Brustel Y";;"Jul 1992";709948800;;"In isolated adipocytes, polymyxin B inhibited insulin-induced glucose incorporation into lipids in a dose-dependent manner, while polymyxin E, a structurally related antibiotic, was ineffective. To approach the mechanism of this effect, the subcellular distribution of the glucose transporter Glut 4 was investigated. Adipocytes were pretreated without or with polymyxin B before insulin stimulation, subcellular fractionation was performed and Glut 4 was detected by immunodetection. Incubation of adipocytes with polymyxin B prevented the insulin-induced appearance of Glut 4 in the plasma membranes, but did not prevent their decrease from the low-density microsomal fraction. A lower purity of the plasma membrane fractions, a detergent effect of polymyxin B on the membranes or an interference of the substance with the immunodetection of the Glut 4 molecules were excluded. These results suggest that polymyxin B was interfering with the Glut 4 translocation process stimulated by insulin in adipocytes. In a similar fashion, polymyxin B inhibited the insulin-induced increase in IGF II binding to adipocytes. This resulted from a blockade of the appearance of IGF II receptors in the plasma membranes. Since low-molecular-mass GTP-binding proteins have been implicated in the regulation of vesicular trafficking, we have used [alpha-32P]GTP binding to analyze such proteins in adipocyte fractions, after SDS/PAGE and transfer to nitrocellulose. Specific and distinct subsets of GTP-binding proteins were revealed in plasma membrane and low-density microsomal fractions of control adipocytes, whether they were stimulated or not with insulin. Polymyxin B treatment of adipocytes markedly modified the profile of the low-molecular-mass GTP-binding proteins in plasma membranes, but not in low-density microsomal fractions. Our results suggest that polymyxin B was interfering with the exocytotic process of the Glut 4 and IGF II receptor-containing vesicles, perhaps at the fusion step between vesicles and plasma membranes." 5288;"Potential involvement of the carboxy-terminus of the Glut 1 transporter in glucose transport.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";1425430;Endocrinology;"Tanti JF, Gautier N, Cormont M, Baron V, Van Obberghen E, Le Marchand-Brustel Y";;"Nov 1992";720576000;;"The role of the carboxy-terminal domain of the Glut 1 glucose transporter was investigated using an antipeptide antibody to the C-terminal part of the molecule. The study was performed in fibroblasts transfected with the cDNA coding for the human insulin receptor. These cells acutely respond to insulin for glucose transport. Using antipeptide antibodies to Glut 1 and Glut 4, we first established that these cells expressed only Glut 1. Then, to define the role of the C-terminal part of Glut 1 in glucose transport, the antibodies were loaded into the cells by electroporation. When anti-Glut 1 immunoglobulins were introduced into the cells, a 60% increase in basal deoxyglucose and 3-O-methylglucose transport was observed compared to that in cells electroporated with nonimmune immunoglobulins. The stimulatory action of the antipeptide was not due to an increase in the total amount of transporters. It was found only at low glucose concentrations, suggesting that the affinity of the transporter, rather than its maximal capacity, was changed. Finally, the effect of antibody was additive to that of insulin. The interaction between the anti-Glut 1 antibody and the carboxy-tail of the transporter seems to lead to an increase in the intrinsic activity of the transporter, suggesting that this part of the molecule could be implicated in the regulation of glucose uptake." 5286;"Defect in skeletal muscle phosphatidylinositol-3-kinase in obese insulin-resistant mice.";"JF. Tanti, S. Giorgetti-Peraldi";"Equipe 07, Team 07";8386184;"The Journal of clinical investigation";"Heydrick SJ, Jullien D, Gautier N, Tanti JF, Giorgetti S, Van Obberghen E, Le Marchand-Brustel Y";;"Apr 1993";733622400;;"Activation of phosphatidylinositol-3-kinase (PI3K) is one of the earliest postreceptor events in the insulin signaling pathway. Incubation of soleus muscles from lean mice with 50 nM insulin caused a 3-10-fold increase in antiphosphotyrosine-immunoprecipitable PI3K (antiPTyr-PI3K) activity within 2 min in muscle homogenates as well as both the cytosolic and membrane fractions. Insulin did not affect total PI3K activity. Both the antiPTyr-PI3K stimulation and activation of insulin receptor tyrosine kinase were dependent on hormone concentration. In muscles from obese, insulin-resistant mice, there was a 40-60% decrease in antiPTyr-PI3K activity after 2 min of insulin that was present equally in the cytosolic and membrane fractions. A significant reduction in insulin sensitivity was also observed. The defect appears to result from alterations in both insulin receptor and postreceptor signaling. Starvation of obese mice for 48 h, which is known to reverse insulin resistance, normalized the insulin response of both PI3K and the receptor tyrosine kinase. The results demonstrate that: (a) antiPTyr-PI3K activity is responsive to insulin in mouse skeletal muscle, (b) both the insulin responsiveness and sensitivity of this activity are blunted in insulin-resistant muscles from obese mice, (c) these alterations result from a combination of insulin receptor and postreceptor defects, and (d) starvation restores normal insulin responses." 5284;"Insulin-like growth factor-I-stimulated glucose transport in myotubes derived from chicken muscle satellite cells.";"JF. Tanti";"Equipe 07, Team 07";8371077;"The Journal of endocrinology";"Duclos MJ, Chevalier B, Le Marchand-Brustel Y, Tanti JF, Goddard C, Simon J";;"Jun 1993";738892800;;"The effects of insulin and insulin-like growth factor-I (IGF-I) on glucose transport were compared in myotubes derived from chicken breast muscle satellite cells in vitro. Myotubes were incubated (for 0.5 or 4 h) with or without glucose in the presence or absence of insulin or IGF-I. Glucose uptake was subsequently measured by the incorporation of 2-[1,2-3H(N)] deoxy-D-glucose ([3H]2DG) in glucose-free medium (10 min at 20 degrees C). Glucose uptake was almost completely abolished by the addition of cytochalasin B or phloretin. It was increased by a decrease in glucose concentration in the incubation medium. Insulin (5 mg/l) stimulated [3H]2DG uptake to a maximum of 43 +/- 10% above basal after 30-min incubation and 101 +/- 15% after 4-h incubation. IGF-I and insulin at equimolar concentrations (25 micrograms/l and 20 micrograms/l respectively) were almost equipotent after 0.5 h but after 4-h incubation IGF-I was 17-fold more potent, suggesting that this 'late' effect was mediated through the IGF-I receptor. Incubation with cycloheximide suggested that the effect of IGF-I involved increased protein synthesis. The results suggest that chicken myotubes express a glucose transporter which is regulated by IGF-I and glucose concentration. However, they do not appear to express a typical insulin-responsive transport system." 5281;"Okadaic acid stimulates IGF-II receptor translocation and inhibits insulin action in adipocytes.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";8392806;"The American journal of physiology";"Tanti JF, Grémeaux T, Cormont M, Van Obberghen E, Le Marchand-Brustel Y";;"Jun 1993";738892800;;"Okadaic acid, an inhibitor of protein phosphatases 2A and 1, stimulates glucose transport in muscle and fat cells, suggesting that serine/threonine phosphorylation steps are involved in the translocation of glucose transporters. Here we have investigated whether such phosphorylation events could also participate in another membrane-associated insulin-stimulated process: insulin-like growth factor II (IGF-II) receptor translocation in adipocytes. Maximally effective concentrations of insulin and okadaic acid stimulated deoxyglucose uptake by 5.5- and 2.5-fold, respectively, whereas IGF-II binding was increased 3.5-fold and 1.5-fold. Subcellular fractionation indicated that the okadaic acid-induced stimulation of IGF-II binding resulted from an increase in the number of IGF-II receptors in the plasma membrane with a concomitant disappearance from the low-density microsomal fraction. These changes occurred in parallel to those observed for the glucose transporter GLUT-4. Both insulin-stimulated glucose transport and IGF-II binding were prevented when cells were pretreated with okadaic acid. To understand the mechanism of this inhibitory effect, insulin receptor autophosphorylation and the tyrosine phosphorylation of endogenous proteins were studied. Insulin induced the tyrosine phosphorylation of its receptor beta-subunit and of proteins at 120 and 185 kDa, whereas okadaic acid alone had no effect. When okadaic acid and insulin were added together, the beta-subunit autophosphorylation was similar to that observed with insulin alone, but the tyrosine phosphorylation of substrates was prevented. Taken together, our data suggest that, in adipocytes, serine/threonine phosphorylation events mimicked by okadaic acid are required for the translocation of IGF-II receptors and glucose transporters.(ABSTRACT TRUNCATED AT 250 WORDS)" 5280;"Differential effects of okadaic acid on insulin-stimulated glucose and amino acid uptake and phosphatidylinositol 3-kinase activity.";"JF. Tanti";"Equipe 07, Team 07";8392070;"The Journal of biological chemistry";"Jullien D, Tanti JF, Heydrick SJ, Gautier N, Grémeaux T, Van Obberghen E, Le Marchand-Brustel Y";;"Jul 1993";741484800;;"The effect of okadaic acid, a serine/threonine phosphatase inhibitor, was analyzed in two insulin-responsive systems, the isolated mouse soleus muscle and 3T3-L1 adipocytes. While okadaic acid alone was a potent stimulator of glucose transport in both systems, it prevented transport stimulation by insulin. To gain insight into this inhibitory action, the activation of phosphatidylinositol 3-kinase (PI3-kinase), one of the earliest postreceptor steps identified so far, was studied. In 3T3-L1 adipocytes and muscle, insulin increased PI3-kinase activity in immunoprecipitates obtained with antibodies to phosphotyrosine. Okadaic acid alone had no effect but strongly inhibited this hormonal action. Okadaic acid treatment did not interfere with insulin-induced receptor autophosphorylation or with its tyrosine kinase activity toward artificial substrates. In contrast, in the presence of the phosphatase inhibitor, we did not observe tyrosine phosphorylation of the insulin receptor cellular substrate p185 (IRS-1) or immunoprecipitation of PI3-kinase by antibodies to phosphotyrosine. These results suggest that okadaic acid interferes with insulin's stimulation of glucose transport by inhibiting IRS-1 phosphorylation and its association with PI3-kinase and/or other signaling molecules. However, okadaic acid did not block the insulin stimulation of aminoisobutyric acid uptake in muscle. This would indicate that IRS-1 phosphorylation and PI3-kinase activation are not required for all the effects of insulin and that the serine/threonine phosphorylation events implicated in the translocation of glucose transporters are not controlling amino acid transport in muscle." 5278;"Insulin and okadaic acid induce Rab4 redistribution in adipocytes.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";8366094;"The Journal of biological chemistry";"Cormont M, Tanti JF, Zahraoui A, Van Obberghen E, Tavitian A, Le Marchand-Brustel Y";;"Sep 1993";748051200;;"Insulin stimulation of glucose transport involves the translocation of vesicles containing the glucose transporter Glut 4 to the plasma membrane. Rab proteins, which have been implicated in the regulation of vesicular traffic, were studied in adipocytes. Rab3B, Rab3C, Rab4, and Rab8 were detected, but Rab3A was not. In the absence of insulin, Rab3B and Rab3C were cytosolic, while Rab4 and Rab8 were associated with membranes. Only Rab4 distribution was modified by insulin. In unstimulated adipocytes, most of Rab4 was found in a low density microsomal fraction, which also contained the majority of Glut 4. After insulin treatment, a 50% decrease in Rab4 content was observed, concomitantly with a departure of transporters to the plasma membrane. The dose responses for the departure of Glut 4 and Rab4 from the microsomal fractions were superimposable, half-maximal effects being obtained with 0.1 nM insulin. Rab4 was redistributed to the cytosol and its movement was reversed by insulin withdrawal. When Glut 4-containing vesicles were immunopurified with antibodies to Glut 4, Rab4 was found in the immune pellets, suggesting that Rab4 was tightly associated with the vesicles. Okadaic acid, an inhibitor of phosphatases 1 and 2A that is known to stimulate Glut 4 translocation, caused the same movement of Rab4 from low density microsomal fraction to the cytosol, while the phorbol ester 12-O-tetradecanoylphorbol-13-acetate had no effect. We suggest that insulin and okadaic acid induce a cycling of Rab4 from a vesicular fraction containing the Glut 4 transporter to the cytosol and that this cycling may participate in the insulin stimulatory action on glucose transporter translocation." 5276;"Rab4 is phosphorylated by the insulin-activated extracellular-signal-regulated kinase ERK1.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";8112321;"European journal of biochemistry";"Cormont M, Tanti JF, Zahraoui A, Van Obberghen E, Le Marchand-Brustel Y";;"Feb 1994";760060800;;"Rab4, a low-molecular-mass GTP-binding protein, is associated with vesicles containing Glut 4 in adipocytes. Following insulin stimulation, the translocation of Glut 4 to the plasma membrane is associated with the movement of Rab4 to the cytosol. The same modifications are induced by the phosphatase inhibitor, okadaic acid. To establish a possible role for phosphorylation in Rab4 cycling, we searched for insulin-stimulated cytosolic kinase(s) which could phosphorylate Rab4. In 3T3-L1 adipocytes, insulin induced a rapid and transient activation of cytosolic kinase(s), which phosphorylated Rab4 in vitro. At least part of the Rab4 phosphorylation can be accounted for by ERK (extracellular-signal-regulated kinases) since immunopurified ERK1 from insulin-stimulated cells phosphorylated Rab4 with a comparable time-course. Both with cytosolic extracts and immunopurified ERK1, only serine residues were phosphorylated on Rab4. The phosphorylation site was localized in the C-terminus of the molecule, and occurred very probably on Ser196. These results indicate that Rab4 is an in vitro substrate for ERK, and suggest that the insulin-induced movement of Rab4 from the Glut-4-containing vesicles to the cytosol could result from phosphorylation of Rab4 by ERK." 5274;"Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling.";"JF. Tanti";"Equipe 07, Team 07";8119950;"The Journal of biological chemistry";"Tanti JF, Grémeaux T, van Obberghen E, Le Marchand-Brustel Y";;"Feb 1994";760060800;;"Treatment of cells with okadaic acid, a protein phosphatase inhibitor, leads to an insulin-resistant state without modification in the tyrosine kinase activity of the receptor toward exogenous substrates. In 3T3-L1 adipocytes, okadaic acid induced a similar dose-dependent inhibition of the insulin effect on deoxyglucose uptake, phosphatidylinositol 3-kinase (PI 3-kinase) activation, and insulin receptor substrate (IRS) 1 tyrosine phosphorylation. Simultaneously, in okadaic acid-treated 3T3-L1 adipocytes, the reduced IRS 1 tyrosine phosphorylation was linked to a decrease in its electrophoretic mobility due to phosphorylation on serine/threonine residues. This phosphorylation appeared to result from the activation of cytosolic kinase(s). Furthermore, using in vitro reconstitution, we show that, compared to IRS 1 immunopurified from untreated cells, the IRS 1 obtained from okadaic acid-treated cells had a reduced capacity to be phosphorylated by insulin receptors and, concomitantly, to bind PI 3-kinase. Taken together these data suggest that serine/threonine phosphorylation of IRS 1 induced by okadaic acid reduces the ability of the insulin receptor to phosphorylate IRS 1 and to dock one of its interacting molecules, i.e. PI 3-kinase. Finally, the inhibitory effect of okadaic acid on the stimulatory action of insulin on glucose transport suggests that the serine/threonine phosphorylation of IRS 1 might represent a key regulatory mechanism of insulin action." 5272;"Expression of guanine-nucleotide-binding proteins in lean and obese insulin-resistant mice.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";8206324;"Molecular and cellular endocrinology";"Cormont M, Tanti JF, Van Obberghen E, Le Marchand-Brustel Y";;"Mar 1994";762480000;;"To examine whether G protein were affected in the obese insulin-resistant state, the level of various G proteins (alpha i1, alpha i2, alpha i3, alpha o and alpha s) was assessed by immunodetection in lean and experimentally induced obese mice. Crude membranes were prepared from adipose tissues, muscle, liver, kidney and brain. G alpha-subunits were similar in lean and obese animals in brain, kidney, skeletal or heart muscle. Hepatic G alpha s, G alpha i2 and G alpha i3 subunits were markedly elevated in obese mice. When total tissue contents were considered, interscapular brown adipose tissue and epididymal fat pads from obese animals contained more alpha i2 than the lean tissues, while alpha i1, alpha i3 and alpha s were similar in both groups. However, when expressed per mg of membrane protein, alpha i1, alpha i3 and alpha s were decreased and alpha i2 was normal in white adipose tissue of obese animals. Thus the expression of the G protein alpha-subunits seems to be regulated by tissue-specific factors rather than by circulating factors." 5270;"Parallel changes in Glut 4 and Rab4 movements in two insulin-resistant states.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";8013658;"FEBS letters";"Ricort JM, Tanti JF, Cormont M, Van Obberghen E, Le Marchand-Brustel Y";;"Jun 1994";770428800;;"Insulin-induced Glut 4 and Rab4 movements were studied in two insulin-resistant states. In adipocytes from streptozotocin diabetic rats, the amount of Glut 4 was decreased by 60%. The remaining Glut 4 molecules were translocated in response to insulin, and in parallel, Rab4 left the intracellular compartment. In contrast, in 3T3-L1 adipocytes rendered insulin-resistant by a prolonged insulin treatment, both Rab4 and Glut 4 remained in the intracellular compartment following an acute insulin stimulation. Those results illustrate a similar behavior of Glut 4 and Rab4 in two situations where insulin resistance results from different mechanisms, and add further support for a role of Rab4 in Glut 4 translocation." 5268;"Insulin receptor substrate 1 is phosphorylated by the serine kinase activity of phosphatidylinositol 3-kinase.";"JF. Tanti";"Equipe 07, Team 07";7998930;"The Biochemical journal";"Tanti JF, Grémeaux T, Van Obberghen E, Le Marchand-Brustel Y";;"Nov 1994";783648000;;"Insulin receptor substrate (IRS) 1, which is tyrosine phosphorylated in response to insulin, presents multiple serine/threonine phosphorylation sites. To search for a serine kinase activity towards IRS 1, immunoprecipitates from basal or stimulated 3T3-L1 adipocytes were used in an in vitro kinase assay. When IRS 1 was isolated from insulin-treated cells, serine phosphorylation of IRS 1 occurred, which we attribute to the kinase activity of the phosphatidylinositol 3-kinase (PI3-kinase). Importantly, in an in vitro reconstitution assay, an excess of the PI3-kinase subunit prevents this phosphorylation. Together, our results suggest that following insulin stimulation, PI3-kinase associates with IRS 1, allowing for its serine phosphorylation. This phosphorylation event could play a role in the modulation of insulin signalling." 5266;"Alterations in insulin signalling pathway induced by prolonged insulin treatment of 3T3-L1 adipocytes.";"JF. Tanti";"Equipe 07, Team 07";8690166;Diabetologia;"Ricort JM, Tanti JF, Van Obberghen E, Le Marchand-Brustel Y";;"Oct 1995";812505600;;"Insulin-induced glucose transport stimulation, which results from the translocation of glucose transporter 4 (GLUT 4)-containing vesicles, is completely blocked after prolonged insulin treatment of 3T3-L1 adipocytes. Since GLUT 4 expression was reduced by only 30%, we looked at the insulin signaling pathway in this insulin-resistant model. Insulin-induced tyrosine phosphorylation of the major insulin receptor substrate IRS 1 was reduced by 50 +/- 7%, while its expression was decreased by 70 +/- 4%. When cells were treated with worthmannin (a PI3-kinase inhibitor) together with insulin, the expression of IRS 1 diminished to a much lower extent. Associated with the decrease in IRS 1 expression and phosphorylation, the activation by insulin of anti-phosphotyrosine immunoprecipitable PI3-kinase activity and of p44mapk activities was altered. However, the expression of these proteins was normal and p44mapk activity remained responsive to the tumour promoter TPA. Those results indicate that prolonged insulin treatment of 3T3-L1 adipocytes induces an insulin-resistant state with a reduced ability of insulin to stimulate the PI3-kinase and the MAP-kinases and a blockade of glucose transporter translocation." 5264;"Different effects of insulin and platelet-derived growth factor on phosphatidylinositol 3-kinase at the subcellular level in 3T3-L1 adipocytes. A possible explanation for their specific effects on glucose transport.";"JF. Tanti";"Equipe 07, Team 07";8706703;"European journal of biochemistry";"Ricort JM, Tanti JF, Van Obberghen E, Le Marchand-Brustel Y";;"Jul 1996";836179200;;"Insulin stimulates glucose uptake by induction of the translocation of vesicles that contain the glucose transporter Glut 4 to the plasma membrane. Phosphatidylinositol 3-kinase (PtdIns 3-kinase), which is thought to be involved in intracellular trafficking, could play a critical role in insulin-induced glucose transport. In 3T3-L1 adipocytes, insulin and platelet-derived-growth-factor (PDGF) stimulated glucose uptake by 5.8-fold and 2.4-fold, respectively, but PDGF had no significant effect on Glut 4 translocation. Nevertheless, both hormones activated PtdIns 3-kinase activity in total cell extracts. However, insulin and PDGF had different effects on the stimulation of PtdIns 3-kinase activity in several subcellular fractions, and the movements of insulin-receptor substrate (IRS) 1 and the p85 subunit of PtdIns 3-kinase between subcellular compartments. PDGF stimulated PtdIns 3-kinase activity almost exclusively in the plasma membrane, and induced translocation of the p85 subunit from the cytosol to the plasma membrane, where the PDGF receptor was phosphorylated on tyrosine residues. In contrast, insulin stimulated PtdIns 3-kinase activity in the plasma membrane, in low-density microsomes (LDM) and in cytosol. Furthermore, insulin induced the translocation of p85 from the cytosol to LDM and the translocation of IRS 1 from LDM to the cytosol. These data indicate that insulin and PDGF have different effects on the activation of PtdIns 3-kinase and on the movement of IRS 1 and PtdIns 3-kinase between subcellular compartments. We would like to suggest that a crucial event in the stimulation of glucose uptake by insulin could be that insulin, but not PDGF, induces activation of PtdIns 3-kinase in the cytosol and in LDM, the compartment enriched in Glut-4-containing vesicles." 5262;"Overexpression of a constitutively active form of phosphatidylinositol 3-kinase is sufficient to promote Glut 4 translocation in adipocytes.";"JF. Tanti";"Equipe 07, Team 07";8810283;"The Journal of biological chemistry";"Tanti JF, Grémeaux T, Grillo S, Calleja V, Klippel A, Williams LT, Van Obberghen E, Le Marchand-Brustel Y";;"Oct 1996";844128000;;"Insulin stimulates glucose transport in its target cells by recruiting the glucose transporter Glut 4 from an intracellular compartment to the cell surface. Previous studies have indicated that phosphatidylinositol 3-kinase (PI 3-kinase) is a necessary step in this insulin action. We have investigated whether PI 3-kinase activation is sufficient to promote Glut 4 translocation in transiently transfected adipocytes. Rat adipose cells were cotransfected with expression vectors that allowed transient expression of epitope-tagged Glut 4 and a constitutively active form of PI 3-kinase (p110*). The expression of p110* induced the appearance of epitope-tagged Glut 4 at the cell surface at a level similar to that obtained after insulin treatment, whereas a kinase-dead version of p110* had no effect. The p110* effect was observed over a wide range of the transfected cDNA. When subcellular fractionation of adipocytes was performed, p110* was found, similar to the endogenous PI 3-kinase, enriched in the low density microsomal compartment, which also contains the Glut 4 vesicles. This could suggest that a specific localization of PI 3-kinase in this compartment is required for the action on Glut 4. The observations made with PI 3-kinase are in contrast with those seen with the MAP kinase cascade. Indeed, a constitutively active form of MAP kinase kinase had no effect on Glut 4 translocation in basal conditions. At the highest degree of expression, the constitutively active form of MAP kinase kinase slightly inhibited the insulin stimulation of Glut 4 translocation. Taken together, our results indicate that Glut 4 translocation can be efficiently promoted by an active form of PI 3-kinase but not by the activation of the MAP kinase pathway." 5260;"Characterization of 6-deoxy-6-iodo-D-glucose: a potential new tool to assess glucose transport.";"JF. Tanti";"Equipe 07, Team 07";9080481;"Nuclear medicine and biology";"Henry C, Tanti JF, Grémeaux T, Morin C, Van Obberghen E, Comet M, Le Marchand-Brustel Y";;"Jan 1997";852076800;;"6-deoxy-6-iodo-D-glucose (6-DIG) was rapidly taken up by adipocytes. Insulin increased 6-DIG transport in adipocytes isolated from both rats and mice. This stimulation was more important in rat than in mouse adipocytes, in agreement with their respective amount of Glut 4 transporters. In two insulin resistant states, the biological behavior of 6-DIG and 3-O-methyl-D-glucose was similar. These results indicated that 6-DIG, which was transported into the cells via the glucose transporters, could be potentially useful to measure modifications of glucose transport." 5258;"Potential role of protein kinase B in glucose transporter 4 translocation in adipocytes.";"JF. Tanti";"Equipe 07, Team 07";9112399;Endocrinology;"Tanti JF, Grillo S, Grémeaux T, Coffer PJ, Van Obberghen E, Le Marchand-Brustel Y";;"May 1997";862444800;;"Phosphatidylinositol 3-kinase (PI 3-kinase) activation promotes glucose transporter 4 (Glut 4) translocation in adipocytes. In this study, we demonstrate that protein kinase B, a serine/threonine kinase stimulated by PI 3-kinase, is activated by both insulin and okadaic acid in isolated adipocytes, in parallel with their effects on Glut 4 translocation. In 3T3-L1 adipocytes, platelet-derived growth factor activated PI 3-kinase as efficiently as insulin but was only half as potent as insulin in promoting protein kinase B (PKB) activation. To look for a potential role of PKB in Glut 4 translocation, adipocytes were transfected with a constitutively active PKB (Gag-PKB) together with an epitope tagged transporter (Glut 4 myc). Gag-PKB was associated with all membrane fractions, whereas the endogenous PKB was mostly cytosolic. Expression of Gag-PKB led to an increase in Glut 4 myc amount at the cell surface. Our results suggest that PKB could play a role in promoting Glut 4 appearance at the cell surface following exposure of adipocytes to insulin and okadaic acid stimulation." 5256;"Cross-talk between the platelet-derived growth factor and the insulin signaling pathways in 3T3-L1 adipocytes.";"JF. Tanti";"Equipe 07, Team 07";9242642;"The Journal of biological chemistry";"Ricort JM, Tanti JF, Van Obberghen E, Le Marchand-Brustel Y";;"Aug 1997";870393600;;"Phosphatidylinositol (PI) 3-kinase is activated by various growth factors such as PDGF (platelet-derived growth factor) and insulin. The aim of the present study was to determine whether PDGF could modulate insulin activation of PI 3-kinase in 3T3-L1 adipocytes. When cells were preincubated for 5-15 min with PDGF, PI 3-kinase activity associated to insulin receptor substrate 1 (IRS 1) in response to insulin was decreased, due to reduced association of the PI 3-kinase p85 subunit with IRS 1. In addition, following this PDGF pretreatment, the tyrosine phosphorylation of IRS 1 in response to insulin and its electrophoretic mobility were diminished. The change in the mobility of IRS 1 could be attributed to PDGF-induced serine/threonine phosphorylation of the protein which was partly inhibited by PI 3-kinase inhibitors. By contrast, epidermal growth factor, which does not stimulate PI 3-kinase, had no effect on the association of PI 3-kinase with IRS 1 in response to insulin. This series of results indicates that the PDGF-induced serine/threonine phosphorylation of IRS 1 could be due to activation of PI 3-kinase pathway. Furthermore, this phosphorylation of IRS 1 is associated with a decrease in its tyrosine phosphorylation by insulin and in its association with the p85 subunit of PI 3-kinase. This study suggests that a cross-talk exists between the different pathways stimulated by PDGF and insulin in intact cells." 5254;"From insulin receptor signalling to Glut 4 translocation abnormalities in obesity and insulin resistance.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";10071760;"Journal of receptor and signal transduction research";"Le Marchand-Brustel Y, Tanti JF, Cormont M, Ricort JM, Grémeaux T, Grillo S";;"Jul Jan 1999";915667200;;"Insulin resistance is commonly associated with obesity in rodents. Using mice made obese with goldthioglucose (GTG-obese mice), we have shown that insulin resistance results from defects at the level of the receptor and from intracellular alterations in insulin signalling pathway, without major alteration in the number of the Glut 4 glucose transporter. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was found to be profoundly affected in response to insulin. This defect appears very early in the development of obesity, together with a marked decrease in IRS 1 tyrosine phosphorylation. In order to better understand the abnormalities in glucose transport in insulin resistance, we have studied the pathway leading from the insulin receptor kinase stimulation to the translocation of the Glut 4 containing vesicles. This stimulation involves the activation of PI 3-kinase, which in turns activates protein kinase B. We have then focussed at the mechanism of vesicle exocytosis, and more specifically at the role of the small GTPase Rab4 in this process. We have shown that Rab4 participates, first in the intracellular retention of the Glut 4 containing vesicles, second in the insulin signalling pathway leading to glucose transporter translocation." 5252;"Peroxovanadate induces tyrosine phosphorylation of phosphoinositide-dependent protein kinase-1 potential involvement of src kinase.";"JF. Tanti";"Equipe 07, Team 07";11054117;"European journal of biochemistry";"Grillo S, Grémeaux T, Casamayor A, Alessi DR, Le Marchand-Brustel Y, Tanti JF";;"Nov 2000";973036800;;"Phosphoinositide-dependent protein kinase-1 (PDK1) is a recently identified kinase that phosphorylates and activates protein kinase B (PKB). Activation of PKB by insulin is linked to its translocation from the cytosol to the plasma membrane. However, no data are available yet concerning the localization of PDK1 in insulin-sensitive tissue. Using isolated adipocytes, we studied the effect of insulin and of an insulin-mimicking agent peroxovanadate on the subcellular localization of PDK1. In unstimulated adipocytes, overexpressed PDK1 was mostly cytosolic with a low amount associated to membranes. Peroxovanadate stimulation induced the redistribution of PDK1 to the membranes while insulin was without effect. This peroxovanadate effect was dependent on phosphatidylinositol 3,4,5 triphosphate [PtdIns(3,4,5)P3] production as inhibition of PtdIns 3-kinase by wortmannin or deletion of the PH domain of PDK1 prevented the peroxovanadate-induced translocation of PDK1. Further, peroxovanadate-treatment induced a tyrosine phosphorylation of PDK1 which was wortmannin insensitive and did not require the PH domain of PDK1. An inhibitor of Src kinase (PP2) decreased the peroxovanadate-induced PDK1 tyrosine phosphorylation and overexpression of v-Src stimulated this phosphorylation. Mutation of tyrosine 373 of PDK1 abolished the v-Src induced PDK1 tyrosine phosphorylation and partially reduced the effect of peroxovanadate. Our findings suggest that PDK1 could be a substrate for tyrosine kinases and identify Src kinase as one of the tyrosine kinases able to phosphorylate PDK1." 5250;"Assays of glucose entry, glucose transporter amount, and translocation.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";11293068;"Methods in molecular biology (Clifton, N.J.)";"Tanti JF, Cormont M, Grémeaux T, Le Marchand-Brustel Y";;"Jan 2001";978307200;; 5248;"The lipid phosphatase SHIP2 controls insulin sensitivity.";"JF. Tanti";"Equipe 07, Team 07";11343120;Nature;"Clément S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S";;"Jan 2001";978307200;;"Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo." 5246;"Molecular mechanism of insulin resistance.";"JF. Tanti";"Equipe 07, Team 07";11994671;"Annales d'endocrinologie";"Le Marchand-Brustel Y, Tanti JF, Grémeaux T, Ricort JM";;"Apr 2002";1017619200;; 5244;"A Crk-II/TC10 signaling pathway is required for osmotic shock-stimulated glucose transport.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";12215429;"The Journal of biological chemistry";"Gual P, Shigematsu S, Kanzaki M, Grémeaux T, Gonzalez T, Pessin JE, Le Marchand-Brustel Y, Tanti JF";;"Nov 2002";1036108800;;"Osmotic shock stimulates the translocation of the glucose transporter Glut 4 to plasma membrane by a tyrosine kinase signaling pathway involving Gab-1 (the Grb2-associated binder-1 protein). We show here that, in response to osmotic shock, Gab-1 acts as a docking protein for phospholipase Cgamma1, the p85 subunit of the phosphoinositide 3-kinase and Crk-II. It has been shown that the adapter Crk-II is constitutively associated with C3G, a GDP to GTP exchange factor for several small GTP-binding proteins. We found that inhibition of the activity of phosphoinositide 3-kinase or phospholipase C did not prevent the stimulation of glucose transport by osmotic shock, whereas inactivation of Rho proteins by Clostridium difficile toxin B severely inhibited glucose uptake. Among the Rho family members, overexpression of dominant-interfering TC10/T31N mutant inhibited osmotic shock-mediated Glut 4 translocation suggesting that TC10 is required for this process. Further, disruption of cortical actin integrity by latrunculin B or jasplakinolide severely impaired osmotic shock-induced glucose transport. In contrast, osmotic shock increased the amount of cortical actin associated with caveolin-enriched plasma membrane domains. These data provide the first evidence that activation of TC10 and remodeling of cortical actin, which could occur through the TC10 signaling, are required for osmotic shock-mediated Glut 4 translocation and glucose uptake." 5242;"Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";12730242;"The Journal of biological chemistry";"Gual P, Gonzalez T, Grémeaux T, Barres R, Le Marchand-Brustel Y, Tanti JF";;"Jul 2003";1057017600;;"In 3T3-L1 adipocytes, hyperosmotic stress was found to inhibit insulin signaling, leading to an insulin-resistant state. We show here that, despite normal activation of insulin receptor, hyperosmotic stress inhibits both tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated phosphoinositide 3 (PI 3)-kinase activity in response to physiological insulin concentrations. Insulin-induced membrane ruffling, which is dependent on PI 3-kinase activation, was also markedly reduced. These inhibitory effects were associated with an increase in IRS-1 Ser307 phosphorylation. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented the osmotic shock-induced phosphorylation of IRS-1 on Ser307. The inhibition of mTOR completely reversed the inhibitory effect of hyperosmotic stress on insulin-induced IRS-1 tyrosine phosphorylation and PI 3-kinase activation. In addition, prolonged osmotic stress enhanced the degradation of IRS proteins through a rapamycin-insensitive pathway and a proteasome-independent process. These data support evidence of new mechanisms involved in osmotic stress-induced cellular insulin resistance. Short-term osmotic stress induces the phosphorylation of IRS-1 on Ser307 by an mTOR-dependent pathway. This, in turn, leads to a decrease in early proximal signaling events induced by physiological insulin concentrations. On the other hand, prolonged osmotic stress alters IRS-1 function by inducing its degradation, which could contribute to the down-regulation of insulin action." 5240;"Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";12765939;Diabetes;"Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP, Laville M, Le Marchand-Brustel Y, Tanti JF, Vidal H";;"Jun 2003";1054425600;;"To understand better the defects in the proximal steps of insulin signaling during type 2 diabetes, we used differentiated human skeletal muscle cells in primary culture. When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. In contrast to IRS-1, the signaling through IRS-2 was not altered. Investigating the causes of the reduced tyrosine phosphorylation of IRS-1, we found a more than twofold increase in the basal phosphorylation of IRS-1 on serine 636 in myotubes from patients with diabetes. Concomitantly, there was a higher basal mitogen-activated protein kinase (MAPK) activity in these cells, and inhibition of the MAPKs with PD98059 strongly reduced the level of serine 636 phosphorylation. These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells." 5238;"MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";14579029;Diabetologia;"Gual P, Grémeaux T, Gonzalez T, Le Marchand-Brustel Y, Tanti JF";;"Nov 2003";1067644800;;"Insulin-induced IRS-1 serine phosphorylation could be physiologically important to regulate insulin action. In a hyperinsulinaemic state such as obesity or Type 2 diabetes, this phosphorylation could be modified and exacerbate insulin resistance. We aimed at identifying serine residues in IRS-1 phosphorylated in response to insulin stimulation and at determining the involved kinases." 5236;"Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";14641015;"Biochemical Society transactions";"Le Marchand-Brustel Y, Gual P, Grémeaux T, Gonzalez T, Barrès R, Tanti JF";;"Dec 2003";1070236800;;"Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor alpha, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser(307) as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser(307) phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes." 5234;"Positive and negative regulation of glucose uptake by hyperosmotic stress.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";14707885;"Diabetes & metabolism";"Gual P, Le Marchand-Brustel Y, Tanti J";;"Dec 2003";1070236800;;"This review will provide insight on the current understanding of the intracellular signaling mechanisms by which hyperosmolarity mimics insulin responses such as Glut 4 translocation and glucose transport but also antagonizes insulin effects. Glucose uptake induced by insulin is largely dependent on the PI 3-kinase/PKB pathway. In both adipocyte and muscle cells, hyperosmolarity promotes glucose uptake by multiple mechanisms which do not require PI 3-kinase/PKB pathway but are dependent on the cell type. In muscle, osmotic stress induces glucose uptake by stimulation of AMP-Kinase and/or inhibition of Glut 4 endocytosis. In adipocytes, activation of Gab1-dependent signaling pathway plays an important role in osmotic stress-mediated glucose uptake. Apart of its insulin-like effects, hyperosmolarity can lead to cellular insulin resistance mediated by both prevention of PKB activation and inhibition of the Insulin Receptor Substrate-1 (IRS1) function. Serine phosphorylation and degradation of IRS1 negatively regulate its functions. Understanding how osmotic stress induces glucose transport or mediates insulin resistance may provide novel targets for strategies to enhance glucose transport or to prevent insulin resistance." 5232;"Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";15122091;"Annales d'endocrinologie";"Tanti JF, Gual P, Grémeaux T, Gonzalez T, Barrès R, Le Marchand-Brustel Y";;"Feb 2004";1075593600;;"Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that ""diabetogenic"" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. Moreover, several kinases able to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which ""diabetogenic"" factors activate IRS-1 kinases and defining the precise role of serine phosphorylation events in IRS-1 regulation represent important goals. Such studies may enable rational drug design to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes." 5229;"Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";15733744;Biochimie;"Gual P, Le Marchand-Brustel Y, Tanti JF";;"Jan 2005";1104537600;;"This review will provide insight on the current understanding of the regulation of insulin signaling in both physiological and pathological conditions through modulations that occur with regards to the functions of the insulin receptor substrate 1 (IRS1). While the phosphorylation of IRS1 on tyrosine residue is required for insulin-stimulated responses, the phosphorylation of IRS1 on serine residues has a dual role, either to enhance or to terminate the insulin effects. The activation of PKB in response to insulin propagates insulin signaling and promotes the phosphorylation of IRS1 on serine residue in turn generating a positive-feedback loop for insulin action. Insulin also activates several kinases and these kinases act to induce the phosphorylation of IRS1 on specific sites and inhibit its functions. This is part of the negative-feedback control mechanism induced by insulin that leads to termination of its action. Agents such as free fatty acids, cytokines, angiotensin II, endothelin-1, amino acids, cellular stress and hyperinsulinemia, which induce insulin resistance, lead to both activation of several serine/threonine kinases and phosphorylation of IRS1. These agents negatively regulate the IRS1 functions by phosphorylation but also via others molecular mechanisms (SOCS expression, IRS degradation, O-linked glycosylation) as summarized in this review. Understanding how these agents inhibit IRS1 functions as well as identification of kinases involved in these inhibitory effects may provide novel targets for development of strategies to prevent insulin resistance." 5228;"Essential role of chicken ovalbumin upstream promoter-transcription factor II in insulin secretion and insulin sensitivity revealed by conditional gene knockout.";"JF. Tanti";"Equipe 07, Team 07";15855320;Diabetes;"Bardoux P, Zhang P, Flamez D, Perilhou A, Lavin TA, Tanti JF, Hellemans K, Gomas E, Godard C, Andreelli F, Buccheri MA, Kahn A, Le Marchand-Brustel Y, Burcelin R, Schuit F, Vasseur-Cognet M";;"May 2005";1114905600;;"Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been implicated in the control of blood glucose by its potent effect on expression and signaling of various nuclear receptors. To understand the role of COUP-TFII in glucose homeostasis, conditional COUP-TFII-deficient mice were generated and crossed with mice expressing Cre under the control of rat insulin II gene promoter, resulting in deletion of COUP-TFII in pancreatic beta-cells. Homozygous mutants died before birth for yet undetermined reasons. Heterozygous mice appeared healthy at birth and showed normal growth and fertility. When challenged intraperitoneally, the animals had glucose intolerance associated with reduced glucose-stimulated insulin secretion. Moreover, these heterozygous mice presented a mild increase in fasting and random-fed circulating insulin levels. In accordance, islets isolated from these animals exhibited higher insulin secretion in low glucose conditions and markedly decreased glucose-stimulated insulin secretion. Their pancreata presented normal microscopic architecture and insulin content up to 16 weeks of study. Altered insulin secretion was associated with peripheral insulin resistance in whole animals. It can be concluded that COUP-TFII is a new, important regulator of glucose homeostasis and insulin sensitivity." 5226;"The interaction between the adaptor protein APS and Enigma is involved in actin organisation.";"JF. Tanti";"Equipe 07, Team 07";15946664;"Experimental cell research";"Barrès R, Gonzalez T, Le Marchand-Brustel Y, Tanti JF";;"Aug 2005";1122854400;;"APS (adaptor protein with PH and SH2 domains) is an adaptor protein phosphorylated by several tyrosine kinase receptors including the insulin receptor. To identify novel binding partners of APS, we performed yeast two-hybrid screening. We identified Enigma, a PDZ and LIM domain-containing protein that was previously shown to be associated with the actin cytoskeleton. In HEK 293 cells, Enigma interacted specifically with APS, but not with the APS-related protein SH2-B. This interaction required the NPTY motif of APS and the LIM domains of Enigma. In NIH-3T3 cells that express the insulin receptor, Enigma and APS were partially co-localised with F-actin in small ruffling structures. Insulin increased the complex formation between APS and Enigma and their co-localisation in large F-actin containing ruffles. While in NIH-3T3 and HeLa cells the co-expression of both Enigma and APS did not modify the actin cytoskeleton organisation, expression of Enigma alone led to the formation of F-actin clusters. Similar alteration in actin cytoskeleton organisation was observed in cells expressing both Enigma and APS with a mutation in the NPTY motif. These results identify Enigma as a novel APS-binding protein and suggest that the APS/Enigma complex plays a critical role in actin cytoskeleton organisation." 5224;"Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.";"JF. Tanti";"Equipe 07, Team 07";16322793;"The Journal of clinical investigation";"Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Grémeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF, Delzenne NM, Postic C, Burcelin R";;"Dec 2005";1133395200;;"Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state." 5221;"Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";16803868;"Molecular endocrinology (Baltimore, Md.)";"Barrès R, Grémeaux T, Gual P, Gonzalez T, Gugenheim J, Tran A, Le Marchand-Brustel Y, Tanti JF";;"Nov 2006";1162339200;;"APS (adaptor protein with PH and SH2 domains) initiates a phosphatidylinositol 3-kinase-independent pathway involved in insulin-stimulated glucose transport. We recently identified Enigma, a PDZ and LIM domain-containing protein, as a partner of APS and showed that APS-Enigma complex plays a critical role in actin cytoskeleton organization in fibroblastic cells. Because actin rearrangement is important for insulin-induced glucose transporter 4 (Glut 4) translocation, we studied the potential involvement of Enigma in insulin-induced glucose transport in 3T3-L1 adipocytes. Enigma mRNA was expressed in differentiated adipocytes and APS and Enigma were colocalized with cortical actin. Expression of an APS mutant unable to bind Enigma increased the insulin-induced Glut 4 translocation to the plasma membrane. By contrast, overexpression of Enigma inhibited insulin-stimulated glucose transport and Glut 4 translocation without alterations in proximal insulin signaling. This inhibitory effect was prevented with the deletion of the LIM domains of Enigma. Using time-lapse fluorescent microscopy of green fluorescent protein-actin, we demonstrated that the overexpression of Enigma altered insulin-induced actin rearrangements, whereas the expression of Enigma without its LIM domains was without effect. A physiological link between increased expression of Enigma and an alteration in insulin-induced glucose uptake was suggested by the increase in Enigma mRNA expression in adipose tissue of diabetic obese patients. Taken together, these data strongly suggest that the interaction between APS and Enigma is involved in insulin-induced Glut 4 translocation by regulating cortical actin remodeling and raise the possibility that modification of APS/Enigma ratio could participate in the alteration of insulin-induced glucose uptake in adipose tissue." 5219;"Differential effects of IRS1 phosphorylated on Ser307 or Ser632 in the induction of insulin resistance by oxidative stress.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";16896943;Diabetologia;"Bloch-Damti A, Potashnik R, Gual P, Le Marchand-Brustel Y, Tanti JF, Rudich A, Bashan N";;"Oct 2006";1159660800;;"Induction of stress kinases leading to serine hyperphosphorylation of IRS1 may link oxidative stress to insulin resistance. The aim of this study was to investigate the roles of the phosphorylated serine residues Ser307 and Ser632, two sites implicated in the inhibition of IRS1 function in insulin signalling." 5217;"Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression.";"JF. Tanti, J. Jager, M. Cormont";"Equipe 07, Team 07";17038556;Endocrinology;"Jager J, Grémeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF";;"Jan 2007";1167609600;;"Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1beta level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. We demonstrated that IL-1beta slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1beta slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes." 5215;"[Obesity, diabetes and insulin resistance. Alterations of insulin signalling].";"F. BOST, JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08, Equipe 05, Team 05";17144167;"Journal de la Societe de biologie";"Le Marchand-Brustel Y, Gual P, Aouadi M, Grémeaux T, Binétruy B, Bost F, Tanti JF";;"Jan 2006";1136073600;;"Obesity is often associated with diabetes and insulin resistance. This review summarizes evidence obtained in our lab on the role of the serine phosphorylation of the insulin receptor substrate 1 in the down regulation of insulin signalling. The role of the ERK1 isoform in the development of adipose tissue and insulin sensitivity is also presented." 5213;"Hepatocyte growth factor induces glucose uptake in 3T3-L1 adipocytes through A Gab1/phosphatidylinositol 3-kinase/Glut4 pathway.";"JF. Tanti, M. Cormont, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";17284447;"The Journal of biological chemistry";"Bertola A, Bonnafous S, Cormont M, Anty R, Tanti JF, Tran A, Le Marchand-Brustel Y, Gual P";;"Apr 2007";1175385600;;"Adipose tissue is a source of hepatocyte growth factor (HGF), and circulating HGF levels have been associated with elevated body mass index in human. However, the effects of HGF on adipocyte functions have not yet been investigated. We show here that in 3T3-L1 adipocytes HGF stimulates the phosphatidylinositol (PI) 3-kinase-dependent protein kinase B (PKB) activity, AS160 phosphorylation, Glut4 translocation, and consequently, glucose uptake. The initial steps involved in HGF- and insulin-induced glucose uptake are different. HGF enhanced the tyrosine phosphorylation of Gab1, leading to the recruitment of the p85-regulated subunit of PI 3-kinase, whereas p85 was exclusively recruited by IRS1 in response to insulin. In adipocytes rendered insulin-resistant by a long-lasting tumor necrosis factor alpha treatment, the protein level of Gab1 was strongly decreased, and HGF-stimulated PKB activation and glucose uptake were also altered. Moreover, treatment of 3T3-L1 adipocytes with thiazolidinedione, an anti-diabetic drug, enhanced the expression of both HGF and its receptor. These data provide the first evidence that in vitro HGF promotes glucose uptake through a Gab1/PI 3-kinase/PKB/AS160 pathway which was altered in tumor necrosis factor alpha-treated adipocytes." 5211;"C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";17426960;Diabetologia;"Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC";;"Jun 2007";1180656000;;"Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding." 5208;"Metabolic endotoxemia initiates obesity and insulin resistance.";"JF. Tanti";"Equipe 07, Team 07";17456850;Diabetes;"Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R";;"Jul 2007";1183248000;;"Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases." 5206;"Osmotic regulation of cellular glucose uptake.";"JF. Tanti, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";17875428;"Methods in enzymology";"Gual P, Gonzalez T, Gremeaux T, Le Marchand-Brustel Y, Tanti JF";;"Jan 2007";1167609600;;"This chapter describes various approaches allowing the study of hyperosmolarity in the functions of 3T3-L1 adipocytes. Hyperosmolarity mimics insulin responses, such as glucose uptake and membrane ruffling, but also antagonizes these insulin effects, which can be evaluated in 3T3-L1 adipocytes. The molecular mechanisms of these effects can be also investigated by measuring the activation of different signaling pathways: (i) the phosphorylation of docking proteins on tyrosine and serine residues (serines 307 and 632), (ii) the phosphorylation of serine/threonine kinases, and (iii) the activation of phosphatidylinositol 3-kinase." 5204;"p38MAP Kinase activity is required for human primary adipocyte differentiation.";"F. BOST, JF. Tanti, J. Jager, M. Cormont";"Equipe 07, Team 07, Equipe 05, Team 05";17997987;"FEBS letters";"Aouadi M, Jager J, Laurent K, Gonzalez T, Cormont M, Binétruy B, Le Marchand-Brustel Y, Tanti JF, Bost F";;"Dec 2007";1196467200;;"Little is known about the role of p38MAPK in human adipocyte differentiation. Here we showed that p38MAPK activity increases during human preadipocytes differentiation. Pharmacological inhibition of p38MAPK during adipocyte differentiation of primary human preadipocytes markedly reduced triglycerides accumulation and adipocyte markers expression. Cell cycle arrest or proliferation was not affected by p38MAPK inhibition. Although induction of C/EBPbeta was not altered by the p38MAPK inhibitor, its phosphorylation on Threonine(188) was decreased as well as PPARgamma expression. These results indicate that p38MAPK plays a positive role in human adipogenesis through regulation of C/EBPbeta and PPARgamma factors." 5202;"The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes.";"JF. Tanti, J. Jager";"Equipe 07, Team 07";19183933;Diabetologia;"Poggi M, Jager J, Paulmyer-Lacroix O, Peiretti F, Gremeaux T, Verdier M, Grino M, Stepanian A, Msika S, Burcelin R, de Prost D, Tanti JF, Alessi MC";;"Jun 2009";1243814400;;"Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation." 5200;"Involvement of TNF-alpha in abnormal adipocyte and muscle sortilin expression in obese mice and humans.";"JF. Tanti, J. Jager, M. Cormont, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";19219422;Diabetologia;"Kaddai V, Jager J, Gonzalez T, Najem-Lendom R, Bonnafous S, Tran A, Le Marchand-Brustel Y, Gual P, Tanti JF, Cormont M";;"May 2009";1241136000;;"Insulin resistance is caused by numerous factors including inflammation. It is characterised by defective insulin stimulation of adipocyte and muscle glucose transport, which requires the glucose transporter GLUT4 translocation towards the plasma membrane. Defects in insulin signalling can cause insulin resistance, but alterations in GLUT4 trafficking could also play a role. Our goal was to determine whether proteins controlling GLUT4 trafficking are altered in insulin resistance linked to obesity." 5198;"Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation.";"JF. Tanti, J. Jager";"Equipe 07, Team 07";19683471;"Current opinion in pharmacology";"Tanti JF, Jager J";;"Dec 2009";1259625600;;"Insulin receptor substrates (IRS) serine phosphorylation is a time-controlled physiological feedback mechanism in insulin signaling that is hijacked by metabolic and inflammatory stresses to promote insulin resistance. Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation. Studies with genetically modified mice reveal that these kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus leading to peripheral and central insulin resistance. Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity. These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication." 5196;"Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis.";"JF. Tanti, J. Jager, M. Cormont, P. GUAL";"Equipe 07, Team 07, Equipe 08, Team 08";19808894;Diabetes;"Jager J, Grémeaux T, Gonzalez T, Bonnafous S, Debard C, Laville M, Vidal H, Tran A, Gual P, Le Marchand-Brustel Y, Cormont M, Tanti JF";;"Jan 2010";1262304000;;"Activation of extracellular signal-regulated kinase-(ERK)-1/2 by cytokines in adipocytes is involved in the alterations of adipose tissue functions participating in insulin resistance. This study aims at identifying proteins regulating ERK1/2 activity, specifically in response to inflammatory cytokines, to provide new insights into mechanisms leading to abnormal adipose tissue function." 5194;"Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy.";"JF. Tanti";"Equipe 07, Team 07";20008564;"The Journal of cell biology";"Risson V, Mazelin L, Roceri M, Sanchez H, Moncollin V, Corneloup C, Richard-Bulteau H, Vignaud A, Baas D, Defour A, Freyssenet D, Tanti JF, Le-Marchand-Brustel Y, Ferrier B, Conjard-Duplany A, Romanino K, Bauché S, Hantaï D, Mueller M, Kozma SC, Thomas G, Rüegg MA, Ferry A, Pende M, Bigard X, Koulmann N, Schaeffer L, Gangloff YG";;"Dec 2009";1259625600;;"Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent." 5192;"Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans.";"F. BOST, JF. Tanti, J. Jager";"Equipe 07, Team 07, Equipe 05, Team 05";20233941;"American journal of physiology. Endocrinology and metabolism";"Dray C, Debard C, Jager J, Disse E, Daviaud D, Martin P, Attané C, Wanecq E, Guigné C, Bost F, Tanti JF, Laville M, Vidal H, Valet P, Castan-Laurell I";;"Jun 2010";1275350400;;"Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/db mice. APJ expression was decreased in both HF-fed and db/db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance." 5190;"Metformin in cancer therapy: a new perspective for an old antidiabetic drug?";"F. BOST, JF. Tanti";"Equipe 07, Team 07, Equipe 05, Team 05";20442309;"Molecular cancer therapeutics";"Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F";;"May 2010";1272672000;;"Metformin is the most widely used antidiabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. First, epidemiological studies show a decrease in cancer incidence in metformin-treated patients. Second, metformin decreases insulin resistance and indirectly reduces insulin level, a beneficial effect because insulin promotes cancer cell growth. Third, several reports outline a direct inhibitory effect of metformin on cancer cell growth and an antitumoral action. Finally, metformin activates the AMP activated protein kinase (AMPK) pathway, a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer." 5188;"The combination of metformin and 2-deoxyglucose inhibits autophagy and induces AMPK-dependent apoptosis in prostate cancer cells.";"F. BOST, JF. Tanti";"Equipe 07, Team 07, Equipe 05, Team 05";20559023;Autophagy;"Ben Sahra I, Tanti JF, Bost F";;"Jul 2010";1277942400;;"Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, and 2-deoxyglucose (2DG) drastically affect cancer cell metabolism. Recently, we showed that the combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone. At the cellular level, this combination leads to p53- and AMPK-dependent apoptosis. Furthermore, we showed that metformin inhibits 2DG-induced autophagy, decreases beclin 1 expression and triggers a switch from a survival process to cell death." 5186;"The combination of metformin and 2 deoxyglucose inhibits autophagy and induces AMPK-dependent apoptosis in prostate cancer cells.";"F. BOST, JF. Tanti";"Equipe 07, Team 07, Equipe 05, Team 05";28157435;Autophagy;"Ben Sahra I, Tanti JF, Bost F";;"Jul 2010";1277942400;;"Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, and 2-deoxyglucose (2DG) drastically affect cancer cell metabolism. Recently, we showed that the combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone. At the cellular level, this combination leads to p53- and AMPK-dependent apoptosis. Furthermore, we showed that metformin inhibits 2DG-induced autophagy, decreases beclin 1 expression and triggers a switch from a survival process to cell death." 5184;"Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity.";"F. BOST, JF. Tanti, J. Jager";"Equipe 07, Team 07, Equipe 05, Team 05";20953578;Diabetologia;"Jager J, Corcelle V, Grémeaux T, Laurent K, Waget A, Pagès G, Binétruy B, Le Marchand-Brustel Y, Burcelin R, Bost F, Tanti JF";;"Jan 2011";1293840000;;"Extracellular signal-regulated kinase (ERK) activity is increased in adipose tissue in obesity and type 2 diabetes mellitus and strong evidences suggests that it is implicated in the downregulation of insulin signalling and action in the insulin-resistant state. To determine the role of ERK1 in obesity-associated insulin resistance in vivo, we inactivated Erk1 (also known as Mapk3) in obese leptin-deficient mice (ob/ob)." 5182;"Metformin and cancer therapy.";"F. BOST, JF. Tanti";"Equipe 07, Team 07, Equipe 05, Team 05";22123231;"Current opinion in oncology";"Bost F, Sahra IB, Le Marchand-Brustel Y, Tanti JF";;"Jan 2012";1325376000;;"To focus on the potential role of metformin, a widely used antidiabetic drug, in cancer treatment." 5180;"Prevention of mutagenesis: new potential mechanisms of metformin action in neoplastic cells.";"F. BOST, JF. Tanti";"Equipe 07, Team 07, Equipe 05, Team 05";22491515;"Cancer prevention research (Philadelphia, Pa.)";"Bost F, Ben-Sahra I, Tanti JF";;"Apr 2012";1333238400;;"Several experimental and epidemiologic studies have shown that the antidiabetes drug metformin has antitumor properties. The report by Algire and colleagues in this issue of the journal (beginning on page 536) shows for the first time that metformin reduces mutagenesis induced by reactive oxygen species. This report offers new perspectives on metformin in cancer prevention and provides a new mechanism for the reduction of cancer risk in diabetic patients treated with this drug." 5178;"Adipose tissue microRNAs as regulators of CCL2 production in human obesity.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";22688341;Diabetes;"Arner E, Mejhert N, Kulyté A, Balwierz PJ, Pachkov M, Cormont M, Lorente-Cebrián S, Ehrlund A, Laurencikiene J, Hedén P, Dahlman-Wright K, Tanti JF, Hayashizaki Y, Rydén M, Dahlman I, van Nimwegen E, Daub CO, Arner P";;"Aug 2012";1343779200;;"In obesity, white adipose tissue (WAT) inflammation is linked to insulin resistance. Increased adipocyte chemokine (C-C motif) ligand 2 (CCL2) secretion may initiate adipose inflammation by attracting the migration of inflammatory cells into the tissue. Using an unbiased approach, we identified adipose microRNAs (miRNAs) that are dysregulated in human obesity and assessed their possible role in controlling CCL2 production. In subcutaneous WAT obtained from 56 subjects, 11 miRNAs were present in all subjects and downregulated in obesity. Of these, 10 affected adipocyte CCL2 secretion in vitro and for 2 miRNAs (miR-126 and miR-193b), regulatory circuits were defined. While miR-126 bound directly to the 3'-untranslated region of CCL2 mRNA, miR-193b regulated CCL2 production indirectly through a network of transcription factors, many of which have been identified in other inflammatory conditions. In addition, overexpression of miR-193b and miR-126 in a human monocyte/macrophage cell line attenuated CCL2 production. The levels of the two miRNAs in subcutaneous WAT were significantly associated with CCL2 secretion (miR-193b) and expression of integrin, α-X, an inflammatory macrophage marker (miR-193b and miR-126). Taken together, our data suggest that miRNAs may be important regulators of adipose inflammation through their effects on CCL2 release from human adipocytes and macrophages." 5176;"Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death.";"F. BOST, JF. Tanti, P. Auberger";"Equipe 07, Team 07, Equipe 02, Team 02, Equipe 05, Team 05";23238567;"Cell death and differentiation";"Ben-Sahra I, Dirat B, Laurent K, Puissant A, Auberger P, Budanov A, Tanti JF, Bost F";;"Apr 2013";1364774400;;"The phosphoinositide-3 kinase/Akt (PI3K/Akt) pathway has a central role in cancer cell metabolism and proliferation. More importantly, it is one of the cardinal pro-survival pathways mediating resistance to apoptosis. The role of Akt in response to an energetic stress is presently unclear. Here, we show that Sestrin2 (Sesn2), also known as Hi95, a p53 target gene that protects cells against oxidative and genotoxic stresses, participates in the protective role of Akt in response to an energetic stress induced by 2-deoxyglucose (2-DG). Sesn2 is upregulated in response to an energetic stress such as 2-DG and metformin, and mediates the inhibition of mammalian target of rapamycin (mTOR), the major cellular regulator of energy metabolism. The increase of Sesn2 is independent of p53 but requires the anti-apoptotic pathway, PI3K/Akt. Inhibition of Akt, as well as loss of Sesn2, sensitizes cells to 2-DG-induced apoptosis. In addition, the rescue of Sesn2 partially reverses the pro-apoptotic effects of 2-DG. In conclusion, we identify Sesn2 as a new energetic stress sensor, which appears to be protective against energetic stress-induced apoptosis that integrates the pro-survival function of Akt and the negative regulation of mTOR." 5174;"Implication of inflammatory signaling pathways in obesity-induced insulin resistance.";"JF. Tanti, J. Jager";"Equipe 07, Team 07";23316186;"Frontiers in endocrinology";"Tanti JF, Ceppo F, Jager J, Berthou F";;"Jan 2012";1325376000;;"Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors (PRRs), including Toll-like receptors (TLR), inflammasome, and nucleotide oligomerization domain (NOD). The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKβ, mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that PRRs and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance." 5172;"[New perspectives for metformin in cancer therapy].";"F. BOST, JF. Tanti";"Equipe 07, Team 07, Equipe 05, Team 05";23587351;"Annales d'endocrinologie";"Loubière C, Dirat B, Tanti JF, Bost F";;"May 2013";1367366400;;"Cancer and type II diabetes are two diseases that appear to be associated. In fact, diabetes increases the incidence of several cancers (colon, endometrium, rectum and breast). Retrospective epidemiological studies show that metformin, a drug commonly used in type II diabetes, has antitumor properties. Therefore, many experimental studies (in vivo and in vitro) have been initiated in recent years to understand the cellular and molecular mechanisms that may explain the protective effects of metformin against cancer. Two main mode of action have been proposed. The first, indirect, involves the decrease of insulinemia. The second, via a direct action on cells, results in the regulation of the activated AMPK kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, which plays a central role in many cellular processes such as energy metabolism, protein synthesis, autophagy and apoptosis. Here, we review recent results concerning the antitumor action of metformin: epidemiological, metabolic, cellular and molecular levels. Ongoing experimental and clinical trials should help us better understand the mechanisms of action of metformin and allow us to determine whether the drug can be used in the treatment of cancer." 5170;"Caloric restriction modulates Mcl-1 expression and sensitizes lymphomas to BH3 mimetic in mice.";"JF. Tanti";"Equipe 07, Team 07";23966420;Blood;"Meynet O, Zunino B, Happo L, Pradelli LA, Chiche J, Jacquin MA, Mondragón L, Tanti JF, Taillan B, Garnier G, Reverso-Meinietti J, Mounier N, Michiels JF, Michalak EM, Carles M, Scott CL, Ricci JE";;"Oct 2013";1380585600;;"Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, the understanding of how CR affects the response to cancer therapy is still rudimentary. Here, using the Eµ-Myc transgenic mouse model of B-cell lymphoma, we report that by reducing protein translation, CR can reduce expression of the prosurvival Bcl-2 family member Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. By using Eµ-Myc lymphoma cells lacking p53, we showed that CR mimetics such as 2-deoxyglucose led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eµ-Myc lymphoma cells lacking the BH3-only proapoptotic members Noxa, Puma, or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim, nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3 mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy. " 5168;"Rab4b controls an early endosome sorting event by interacting with the γ-subunit of the clathrin adaptor complex 1.";"JF. Tanti, J. GILLERON, M. Cormont";"Equipe 07, Team 07";24006255;"Journal of cell science";"Perrin L, Laura P, Lacas-Gervais S, Sandra LG, Gilleron J, Jérôme G, Ceppo F, Franck C, Prodon F, François P, Benmerah A, Alexandre B, Tanti JF, Jean-François T, Cormont M, Mireille C";;"Nov 2013";1383264000;;"The endocytic pathway is essential for cell homeostasis and numerous small Rab GTPases are involved in its control. The endocytic trafficking step controlled by Rab4b has not been elucidated, although recent data suggested it could be important for glucose homeostasis, synaptic homeostasis or adaptive immunity. Here, we show that Rab4b is required for early endosome sorting of transferrin receptors (TfRs) to the recycling endosomes, and we identified the AP1γ subunit of the clathrin adaptor AP-1 as a Rab4b effector and key component of the machinery of early endosome sorting. We show that internalised transferrin (Tf) does not reach Vamp3/Rab11 recycling endosomes in the absence of Rab4b, whereas it is rapidly recycled back to the plasma membrane. By contrast, overexpression of Rab4b leads to the accumulation of internalised Tf within AP-1- and clathrin-coated vesicles. These vesicles are poor in early and recycling endocytic markers except for TfR and require AP1γ for their formation. Furthermore, the targeted overexpression of the Rab4b-binding domain of AP1γ to early endosome upon its fusion with FYVE domains inhibited the interaction between Rab4b and endogenous AP1γ, and perturbed Tf traffic. We thus proposed that the interaction between early endocytic Rab4b and AP1γ could allow the budding of clathrin-coated vesicles for subsequent traffic to recycling endosomes. The data also uncover a novel type of endosomes, characterised by low abundance of either early or recycling endocytic markers, which could potentially be generated in cell types that naturally express high level of Rab4b." 5166;"Implication of the Tpl2 kinase in inflammatory changes and insulin resistance induced by the interaction between adipocytes and macrophages.";"JF. Tanti, J. Jager, M. Cormont";"Equipe 07, Team 07";24424060;Endocrinology;"Ceppo F, Berthou F, Jager J, Dumas K, Cormont M, Tanti JF";;"Mar 2014";1393632000;;"Adipose tissue inflammation is associated with the development of insulin resistance. In obese adipose tissue, lipopolysaccharides (LPSs) and saturated fatty acids trigger inflammatory factors that mediate a paracrine loop between adipocytes and macrophages. However, the inflammatory signaling proteins underlying this cross talk remain to be identified. The mitogen-activated protein kinase kinase kinase tumor progression locus 2 (Tpl2) is activated by inflammatory stimuli, including LPS, and its expression is up-regulated in obese adipose tissue, but its role in the interaction between adipocytes and macrophages remains ill-defined. To assess the implication of Tpl2 in the cross talk between these 2 cell types, we used coculture system and conditioned medium (CM) from macrophages. Pharmacological inhibition of Tpl2 in the coculture markedly reduced lipolysis and cytokine production and prevented the decrease in adipocyte insulin signaling. Tpl2 knockdown in cocultured adipocytes reduced lipolysis but had a weak effect on cytokine production and did not prevent the alteration of insulin signaling. By contrast, Tpl2 silencing in cocultured macrophages resulted in a marked inhibition of cytokine production and prevented the alteration of adipocyte insulin signaling. Further, when Tpl2 was inhibited in LPS-activated macrophages, the produced CM did not alter adipocyte insulin signaling and did not induce an inflammatory response in adipocytes. By contrast, Tpl2 silencing in adipocytes did not prevent the deleterious effects of a CM from LPS-activated macrophages. Together, these data establish that Tpl2, mainly in macrophages, is involved in the cross talk between adipocytes and macrophages that promotes inflammatory changes and alteration of insulin signaling in adipocytes. " 5164;"Inhibition of the GTPase Rac1 mediates the antimigratory effects of metformin in prostate cancer cells.";"F. BOST, F. LARBRET, JF. Tanti, M. Cormont";"Equipe 11, Team 11, Equipe 07, Team 07, Equipe 05, Team 05";25527635;"Molecular cancer therapeutics";"Dirat B, Ader I, Golzio M, Massa F, Mettouchi A, Laurent K, Larbret F, Malavaud B, Cormont M, Lemichez E, Cuvillier O, Tanti JF, Bost F";;"Feb 2015";1422748800;;"Cell migration is a critical step in the progression of prostate cancer to the metastatic state, the lethal form of the disease. The antidiabetic drug metformin has been shown to display antitumoral properties in prostate cancer cell and animal models; however, its role in the formation of metastases remains poorly documented. Here, we show that metformin reduces the formation of metastases to fewer solid organs in an orthotopic metastatic prostate cancer cell model established in nude mice. As predicted, metformin hampers cell motility in PC3 and DU145 prostate cancer cells and triggers a radical reorganization of the cell cytoskeleton. The small GTPase Rac1 is a master regulator of cytoskeleton organization and cell migration. We report that metformin leads to a major inhibition of Rac1 GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex1 (a Guanine nucleotide exchange factor and activator of Rac1), cAMP, and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1, or P-Rex, as well as the inhibition of the adenylate cyclase, was able to reverse the antimigratory effects of metformin. These results establish a novel mechanism of action for metformin and highlight its potential antimetastatic properties in prostate cancer." 5162;"Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells.";"F. BOST, JF. Tanti";"Equipe 07, Team 07, Equipe 05, Team 05";26002551;Oncotarget;"Loubière C, Goiran T, Laurent K, Djabari Z, Tanti JF, Bost F";;"Jun 2015";1433116800;;"The deregulation of lipid metabolism is a hallmark of tumor cells, and elevated lipogenesis has been reported in prostate cancer. Metformin, a drug commonly prescribed for type II diabetes, displays antitumor properties. Here, we show that metformin inhibits lipogenesis in several prostate cancer cell lines. In LNCaP cells, this effect parallels the decrease of key lipogenic proteins: ACC (acetyl-CoA carboxylase), FASN (fatty acid synthase) and SREBP1c (sterol regulatory element binding protein-1c), whereas there is no modification in DU145 and PC3 cells. Despite the relatively high level of lipogenic proteins induced by the overexpression of a constitutively active form of SREBP1c or treatment with androgens, metformin is still able to inhibit lipogenesis. Metformin does not alter the concentration of malonyl-CoA (the fatty acid precursor), and it only slightly decreases the NADPH levels, which is a co-factor required for lipogenesis, in LNCaP. Finally, we show that the inhibitory effect of metformin on lipogenesis is primarily due to a cellular energy deficit. Metformin decreases ATP in a dose-dependent manner, and this diminution is significantly correlated with the inhibition of lipogenesis in LNCaP and DU145. Indeed, the effect of metformin is linked to changes in the ATP content rather than the regulation of protein expression. Our results describe a new mechanism of action for metformin on prostate cancer metabolism. " 5160;"The Tpl2 Kinase Regulates the COX-2/Prostaglandin E2 Axis in Adipocytes in Inflammatory Conditions.";"JF. Tanti, M. Cormont";"Equipe 07, Team 07";26020725;"Molecular endocrinology (Baltimore, Md.)";"Berthou F, Ceppo F, Dumas K, Massa F, Vergoni B, Alemany S, Cormont M, Tanti JF";;"Jul 2015";1435708800;;"Bioactive lipid mediators such as prostaglandin E2 (PGE2) have emerged as potent regulator of obese adipocyte inflammation and functions. PGE2 is produced by cyclooxygenases (COXs) from arachidonic acid, but inflammatory signaling pathways controlling COX-2 expression and PGE2 production in adipocytes remain ill-defined. Here, we demonstrated that the MAP kinase kinase kinase tumor progression locus 2 (Tpl2) controls COX-2 expression and PGE2 secretion in adipocytes in response to different inflammatory mediators. We found that pharmacological- or small interfering RNA-mediated Tpl2 inhibition in 3T3-L1 adipocytes decreased by 50% COX-2 induction in response to IL-1β, TNF-α, or a mix of the 2 cytokines. PGE2 secretion induced by the cytokine mix was also markedly blunted. At the molecular level, nuclear factor κB was required for Tpl2-induced COX-2 expression in response to IL-1β but was inhibitory for the TNF-α or cytokine mix response. In a coculture between adipocytes and macrophages, COX-2 was mainly increased in adipocytes and pharmacological inhibition of Tpl2 or its silencing in adipocytes markedly reduced COX-2 expression and PGE2 secretion. Further, Tpl2 inhibition in adipocytes reduces by 60% COX-2 expression induced by a conditioned medium from lipopolysaccharide (LPS)-treated macrophages. Importantly, LPS was less efficient to induce COX-2 mRNA in adipose tissue explants of Tpl2 null mice compared with wild-type and Tpl2 null mice displayed low COX-2 mRNA induction in adipose tissue in response to LPS injection. Collectively, these data established that activation of Tpl2 by inflammatory stimuli in adipocytes and adipose tissue contributes to increase COX-2 expression and production of PGE2 that could participate in the modulation of adipose tissue inflammation during obesity." 5158;"Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation.";"JF. Tanti, L. Yvan-Charvet";"Equipe 07, Team 07, Equipe 13, Team 13";26411684;"Cell reports";"Sarrazy V, Sore S, Viaud M, Rignol G, Westerterp M, Ceppo F, Tanti JF, Guinamard R, Gautier EL, Yvan-Charvet L";;"Oct 2015";1443657600;;"Enhanced glucose utilization can be visualized in atherosclerotic lesions and may reflect a high glycolytic rate in lesional macrophages, but its causative role in plaque progression remains unclear. We observe that the activity of the carbohydrate-responsive element binding protein ChREBP is rapidly downregulated upon TLR4 activation in macrophages. ChREBP inactivation refocuses cellular metabolism to a high redox state favoring enhanced inflammatory responses after TLR4 activation and increased cell death after TLR4 activation or oxidized LDL loading. Targeted deletion of ChREBP in bone marrow cells resulted in accelerated atherosclerosis progression in Ldlr(-/-) mice with increased monocytosis, lesional macrophage accumulation, and plaque necrosis. Thus, ChREBP-dependent macrophage metabolic reprogramming hinders plaque progression and establishes a causative role for leukocyte glucose metabolism in atherosclerosis. " 5156;"Energy disruptors: rising stars in anticancer therapy?";"F. BOST, JF. Tanti";"Equipe 05, Team 05, Equipe 07, Team 07";26779810;Oncogenesis;"Bost F, Decoux-Poullot AG, Tanti JF, Clavel S";;"Jan 2016";1451606400;;"The metabolic features of tumor cells diverge from those of normal cells. Otto Warburg was the first to observe that cancer cells dramatically increase their glucose consumption to generate ATP. He also claimed that cancer cells do not have functional mitochondria or oxidative phosphorylation (OXPHOS) but simply rely on glycolysis to provide ATP to the cell, even in the presence of oxygen (aerobic glycolysis). Several studies have revisited this observation and demonstrated that most cancer cells contain metabolically efficient mitochondria. Indeed, to sustain high proliferation rates, cancer cells require functional mitochondria to provide ATP and intermediate metabolites, such as citrate and cofactors, for anabolic reactions. This difference in metabolism between normal and tumors cells causes the latter to be more sensitive to agents that can disrupt energy homeostasis. In this review, we focus on energy disruptors, such as biguanides, 2-deoxyglucose and 5-aminoimidazole-4-carboxamide ribonucleotide, that interfere with the main metabolic pathways of the cells, OXPHOS, glycolysis and glutamine metabolism. We discuss the preclinical data and the mechanisms of action of these disruptors at the cellular and molecular levels. Finally, we consider whether these drugs can reasonably contribute to the antitumoral therapeutic arsenal in the future. " 5154;"Inhibition of the MAP3 kinase Tpl2 protects rodent and human β-cells from apoptosis and dysfunction induced by cytokines and enhances anti-inflammatory actions of exendin-4.";"JF. Tanti";"Equipe 07, Team 07";26794660;"Cell death & disease";"Varin EM, Wojtusciszyn A, Broca C, Muller D, Ravier MA, Ceppo F, Renard E, Tanti JF, Dalle S";;"Jan 2016";1451606400;;"Proinflammatory cytokines exert cytotoxic effects on β-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of β-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated β-cells. Although the MAP3 kinase tumor progression locus 2 (Tpl2) is known to integrate signals from inflammatory stimuli in macrophages, fibroblasts and adipocytes, its role in β-cells is unknown. We demonstrate that Tpl2 is expressed in INS-1E β-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation. Tpl2 inhibition protects β-cells, mouse and human islets from cytokine-induced apoptosis and preserves glucose-induced insulin secretion in mouse and human islets exposed to cytokines. Moreover, Tpl2 inhibition does not affect survival or positive effects of glucose (i.e., ERK1/2 phosphorylation and basal insulin secretion). The protection against cytokine-induced β-cell apoptosis is strengthened when Tpl2 inhibition is combined with the glucagon-like peptide-1 (GLP-1) analog exendin-4 in INS-1E cells. Furthermore, when combined with exendin-4, Tpl2 inhibition prevents cytokine-induced death and dysfunction of human islets. This study proposes that Tpl2 inhibitors, used either alone or combined with a GLP-1 analog, represent potential novel and effective therapeutic strategies to protect diabetic β-cells. " 5152;"DNA Damage and the Activation of the p53 Pathway Mediate Alterations in Metabolic and Secretory Functions of Adipocytes.";"A. Jacquel, JF. Tanti, J. GILLERON, M. Cormont, P. Auberger";"Equipe 02, Team 02, Equipe 07, Team 07";27388216;Diabetes;"Vergoni B, Cornejo PJ, Gilleron J, Djedaini M, Ceppo F, Jacquel A, Bouget G, Ginet C, Gonzalez T, Maillet J, Dhennin V, Verbanck M, Auberger P, Froguel P, Tanti JF, Cormont M";;"10 2016";1475280000;;"Activation of the p53 pathway in adipose tissue contributes to insulin resistance associated with obesity. However, the mechanisms of p53 activation and the effect on adipocyte functions are still elusive. Here we found a higher level of DNA oxidation and a reduction in telomere length in adipose tissue of mice fed a high-fat diet and an increase in DNA damage and activation of the p53 pathway in adipocytes. Interestingly, hallmarks of chronic DNA damage are visible at the onset of obesity. Furthermore, injection of lean mice with doxorubicin, a DNA damage-inducing drug, increased the expression of chemokines in adipose tissue and promoted its infiltration by proinflammatory macrophages and neutrophils together with adipocyte insulin resistance. In vitro, DNA damage in adipocytes increased the expression of chemokines and triggered the production of chemotactic factors for macrophages and neutrophils. Insulin signaling and effect on glucose uptake and Glut4 translocation were decreased, and lipolysis was increased. These events were prevented by p53 inhibition, whereas its activation by nutlin-3 reproduced the DNA damage-induced adverse effects. This study reveals that DNA damage in obese adipocytes could trigger p53-dependent signals involved in alteration of adipocyte metabolism and secretory function leading to adipose tissue inflammation, adipocyte dysfunction, and insulin resistance." 5150;"Transfer of dysbiotic gut microbiota has beneficial effects on host liver metabolism.";"JF. Tanti, J. GILLERON, M. Cormont";"Equipe 07, Team 07";28302863;"Molecular systems biology";"Nicolas S, Blasco-Baque V, Fournel A, Gilleron J, Klopp P, Waget A, Ceppo F, Marlin A, Padmanabhan R, Iacovoni JS, Tercé F, Cani PD, Tanti JF, Burcelin R, Knauf C, Cormont M, Serino M";;"03 2017";1488326400;;"Gut microbiota dysbiosis has been implicated in a variety of systemic disorders, notably metabolic diseases including obesity and impaired liver function, but the underlying mechanisms are uncertain. To investigate this question, we transferred caecal microbiota from either obese or lean mice to antibiotic-free, conventional wild-type mice. We found that transferring obese-mouse gut microbiota to mice on normal chow (NC) acutely reduces markers of hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non-inoculated mice, a phenotypic trait blunted in conventional NOD2 KO mice. Furthermore, transferring of obese-mouse microbiota changes both the gut microbiota and the microbiome of recipient mice. We also found that transferring obese gut microbiota to NC-fed mice then fed with a high-fat diet (HFD) acutely impacts hepatic metabolism and prevents HFD-increased hepatic gluconeogenesis compared to non-inoculated mice. Moreover, the recipient mice exhibit reduced hepatic PEPCK and G6Pase activity, fed glycaemia and adiposity. Conversely, transfer of lean-mouse microbiota does not affect markers of hepatic gluconeogenesis. Our findings provide a new perspective on gut microbiota dysbiosis, potentially useful to better understand the aetiology of metabolic diseases." 5146;"ERK1 is dispensable for mouse pancreatic beta cell function but is necessary for glucose-induced full activation of MSK1 and CREB.";"JF. Tanti";"Equipe 07, Team 07";28721437;Diabetologia;"Leduc M, Richard J, Costes S, Muller D, Varrault A, Compan V, Mathieu J, Tanti JF, Pagès G, Pouyssegur J, Bertrand G, Dalle S, Ravier MA";;"10 2017";1506816000;;"Insufficient insulin secretion from pancreatic beta cells, which is associated with a decrease in beta cell mass, is a characteristic of type 2 diabetes. Extracellular signal-related kinase 1 and 2 (ERK1/2) inhibition in beta cells has been reported to affect insulin secretion, gene transcription and survival, although whether ERK1 and ERK2 play distinct roles is unknown. The aim of this study was to assess the individual roles of ERK1 and ERK2 in beta cells using ERK1 (also known as Mapk3)-knockout mice (Erk1 mice) and pharmacological approaches." 5144;"Sirtuin 7: a new marker of aggressiveness in prostate cancer.";"F. BOST, G. Robert, JF. Tanti";"Equipe 05, Team 05, Equipe 02, Team 02, Equipe 07, Team 07";29100388;Oncotarget;"Haider R, Massa F, Kaminski L, Clavel S, Djabari Z, Robert G, Laurent K, Michiels JF, Durand M, Ricci JE, Tanti JF, Bost F, Ambrosetti D";;"Sep 2017";1504224000;;"Predictive biomarkers for advanced prostate cancer (PCa) are still missing. The sirtuin 7 (SIRT7) has been linked to tumorogenesis but its role in prostate cancer is poorly documented. To determine if SIRT7 can be a biomarker for aggressive prostate cancer and plays a role in PCa aggressiveness. We analyzed the expression of SIRT7 by immunohistochemistry in 57 patients comparing healthy with adjacent cancer tissue. SIRT7 levels were significantly elevated in tumors and its expression was positively associated with the grade. We also demonstrated that the knock down of SIRT7 decreased the migration of DU145 and PC3 cells (two androgen-independent prostate cancer cell lines) whereas the overexpression of the native protein but not the mutated form increased the cell migration and the invasion of the poorly aggressive prostate cancer cell line LNCaP. Finally, we also showed that SIRT7 overexpression induced the resistance to docetaxel. Our results demonstrate that SIRT7 promotes prostate cancer cell aggressiveness and chemoresistance and suggest that SIRT7 is a good predictive biomarker of PCa aggressiveness." 5142;"Circulating Levels of Soluble Dipeptidyl Peptidase-4 Are Dissociated from Inflammation and Induced by Enzymatic DPP4 Inhibition.";"JF. Tanti";"Equipe 07, Team 07";30393019;"Cell metabolism";"Varin EM, Mulvihill EE, Beaudry JL, Pujadas G, Fuchs S, Tanti JF, Fazio S, Kaur K, Cao X, Baggio LL, Matthews D, Campbell JE, Drucker DJ";;"02 2019";1548979200;;"Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte Dpp4 expression reduced plasma DPP-4 activity in older mice but did not perturb incretin levels or glucose homeostasis. Knockdown of hepatocyte Dpp4 completely abrogated the obesity-associated increase in plasma DPP-4 activity, reduced liver cytokine expression, and partially attenuated inflammation in adipose tissue without changes in incretin levels or glucose homeostasis. In contrast, circulating levels of soluble DPP4 (sDPP4) were dissociated from inflammation in mice with endothelial-selective or global genetic inactivation of Dpp4. Remarkably, inhibition of DPP-4 enzymatic activity upregulated circulating levels of sDPP4 originating from endothelial or hematopoietic cells without inducing systemic or localized inflammation. Collectively, these findings reveal unexpected complexity in regulation of soluble versus enzymatic DPP-4 and control of inflammation and glucose homeostasis." 5140;"Rab4b Deficiency in T Cells Promotes Adipose Treg/Th17 Imbalance, Adipose Tissue Dysfunction, and Insulin Resistance.";"A. Jacquel, JF. Tanti, J. GILLERON, L. Yvan-Charvet, M. Cormont";"Equipe 02, Team 02, Equipe 07, Team 07, Equipe 13, Team 13";30566860;"Cell reports";"Gilleron J, Bouget G, Ivanov S, Meziat C, Ceppo F, Vergoni B, Djedaini M, Soprani A, Dumas K, Jacquel A, Yvan-Charvet L, Venteclef N, Tanti JF, Cormont M";;"12 2018";1543622400;;"Obesity modifies T cell populations in adipose tissue, thereby contributing to adipose tissue inflammation and insulin resistance. Here, we show that Rab4b, a small GTPase governing endocytic trafficking, is pivotal in T cells for the development of these pathological events. Rab4b expression is decreased in adipose T cells from mice and patients with obesity. The specific depletion of Rab4b in T cells causes adipocyte hypertrophy and insulin resistance in chow-fed mice and worsens insulin resistance in obese mice. This phenotype is driven by an increase in adipose Th17 and a decrease in adipose Treg due to a cell-autonomous skew of differentiation toward Th17. The Th17/Treg imbalance initiates adipose tissue inflammation and reduces adipogenesis, leading to lipid deposition in liver and muscles. Therefore, we propose that the obesity-induced loss of Rab4b in adipose T cells may contribute to maladaptive white adipose tissue remodeling and insulin resistance by altering adipose T cell fate." 5135;"Exploring Adipose Tissue Structure by Methylsalicylate Clearing and 3D Imaging.";"JF. Tanti, J. Jager, J. GILLERON, M. Cormont";"Equipe 07, Team 07";32894273;"Journal of visualized experiments : JoVE";"Gilleron J, Meziat C, Sulen A, Ivanov S, Jager J, Estève D, Muller C, Tanti JF, Cormont M";;"08 2020";1596240000;;"Obesity is a major worldwide public health issue that increases the risk to develop cardiovascular diseases, type-2 diabetes, and liver diseases. Obesity is characterized by an increase in adipose tissue (AT) mass due to adipocyte hyperplasia and/or hypertrophia, leading to profound remodeling of its three-dimensional structure. Indeed, the maximal capacity of AT to expand during obesity is pivotal to the development of obesity-associated pathologies. This AT expansion is an important homeostatic mechanism to enable adaptation to an excess of energy intake and to avoid deleterious lipid spillover to other metabolic organs, such as muscle and liver. Therefore, understanding the structural remodeling that leads to the failure of AT expansion is a fundamental question with high clinical applicability. In this article, we describe a simple and fast clearing method that is routinely used in our laboratory to explore the morphology of mouse and human white adipose tissue by fluorescent imaging. This optimized AT clearing method is easily performed in any standard laboratory equipped with a chemical hood, a temperature-controlled orbital shaker and a fluorescent microscope. Moreover, the chemical compounds used are readily available. Importantly, this method allows one to resolve the 3D AT structure by staining various markers to specifically visualize the adipocytes, the neuronal and vascular networks, and the innate and adaptive immune cells distribution." 5133;"A Citrullus colocynthis fruit extract acutely enhances insulin-induced GLUT4 translocation and glucose uptake in adipocytes by increasing PKB phosphorylation.";"JF. Tanti";"Equipe 07, Team 07";33418030;"Journal of ethnopharmacology";"Drissi F, Lahfa F, Gonzalez T, Peiretti F, Tanti JF, Haddad M, Fabre N, Govers R";;"Apr 2021";1617235200;;"Citrullus colocynthis (L.) Schrad is a common fruit in traditional medicine and used as remedy against various diseases, especially diabetes. Up to now, its anti-diabetic effects have been fully attributed to its enhancement of pancreatic insulin secretion. Whether C. colocynthis also ameliorates insulin action in peripheral tissues has not been investigated." 5131;"Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney.";"JF. Tanti";"Equipe 07, Team 07";33731685;"Cell death & disease";"Cougnon M, Carcy R, Melis N, Rubera I, Duranton C, Dumas K, Tanti JF, Pons C, Soubeiran N, Shkreli M, Hauet T, Pellerin L, Giraud S, Blondeau N, Tauc M, Pisani DF";;"03 2021";1614556800;;"Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin." 5129;"An Adipocyte Cell Culture Model to Study the Impact of Protein and Micro-RNA Modulation on Adipocyte Function.";"JF. Tanti, J. Jager, J. GILLERON, M. Gaudfrin, M. Cormont";"Equipe 07, Team 07";34028435;"Journal of visualized experiments : JoVE";"Jager J, Gaudfrin M, Gilleron J, Cormont M, Tanti JF";;"05 2021";1619827200;;"Alteration of adipocyte function contributes to the pathogenesis of metabolic diseases including Type 2 diabetes and insulin resistance. This highlights the need to better understand the molecular mechanism involved in adipocyte dysfunction to develop new therapies against obesity-related diseases. Modulating the expression of proteins and micro-RNAs in adipocytes remains highly challenging. This paper describes a protocol to differentiate murine fibroblasts into mature adipocytes and to modulate the expression of proteins and micro-RNAs in mature adipocytes through reverse-transfection using small-interfering RNA (siRNA) and micro-RNA mimicking (miR mimic) oligonucleotides. This reverse-transfection protocol involves the incubation of the transfection reagent and the oligonucleotides to form a complex in the cell culture plate to which the mature adipocytes are added. The adipocytes are then allowed to reattach to the adherent plate surface in the presence of the oligonucleotides/transfection reagent complex. Functional analyses such as the study of insulin signaling, glucose uptake, lipogenesis, and lipolysis can be performed on the transfected 3T3-L1 mature adipocytes to study the impact of protein or micro-RNA manipulation on adipocyte function." 5127;"TAXOMET: A French Prospective Multicentric Randomized Phase II Study of Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in Metastatic Castration-Resistant Prostate Cancer.";"F. BOST, JF. Tanti, JM. Ferrero";"Equipe 07, Team 07, Equipe 05, Team 05";34629300;"Clinical genitourinary cancer";"Pujalte Martin M, Borchiellini D, Thamphya B, Guillot A, Paoli JB, Besson D, Hilgers W, Priou F, El Kouri C, Hoch B, Deville JL, Schiappa R, Cheli S, Milano G, Tanti JF, Bost F, Ferrero JM";;"Dec 2021";1638316800;;"Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective studies suggested a decrease in Prostate Cancer incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in Prostate Cancer preclinical models, with increased apoptosis when added to DOCE. We aimed at exploring the role of MET in combination with DOCE in mCRPC." 5119;"L-O-(2-malonyl)tyrosine: a new phosphotyrosyl mimetic for the preparation of Src homology 2 domain inhibitory peptides.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";7473554;"Journal of medicinal chemistry";"Ye B, Akamatsu M, Shoelson SE, Wolf G, Giorgetti-Peraldi S, Yan X, Roller PP, Burke TR";;"Oct 1995";812505600;;"Inhibition of Src homology 2 (SH2) domain-binding interactions affords one potential means of modulating protein-tyrosine kinase-dependent signaling. Small phosphotyrosyl (pTyr)-containing peptides are able to bind to SH2 domains and compete with larger pTyr peptides or native pTyr-containing protein ligands. Such pTyr-containing peptides are limited in their utility as SH2 domain inhibitors in vivo due to their hydrolytic lability to protein-tyrosine phosphatases (PTPs) and the poor cellular penetration of the ionized phosphate moiety. An important aspect of SH2 domain inhibitor design is the creation of pTyr mimetics which are stable to PTPs and have reasonable bioavailability. To date, most PTP-resistant pTyr mimetics which bind to SH2 domains are phosphonates such as (phosphonomethyl)phenylalanine (Pmp, 2), [(monofluorophosphono)methyl]phenylalanine (FPmp, 3) or [(difluorophosphono)methyl]-phenylalanine (F2Pmp, 4). Herein we report the incorporation of a new non-phosphorus-containing pTyr mimetic, L-O-(2-malonyl)tyrosine (L-OMT, 5), into SH2 domain inhibitory peptides using the protected analogue L-N alpha-Fmoc-O'-(O"",O""-di-tert-butyl-2-malonyl)tyrosine (6) and solid-phase peptide synthesis techniques. Five OMT-containing peptides were prepared against the following SH2 domains: the PI-3 kinase C-terminal p85 SH2 domain (Ac-D-(L-OMT)-V-P-M-L-amide, 10, IC50 = 14.2 microM), the Src SH2 domain (Ac-Q-(L-OMT)-E-E-I-P-amide, 11, IC50 = 25 microM, and Ac-Q-(L-OMT)-(L-OMT)-E-I-P-amide, 14, IC50 = 23 microM), the Grb2 SH2 domain (Ac-N-(L-OMT)-V-N-I-E-amide, 12, IC50 = 120 microM), and the N-terminal SH-PTP2 SH2 domain (Ac-L-N-(L-OMT)-I-D-L-D-L-V-amide, 13, IC50 = 22.0 microM). These results show that peptides 10, 11, 13, and 14 have reasonable affinity for their respective SH2 domains, with the IC50 value for the SH-PTP2 SH2 domain-directed peptide 13 being equivalent to that previously observed for the corresponding F2Pmp-containing peptide. OMT may afford a new structural starting point for the development of novel and useful SH2 domain inhibitors." 5117;"Involvement of Janus kinases in the insulin signaling pathway.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";8536716;"European journal of biochemistry";"Giorgetti-Peraldi S, Peyrade F, Baron V, Van Obberghen E";;"Dec 1995";817776000;;"The adaptor molecule growth-factor-receptor-bound protein-2 (Grb2) plays a role in insulin action since it links tyrosine phosphorylated IRS-1 and Shc to the guanine-nucleotide-exchange factor, Sos, which initiates the mitogen-activated-protein (MAP) kinase cascade by producing Ras-GTP. Both IRS-1 and Shc are phosphorylated by the insulin-receptor tyrosine kinase. In the present study, we have investigated whether the tyrosine kinases of the Janus kinase family (JAK) could be involved in insulin signaling by acting on Grb2. In fibroblasts over-expressing insulin receptors we observed that two tyrosine-phosphorylated proteins interact with Grb2 and with a mutant of Grb2, which lacks the Src homology 2 (SH2) domain, indicating that these proteins associate with the SH3 domains of Grb2. Further, we found that both JAK1 and JAK2 constitutively associate with Grb2, through interaction with the SH3 domains of Grb2. Finally, insulin appears to induce the tyrosine phosphorylation of JAK1, but does not modify the tyrosine phosphorylation state of JAK2. In conclusion, our results suggest that the JAK proteins could participate in insulin signal transduction, and could therefore constitute an alternative pathway for mediating some of the pleiotropic responses induced by insulin." 5115;"Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";9006901;"The Journal of biological chemistry";"Frantz JD, Giorgetti-Peraldi S, Ottinger EA, Shoelson SE";;"Jan 1997";852076800;;"cDNA clones encoding human (h) Grb7 and a previously unknown protein with high homology to hGrb-IR and mGrb10 (where m indicates mouse) were found by screening expressed sequence tag data bases. hGrb7 mRNA expression is greatest in pancreas and restricted to a few other tissues. The second protein termed hGrb-IRbeta/Grb10 contains an intact PH domain and lacks the 80-residue mGrb10 insertion. Expression is greatest in pancreas and muscle but occurs in nearly all tissues. hGrb-IRbeta/Grb10 and hGrb-IR likely arise as alternative mRNA splicing products of a common gene. Reverse transcriptase-coupled polymerase chain reaction shows both mRNAs in muscle. In cells, Grb-IRbeta/Grb10 protein translocates from cytosol to membrane upon insulin stimulation, most likely due to direct interactions with the insulin receptor. These interactions are mediated by the SH2 domain and additional regions of the protein. Studies with mutated receptors and synthetic phosphopeptides show that the hGrb-IRbeta/Grb10 SH2 domain binds at least two sites in the insulin receptor: the kinase activation loop > the juxtamembrane site. hGrb-IRbeta/Grb10 also binds a 135-kDa phosphoprotein in unstimulated 3T3-L1 adipocytes; binding is reduced upon insulin stimulation. In addition, the c-Abl SH3 domain binds Grb-IR/Grb10, whereas Fyn, phosphatidylinositol 3-kinase p85, and Grb2 SH3 domains do not. The site of c-Abl SH3 domain interaction is highly conserved within the Grb-IR/Grb10/Grb7/Grb14 family. hGrb-IRbeta/Grb10 also binds platelet-derived growth factor and epidermal growth factor receptors, suggesting a broader role in the signaling pathways of numerous receptors. We conclude that hGrb-IRbeta/Grb10 is a widely expressed, PH and SH2 domain-containing, SH3 domain-binding protein that functions downstream from activated insulin and growth factor receptors." 5113;"Cellular effects of phosphotyrosine-binding domain inhibitors on insulin receptor signaling and trafficking.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";9032245;"Molecular and cellular biology";"Giorgetti-Peraldi S, Ottinger E, Wolf G, Ye B, Burke TR, Shoelson SE";;"Mar 1997";857174400;;"Shc and insulin receptor substrate 1 (IRS-1) are cytoplasmic substrates of tyrosine kinase receptors that engage, localize, and activate downstream SH2 enzymes. Each contains a phosphotyrosine-binding (PTB) domain that is structurally unrelated to SH2 domains. We have designed high-affinity, cellular inhibitors of the Shc PTB domain by incorporating nonnatural, phosphatase-resistant amino acids into short peptides. None of the inhibitors bind the IRS-1 PTB domain, consistent with distinct specificities for domains. The best inhibitor of the Shc domain was introduced by electroporation into Rat1 fibroblasts that express human insulin receptors. Insulin-stimulated phosphorylation of Shc was inhibited, with no effect on IRS-1, and downstream effects on mitogen-activated protein kinase and DNA synthesis were both inhibited. The PTB domain inhibitor had less influence on epidermal growth factor-induced effects and essentially no impact on serum- or phorbol ester-induced effects. The inhibitor did not affect insulin internalization and its degradation. We conclude that the PTB domain of Shc is critical for its phosphorylation by the insulin receptor, that Shc is an important mediator of insulin's mitogenic effects, and that Shc is not central to insulin receptor cycling in these cells. PTB domains can be inhibited selectively in cells and represent potential targets for drug discovery." 5111;"Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";10777488;"The Journal of biological chemistry";"Miele C, Rochford JJ, Filippa N, Giorgetti-Peraldi S, Van Obberghen E";;"Jul 2000";962409600;;"In this study we have investigated the molecular mechanisms of insulin and insulin-like growth factor-I (IGF-I) action on vascular endothelial growth factor (VEGF) gene expression. Treatment with insulin or IGF-I for 4 h increased the abundance of VEGF mRNA in NIH3T3 fibroblasts expressing either the human insulin receptor (NIH-IR) or the human IGF-I receptor (NIH-IGFR) by 6- and 8-fold, respectively. The same elevated levels of mRNA were maintained after 24 h of stimulation with insulin, whereas IGF-I treatment further increased VEGF mRNA expression to 12-fold after 24 h. Pre-incubation with the phosphatidylinositol 3-kinase inhibitor wortmannin abolished the effect of insulin on VEGF mRNA expression in NIH-IR cells but did not modify the IGF-I-induced VEGF mRNA expression in NIH-IGFR cells. Blocking mitogen-activated protein kinase activation with the MEK inhibitor PD98059 abolished the effect of IGF-I on VEGF mRNA expression in NIH-IGFR cells but had no effect on insulin-induced VEGF mRNA expression in NIH-IR cells. Expression of a constitutively active PKB in NIH-IR cells induced the expression of VEGF mRNA, which was not further modified by insulin treatment. We conclude that VEGF induction by insulin and IGF-I occurs via different signaling pathways, the former involving phosphatidylinositol 3-kinase/protein kinase B and the latter involving MEK/mitogen-activated protein kinase." 5109;"The adapter protein, Grb10, is a positive regulator of vascular endothelial growth factor signaling.";"S. Giorgetti-Peraldi, J. Murdaca";"Equipe 07, Team 07, Equipe 09, Team 09";11494124;Oncogene;"Giorgetti-Peraldi S, Murdaca J, Mas JC, Van Obberghen E";;"Jul 2001";993945600;;"Vascular endothelial growth factor (VEGF) is an important regulator of vasculogenesis and angiogenesis. Activation of VEGF receptors leads to the recruitment of SH2 containing proteins which link the receptors to the activation of signaling pathways. Here we report that Grb10, an adapter protein of which the biological role remains unknown, is tyrosine phosphorylated in response to VEGF in endothelial cells (HUVEC) and in 293 cells expressing the VEGF receptor KDR. An intact SH2 domain is required for Grb10 tyrosine phosphorylation in response to VEGF, and this phosphorylation is mediated in part through the activation of Src. In HUVEC, VEGF increases Grb10 mRNA level. Expression of Grb10 in HUVEC or in KDR expressing 293 cells results in an increase in the amount and in the tyrosine phosphorylation of KDR. In 293 cells, this is correlated with the activation of signaling molecules, such as MAP kinase. By expressing mutants of Grb10, we found that the positive action of Grb10 is independent of its SH2 domain. Moreover, these Grb10 effects on KDR seem to be specific since Grb10 has no effect on the insulin receptor, and Grb2, another adapter protein, does not mimic the effect of Grb10 on KDR. In conclusion, we propose that VEGF up-regulates Grb10 level, which in turn increases KDR molecules, suggesting that Grb10 could be involved in a positive feedback loop in VEGF signaling." 5107;"Regulation of vascular endothelial growth factor expression by advanced glycation end products.";"S. Giorgetti-Peraldi, J. Murdaca";"Equipe 07, Team 07, Team 09, Equipe 09";11571295;"The Journal of biological chemistry";"Treins C, Giorgetti-Peraldi S, Murdaca J, Van Obberghen E";;"Nov 2001";1004572800;;"Advanced glycation end products (AGEs) are generated during long term diabetes and are correlated with the development of diabetic complications, such as retinopathy. Diabetic retinopathy is characterized by an increased retinal neovascularization due to the action of the angiogenic factor, vascular endothelial growth factor (VEGF). In this report, we show that injection of insulin and glycated albumin (Alb-AGE) to mice increases VEGF mRNA expression in eyes. Insulin and Alb-AGE stimulate VEGF mRNA and protein expression in retinal epithelial cells (ARPE-19). Alb-AGE-induced VEGF expression is not modulated by the use of antioxidants, N-acetyl-l-cysteine or pyrrolidinedithiocarbamate, or by an inhibitor of phosphatidylinositol 3-kinase (PI3K), wortmannin. However, using an inhibitor of ERK activation, U0126, we show that Alb-AGE stimulates VEGF expression through an ERK-dependent pathway. Accordingly, we found that Alb-AGE activated mitogen-activate protein kinase, ERK1/2, JNK1/2, but not p38, and that Alb-AGE did not activate PI3K and PKB. Moreover, Alb-AGE activated the transcription factor, hypoxia inducible factor-1 (HIF-1) DNA binding activity. This activation is mediated by an increase in accumulation of the HIF-1alpha protein through an ERK-dependent pathway. Thus, stimulation of VEGF expression by Alb-AGE, through the activation of HIF-1, could play an important role in the development of diabetic retinopathy." 5103;"Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway.";"S. Giorgetti-Peraldi, J. Murdaca";"Equipe 07, Team 07, Equipe 09, Team 09";12032158;"The Journal of biological chemistry";"Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E";;"Aug 2002";1028160000;;"Hypoxia-inducible factor 1 (HIF-1) is a transcription factor involved in normal mammalian development and in the pathogenesis of several disease states. It consists of two subunits, HIF-1alpha, which is degraded during normoxia, and HIF-1beta, which is constitutively expressed. Activated HIF-1 induces the expression of genes involved in angiogenesis, erythropoiesis, and glucose metabolism. We have previously reported that insulin stimulates vascular endothelial growth factor (VEGF) expression (). In this study, we show that insulin activates HIF-1, leading to VEGF expression in retinal epithelial cells. Insulin activates HIF-1alpha protein expression in a dose-dependent manner with a maximum reached within 6 h. The expression of HIF-1alpha is correlated with the activation of HIF-1 DNA binding activity and the transactivation of a HIF-1-dependent reporter gene. Insulin does not appear to affect HIF-1alpha mRNA transcription but regulates HIF-1alpha protein expression through a translation-dependent pathway. The expression of an active form of protein kinase B and treatment of cells with specific inhibitors of phosphatidylinositol 3-kinase (PI3K), MAPK, and target of rapamycin (TOR) show that mainly PI3K and to a lesser extent TOR are required for insulin-induced HIF-1alpha expression. HIF-1 activity and VEGF expression are also dependent on PI3K- and TOR-dependent signaling. In conclusion, we show here that insulin regulates HIF-1 action through a PI3K/TOR-dependent pathway, resulting in increased VEGF expression." 5101;"Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation.";"S. Giorgetti-Peraldi, J. Murdaca";"Equipe 07, Team 07, Equipe 09, Team 09";15060076;"The Journal of biological chemistry";"Murdaca J, Treins C, Monthouël-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E, Giorgetti-Peraldi S";;"Jun 2004";1086048000;;"One of the cellular mechanisms used to prevent continuous and enhanced activation in response to growth factors is the internalization and degradation of their receptors. Little is known about the molecular mechanisms involved in vascular endothelial growth factor receptor-2 (VEGF-R2) degradation. In a previous work, we have shown that the adaptor protein Grb10 is a positive regulator of the VEGF signaling pathway. Indeed, VEGF stimulates Grb10 expression, and Grb10 overexpression induces an increase in the amount and the tyrosine phosphorylation of VEGF-R2. In the present manuscript, we demonstrate that Grb10 stimulates VEGF-R2 expression by inhibiting the Nedd4-mediated VEGF-R2 degradation. First, we show that proteasome inhibition by MG132 induces an increase in VEGF-R2 amount, and that VEGF-R2 is ubiquitinated in response to VEGF. Expression of Nedd4, a HECT domain-containing ubiquitin ligase, induces the disappearance of VEGF-R2 in cells, suggesting that Nedd4 is involved in VEGF-R2 degradation. To determine whether Nedd4 directly ubiquitinates VEGF-R2, we expressed a ubiquitin ligase-deficient mutant Nedd4C854S. In the presence of Nedd4C854S, VEGF-R2 is expressed and ubiquitinated. These results suggest that VEGF-R2 is ubiquitinated but that Nedd4 is not involved in this process. Finally, we show that Grb10 constitutively associates with Nedd4. Co-expression of Nedd4 and Grb10 restores the expression of VEGF-R2, suggesting that Grb10 inhibits the Nedd4-mediated degradation of VEGF-R2. In this study, we show that Grb10 acts as a positive regulator in VEGF-R2 signaling and protects VEGF-R2 from degradation by interacting with Nedd4, a component of the endocytic machinery." 5099;"Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I.";"S. Giorgetti-Peraldi, J. Murdaca";"Equipe 07, Team 07, Equipe 05, Team 05";15695372;"Molecular endocrinology (Baltimore, Md.)";"Treins C, Giorgetti-Peraldi S, Murdaca J, Monthouël-Kartmann MN, Van Obberghen E";;"May 2005";1114905600;;"Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of two subunits (HIF-1alpha and HIF-1beta), initially described as a mediator of adaptive responses to changes in tissue oxygenation, has been shown to be activated in an oxygen-independent manner. In this report, we studied the action of IGF-I on the regulation of HIF-1 in human retinal epithelial cells. We show that IGF-I stimulates HIF-1alpha accumulation, HIF-1alpha nuclear translocation, and HIF-1 activity by regulation of HIF-1alpha expression through a posttranscriptional mechanism. In addition, we demonstrate that IGF-I stimulates HIF-1 activity through phosphatidylinositol-3-kinase/ mammalian target of rapamycin and MAPK-dependent signaling pathways leading to VEGF (vascular endothelial growth factor) mRNA expression. Three human prolyl-hydroxylases PHD-1, -2, and -3 (PHD-containing protein) and an asparaginyl-hydroxylase factor inhibiting HIF-1, which regulate HIF-1alpha stability and HIF-1 activity in response to hypoxia, have been described. Our analysis of their mRNA expression showed a different magnitude and time course of expression pattern in response to insulin and IGF-I compared with CoCl(2). Taken together, our data reveal that growth factors and CoCl(2), which mimics hypoxia, lead to HIF-1 activation and ensuing VEGF expression by different mechanisms. Their joined actions are likely to lead to an important and sustained increase in VEGF action on retinal blood vessels, and hence to have devastating effects on the development of diabetic retinopathy." 5097;"AMPK activation inhibits the expression of HIF-1alpha induced by insulin and IGF-1.";"S. Giorgetti-Peraldi, J. Murdaca";"Equipe 07, Team 07, Equipe 09, Team 09";16516166;"Biochemical and biophysical research communications";"Treins C, Murdaca J, Van Obberghen E, Giorgetti-Peraldi S";;"Apr 2006";1143849600;;"Insulin, insulin like growth factor (IGF)-1, and AMP-activated protein kinase (AMPK) signaling regulate independently angiogenesis through vascular endothelial growth factor (VEGF) expression. In the present study, we investigated a potential cross-talk between these signaling pathways on hypoxia-inducible factor (HIF)-1alpha and VEGF expression. Retinal epithelial ARPE-19 cells were treated with AICAR, an AMPK activator, alone or in combination with insulin and IGF-1. AICAR stimulated VEGF mRNA expression, but did not modify the insulin- and IGF-1-induced VEGF expression. We have investigated the effect of AICAR on insulin and IGF-1 signaling pathways. We observed that AICAR increased insulin- and IGF-1-induced phosphorylation of PKB, whereas phosphorylation of S6K-1 was decreased. Moreover, AICAR and metformin inhibited the ability of insulin and IGF-1 to induce HIF-1alpha expression. These results show that AICAR and insulin/IGF-1 regulate VEGF expression through different mechanisms." 5095;"Hrs is a positive regulator of VEGF and insulin signaling.";"S. Giorgetti-Peraldi, J. Murdaca";"Equipe 07, Team 07, Equipe 09, Team 09";17445799;"Experimental cell research";"Hasseine LK, Murdaca J, Suavet F, Longnus S, Giorgetti-Peraldi S, Van Obberghen E";;"May 2007";1177977600;;"Both VEGF and insulin are implicated in the pathogenesis of diabetic retinopathy. While it has been established for many years that the number of cell surface receptors impacts upon VEGF and insulin action, little is known about the precise machinery and proteins driving VEGF-R2 and IR degradation. Here, we investigate the role of Hepatocyte growth factor-Regulated tyrosine kinase Substrate (Hrs), a regulator of RTK trafficking, in VEGF and insulin signaling. We report that ectopic expression of Hrs increases VEGF-R2 and IR number and tyrosine phosphorylation, leading to amplification of their downstream signaling. The UIM (Ubiquitin Interacting Motif) domain of Hrs is required for Hrs-induced increases in VEGF-R2, but not in IR. Furthermore, Hrs is tyrosine-phosphorylated in response to VEGF and insulin. We show that the UIM domain is required for Hrs phosphorylation in response to VEGF, but not to insulin. Importantly, Hrs co-localizes with both VEGF-R2 and IR and co-immunoprecipitates with both in a manner independent of the Hrs-UIM domain. Finally, we demonstrate that Hrs inhibits Nedd4-mediated VEGF-R2 degradation and acts additively with Grb10. We conclude that Hrs is a positive regulator of VEGF-R2 and IR signaling and that ectopic expression of Hrs protects both VEGF-R2 and IR from degradation." 5093;"The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.";"F. BOST, JF. Tanti, P. Auberger, S. Giorgetti-Peraldi";"Equipe 07, Team 07, Equipe 02, Team 02, Equipe 05, Team 05";18212742;Oncogene;"Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F";;"Jun 2008";1212278400;;"Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies." 5087;"Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells.";"F. BOST, F. LARBRET, JF. Tanti, M. Deckert, M. Cormont, P. Auberger, S. Giorgetti-Peraldi";"Equipe 05, Team 05, Equipe 11, Team 11, Equipe 07, Team 07, Equipe 02, Team 02";20215500;"Cancer research";"Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F";;"Mar 2010";1267401600;;"Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, exerts antitumoral and antiproliferative action. In this study, the addition of metformin to 2-deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to 96% inhibition of cell viability in LNCaP prostate cancer cells. In contrast, a moderate effect on cell viability was observed in normal prostate epithelial cells. At the cellular level, the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase, and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity. In addition to apoptosis, the combination of metformin and 2DG arrested prostate cancer cells in G(2)-M. This G(2)-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug. Finally, metformin inhibited 2DG-induced autophagy, decreased beclin 1 expression, and triggered a switch from a survival process to cell death. Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment." 5085;"A serum factor induces insulin-independent translocation of GLUT4 to the cell surface which is maintained in insulin resistance.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";21187969;"PloS one";"Berenguer M, Martinez L, Giorgetti-Peraldi S, Le Marchand-Brustel Y, Govers R";;"Dec 2010";1291161600;;"In response to insulin, glucose transporter GLUT4 translocates from intracellular compartments towards the plasma membrane where it enhances cellular glucose uptake. Here, we show that sera from various species contain a factor that dose-dependently induces GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes, human adipocytes, myoblasts and myotubes. Notably, the effect of this factor on GLUT4 is fully maintained in insulin-resistant cells. Our studies demonstrate that the serum-induced increase in cell surface GLUT4 levels is not due to inhibition of its internalization and is not mediated by insulin, PDGF, IGF-1, or HGF. Similarly to insulin, serum also augments cell surface levels of GLUT1 and TfR. Remarkably, the acute effect of serum on GLUT4 is largely additive to that of insulin, while it also sensitizes the cells to insulin. In accordance with these findings, serum does not appear to activate the same repertoire of downstream signaling molecules that are implicated in insulin-induced GLUT4 translocation. We conclude that in addition to insulin, at least one other biological proteinaceous factor exists that contributes to GLUT4 regulation and still functions in insulin resistance. The challenge now is to identify this factor." 5083;"Inhibition of hedgehog signaling decreases proliferation and clonogenicity of human mesenchymal stem cells.";"S. Giorgetti-Peraldi, P. Peraldi";"Equipe 07, Team 07, Equipe 05, Team 05";21304817;"PloS one";"Plaisant M, Giorgetti-Peraldi S, Gabrielson M, Loubat A, Dani C, Peraldi P";;"Feb 2011";1296518400;;"Human mesenchymal stem cells (hMSC) have the ability to differentiate into osteoblasts, adipocytes and chondrocytes. We have previously shown that hMSC were endowed with a basal level of Hedgehog signaling that decreased after differentiation of these cells. Since hMSC differentiation is associated with growth-arrest we investigated the function of Hh signaling on cell proliferation. Here, we show that inhibition of Hh signaling, using the classical inhibitor cyclopamine, or a siRNA directed against Gli-2, leads to a decrease in hMSC proliferation. This phenomenon is not linked to apoptosis but to a block of the cells in the G0/G1 phases of the cell cycle. At the molecular level, it is associated with an increase in the active form of pRB, and a decrease in cyclin A expression and MAP kinase phosphorylation. Inhibition of Hh signaling is also associated with a decrease in the ability of the cells to form clones. By contrast, inhibition of Hh signaling during hMSC proliferation does not affect their ability to differentiate. This study demonstrates that hMSC are endowed with a basal Hedgehog signaling activity that is necessary for efficient proliferation and clonogenicity of hMSC. This observation unravels an unexpected new function for Hedgehog signaling in the regulation of human mesenchymal stem cells and highlights the critical function of this morphogen in hMSC biology." 5077;"[Implication of MAP kinases in obesity-induced inflammation and insulin resistance].";"F. BOST, JF. Tanti, J. Jager, M. Cormont, S. Giorgetti-Peraldi";"Equipe 07, Team 07, Equipe 05, Team 05";25190570;"Biologie aujourd'hui";"Ceppo F, Jager J, Berthou F, Giorgetti-Peraldi S, Cormont M, Bost F, Tanti JF";;"Jan 2014";1388534400;;"Insulin resistance is often associated with obesity and is a major risk factor for development of type 2 diabetes as well as cardiovascular and hepatic diseases. Insulin resistance may also increase the incidence or the aggressiveness of some cancers. Insulin resistance occurs owing to defects in insulin signaling in target tissues of this hormone. During the last ten years, it became evident that the chronic low-grade inflammatory state that develops during obesity plays an important role in insulin resistance development. Indeed, inflammatory cytokines activate several signaling pathways that impinge on the insulin signaling pathway. Among them, this review will focus on the implication of the MAP kinases JNK and ERK1/2 signaling in the development of insulin signaling alterations and will discuss the possibility to target these pathways in order to fight insulin resistance. " 5073;"Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletal muscle.";"S. Giorgetti-Peraldi, P. Peraldi";"Equipe 07, Team 07, Equipe 05, Team 05";25906156;"Cell death & disease";"Arrighi N, Moratal C, Clément N, Giorgetti-Peraldi S, Peraldi P, Loubat A, Kurzenne JY, Dani C, Chopard A, Dechesne CA";;"Apr 2015";1427846400;;"A population of fibro/adipogenic but non-myogenic progenitors located between skeletal muscle fibers was recently discovered. The aim of this study was to determine the extent to which these progenitors differentiate into fully functional adipocytes. The characterization of muscle progenitor-derived adipocytes is a central issue in understanding muscle homeostasis. They are considered as being the cellular origin of intermuscular adipose tissue that develops in several pathophysiological situations. Here fibro/adipogenic progenitors were isolated from a panel of 15 human muscle biopsies on the basis of the specific cell-surface immunophenotype CD15+/PDGFRα+CD56-. This allowed investigations of their differentiation into adipocytes and the cellular functions of terminally differentiated adipocytes. Adipogenic differentiation was found to be regulated by the same effectors as those regulating differentiation of progenitors derived from white subcutaneous adipose tissue. Similarly, basic adipocyte functions, such as triglyceride synthesis and lipolysis occurred at levels similar to those observed with subcutaneous adipose tissue progenitor-derived adipocytes. However, muscle progenitor-derived adipocytes were found to be insensitive to insulin-induced glucose uptake, in association with the impairment of phosphorylation of key insulin-signaling effectors. Our findings indicate that muscle adipogenic progenitors give rise to bona fide white adipocytes that have the unexpected feature of being insulin-resistant." 5071;"Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice.";"L. Yvan-Charvet, S. Giorgetti-Peraldi";"Equipe 13, Equipe 07, Team 07, Team 13";26926469;"Circulation research";"Sarrazy V, Viaud M, Westerterp M, Ivanov S, Giorgetti-Peraldi S, Guinamard R, Gautier EL, Thorp EB, De Vivo DC, Yvan-Charvet L";;"Apr 2016";1459468800;;"Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with (18)F-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood." 5067;"The primary cilium is necessary for the differentiation and the maintenance of human adipose progenitors into myofibroblasts.";"S. Giorgetti-Peraldi, P. Peraldi";"Equipe 07, Team 07, Equipe 05, Team 05";29127365;"Scientific reports";"Arrighi N, Lypovetska K, Moratal C, Giorgetti-Peraldi S, Dechesne CA, Dani C, Peraldi P";;"11 2017";1509494400;;"The primary cilium is an organelle, present at the cell surface, with various biological functions. We, and others, have shown that it plays a role in the differentiation of adipose progenitors (APs) into adipocytes. APs can also differentiate into myofibroblasts when treated with TGF-β1. Several components of the TGF-β1 pathway are located within the cilium suggesting a function for this organelle in AP myofibrogenesis. We studied differentiation of APs into myofibroblasts in two human models: APs of the adipose tissue (aAPs) and APs resident in the skeletal muscles (mAPs). We showed that, in vivo, myofibroblasts within muscles of patients with Duchenne Muscular Dystrophy were ciliated. In vitro, myofibroblasts derived from APs maintained a functional primary cilium. Using HPI4, a small molecule that inhibits ciliogenesis, and siRNA against Kif-3A, we provide evidence that the primary cilium is necessary both for the differentiation of APs into myofibroblasts and the maintenance of the phenotype. Disruption of the primary cilium inhibited TGF-β1-signalisation providing a molecular mechanism by which the cilium controls myofibroblast differentiation. These data suggest that myofibroblasts from various origins are controlled differently by their primary cilium." 5065;"Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";29895328;"BMC biology";"Britto FA, Cortade F, Belloum Y, Blaquière M, Gallot YS, Docquier A, Pagano AF, Jublanc E, Bendridi N, Koechlin-Ramonatxo C, Chabi B, Francaux M, Casas F, Freyssenet D, Rieusset J, Giorgetti-Peraldi S, Carnac G, Ollendorff V, Favier FB";;"06 2018";1527811200;;"Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses." 5063;"Is REDD1 a metabolic double agent? Lessons from physiology and pathology.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";32877205;"American journal of physiology. Cell physiology";"Britto FA, Dumas K, Giorgetti-Peraldi S, Ollendorff V, Favier FB";;"11 2020";1604188800;;"The Akt/mechanistic target of rapamycin (mTOR) signaling pathway governs macromolecule synthesis, cell growth, and metabolism in response to nutrients and growth factors. Regulated in development and DNA damage response (REDD)1 is a conserved and ubiquitous protein, which is transiently induced in response to multiple stimuli. Acting like an endogenous inhibitor of the Akt/mTOR signaling pathway, REDD1 protein has been shown to regulate cell growth, mitochondrial function, oxidative stress, and apoptosis. Recent studies also indicate that timely REDD1 expression limits Akt/mTOR-dependent synthesis processes to spare energy during metabolic stresses, avoiding energy collapse and detrimental consequences. In contrast to this beneficial role for metabolic adaptation, REDD1 chronic expression appears involved in the pathogenesis of several diseases. Indeed, REDD1 expression is found as an early biomarker in many pathologies including inflammatory diseases, cancer, neurodegenerative disorders, depression, diabetes, and obesity. Moreover, prolonged REDD1 expression is associated with cell apoptosis, excessive reactive oxygen species (ROS) production, and inflammation activation leading to tissue damage. In this review, we decipher several mechanisms that make REDD1 a likely metabolic double agent depending on its duration of expression in different physiological and pathological contexts. We also discuss the role played by REDD1 in the cross talk between the Akt/mTOR signaling pathway and the energetic metabolism." 5061;"The Primary Cilium of Adipose Progenitors Is Necessary for Their Differentiation into Cancer-Associated Fibroblasts that Promote Migration of Breast Cancer Cells In Vitro.";"S. Giorgetti-Peraldi, P. Peraldi";"Equipe 07, Team 07, Equipe 05, Team 05";33049976;Cells;"Peraldi P, Ladoux A, Giorgetti-Peraldi S, Dani C";;"10 2020";1601510400;;"Cancer associated fibroblasts (CAFs) are central elements of the microenvironment that control tumor development. In breast cancer, CAFs can originate from adipose progenitors (APs). We, and others, have shown that the primary cilium, an antenna-shaped organelle, controls several aspects of APs' biology. We studied the conversion of human APs into CAFs by breast cancer cell lines (BCCs). Deletion of the cilium of APs by a pharmacological inhibitor, or by siRNA, allow us to demonstrate that the cilium is necessary for the differentiation of APs into CAFs. BCCs increase production of TGF-β1 by APs, which is a known inducer of CAFs. Pharmacological inhibition of TGF-β1 signaling in APs prevents their conversion into CAFs. Since we previously showed that deletion of the APs' cilium inhibits TGF-β1 signaling, we propose that BCCs induce TGF-β1 production in Aps, which binds to the primary cilium of Aps and leads to their differentiation into CAFs. Inhibition of APs conversion into CAFs induces a loss in some of the biological effects of CAFs since deletion of the cilium of APs decreases their effect on the migration of BCCs. This is the first observation of a function of the cilium of APs in their conversion into CAFs, and its consequences on BCCs." 5059;"Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics.";"F. BOST, S. Giorgetti-Peraldi";"Equipe 07, Team 07, Equipe 05, Team 05";33075093;"PLoS pathogens";"Cambien B, Lebrigand K, Baeri A, Nottet N, Compin C, Lamit A, Ferraris O, Peyrefitte CN, Magnone V, Henriques J, Zaragosi LE, Giorgetti-Peraldi S, Bost F, Gautier-Isola M, Rezzonico R, Barbry P, Barthel R, Mari B, Vassaux G";;"10 2020";1601510400;;"Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumor-types for which human and canine pathologies are closely related at the molecular level. The efficacy of an oncolytic vaccinia virus (VV) was compared in low-passage primary carcinoma cells from TNBC versus non-TNBC. Non-TNBC cells were 28 fold more sensitive to VV than TNBC cells in which VV replication is impaired. Single-cell RNA-seq performed on two different TNBC cell samples, infected or not with VV, highlighted three distinct populations: naïve cells, bystander cells, defined as cells exposed to the virus but not infected and infected cells. The transcriptomes of these three populations showed striking variations in the modulation of pathways regulated by cytokines and growth factors. We hypothesized that the pool of genes expressed in the bystander populations was enriched in antiviral genes. Bioinformatic analysis suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. In addition, we demonstrated experimentally that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, our data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. This information could be used to design new generations of oncolytic poxviruses. Beyond the field of gene therapy, this study demonstrates that single-cell transcriptomics can be used to identify cellular factors influencing viral replication." 5057;"Intermittent Hypoxia Mediates Caveolae Disassembly That Parallels Insulin Resistance Development.";"S. Giorgetti-Peraldi";"Equipe 07, Team 07";33324235;"Frontiers in physiology";"Varela-Guruceaga M, Belaidi E, Lebeau L, Aka E, Andriantsitohaina R, Giorgetti-Peraldi S, Arnaud C, Le Lay S";;"Jan 2020";1577836800;;"Repetitive complete or incomplete pharyngeal collapses are leading to chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA) syndrome responsible for many metabolic disorders. In humans, an association between OSA and insulin resistance has been found independently of the degree of obesity. Based on our previous work showing that hypoxia applied to adipocytes led to cellular insulin resistance associated with caveolae flattening, we have investigated the effects of CIH on caveolae structuration in adipose tissue. Original exploratory experiences demonstrate that 6 weeks-exposure of lean mice to CIH is characterized by systemic insulin resistance and translates into adipocyte insulin signaling alterations. Chronic intermittent hypoxia also induces caveolae disassembly in white adipose tissue (WAT) illustrated by reduced plasma membrane caveolae density and enlarged caveolae width, concomitantly to WAT insulin resistance state. We show that CIH downregulates caveolar gene and protein expressions, including cavin-1, cavin-2, and EHD2, underlying molecular mechanisms responsible for such caveolae flattening. Altogether, we provide evidences for adipose tissue caveolae disassembly following CIH exposure, likely linked to cavin protein downregulation. This event may constitute the molecular basis of insulin resistance development in OSA patients." 5055;"TNFα Mediates Inflammation-Induced Effects on Splicing in Adipose Tissue and Mesenchymal Precursor Cells.";"I. Mucel, JF. Tanti, M. Cormont, S. Giorgetti-Peraldi";"Equipe 07, Team 07";35011604;Cells;"Cataldi S, Aprile M, Melillo D, Mucel I, Giorgetti-Peraldi S, Cormont M, Italiani P, Blüher M, Tanti JF, Ciccodicola A, Costa V";;"Dec 2021";1638316800;;"Low-grade chronic inflammation and reduced differentiation capacity are hallmarks of hypertrophic adipose tissue (AT) and key contributors of insulin resistance. We identified PPARGΔ5 as a dominant-negative splicing isoform overexpressed in the AT of obese/diabetic patients able to impair adipocyte differentiation and PPARγ activity in hypertrophic adipocytes. Herein, we investigate the impact of macrophage-secreted pro-inflammatory factors on splicing, focusing on PPARGΔ5. We report that the epididymal AT of LPS-treated mice displays increased PpargΔ5/cPparg and reduced expression of -regulated genes. Interestingly, pro-inflammatory factors secreted from murine and human pro-inflammatory macrophages enhance the PPARGΔ5/cPPARG in exposed adipogenic precursors. TNFα is identified herein as factor able to alter splicing-increasing PPARGΔ5/cPPARG -through PI3K/Akt signaling and SRp40 splicing factor. In line with in vitro data, TNFA expression is higher in the SAT of obese (vs. lean) patients and positively correlates with PPARGΔ5 levels. In conclusion, our results indicate that inflammatory factors secreted by metabolically-activated macrophages are potent that modulate the expression and splicing of . The resulting imbalance between canonical and dominant negative isoforms may crucially contribute to impair PPARγ activity in hypertrophic AT, exacerbating the defective adipogenic capacity of precursor cells." 5053;"Identification of new F8 deep intronic variations in patients with haemophilia A.";"PS. ROHRLICH";"Equipe 04, Team 04";32812322;"Haemophilia : the official journal of the World Federation of Hemophilia";"Dericquebourg A, Jourdy Y, Fretigny M, Lienhart A, Claeyssens S, Ternisien C, Boisseau P, Rohrlich PS, Négrier C, Vinciguerra C";;"Sep 2020";1598918400;;"With current molecular diagnosis, about 1 to 5% of haemophilia A (HA) patients remain genetically unresolved. In these cases, deep intronic variation or structural variation disrupting the F8 gene could be causal." 5051;"Bone Mineral Density Evolution and Its Determinants in Long-term Survivors of Childhood Acute Leukemia: A Leucémies Enfants Adolescents Study.";"PS. ROHRLICH";"Equipe 04, Team 04";33458594;HemaSphere;"Tabone MD, Kolta S, Auquier P, Vercasson C, Chastagner P, Kanold J, Rohrlich PS, Bertrand Y, Baruchel A, Plantaz D, Gandemer V, Ducassou S, Petit A, Paillard C, Leverger G, Dalle JH, Berbis J, Roux C, Michel G";;"Feb 2021";1612137600;;"This prospective study aimed to analyze determinants that can influence bone mineral density evolution in childhood acute leukemia survivors. Patients included were selected from the long-term follow-up LEA cohort and had dual energy radiograph absorptiometry scan between 10 and 18 years and after the age of 18. All scans were centrally reviewed. Bone mineral density was measured at the lumbar spine, femoral neck, total hip, and whole body, and expressed as z-score. Eighty-nine patients (female 39, lymphoblastic leukemia 68, relapse 25, hematopoietic stem cell transplantation 44, and mean age 15.4 and 20.1 years at the first and second scans, respectively) were studied. The first and second scan z-scores were significantly correlated ( < 10). Mean femoral neck and total hip z-scores improved significantly between the first and second scans, whereas no significant evolution occurred at the lumbar spine and whole-body level. On the second evaluation, 14.6% of patients had z-score <-2 at the lumbar spine and 4.3% at the femoral neck level. Gender, type of leukemia, transplantation, relapse, cumulative corticosteroid doses, or growth hormone deficiency did not have any significant impact on z-score variation. Younger age at diagnosis (≤8.5 years) proved an unfavorable risk factor for z-score evolution at the lumbar spine ( = 0.041); the trend did not reach statistical significance for metabolic syndrome ( = 0.054). At the femoral neck, both were associated with unfavorable z-score evolution ( = 0.003 and 0.025, respectively). Patients treated at a younger age and those with metabolic syndrome seem to be at higher risk of bone mineral density decline and should benefit from specific interventions." 5049;"COVID19 and acute lymphoblastic leukemias of children and adolescents: Updated recommendations (Version 2) of the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE).";"PS. ROHRLICH";"Equipe 04, Team 04";33781551;"Bulletin du cancer";"Rouger-Gaudichon J, Bertrand Y, Boissel N, Brethon B, Ducassou S, Gandemer V, Halfon-Domenech C, Leblanc T, Leverger G, Michel G, Petit A, Ray-Lunven AF, Rohrlich PS, Schneider P, Sirvent N, Strullu M, Baruchel A, ";;"May 2021";1619827200;;"Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19." 5045;"Therapeutic potential of ruxolitinib and ponatinib in patients with -rearranged Philadelphia chromosome-like acute lymphoblastic leukemia.";"PS. ROHRLICH";"Equipe 04, Team 04";34196168;Haematologica;"Niswander LM, Loftus JP, Lainey É, Caye-Eude A, Pondrom M, Hottman DA, Iacobucci I, Mullighan CG, Jain N, Konopleva M, Cavé H, Baruchel A, Rohrlich PS, Tasian SK";;"10 2021";1633046400;; 5038;"Estrogen-induced growth inhibition of human seminoma cells expressing estrogen receptor beta and aromatase.";"M. NEBOUT";"Equipe 04, Team 04";16087732;"Journal of molecular endocrinology";"Roger C, Lambard S, Bouskine A, Mograbi B, Chevallier D, Nebout M, Pointis G, Carreau S, Fenichel P";;"Aug 2005";1122854400;;"It is now well established that estrogens participate in the control of normal spermatogenesis and endogenous or environmental estrogens are involved in pathological germ cell proliferation including testicular germ cell tumors. Studying a human testicular seminoma cell line, JKT-1, we show here that 17beta-estradiol (10(-12) to 10(-6) M) induced in vitro a significant dose-dependent decrease of cell growth. This antiproliferative effect was maximum after 4 days of exposure at a physiologically intratesticular concentration of 10(-9) M, close to the K(d) of ER, and reversed by ICI 182780, an ER antagonist, suggesting an ER-mediated pathway. By RT-PCR and Western blot we were able to confirm that JKT-1, like tumoral seminoma cells and normal human testicular basal germ cells, expresses estrogen receptor beta (ERbeta), including ERbeta1 and ERbeta2, a dominant negative variant, but not ERalpha. Using immunofluorescence and confocal microscopy, ERbeta was observed as perinuclear intracytoplasmic spots in JKT-1 and tumoral seminoma cells without significant translocation of ERbeta into the nucleus, under 17beta-estradiol exposure. Double staining observed by confocal microscopy revealed that ERbeta colocalized in JKT-1 cells with cytochrome C, a mitochondrial marker. We report for the first time the expression of a functional aromatase complex in seminoma cells as assessed by RT-PCR, Western blot and enzymatic assay. Seminoma cells are able to respond to estrogens through a possible autocrine or paracrine loop. These preliminary results support estrogen-dependency of human testicular seminoma, the most frequent tumor of young men, and suggest potential pharmacological use. Whether this estrogen control, however, involves an ERbeta-mediated stimulation of cell apoptosis and/or an ERbeta-mediated inhibition of cell proliferation, remains to be further determined." 5036;"RET gene mutations are not involved in the origin of human testicular seminoma.";"M. NEBOUT";"Equipe 04, Team 04";20201982;"International journal of andrology";"Chevalier N, Barlier A, Roche C, Mograbi B, Camparo P, Devouassoux-Shisheboran M, Michiels JF, Nebout M, Chevallier D, Benahmed M, Enjalbert A, Fénichel P";;"Dec 2010";1291161600;;"Testicular germ cell cancers are the most common solid malignancies in young men, but their pathogenesis remains undetermined although some epidemiological data have implicated both environmental and genetic factors. Glial cell-derived neurotrophic factor (GDNF) is secreted by Sertoli cells, and promotes germ stem cell proliferation by activating RET, a tyrosine kinase receptor. Over-expression of GDNF in adult transgenic mice induces the development of testicular tumours that mimic human seminoma, the most frequent testicular germ cell tumour. Activating mutations of RET were previously reported in several types of cancer, including thyroid, pituitary, adrenal and melanoma cancer. Both mouse experimental model and clinical studies suggested that mutations or selective polymorphisms of RET might be associated with human seminoma. To verify this hypothesis, we conducted this study in a French University Hospital and carried out an association study using tissue samples from 66 paraffin-embedded seminoma tumours. The most frequently mutated exons of the RET proto-oncogene were sequenced to identify mutations or selective polymorphisms. No somatic mutations were identified. The polymorphic variants frequencies did not differ from those in a control Caucasian population. Human classical seminoma that occurs in young men does not appear to be linked with mutations or relevant polymorphisms of RET." 5034;"Aberrant Connexin 43 endocytosis by the carcinogen lindane involves activation of the ERK/mitogen-activated protein kinase pathway.";"M. NEBOUT";"Equipe 04, Team 04";12807735;Carcinogenesis;"Mograbi B, Corcelle E, Defamie N, Samson M, Nebout M, Segretain D, Fénichel P, Pointis G";;"Aug 2003";1059696000;;"Although worldwide concerns have emerged about environmental factors that display carcinogenic and reprotoxic effects, little is known about the mechanism(s) by which these chemicals alter testicular function. Using the 42GPA9 Sertoli cell line, we recently reported that one widely used lipid-soluble pesticide, Lindane impairs gap junctional intercellular communication by promoting the intracellular localization of Connexin 43 (Cx43), a tumor suppressor. We showed here that this chemical triggered the accumulation of Cx43 within Rab5 positive endosomes. Interestingly, evidence is provided that Lindane-induced Cx43 endocytosis did not stem on alteration of Cx43 partition in lipid rafts. Lindane induced concomitantly Cx43 phosphorylation and activation of extracellular signal-regulated kinases (ERK) but not of JNK and p38 mitogen- activated protein kinases. Inhibition of ERK pathway by PD98059, a MEK1-specific inhibitor, prevented Lindane-induced Cx43 phosphorylation, restored Cx43 membranous localization and gap junction coupling. Altogether, these findings provide the first evidence that Lindane-altered Cx43 endocytosis requires ERK activation. Such inappropriate activation of the mitogenic MAPK pathway and inactivation of the tumor suppressor Cx43 by Lindane may participate in the promotion of neoplastic cell growth." 5032;"Dominant negative effect of connexin33 on gap junctional communication is mediated by connexin43 sequestration.";"M. NEBOUT";"Equipe 04, Team 04";15331631;"Journal of cell science";"Fiorini C, Mograbi B, Cronier L, Bourget I, Decrouy X, Nebout M, Ferrua B, Malassine A, Samson M, Fénichel P, Segretain D, Pointis G";;"Sep 2004";1093996800;;"Gap junctional intercellular communication is involved in the control of cell proliferation and differentiation. Connexin33, a member of the multi-gene family of gap junction proteins, exerts an inhibitory effect on intercellular communication when injected into Xenopus oocytes. However, the molecular mechanisms involved remain to be elucidated. Our results show that connexin33 was only expressed within the seminiferous tubules in the testis. In contrast to the majority of connexins, connexin33 was unphosphorylated. Immunoprecipitation experiments revealed that connexin33 physically interacted with connexin43, mainly with the phosphorylated P1 isoform of connexin43 but not with connexin26 and connexin32, two other connexins expressed in the tubular compartment. In Sertoli cells and COS-7 cells, connexin43 was located at the plasma membrane, whereas in connexin33 transfected cells, the specific association of connexin33/43 was sequestered in the intracellular compartment. High-resolution fluorescent deconvolution microscopy indicated that the connexin33/43 complex was mainly found within early endosomes. Sequestration of connexin33/43 complex was associated with a complete inhibition of the gap junctional coupling between adjacent cells. These findings provide the first evidence of a new mechanistic model by which a native connexin, exerting a dominant negative effect, can inhibit gap junctional intercellular communication. In the testis, connexin33 could exert a specific role on germ cell proliferation by suppressing the regulatory effect of connexin43." 5030;"Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity.";"M. NEBOUT";"Equipe 04, Team 04";16818664;"Cancer research";"Corcelle E, Nebout M, Bekri S, Gauthier N, Hofman P, Poujeol P, Fénichel P, Mograbi B";;"Jul 2006";1151712000;;"Macroautophagy (hereafter referred to as autophagy) has emerged as a key tumor suppressor pathway. During this process, the cytosolic constituents are sequestered into autophagosomes, which subsequently fuse with lysosomes to become autolysosomes where their contents are finally degraded. Although a reduced autophagy has been shown in human tumors or in response to oncogenes and carcinogens, the underlying mechanism(s) remain(s) unknown. Here, we show that widely used carcinogen Lindane promotes vacuolation of Sertoli cells. By electron and immunofluorescent microscopy analyses, we showed that these structures are acid autolysosomes, containing cellular debris, and labeled by LC3, Rab7, and LAMP1, markers of autophagosomes, late endosomes, and lysosomes, respectively. Such Lindane-induced vacuolation results from significant delay in autophagy degradation, in relation with a decline of the lysosomal activity of aryl sulfatase A. At molecular level, we show that this defect in autolysosomal maturation is independent of mammalian target of rapamycin and p38 inhibitions. Rather, the activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is required for Lindane to disrupt the autophagic pathway. Most importantly, we provide the first evidence that sustained activation of ERK pathway is sufficient to commit cell to autophagic vacuolation. Taken together, these findings strongly support that the aberrant sustained activation of ERK by the carcinogen Lindane disrupts the maturation of autophagosomes into functional autolysosomes. Our findings therefore suggest the possibility that high constitutive ERK activity found in all cancers may provide a malignant advantage by impeding the tumor suppressive function of autophagy." 5028;"A potential novel mechanism involving connexin 43 gap junction for control of sertoli cell proliferation by thyroid hormones.";"J. GILLERON, M. NEBOUT";"Equipe 07, Team 07, Equipe 04, Team 04";16823880;"Journal of cellular physiology";"Gilleron J, Nebout M, Scarabelli L, Senegas-Balas F, Palmero S, Segretain D, Pointis G";;"Oct 2006";1159660800;;"There is strong evidence that thyroid hormones through triiodothyronine (T3) regulate Sertoli cell proliferation and differentiation in the neonatal testis. However, the mechanism(s) by which they are able to control Sertoli cell proliferation is unclear. In the present study in vivo approaches (PTU-induced neonatal hypothyroidism known to affect Sertoli cell proliferation) associated with in vitro experiments on a Sertoli cell line were developed to investigate this question. We demonstrated that the inhibitory effect of T3 on Sertoli cell growth, analyzed by evaluating DNA-incorporated [3H] thymidine, was associated with a time and dose-dependent increase in the levels of Cx43, a constitutive protein of gap junctions, known to participate in the control of cell proliferation and the most predominant Cx in the testis. These Cx43 changes were associated with increased gap junction communication measured by gap FRAP. Consistent with these results two specific inhibitors of gap junction coupling, AGA and oleamide, were able to significantly reverse the T3 inhibitory effect on Sertoli cell proliferation. The present data also revealed a nongenomic effect of T3 on Cx43 Sertoli cells that was evidenced by a rapid up-regulation of gap junction plaque number as identified in Cx43-GFP transfected cells exposed to the hormone. This process appears mediated through actin cytoskeleton since incubation of the cells with cytochalasin D totally reversed the T3 stimulatory effect on Cx43-GFP gap junction plaques. Based on these data, we propose a working hypothesis in which Cx43 could be an intermediate target for T3 inhibition of neonatal Sertoli cell proliferation." 5026;"Control of the autophagy maturation step by the MAPK ERK and p38: lessons from environmental carcinogens.";"M. NEBOUT";"Equipe 04, Team 04";17102581;Autophagy;"Corcelle E, Djerbi N, Mari M, Nebout M, Fiorini C, Fénichel P, Hofman P, Poujeol P, Mograbi B";;"Feb Jan 2007";1167696000;;"Macroautophagy (hereafter referred to as autophagy) is the major degradative pathway of long-lived proteins and organelles that fulfils key functions in cell survival, tissue remodeling and tumor suppression. Consistently, alterations in autophagy have been involved in a growing list of pathologies including toxic injury, infections, neurodegeneration, myopathies and cancers. Although critical, the molecular mechanisms that control autophagy remain largely unknown. We have recently exploited the disruption of autophagy by environmental carcinogens as a powerful model to uncover the underlying signaling pathways. Our work published in Cancer Research revealed that the sustained activation of the MAPK ERK pathway by the carcinogen Lindane or the MEK1(+) oncogene alters autophagy selectively at the maturation step resulting in the accumulation of large defective autolysosomes. Consistent with our findings, a similar defect is observed with other common xenobiotics such as dichlorodiphenyltrichloroethane and biphenol A that specifically activate ERK. Conversely, Pentachlorophenol that activates both ERK and p38, fails to induce autophagic vacuolation. In addition, evidence is provided that abrogation of p38 by SB203580 is sufficient to interfere with the normal autophagic maturation step. Altogether, these findings underscore the critical role played by MAPK ERK and p38 in the tight control of the autophagy process at the maturation step." 5024;"Estrogens promote human testicular germ cell cancer through a membrane-mediated activation of extracellular regulated kinase and protein kinase A.";"M. NEBOUT";"Equipe 04, Team 04";18039775;Endocrinology;"Bouskine A, Nebout M, Mograbi B, Brücker-Davis F, Roger C, Fenichel P";;"Feb 2008";1201824000;;"Clinical and experimental studies have suggested that estrogens, the archetype of female hormones, participate in the control of male germ cell proliferation and that fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, the underlying mechanisms remain to be elucidated. 17beta-Estradiol (E2) conjugated to BSA was able to stimulate human testicular seminoma cell proliferation by triggering a rapid, nongenomic, membrane-mediated activation of ERK1/2 and cAMP-dependent protein kinase A (PKA). Both ERK1/2 and PKA participated in this promoting effect. This activation was associated with phosphorylation of the transcription factor cAMP response element-binding protein and the nuclear factor retinoblastoma protein. Enhanced proliferation together with ERK activation could be reversed by pertussis toxin, a G protein inhibitor. Estrogen receptors (ERs) in JKT-1 were characterized by immunofluorescence, subcellular fractioning, and Western blot. JKT-1 cells did not express ERalpha but ERbeta, which localized to the mitochondria and the nucleus but not to the membrane. Moreover, neither ICI-182,780, a classical ER antagonist, nor tamoxifen, a selective ER modulator, could reverse the 17beta-estradiol-BSA-induced promoting effect. Estrogens contribute to human testicular germ cell cancer proliferation by rapid activation of ERK1/2 and PKA through a membrane nonclassical ER. This nongenomic effect represents a new basis for understanding the estrogenic control of spermatogenesis and evaluating the role of fetal exposure to xenoestrogens during malignant transformation of testicular germ stem cells." 5022;"Expression of embryonic stem cell markers in cultured JKT-1, a cell line derived from a human seminoma.";"M. NEBOUT";"Equipe 04, Team 04";19226408;"International journal of andrology";"Bouskine A, Vega A, Nebout M, Benahmed M, Fénichel P";;"Feb 2010";1264982400;;"Testicular germ cell tumours (TGCTs), the most frequent solid tumour of the young men, originate from the primitive germ cells. They share some pluripotency stem-cell markers which may help to distinguish between seminoma, the most frequent TGCTs and non-seminoma tumours, such as embryonal carcinoma, teratocarcinoma or choriocarcinoma. Due probably to the propensity of seminoma to apoptosis, only two cell lines originated from pure testicular seminoma, TCam-2 and JKT-1 have been up to now, established, maintained and proposed as representative models of human testicular seminoma. However, both seem, following recent reports, to be able to drift. Thus, the molecular signature of embryonic stem-cell markers of the JKT-1 cells cultured in our laboratory, were studied by RT-PCR, Western blot and immunofluorescence (IF). JKT-1 cells analysed after 30 passages, expressed placenta alkaline phosphatase but not alphafoetoprotein (alphaFP) nor beta-human chorionic gonadotropin. JKT-1 cells also expressed markers of pluripotency such as NANOG and OCT3/4 and more specific seminoma markers, such as AP2gamma and HIWI. However, protein expression of OCT3/4 and AP2y was weak and these JKT-1 cells expressed SOX2, a marker of embryonal carcinoma and did not express c-KIT usually expressed in most seminoma. Possible derivation through in vitro culture conditions was supported by looking at later passages (61) which showed a decrease of NANOG and HIWI protein expression. JKT-1 cells express a signature of markers which is still near from the one express by seminoma cells, allowing carcinogenetic studies. However, because of their great ability to drift as shown for TCam-2, it is recommended to verify and to precise this molecular signature before reporting functional results." 5020;"Low doses of bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor.";"M. NEBOUT";"Equipe 04, Team 04";19654912;"Environmental health perspectives";"Bouskine A, Nebout M, Brücker-Davis F, Benahmed M, Fenichel P";;"Jul 2009";1246406400;;"Fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, many of these xenoestrogens have only a weak affinity for the classical estrogen receptors (ERs,) which is 1,000-fold less potent than the affinity of 17beta-estradiol (E(2)). Thus, several mechanisms have been suggested to explain how they could affect male germ cell proliferation at low environmental relevant concentrations." 5016;"Appearance of a functional insulin receptor during rabbit embryogenesis.";"JF. PEYRON";"Equipe 04, Team 04";3899821;Diabetologia;"Peyron JF, Samson M, Van Obberghen E, Brandenburg D, Fehlmann M";;"Jun 1985";486432000;;"The domain structure of the insulin receptor was investigated in liver and brown adipose tissue of developing rabbits. The structure of the binding domain (alpha-subunit) was analysed after covalent labelling with a 125I photo-reactive insulin analogue. The structure of the tyrosine kinase domain (beta-subunit) and the transmission of the hormonal signal from the alpha-to the beta-subunit were analysed by stimulating with insulin the autophosphorylation of the beta-subunit. Finally, the immunoreactivity of the receptor in developing tissues was assessed with anti-receptor antibodies. The results show that a functional insulin receptor can be detected at the early stages of fetal development in both tissues and is conserved throughout ontogenesis to adulthood." 5014;"Molecular association between major histocompatibility complex class I antigens and insulin receptors in mouse liver membranes.";"JF. PEYRON";"Equipe 04, Team 04";3866245;"Proceedings of the National Academy of Sciences of the United States of America";"Fehlmann M, Peyron JF, Samson M, Van Obberghen E, Brandenburg D, Brossette N";;"Dec 1985";502243200;;"Molecular association between major histocompatibility complex (MHC) antigens and cellular proteins are thought to be involved in various immunological and nonimmunological functions of MHC antigens, including hormone signaling. The existence of physical interactions between insulin receptors and MHC class I antigens was investigated in liver plasma membranes from congenic H-2k mice. Insulin receptors were specifically labeled with a 125I-labeled photoreactive insulin analogue, and cellular proteins were solubilized and incubated with various monoclonal antibodies. Immunoprecipitates were analyzed by polyacrylamide gel electrophoresis followed by autoradiography. Antibodies reacting with distinct epitopes on H-2k class I antigens were all able to precipitate up to 25% of the labeled insulin receptors in H-2k mouse liver membranes, whereas no insulin receptors were precipitated in H-2b mouse liver membranes. Sequential immunoprecipitations showed that insulin receptors and H-2 antigens were coprecipitated and that no cross-reactivity occurred. The specificity of the interaction between insulin receptors and H-2 antigens was demonstrated after double labeling of membrane proteins by photoreactive insulin and lactoperoxidase-catalyzed iodination. These results thus show that, in mouse liver membranes, insulin receptors are physically associated to class I antigens of the MHC." 5012;"T cell activation: distinct pathways involve phosphorylation of different cellular proteins.";"JF. PEYRON";"Equipe 04, Team 04";2900150;"European journal of immunology";"Peyron JF, Pont S, Pierres M, Fehlmann M";;"Jul 1988";583718400;;"The murine T cell clone D10.G4.1 can be induced to proliferate by monoclonal antibodies (mAb) to the T cell receptor (TcR) or to Thy-1 molecules. When cells were stimulated by anti-TcR mAb, a group of 4 proteins (19-25 kDa) was specifically phosphorylated. This effect was completely mimicked by the Ca2+ ionophore A23187, whereas only two of these proteins (19 kDa and 25 kDa) were phosphorylated after cell exposure to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate. By contrast, anti-Thy-1 mAb had no effect on the phosphorylation of these proteins, but induced specifically the phosphorylation of a protein of 32 kDa. These results therefore demonstrate that distinct activating pathways in T cells involve the phosphorylation of different proteins, suggesting that the stimulation of protein kinases in T lymphocytes is an early event in cell activation." 5010;"Phosphorylation of class I histocompatibility antigens in human B lymphocytes. Regulation by phorbol esters and insulin.";"JF. PEYRON";"Equipe 04, Team 04";3066355;"The Biochemical journal";"Peyron JF, Fehlmann M";;"Dec 1988";596937600;;"Phosphorylation of membrane proteins is one of the earliest steps in cell activation induced by growth-promoting agents. Since MHC (major histocompatibility complex) class I molecules are known to contain phosphorylation sites in their C-terminal intracellular domain, we have studied the regulation of HLA (human leucocyte antigen) phosphorylation in intact cells by two mitogens, namely TPA (12-O-tetradecanoylphorbol 13-acetate), a phorbol ester, and insulin, which are thought to exert their mitogenic effects through the stimulation of different protein kinases (protein kinase C and a tyrosine kinase respectively). Human B lymphoblastoid cells (526 cell line) were pulsed with [32P]Pi to label the intracellular ATP pool. Cells were then stimulated for 10 min with TPA, insulin, cyclic AMP or EGF (epidermal growth factor). The reaction was stopped by cell lysis in the presence of kinase and phosphatase inhibitors, and class I HLA antigens were immunoprecipitated with monoclonal antibodies. Analysis of labelled proteins by gel electrophoresis and autoradiography revealed that TPA increased the phosphorylation of the 45 kDa class I heavy chain by 5-7-fold, and insulin increased it by 2-3-fold. Cyclic AMP and EGF had no stimulatory effect. Analysis of immunoprecipitated HLA molecules by two-dimensional gel electrophoresis showed that TPA and insulin stimulated the incorporation of 32P into different 45 kDa molecular species, suggesting that different sites were phosphorylated by two agents. Moreover, incubation of purified class I MHC antigens with partially purified insulin-receptor tyrosine kinase and [gamma-32P]ATP revealed that class I antigens could also be phosphorylated in vitro by this tyrosine kinase. Altogether, these results therefore confirm that insulin receptors and HLA class I molecules are not only structurally [Fehlmann, Peyron, Samson, Van Obberghen, Brandenburg & Brossette (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 8634-8637] but also functionally associated in the membranes of intact cells." 5008;"Activation of human T cells is associated with tyrosine phosphorylation of several cellular proteins.";"JF. PEYRON";"Equipe 04, Team 04";2642028;"Cellular signalling";"Peyron JF, Ferrua B, Fehlmann M";;"Jan 1989";599616000;;"Human T lymphocytes are activated to proliferate after triggering the T Cell Antigen Receptor Complex. CD3-Ti, with either antigen, mitogenic lectins or monoclonal antibodies against its different subunits. Stimulation of Jurkat leukemic human T cells with anti-CD3 or anti-Ti monoclonal antibodies was found to induce, within 1 min, an increase in the phosphorylation of a set of cellular proteins that can be precipitated with anti-phosphotyrosine antibodies. Seven phosphotyrosine-containing proteins were separated with respective mol. wt of 21, 25, 38, 55, 70, 80 and 110 kDa, among which the 38 kDa species is predominant. Moreover, incubation of Jurkat T cells with sodium orthovanadate, a potent inhibitor of phosphotyrosine protein-phosphatases, was found to potentiate the effects of anti-CD3 mAb on tyrosine phosphorylation. In addition vanadate also induced IL-2 secretion in Jurkat cells when associated with the phorbol ester TPA, further demonstrating the importance of these phosphorylation reactions in the process of T cell activation. Our results therefore allow us to identify several protein substrates of a tyrosine kinase activity, whose stimulation appears to be an early event in human T cell activation through the antigen receptor pathway." 5006;"Phosphorylation of two cytosolic proteins. An early event of T-cell activation.";"JF. PEYRON";"Equipe 04, Team 04";2495793;"The Biochemical journal";"Peyron JF, Aussel C, Ferrua B, Häring H, Fehlmann M";;"Mar 1989";604713600;;"T lymphocytes can be activated to proliferate by triggering the T-cell antigen-receptor complex (CD3-Ti) with anti-CD3 (Cluster of Differentiation 3) monoclonal antibody (mAb) or with the mitogenic lectin phytohaemagglutinin A (PHA). We have investigated the relationship between lymphocyte activation and protein phosphorylation in the human leukaemic T-cell line Jurkat. Incubation of 32P-labelled Jurkat cells with anti-CD3 mAb or PHA induced the phosphorylation of two cytosolic proteins that migrate with apparent Mr values of 21,000 (pp21) and 23,000 (pp23) and pI values of 5.1 and 5.0 respectively. Peptide mapping of the two proteins produced the same phosphopeptides pattern, suggesting that pp21 and pp23 are closely related. The phosphorylation of pp21 and pp23 induced by anti-CD3 mAb appeared to be transient, since it was already detected 2 min after the addition of the mAb, reached a maximum at 10 min and recovered its basal level after 1 h. Phosphorylation of pp21 and pp23 could also be elicited by the Ca2+ ionophore A23187 and sodium orthovanadate (Na3VO4), two agents that bypass the T-cell-receptor complex and produced an increase in cytosolic Ca2+ concentration. In addition, we found that vanadate, like the Ca2+ ionophore, induced the secretion of interleukin-2 (IL-2) when used in combination with a submitogenic concentration of the phorbol ester 12-O-tetradecanoylphorbol 13-acetate. These results show that the Ca2+-dependent phosphorylation of pp21 and pp23 represents an early event in the process of signal transduction through the CD3-Ti receptor complex." 5004;"Isolation and characterization of a T lymphocyte mutant defective in the protein kinase C signal transduction pathway.";"JF. PEYRON, P. Auberger";"Equipe 04, Team 04, Equipe 02, Team 02";1922109;"Molecular immunology";"Peyron JF, Tanti JF, Limouse M, Farahifar D, Auberger P, Fehlmann M";;"Sep 1991";683683200;;"The phorbol ester TPA is a potent protein kinase C (PKC) activator and a cofactor in the activation of the human Jurkat leukemic T cell line. We have studied the implication of the PKC signaling pathway in the process of T cell activation by generating TPA resistant mutants of Jurkat. These mutants were obtained by recovery of cells that survived a growth arrest induced by TPA. Several cellular phenomena dependent on TPA were dramatically altered in the mutated cells. The mutants were unable to form homoaggregates upon TPA stimulation. Moreover, they did not produce interleukin-2 after activation through engagement of the T cell receptor, in the presence of TPA. These results suggest that the PKC signaling pathway activated by TPA is defective in these cells. In an attempt to define and locate the defect present in the mutants, we have analysed the biochemical properties of PKC, the cellular receptor of TPA. The increase in kinase activity and the translocation of the enzyme to the plasma membrane after stimulation by TPA appeared to be normal in the mutants. We hypothesize that a metabolic step, critical for the completion of T cell activation, distinct from protein kinase C, is impaired in the mutant cells." 5002;"Jurkat T cells express a functional neutral endopeptidase activity (CALLA) involved in T cell activation.";"JF. PEYRON, P. Auberger";"Equipe 04, Team 04, Equipe 02, Team 02";1396581;"The EMBO journal";"Mari B, Checler F, Ponzio G, Peyron JF, Manie S, Farahifar D, Rossi B, Auberger P";;"Nov 1992";720576000;;"We have characterized a T lymphocyte endopeptidase activity that hydrolyses succinyl-alanine-alanine-phenylalanine-paranitroanilide (Suc-Ala-Ala-Phe-pNa). Hydrolysis of this substrate by intact Jurkat T cells was markedly enhanced when exogenous aminopeptidase N was added to the incubation medium. It thus appears that the release of paranitroaniline from Suc-Ala-Ala-Phe-pNA results from the combination of two distinct enzymatic activities: (i) an endopeptidase activity that cleaves the substrate at the alanyl bond and (ii) an aminopeptidase activity that ultimately cleaves the phenylalanyl bond. This cleavage was further confirmed by HPLC analysis. Specific endopeptidase 24.11 inhibitors were shown to inhibit the endopeptidase activity. These features are reminiscent of the characteristics of neutral endopeptidase (NEP, also known as endopeptidase 24.11, CALLA or CD10). Anti-CD10 monoclonal antibodies (mAbs) recognized the CD10+ B cell line Raji, but not Jurkat cells as assessed by FACS analysis. This is probably due to a lack of sensitivity of this method, the level of NEP activity in Jurkat T cells being 3-5% of that measured in B cell lines. Anti-CD10 mAbs immunoprecipitated endopeptidase 24.11 activities in both Jurkat T cells and Raji B cells, demonstrating that T lymphocytes express a CALLA-related endopeptidase. We also demonstrate that T and B cell endopeptidases have the same molecular weight, that T cells express less functional CALLA mRNA than B cells and that there are at least two shorter transcripts (1.8 and 0.8 kb) in both T and B cells.(ABSTRACT TRUNCATED AT 250 WORDS)" 5000;"CD3-stimulated Jurkat T cells mediate IL-1 beta production in monocytic THP-1 cells. Role of LFA-1 molecule and participation of CD69 T cell antigen.";"JF. PEYRON";"Equipe 04, Team 04";8490106;"European cytokine network";"Manié S, Kubar J, Limouse M, Ferrua B, Ticchioni M, Breittmayer JP, Peyron JF, Schaffar L, Rossi B";;"Feb Jan 1993";725932800;;"In this study we investigated the T cell signals required for monocyte activation. We used an in vitro co-culture system involving two human cell lines: Jurkat T cells and THP-1 monocytes. Monocyte activation was monitored by measuring IL-1 beta production, whereas IL-2 secretion reflected Jurkat activation. We showed that CD-3 -stimulated Jurkat cells delivered an IL-1-inductive signal to THP-1 cells through a cellular contact which was independent of THP-1 Fc receptors cross-linking. Stimulation of IL-1 beta production did not appear to require lymphokine secretion by T cell since a lymphokine defective mutant of Jurkat cell was able to deliver the stimulatory signal. The LFA-1 molecule was clearly shown to participate in the cooperation process, but its role was likely to be restricted to mediating initial adhesive interaction rather than to transducing the IL-1 -inductive signal. Interestingly, the co-culture stimulated by (Fab')2 fragments of CD3 mAb displayed an enhanced IL-1 beta production without any increase of IL-2 secretion. This result indicated that Jurkat cells could stimulate THP-1 cells even when they were only partially activated. The kinetics and conditions of IL-1 beta production called our attention to the early T cell activation antigen CD69. We then showed that CD69 mAb interfered with transmission of the IL-1 inductive signal (40-50% inhibition of IL-1 production). Our results are suggestive of a new role for CD69 molecule intervening in the T lymphocyte-dependent monocyte activation process." 4998;"Altered glycosylation of leukosialin, CD43, in HIV-1-infected cells of the CEM line.";"JF. PEYRON";"Equipe 04, Team 04";7964449;"The Journal of experimental medicine";"Lefebvre JC, Giordanengo V, Limouse M, Doglio A, Cucchiarini M, Monpoux F, Mariani R, Peyron JF";;"Nov 1994";783648000;;"CD43 (leukosialin, gpL115, sialophorin) is a major sialoglycoprotein widely expressed on hematopoietic cells that is defective in the congenital immunodeficiency Wiskott-Aldrich syndrome. It is thought to play an important role in cell-cell interactions and to be a costimulatory molecule for T lymphocyte activation. Using a metabolic 35SO4(2-) radiolabeling assay or biotinylation of cell surface proteins, we describe here that CD43 are sulfated molecules the glycosylation of which is altered in human immunodeficiency virus type 1 (HIV-1)-infected leukemic T cells of the CEM line. Hyposialylation of O-glycans and changed substitution on N-acetylgalactosamine residues are observed. The glycosylation defect is associated with an impairment of CD43-mediated homotypic aggregation which can be restored by resialylation. The hyposialylation of CD43 on HIV-1+ cells may explain the high prevalence of autoantibodies directed against nonsialylated CD43 that have been detected in HIV-1-infected individuals. A defect in glycosylation of important molecules such as CD43 or, as we recently described, CD45 may explain alterations of T cell functions and viability in HIV-1-infected individuals. In addition, a possible implication of hyposialylation in the HIV-1-infected cells entrapment in lymph nodes could be envisioned." 4996;"Thrombin and trypsin-induced Ca(2+) mobilization in human T cell lines through interaction with different protease-activated receptors.";"JF. PEYRON, P. Auberger";"Equipe 04, Team 04, Equipe 02, Team 02";8641564;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Mari B, Guerin S, Far DF, Breitmayer JP, Belhacene N, Peyron JF, Rossi B, Auberger P";;"Feb 1996";823132800;;"This study was conducted to determine whether serine proteinases may induce [Ca(2+)]i mobilization in different hematopoietic cell lines and to analyze their mechanisms of action. We show that in addition to thrombin and thrombin receptor agonist peptide (TRP, SFLLRN), trypsin induced [Ca(2+)]i mobilization in a highly thrombin-sensitive Jurkat T cell clone. Thrombin, TRP, and trypsin were found to induce [Ca(2+)]i release in three different Jurkat T cell clones differing in the level of T cell receptor expression. Similar results were obtained with a prothymocytic leukemic cell line, HPB.ALL, although these cells were much more responsive to trypsin than to thrombin and TRP. Other cell types such as THP1, a myelomonocytic cell line, or CEM, a CD4(+) positive leukemic cell line, were unresponsive to thrombin, TRP, and trypsin. The effect of trypsin was mimicked by SLIGRL, a peptide corresponding to the cleaved amino-terminal sequence of the recently characterized murine trypsin-activated receptor (PAR2). At suboptimal concentrations, the effects of SFLLRN and SLIGRL were additive, whereas saturating doses of peptides did not further increase [Ca(2+)]i mobilization in Jurkat T cells, indicating that both peptides were able to mobilize the same pool of calcium. Northern blot analysis of mRNAs from different leukemic cell lines indicated a remarkable correlation between PAR2 expression in different cell lines and SLIGRL or trypsin responses in the same cells. The expression of the ""trypsin receptor"" was also confirmed by polymerase chain reaction analysis. Moreover, a 24 h treatment of Jurkat cells by an anti-CD3 monoclonal antibody, a condition known to down-regulate thrombin receptor expression, induced loss of thrombin and TRP responses but only partially affected trypsin stimulation of [Ca(2+)]i release. Finally, after a first stimulation with either thrombin or trypsin, Jurkat cells were still able to respond to trypsin or thrombin, respectively, demonstrating that thrombin and trypsin essentially activated their own receptors. Our data provided evidence that 1) the human T leukemic cell line Jurkat and other T cell lines express at least two different functional protease-activated receptors, the thrombin receptor and a highly sensitive trypsin receptor, likely the human counterpart of the murine PAR2, and 2) at variance with the commonly accepted model, trypsin exerts most of its effect in T leukemic cell lines by thrombin receptor-independent mechanisms." 4994;"The Syk protein tyrosine kinase can function independently of CD45 or Lck in T cell antigen receptor signaling.";"JF. PEYRON";"Equipe 04, Team 04";8947048;"The EMBO journal";"Chu DH, Spits H, Peyron JF, Rowley RB, Bolen JB, Weiss A";;"Nov 1996";846806400;;"The protein tyrosine phosphatase CD45 is a critical component of the T cell antigen receptor (TCR) signaling pathway, acting as a positive regulator of Src family protein tyrosine kinases (PTKs) such as Lck. Most CD45-deficient human and murine T cell lines are unable to signal through their TCRs. However, there is a CD45-deficient cell line that can signal through its TCR. We have studied this cell line to identify a TCR signaling pathway that is independent of CD45 regulation. In the course of these experiments, we found that the Syk PTK, but not the ZAP-70 PTK, is able to mediate TCR signaling independently of CD45 and of Lck. For this function, Syk requires functional kinase and SH2 domains, as well as intact phosphorylation sites in the regulatory loop of its kinase domain. Thus, differential expression of Syk is likely to explain the paradoxical phenotypes of different CD45-deficient T cells. Finally, these results suggest differences in activation requirements between two closely related PTK family members, Syk and ZAP-70. The differential activities of these two kinases suggest that they may play distinct, rather than completely redundant, roles in lymphocyte signaling." 4992;"The protein tyrosine kinase p56(lck) regulates the serine-base exchange activity in Jurkat T cells.";"JF. PEYRON";"Equipe 04, Team 04";9089283;"FEBS letters";"Marhaba R, Dumaurier MJ, Pelassy C, Batoz M, Peyron JF, Breittmayer JP, Aussel C";;"Mar 1997";857174400;;"Different classes of protein kinase inhibitors for protein kinase C, cAMP-dependent protein kinase or protein tyrosine kinases have been studied for their effect on phospholipid metabolism. The results show that among the compounds studied, only 4'-aminohydroxyflavone (AHF), previously described as a specific inhibitor of the protein tyrosine kinase p56(lck), markedly increased phosphatidylserine synthesis in Jurkat T cells. The biosyntheses of phosphatidylcholine and phosphatidylethanolamine were not affected. Also, the synthesis of phospholipids from tritium-labeled fatty acid as precursor was left unchanged by the p56(lck) inhibitor. The decreased phosphatidylserine synthesis induced when triggering the CD3-TCR complex was impaired by AHF, suggesting that p56(lck) could be implicated in the regulation of the serine-base exchange enzyme system. Direct evidence for the participation of p56(lck) in the regulation of the serine-base exchange enzyme system was obtained by using p56(lck)-deficient Jurkat cells (J.CaM 1.6) in which the basal base exchange activity was markedly increased and on the other hand AHF had no effect. In addition, transfection of J.Cam 1.6 cells with p56(lck)-cDNA allowed recovery of the AHF activity." 4990;"Inhibition of HIV-1 replication by a monoclonal antibody directed toward the complementarity determining region 3-like domain of CD4 in CD45 expressing and CD45-deficient cells.";"JF. PEYRON";"Equipe 04, Team 04";9501032;Virology;"Péléraux A, Peyron JF, Devaux C";;"Mar 1998";888710400;;"Monoclonal antibodies directed toward the complementarity determining region (CDR)3-like loop of the aminoterminal domain of CD4 have been shown to inhibit the replication of human immunodeficiency virus (HIV) in CD4 positive T cells. The mechanism of action of these antibodies is not yet elucidated, although several observations suggest that they inhibit viral transcription by signal transduction through the CD4 molecule, potentially implicating the activation of a protein tyrosine kinase (PTK) cascade. Since CD45 is the major protein tyrosine phosphatase associated to the plasma membrane in T cells, and has been shown to regulate the activity of several PTK, we postulated that CD45 may be necessary for the inhibitory action of the CDR3-like specific anti-CD4 antibodies. Therefore we tested the effect of one such anti-CD4 monoclonal antibody, 13B8.2, in repressing HIV replication in CD45 positive cell lines and CD45 deficient variants. Our data show that cells respond to 13B8.2 postinfection treatment regardless of CD45 expression, indicating that neither CD45 nor PTK regulated by CD45 are implicated in the mechanism of action of this antibody." 4988;"Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of Ikappa Balpha.";"JF. PEYRON";"Equipe 04, Team 04";9792645;"The Journal of biological chemistry";"Abu-Amer Y, Ross FP, McHugh KP, Livolsi A, Peyron JF, Teitelbaum SL";;"Nov 1998";909878400;;"Tumor necrosis factor-alpha (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-kappa B (NF-kappaB). NF-kappaB is sequestered in the cytosol by Ikappa Balpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. In contrast, we find TNF induction of NF-kappaB in murine bone marrow macrophages (BMMs), is mediated, by c-Src, in a cell, and cytokine specific manner. The non-receptor tyrosine kinase is rapidly mobilized and activated upon TNF exposure. Within the same time frame, TNF induced c-Src associates with Ikappa Balpha in a long lived complex. The proto-oncogene, when associated with Ikappa Balpha phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced Ikappa Balpha tyrosine phosphorylation, NF-kappaB activation, by the cytokine, is markedly delayed and reduced in c-src-/- BMMs. Underscoring the physiological significance of c-Src activation of NF-kappaB, TNF induction of IL-6, which is an NF-kappaB mediated event, is substantially diminished in c-src-/- BMMs." 4986;"Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation.";"JF. PEYRON";"Equipe 04, Team 04";10102625;Oncogene;"Englaro W, Bahadoran P, Bertolotto C, Buscà R, Dérijard B, Livolsi A, Peyron JF, Ortonne JP, Ballotti R";;"Feb 1999";917827200;;"Melanogenesis is a physiological process resulting in the synthesis of melanin pigments which play a crucial protective role against skin photocarcinogenesis. In vivo, solar ultraviolet light triggers the secretion of numerous keratinocyte-derived factors that are implicated in the regulation of melanogenesis. Among these, tumor necrosis factor alpha (TNFalpha), a cytokine implicated in the pro-inflammatory response, down-regulates pigment synthesis in vitro. In this report, we aimed to determine the molecular mechanisms by which this cytokine inhibits melanogenesis in B16 melanoma cells. First, we show that TNFalpha inhibits the activity and protein expression of tyrosinase which is the key enzyme of melanogenesis. Further, we demonstrate that this effect is subsequent to a down-regulation of the tyrosinase promoter activity in both basal and cAMP-induced melanogenesis. Finally, we present evidence indicating that the inhibitory effect of TNFalpha on melanogenesis is dependent on nuclear factor kappa B (NFkappaB) activation. Indeed, overexpression of this transcription factor in B16 cells is sufficient to inhibit tyrosinase promoter activity. Furthermore, a mutant of inhibitory kappa B (IkappaB), that prevents NFkappaB activation, is able to revert the effect of TNFalpha on the tyrosinase promoter activity. Taken together, our results clarify the mechanisms by which TNFalpha inhibits pigmentation and point out the key role of NFkappaB in the regulation of melanogenesis." 4984;"Cleavage and relocation of the tyrosine kinase P59FYN during Fas-mediated apoptosis in T lymphocytes.";"JF. PEYRON, P. Auberger";"Equipe 04, Team 04, Equipe 02, Team 02";10435619;Oncogene;"Ricci JE, Maulon L, Luciano F, Guerin S, Livolsi A, Mari B, Breittmayer JP, Peyron JF, Auberger P";;"Jul 1999";930787200;;"Ligation of Fas with its natural ligand or with anti-Fas antibodies induces an apoptotic program in Fas sensitive cells. We report here the identification of the tyrosine kinase p59Fyn as a substrate for CPP32-like proteinases and more particularly caspase 3 during Fas-mediated apoptosis in Jurkat T cells. Inhibition of CPP32-like proteinases by Ac-Asp-Glu-Val-Asp-aldehyde but not by Ac-Tyr-Val-Ala-Asp-aldehyde prevents CPP32, PARP and p59Fyn cleavage indicating that CPP32 or CPP32-like proteinases are responsible for the cleavage of p59Fyn. Cleavage occurs in the N-terminal domain of p59Fyn between Asp19 and Gly20 and is accompanied by relocation of an active p57Fyn kinase to cytoplasm of Fas-stimulated Jurkat cells as judged by both biochemical and confocal microscopy experiments. Thus, p59Fyn relocation and activity may play an important role during Fas-mediated cell death in human T lymphocytes." 4982;"Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha.";"JF. PEYRON";"Equipe 04, Team 04";11266466;"The Journal of cell biology";"Bui NT, Livolsi A, Peyron JF, Prehn JH";;"Feb 2001";980985600;;"NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-kappaB (NFkappaB). We investigated the effect of NGF on the expression of Bcl-xL, an anti-apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1-10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFkappaB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFkappaB p65 subunit. NGF-induced NFkappaB activity and Bcl-xL expression were inhibited in cells overexpressing the NFkappaB inhibitor, IkappaBalpha. Unlike tumor necrosis factor-alpha (TNF-alpha), however, NGF-induced NFkappaB activation occurred without significant degradation of IkappaBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein-tagged IkappaBalpha. Moreover, in contrast to TNF-alpha, NGF failed to phosphorylate IkappaBalpha at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IkappaBalpha potently suppressed NFG-, but not TNF-alpha-induced NFkappaB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-alpha-, but not NGF-induced NFkappaB activation. We conclude that NGF and TNF-alpha induce different signaling pathways in neurons to activate NFkappaB and bcl-x gene expression." 4980;"Ikappa b-alpha, the NF-kappa B inhibitory subunit, interacts with ANT, the mitochondrial ATP/ADP translocator.";"JF. PEYRON";"Equipe 04, Team 04";11287411;"The Journal of biological chemistry";"Bottero V, Rossi F, Samson M, Mari M, Hofman P, Peyron JF";;"Jun 2001";991353600;;"The transcription factor NF-kappaB regulates a wide set of genes involved in the establishment of many cellular processes that control cell activation, proliferation, and apoptosis. IkappaB inhibitory subunits integrate NF-kappaB activation signals through phosphorylation and ubiquitination of its N-terminal domain. Using the two-hybrid system in yeast, we searched for IkappaB-alpha N-terminal domain interactors and therefore potential NF-kappaB regulators. An interaction of IkappaB-alpha with the mitochondrial ATP/ADP translocator ANT was detected in yeast and confirmed in glutathione S-transferase pull-down assays and co-precipitation experiments in transfected cells. Subcellular cell fractionation, resistance to proteinase K treatment, and electron microscopy experiments demonstrated the presence of IkappaB-alpha and associated p65 NF-kappaB in the mitochondrial intermembrane space. IkappaB-alpha.NF-kappaB appeared to be released from mitochondria upon the induction of apoptosis by engagement of the Fas receptor. These data suggest that the mitochondrial IkappaB-alpha.NF-kappaB pool participates in the regulation of apoptosis." 4978;"Activation of nuclear factor kappaB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to apoptosis in HeLa human carcinoma cells.";"JF. PEYRON";"Equipe 04, Team 04";11691793;"Cancer research";"Bottero V, Busuttil V, Loubat A, Magné N, Fischel JL, Milano G, Peyron JF";;"Nov 2001";1004572800;;"The transcription factor nuclear factor (NF) kappaB is involved in the regulation of cell survival. NFkappaB is activated in many malignant tumors and seems to play a role in the resistance to cytostatic treatments and escape from apoptosis. We have studied the effects on NFkappaB activation of two topoisomerase poisons and DNA damaging agents that are used in chemotherapy: SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of CPT11, and doxorubicin. In HeLa cells, both drugs activate NFkappaB using a preexisting pathway that requires a functional IkappaB-specific kinase complex, IkappaB-specific kinase activation, IkappaB-alpha phosphorylation, and degradation. Blocking NFkappaB activation by stable expression of a mutant super-repressor IkappaB-alpha molecule sensitized HeLa cells to the apoptotic actions of drugs and tumor necrosis factor. RNase protection assay analysis demonstrate that NFkappaB is involved in the regulation of a complex pattern of gene activation and repression during the cellular response of HeLa cells to topoisomerase poisons. The blockade of NF-kappaB activation seems to shift the death/survival balance toward apoptosis." 4976;"Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome.";"JF. PEYRON";"Equipe 04, Team 04";18194987;Gut;"Piche T, Saint-Paul MC, Dainese R, Marine-Barjoan E, Iannelli A, Montoya ML, Peyron JF, Czerucka D, Cherikh F, Filippi J, Tran A, Hébuterne X";;"Apr 2008";1207008000;;"A subset of patients with irritable bowel syndrome (IBS) have an increased number of mast cells (MCs) in the colonic mucosa. Psychological factors are believed to contribute to the course of IBS." 4974;"Nuclear factor-κB regulates βAPP and β- and γ-secretases differently at physiological and supraphysiological Aβ concentrations.";"JF. PEYRON";"Equipe 04, Team 04";22654105;"The Journal of biological chemistry";"Chami L, Buggia-Prévot V, Duplan E, Del Prete D, Delprete D, Chami M, Peyron JF, Checler F";;"Jul 2012";1341100800;;"Anatomical lesions in Alzheimer disease-affected brains mainly consist of senile plaques, inflammation stigmata, and oxidative stress. The nuclear factor-κB (NF-κB) is a stress-activated transcription factor that is activated around senile plaques. We have assessed whether NF-κB could be differentially regulated at physiological or supraphysiological levels of amyloid β (Aβ) peptides. Under these experimental conditions, we delineated the putative NF-κB-dependent modulation of all cellular participants in Aβ production, namely its precursor βAPP (β-amyloid precursor protein) and the β- and γ-secretases, the two enzymatic machines involved in Aβ genesis. Under physiological conditions, NF-κB lowers the transcriptional activity of the promoters of βAPP, β-secretase (β-site APP-cleaving enzyme 1, BACE1), and of the four protein components (Aph-1, Pen-2, nicastrin, presenilin-1, or presenilin-2) of the γ-secretase in HEK293 cells. This was accompanied by a reduction of both protein levels and enzymatic activities, thereby ultimately yielding lower amounts of Aβ and AICD (APP intracellular domain). In stably transfected Swedish βAPP-expressing HEK293 cells triggering supraphysiological concentrations of Aβ peptides, NF-κB activates the transcription of βAPP, BACE1, and some of the γ-secretase members and increases protein expression and enzymatic activities, resulting in enhanced Aβ production. Our pharmacological approach using distinct NF-κB kinase modulators indicates that both NF-κB canonical and alternative pathways are involved in the control of Aβ production. Overall, our data demonstrate that under physiological conditions, NF-κB triggers a repressive effect on Aβ production that contributes to maintaining its homeostasis, while NF-κB participates in a degenerative cycle where Aβ would feed its own production under pathological conditions." 4972;"Prostaglandin synthesis in human T cells: its partial inhibition by lectins and anti-CD3 antibodies as a possible step in T cell activation.";"D. MARY";"Equipe 04, Team 04";3106472;"Journal of immunology (Baltimore, Md. : 1950)";"Aussel C, Mary D, Fehlmann M";;"May 1987";546825600;;"The human leukemic T cell line Jurkat was used to study arachidonic acid (AA) metabolism. We demonstrated that Jurkat cells are able to convert AA into prostaglandins (PG) and thromboxanes. The presence of tritiated 6-keto-PGF1 alpha, PGE2, PGA2 (B2), and thromboxane B2 in the culture medium was shown either by thin-layer chromatography after a 4-hr incubation period of [3H]AA-prelabeled Jurkat cells or by using specific radioimmuno assays. PG synthesis was inhibited by both indomethacin and niflumic acid, two cyclooxygenase inhibitors. AA metabolism through the cyclooxygenase pathway was followed during T cell activation. T cells were activated by lectins or anti-CD3 monoclonal antibodies (mAb) to trigger the T3-Ti complex and by 12-0-tetradecanoylphorbol 13-acetate (TPA) to mimic IL 1-dependent pathways. Our results show that lectins and anti-CD3 mAb both reduce the amount of PG released by the cells, whereas TPA did not. We confirmed that a combination of TPA and lectins or TPA and anti-CD3 mAb is necessary to obtain full activation of Jurkat cells if this event is monitored by using measurement of IL 2 synthesis. In addition, lectins and anti-CD3 mAb can be replaced by the cyclooxygenase inhibitors indomethacin or niflumic acid. Indeed, a combination of TPA and one of these two drugs induced maximal IL 2 synthesis. These results thus suggest that a reduction in PG synthesis might be a prerequisite to allow the cascade of events involved in T cell activation." 4970;"Regulation of interleukin 2 synthesis by cAMP in human T cells.";"D. MARY";"Equipe 04, Team 04";3038999;"Journal of immunology (Baltimore, Md. : 1950)";"Mary D, Aussel C, Ferrua B, Fehlmann M";;"Aug 1987";554774400;;"T cell activation requires two initial signals that first lead to the expression of interleukin 2 (IL 2) receptors and the initiation of IL 2 synthesis and then to T cell proliferation. Jurkat T lymphoma cells have been shown to be a good model for studying IL 2 synthesis because these cells also require two signals for activation. The first signal can be provided by the lectin phytohaemagglutinin (PHA), and the second one by the phorbol ester, 12-o-tetradecanoylphorbol 13-acetate (TPA). The regulation of IL 2 synthesis in Jurkat cells, however, is unclear, and the present study deals with the role of cAMP on IL 2 synthesis. In Jurkat cells, IL 2 synthesis appears to be highly regulated by the activity of adenylate cyclase. This was demonstrated by using different means to increase intracellular cAMP level, namely by using permeant cAMP analogs, using the activator of adenylate cyclase, forskolin, using the activator of the alpha subunit of the stimulatory GTP binding protein cholera toxin, and using inhibitors of phosphodiesterase. In addition, prostaglandins E1 and E2 were shown to bind specifically to Jurkat cells, to induce a rise in intracellular cAMP level, and to markedly decrease IL 2 synthesis. All together, these results suggest that in T lymphocytes, the prostaglandin E2 receptor is linked to adenylate cyclase through a GTP binding protein and regulates the production of IL 2 by controlling the intracellular cAMP level." 4968;"Chymotryptic-type protease inhibitors block the increase in Ca2+ and Il-2 production in activated Jurkat T cells.";"D. MARY, P. Auberger";"Equipe 04, Team 04, Equipe 02, Team 02";2521661;"Journal of immunology (Baltimore, Md. : 1950)";"Auberger P, Mary D, Breittmayer JP, Aussel C, Fehlmann M";;"Feb 1989";602294400;;"Several chymotryptic-type protease inhibitors were found to inhibit both anti-CD3 mAb- and PHA-induced rise in Ca2+ and IL-2 production in Jurkat T cells. The magnitude of inhibition was a function of the effectors used to stimulate Ca2+ entry and depended on the concentration of the inhibitors. Neither tryptic-type protease inhibitors nor an elastase substrate prevented anti-CD3 mAb- or PHA-induced Ca2+ rise in Jurkat cells. The inhibitory effect of N-alpha-p-tosyl-L-phenylalanine chloromethyl-ketone on anti-CD3 mAb- and PHA-induced rise in Ca2+ resulted from a rapid increase in Ca2+ efflux. The inhibitors which were effective on Ca2+ mobilization also inhibited IL-2 production initiated by an anti-CD3 mAb in the presence of 12-O-tetradecanoylphorbol-13-acetate, and to a lesser extent by PHA or the calcium ionophore A23187. No inhibition of IL-2 production was observed when tryptic-type protease inhibitors or the elastase inhibitor were used. In addition, membrane preparations from Jurkat cells were found to hydrolyze the chymotryptic substrate Suc-Ala-Ala-Phe-paranitroaniline, an effect markedly inhibited by N-alpha-p-tosyl-L-phenylalanine chloromethylketone. Moreover, this inhibitor protected one potential endogenous substrate (Mr 38 kDa) from proteolysis. Taken together, these observations show that chymotryptic-type protease inhibitors block the responses generated by the binding of anti-CD3 mAb to Jurkat cells, and suggest that a chymotryptic-like membrane protease contributes to T cell activation." 4966;"Modulation of T cell activation by differential regulation of the phosphorylation of two cytosolic proteins. Implication of both Ca2+ and cyclic AMP-dependent protein kinases.";"D. MARY, JF. PEYRON, P. Auberger";"Equipe 04, Team 04, Equipe 02, Team 02";2547797;"The Journal of biological chemistry";"Mary D, Peyron JF, Auberger P, Aussel C, Fehlmann M";;"Aug 1989";617932800;;"Interleukin 2 production by activated Jurkat T cells is markedly decreased by prostaglandin E2 (PGE2). The target of PGE2 action has been investigated in the present study. Among the biochemical events occurring after CD3.TCR triggering by anti-CD3 monoclonal antibody, phosphorylation of two cytosolic proteins, pp21 and pp23, was strongly inhibited by PGE2, forskolin, and 8-bromo-cAMP, whereas anti-CD3 monoclonal antibody-induced CD3.TCR modulation and Ca2+ influx were not affected. The inhibition of both pp21 and pp23 phosphorylation and interleukin 2 synthesis by PGE2 can be largely reversed by the cAMP-dependent protein kinase inhibitor, N-[2-(methylamino)-ethyl-1]-5-isoquinoline sulfonamide. Together with the demonstration of a cAMP-dependent protein kinase activity in Jurkat T cells, these results are consistent with the participation of the cAMP-dependent protein kinase mediating the inhibitory action of PGE2, probably through the inhibition of pp21 and pp23 phosphorylation. Thus, it appears that the modulation of the phosphorylation of these cytosolic proteins represents an essential step in the regulation of T lymphocyte activation." 4964;"Regulation of interleukin-2 production and phosphatidylserine synthesis in Jurkat T lymphocytes by K+ channel antagonists.";"D. MARY";"Equipe 04, Team 04";2266004;Immunopharmacology;"Aussel C, Pelassy C, Mary D, Choquet D, Rossi B";;"Oct Sep 1990";652924800;;"Modification of phospholipid metabolism during T cell activation has been repeatedly reported. Recently, we have shown that phytohaemagglutinin, CD3 and CD2 mAbs, which are potent in vitro activators of helper T lymphocytes, markedly inhibit phosphatidylserine synthesis concomitantly as they induce the secretion of IL-2. In this paper, we show evidence that in T lymphocytes K+ channels, which have been shown to participate in the cell activation process, are also reciprocally related to phosphatidylserine synthesis. In fact, in resting T cells the drugs affecting the activity of K+ channels, such as quinine and 4-aminopyridine, induce a rise of phosphatidylserine synthesis. In activated cells, quinine and 4-amidopyridine also caused a rise in phosphatidylserine synthesis which paralleled a decreased production of IL-2, strongly suggesting that these two events are correlated in a reciprocal manner. More precisely, phosphatidylserine synthesis was stimulated by drugs which have been reported to inhibit potassium channels in lymphocytes, e.g. quinine, 4-aminopyridine, tetraethylammonium. These data suggest that the decreased PS synthesis observed during T cell activation intervenes in the cascade of events leading to IL-2 secretion. The decrease in the biosynthesis of this phospholipid seems to be dependent on the activity of K+ channels." 4962;"Diacylglycerol production in Jurkat T-cells: differences between CD3, CD2 and PHA activation pathways.";"D. MARY";"Equipe 04, Team 04";1674659;"Cellular signalling";"Pelassy C, Mary D, Aussel C";;"Jan 1991";662688000;;"Diacylglycerol (DAG) production induced after stimulation with either CD3 mAb, a pair of CD2 mAbs or phytohaemagglutinin has been monitored in Jurkat T-cells prelabelled to isotopic equilibrium with seven [3H]- or [14C] fatty acids. It was found that CD3 induced a high production of arachidonic acid-labelled DAG and a modest production of oleic acid-DAG. The reverse was observed when using CD2 as activator. Phytohaemagglutinin induced a high production of these two DAG subspecies and in addition induced the production of linolenic acid-labelled DAG. Whatever the activator used no changes were observed in DAG production when cellular phospholipids were prelabelled with either myristic, palmitic, stearic or linoleic acids. All together our results strongly suggest that the three activation pathways previously described in T-lymphocytes might differ either at the level of the transduction mechanism or the phospholipid pools solicited during the activation process." 4960;"Effects of the serine analogues isoserine and serinol on interleukin-2 synthesis and phospholipid metabolism in a human T cell line Jurkat.";"D. MARY";"Equipe 04, Team 04";1768842;"Journal of lipid mediators";"Pelassy C, Mary D, Aussel C";;"Feb Jan 1991";662774400;;"Phosphatidylserine has been implicated both in the regulation of protein kinase C activity and in the regulation of T lymphocyte activation. Taking into account the fact that some serine analogues modify the activity of the base exchange enzyme system responsible for the synthesis of phosphatidylserine and to a lesser extent the synthesis of phosphatidylcholine and phosphatidylethanolamine, in vitro, we have tested the ability of both isoserine and serinol to modify phospholipid synthesis in the T cell line Jurkat. It was found that serinol was able to decrease by 75% the amount of phosphatidylserine synthesized by the cells and also to decrease the synthesis of phosphatidylcholine and phosphatidylethanolamine, while phosphatidylinositol synthesis was not affected. Concomitantly, in serinol-treated Jurkat cells, interleukin-2 production was markedly inhibited. Monitoring the production of second messengers generated by T cell activators showed that in serinol-treated cells the production of diacylglycerol was impaired while Ca2+ mobilization remained unaffected. Serinol thus appeared to be a potential immunoregulatory molecule active at the level of protein kinase C regulation either through its interaction with phosphatidylserine or through diacylglycerol production." 4958;"Calcium-dependent regulation of phosphatidylserine synthesis in control and activated Jurkat T cells.";"D. MARY";"Equipe 04, Team 04";1685336;"Journal of lipid mediators";"Aussel C, Pelassy C, Mary D, Breittmayer JP, Cousin JL, Rossi B";;"Jun May 1991";673488000;;"Activation of Jurkat T cells with phytohemagglutinin (PHA), CD3 or CD2 monoclonal antibodies (mAbs) results in a marked inhibition of phosphatidylserine (PS) synthesis. Activation of Jurkat T cells with PHA in a Ca(2+)-free medium resulted in an arrest of PS synthesis which was not reversed by the addition of Ca2+. The use of BAPTA to chelate Ca2+ ions released from intracellular stores prevented PHA-induced inhibition of PS synthesis. In addition, it was found that during activation, in the presence of BAPTA, a net Ca2+ influx paralleled an increase in PS synthesis, demonstrating that Ca2+ uptake caused an enhanced PS synthesis rather than an inhibition. The use of a CD2 mAb, D66, able to mobilize exclusively Ca2+ from intracellular stores, resulted in 51% inhibition of PS synthesis. N-Ethylmaleimide (NEM), which inhibits both the release of Ca2+ from internal stores and the influx of Ca2+, totally prevents the inhibition of PS synthesis induced by PHA, anti-CD3 or anti-CD2 mAbs. The presence, in the incubation medium, of either NDGA, TPCK or TPA, three drugs able to markedly inhibit Ca2+ influx without modifying the release of Ca2+ from internal stores, did not modify the inhibition of PS synthesis induced by PHA. Moreover all the drugs known to interact with calmodulin were also found to prevent the PHA-induced inhibition of this phospholipid. Taken together, these results show that the inhibition of PS synthesis induced by T cell activators is regulated by both calmodulin and Ca2+ ions recruited from intracellular compartments." 4956;"Inhibition of phosphatidylserine synthesis by phosphatidic acid in the Jurkat T cell line: role of calcium ions released from intracellular stores.";"D. MARY";"Equipe 04, Team 04";1835407;"Journal of lipid mediators";"Pelassy C, Breittmayer JP, Mary D, Aussel C";;"Oct Sep 1991";684460800;;"Phosphatidic acid exogenously added to Jurkat T-cells, provokes a marked inhibition of phosphatidylserine (PS) synthesis. Comparison of the efficiency of synthetic phosphatidic acids, differing in their fatty acid content, to induce inhibition of PS-synthesis have shown that short chain saturated and long chain unsaturated fatty acid-containing phosphatidic acids were the best inhibitors. Treatment of Jurkat cells with phosphatidic acid, induced a mobilization of calcium ions arising exclusively from intracellular stores, suggesting that Ca2+ from intracellular compartments might play a key role in the inhibition of PS synthesis. In activated cells, the use of R59022, a diacylglycerolkinase inhibitor, suggests that PA and probably calcium ions released by PA are the messengers responsible for the inhibition of PS synthesis in Jurkat T cells." 4954;"The glycosylphosphatidylinositol-anchored CD59 protein stimulates both T cell receptor zeta/ZAP-70-dependent and -independent signaling pathways in T cells.";"D. MARY, M. Deckert";"Equipe 04, Team 04, Equipe 11, Team 11";7542590;"European journal of immunology";"Deckert M, Ticchioni M, Mari B, Mary D, Bernard A";;"Jul 1995";804556800;;"The glycosylphosphatidylinositol (GPI)-anchored CD59 protein (human protectin) protects cells against complement-induced lysis, binds to CD2 and also transduces activation signals within T cells. We have further examined the biochemical signals transduced by CD59 and addressed its role in regard to the CD3-mediated signaling cascade. We show here that CD59 cross-linking induces a time-dependent activation of p56lck and of p70zap (ZAP-70) in CD3-positive Jurkat cells, leading to the stimulation of the T cell receptor zeta/ZAP-70 signaling cascade and interleukin-2 (IL-2) synthesis. Cross-linking of CD59 on peripheral T cells and thymocytes induces tyrosine phosphorylations identical to those seen in Jurkat cells and this is followed by lymphokine production and proliferation. In contrast, only activation of CD59-associated p56lck occurs in CD3-negative Jurkat cells, while IL-2 production is impaired, consistent with the lack of ZAP-70 tyrosine phosphorylation observed in these cells. CD59 triggers activation events even in the absence of CD3/T cell receptor expression in Jurkat cells. CD59 cross-linking synergizes with sub-optimal doses of phorbol ester for activation of the protein kinase C and of the p42mapk, as shown by in vitro phosphorylation of histone HIIIS and myelin basic protein, respectively, and leads to CD25 but not CD69 expression. In conclusion, at least two signaling pathways are triggered through CD59, the first one involving ZAP-70 activation and leading to IL-2 secretion and a second pathway observed in the absence of ZAP-70 activation leading to CD25 expression. These two pathways are likely to be involved in the modulation of T cell activation by CD59 protein." 4952;"Activation of T cells via CD55: recruitment of early components of the CD3-TCR pathway is required for IL-2 secretion.";"D. MARY";"Equipe 04, Team 04";9368189;"Journal of inflammation";"Tosello AC, Mary F, Amiot M, Bernard A, Mary D";;"Jan 1998";883612800;;"It was previously reported that the glycosylphosphatidylinositol (GPI)-anchored CD55 molecule provides a co-stimulatory signal for T lymphocytes and is constitutively associated with the Src-related kinase p56lck. The present studies were undertaken to clarify the mechanism of action of CD55 in T cells. We describe the failure of cross-linking of CD55 alone to induce both the elevation of the intracellular calcium concentration and the tyrosine phosphorylation of PLC-gamma in CD3+ Jurkat cells. By contrast, it is sufficient to induce the phosphorylation of tyrosine residues on p56lck, the TCR-zeta chain as well as ZAP-70. Surprisingly, the observed TCR-zeta and ZAP-70 tyrosine phosphorylations appear delayed compared to stimulation via CD3. Calcium ionophore A23187 in combination with cross-linked CD55 mAb initially caused an acceleration in the kinetic of these two phosphorylation events, followed by IL-2 secretion. Furthermore, transfection of the cytoplasmic domain of TCR-zeta in CD3- Jurkat cells, using a CD16-zeta chimera, demonstrates that CD55-mediated T-cell activation depends on the expression of this chain of the CD3-TCR complex." 4950;"Modulation of TCR signaling by beta1 integrins: role of the tyrosine phosphatase SHP-1.";"D. MARY";"Equipe 04, Team 04";10601996;"European journal of immunology";"Mary F, Moon C, Venaille T, Thomas ML, Mary D, Bernard A";;"12 1999";944006400;;"When cross-linked, beta1 integrins co-activate T cells together with a TCR-CD3 signal. Soluble anti-beta1 monoclonal antibodies, however, inhibit T cell activation. We report inhibition of early tyrosine kinases, including ZAP-70, p59(fyn), CD4-associated p56(lck) and TCR components under this condition. The tyrosine phosphatase SHP-1 is activated by engagement of beta1 integrins and is implicated in this negative regulation since no inhibition occurs in SHP-1 dominant-negative T cells. As shown by the use of Lck-deficient cells, the activation of the protein tyrosine phosphatase depends on a pool of p56(lck) that is not associated with CD4. These cross-talk events were also observed with the alpha4beta1 integrin ligand, VCAM-1. We propose that these results may be important in terms of lymphocyte circulation; while T cells migrate through the vascular endothelium, they are primed for an amplified response; as inflammation develops, a local accumulation of soluble integrin ligands may help to turn it off." 4948;"Prostaglandin B(2) delivers a co-stimulatory signal leading to T cell activation.";"D. MARY";"Equipe 04, Team 04";10903809;"European cytokine network";"Cattan N, Mary D, Peleraux A, Mari B, Aussel C, Rossi B";;"Jun 2000";959817600;;"Most of the data accumulated to date on the immunoregulatory effects of prostaglandins (PG) on T cell activation stem from the archetypal inhibitory effect of PGE(2). In this study we provide instead, the first evidence that exogenous PGB(2), a catabolic metabolite of PGE(2), synergizes with signals delivered by T cell receptor (TCR) engagement to induce interleukin-2 (IL-2) production and IL-2 receptor (IL-2R) alpha-expression in Jurkat cells. Accordingly, PGB(2) enhances the proliferation of anti-CD3-activated peripheral blood lymphocytes (PBL). In terms of cellular signaling, we present evidence that PGB(2) activates tyrosine kinase activities and efficiently increases c-fos mRNA expression and nuclear factor-kappa B (NF-kappa B) translocation to the nucleus. Owing to these features, PGB(2) appears as a new lipid mediator capable of delivering an ancillary signal leading to T lymphocyte activation." 4946;"The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells.";"D. MARY, JF. PEYRON, M. NEBOUT, V. Imbert";"Equipe 04, Team 04";25925206;Leukemia;"Mourgues L, Imbert V, Nebout M, Colosetti P, Neffati Z, Lagadec P, Verhoeyen E, Peng C, Duprez E, Legros L, Rochet N, Maguer-Satta V, Nicolini FE, Mary D, Peyron JF";;"Oct 2015";1443657600;;"The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response." 4944;"The placental-umbilical unit in sickle cell disease pregnancy: a model for studying in vivo functional adjustments to hypoxia in humans.";"D. MARY";"Equipe 04, Team 04";15668892;"Human pathology";"Trampont P, Roudier M, Andrea AM, Nomal N, Mignot TM, Leborgne-Samuel Y, Ravion S, Clayton J, Mary D, Elion J, Decastel M";;"Nov 2004";1099267200;;"The placental-umbilical unit in sickle cell disease (SCD) pregnancy was used to explore hypoxia in vivo, an important factor in the pathophysiology of this disease. Gross examination and microscopic analysis of the placentas, taken immediately after delivery, indicate good concordance between maturity and term as controls, but higher frequency of vascular injuries such as excess syncytial knots, excess fibrin deposits, congestion and villous necroses. Unexpectedly, neither leukocyte recruitment nor alteration in extraplacental membrane was observed, suggesting the absence of inflammation. Additionally, interleukin (IL)-6 and IL-8 concentrations, measured by enzyme-linked immunosorbent assay (ELISA), were similar in the placental maternal blood from controls and SCD. There were also no significant differences found in IL-6 vein blood concentrations between controls and SCD, IL-8 being not detected. Immunostaining of umbilical vein endothelium in SCD pregnancies showed redistribution of PECAM-1 (CD31), von Willebrand factor (vWF), and P-selectin to the cell surface, controls exhibiting the classical pattern. Staining quantification indicated increases in vWF (+36.2%; P=.006) and vascular endothelial growth factor (VEGF) expression (+96.0%; P=.006) over control, but a reduction in endothelial nitric oxide synthase (eNOS) (-45.5%; P=.029). These results document, for the first time, direct functional adjustments in response to hypoxia in human in vivo. The mechanism for these changes has not been clearly established, but it may reflect increased tolerance to SCD hypoxic conditions and hypoxia in general." 4939;"Induction of tyrosine phosphorylation and T-cell activation by vanadate peroxide, an inhibitor of protein tyrosine phosphatases.";"JF. PEYRON, P. Auberger, V. Imbert";"Equipe 04, Team 04, Equipe 02, Team 02";7506531;"The Biochemical journal";"Imbert V, Peyron JF, Farahi Far D, Mari B, Auberger P, Rossi B";;"Jan 1994";757382400;;"Rapid tyrosine phosphorylation of key cellular proteins is a crucial event in the transduction of activation signals to T-lymphocytes. The regulatory role of protein tyrosine phosphatases (PTPases) in this process was explored by studying the effects of a powerful PTPase inhibitor, vanadate peroxide (pervanadate), on the activation cascade of Jurkat human leukaemic T-cells. Pervanadate induced activation of the tyrosine kinases lck and fyn (4- and 3-fold respectively) and a dramatic increase in tyrosine phosphorylation of cellular proteins, notably phospholipase C gamma 1. After this event, we observed a rise in intracellular Ca2+ concentration, corresponding to an influx. This effect required surface expression of the CD45 PTPase and was not observed in CD45-deficient variants of Jurkat cells. In the CD45-negative variant, the effect of pervanadate on tyrosine phosphorylation was globally decreased and some phosphorylated substrates were specifically missing. Pervanadate also stimulated transcription of the c-fos gene and accumulation of its mRNA as well as several other hallmarks of T-lymphocyte activation such as surface expression of the CD69 antigen and the interleukin 2 receptor alpha-chain (CD25). Pervanadate synergized with signals delivered by T-cell antigen receptor engagement or by a phorbol ester to induce interleukin 2 production. Pervanadate activated NF-kappa B, as shown by an increase in DNA-binding activity of this transcription factor. We thus conclude that PTPases play a crucial role in the negative regulation of signal transduction culminating in T-lymphocyte activation. Moreover, induction of tyrosine phosphorylation appears sufficient per se to initiate a complete activation programme." 4936;"Thrombin and thrombin receptor agonist peptide induce early events of T cell activation and synergize with TCR cross-linking for CD69 expression and interleukin 2 production.";"JF. PEYRON, P. Auberger, V. Imbert";"Equipe 04, Team 04, Equipe 02, Team 02";7510689;"The Journal of biological chemistry";"Mari B, Imbert V, Belhacene N, Far DF, Peyron JF, Pouysségur J, Van Obberghen-Schilling E, Rossi B, Auberger P";;"Mar 1994";762480000;;"Thrombin stimulation of the T leukemic cell line Jurkat induced a transient increase in [Ca2+]i. Proteolytic activity of the enzyme was required for this effect since diisopropyl fluorophosphate-thrombin failed to increase [Ca2+]i. Furthermore, hirudin and anti-thrombin III inhibited the thrombin-induced [Ca2+]i rise in Jurkat T cells. A synthetic thrombin receptor agonist peptide (TRP) of 7 residues (SFLLRNP) was found to be as effective as thrombin for [Ca2+]i mobilization, and both agonists induced Ca2+ release exclusively from internal stores. Thrombin stimulated tyrosine phosphorylation of several proteins of molecular mass 40, 42, 70, 120, and 130 kDa. There was a good correlation between thrombin-induced tyrosine phosphorylation of the latter three proteins and Ca2+ mobilization. Thrombin and TRP also caused translocation of protein kinase C from the cytosol to the plasma membrane. As a likely consequence of these events, thrombin activated the nuclear factor NF-kB. Several cell lines of hematopoietic origin including the leukemic T cell line HPB.ALL and the erythroleukemic cell line K562 were responsive to thrombin, whereas others such as THP1, a myelomonocytic cell line, and BL2, a Burkitt lymphoma were refractory to thrombin or TRP stimulation. The magnitude of the thrombin response in the different cell types paralleled the expression of the thrombin receptor mRNA. We found that activation of Jurkat T cells by a combination of phytohemagglutinin and phorbol 12-myristate 13-acetate led to a dramatic inhibition of thrombin receptor mRNA expression and to a concomitant loss of the thrombin response. Finally, we demonstrate that thrombin and TRP enhanced CD69 expression and interleukin 2 production induced by T cell receptor cross-linking in both Jurkat T cells and peripheral blood lymphocytes. These findings highlight the role of thrombin as a potential regulator of T lymphocyte activation." 4934;"Immunofluorescent quantification of tyrosine phosphorylation of cellular proteins in whole cells by flow cytometry.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";7517816;Cytometry;"Far DF, Peyron JF, Imbert V, Rossi B";;"Apr 1994";765158400;;"Tyrosine phosphorylation of proteins, a major event in the transduction of mitogenic signals, was analysed by flow cytometry with a fluorescent antiphosphotyrosine monoclonal antibody, on formaldehyde-fixed, permeabilized cells. We have used this method (PY-Facs) to study activation of normal human T lymphocytes and cells of a leukemic T-cell line: Jurkat. In contrast to normal T cells, Jurkat cells as well as three other leukemic cell lines display a higher constitutive level of tyrosine phosphorylation. This level of tyrosine phosphorylation results from an equilibrium that can be up-regulated by the tyrosine phosphatase inhibitor, vanadate peroxide, and down-regulated by the tyrosine kinase inhibitors, genistein and staurosporine. We have also observed an increased tyrosine phosphorylation of proteins after mitogenic stimulation of Jurkat cells via T-cell receptor triggering. In addition, the entry of normal purified T cells from G0 phase into the cell cycle after co-stimulation with a phorbol ester and an anti-receptor antibody is correlated with a pronounced increase in tyrosine phosphorylation. We thus confirmed that this biochemical event was tightly associated with the activation status of the cells. The rapidity and sensitivity of the method we describe here make it particularly convenient for routine use and processing of a large number of samples, e.g., during analysis of human tumors. Moreover, because it retains sufficiently the integrity of treated cells and does not alter expression of membrane antigens, this method is suitable for multiparametric analysis, particularly for simultaneous studies associating the measure of tyrosine phosphorylation levels with possible modifications of membrane or intracellular structures as well as with cell cycle status.(ABSTRACT TRUNCATED AT 250 WORDS)" 4932;"Stimulation of the T-cell antigen receptor-CD3 complex signaling pathway by the tyrosine phosphatase inhibitor pervanadate is mediated by inhibition of CD45: evidence for two interconnected Lck/Fyn- or zap-70-dependent signaling pathways.";"D. MARY, JF. PEYRON, P. Auberger, V. Imbert";"Equipe 04, Team 04, Equipe 02, Team 02";8734787;"Journal of inflammation";"Imbert V, Farahifar D, Auberger P, Mary D, Rossi B, Peyron JF";;"Jan 1996";820454400;;"The tyrosine phosphatase specific inhibitor pervanadate is a potent activator of T lymphocytes through induction of tyrosine phosphorylation and downstream events of the activation cascade. Using CD45- or CD3-negative variants of the Jurkat leukemic T-cell line we show that the different biochemical events induced by pervanadate appeared to be dependent on the presence at the cell surface of either CD45 or CD3. CD45-dependent events such as tyrosine phosphorylation of Shc, activation of nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1), transcription factors, and stimulation of interleukin-2 (IL-2) promoter and of CD69 and CD25 surface expression paralleled activation of the tyrosine kinases lck and fyn. By contrast, stimulation of calcium influx, a CD3-dependent event, paralleled zap-70 activation. The data demonstrate that the T-cell antigen receptor-CD3 (TcR-CD3) complex is functionally linked to two different protein tyrosine kinase (PTK) modules with separate specific functions and that CD45 may be an important regulator of this coupling." 4930;"Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha.";"JF. PEYRON, P. Auberger, V. Imbert";"Equipe 04, Equipe 02, Team 02";8797825;Cell;"Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner EB, Mueller-Dieckmann C, Farahifar D, Rossi B, Auberger P, Baeuerle PA, Peyron JF";;"Sep 1996";841536000;;"The transcription factor NF-kappa B regulates genes participating in immune and inflammatory responses. In T lymphocytes, NF-kappa B is sequestered in the cytosol by the inhibitor I kappa B-alpha and released after serine phosphorylation of I kappa B-alpha that regulates its ubiquitin-dependent degradation. We report an alternative mechanism of NF-kappa B activation. Stimulation of Jurkat T cells with the protein tyrosine phosphatase inhibitor and T cell activator pervanadate led to NF-kappa B activation through tyrosine phosphorylation but not degradation of I kappa B-alpha. Pervanadate-induced I kappa B-alpha phosphorylation and NF-kappa B activation required expression of the T cell tyrosine kinase p56ick. Reoxygenation of hypoxic cells appeared as a physiological effector of I kappa B-alpha tyrosine phosphorylation. Tyrosine phosphorylation of I kappa B-alpha represents a proteolysis-independent mechanism of NF-kappa B activation that directly couples NF-kappa B to cellular tyrosine kinase." 4928;"Human monocytes express amphiregulin and heregulin growth factors upon activation.";"V. Imbert";"Equipe 04, Team 04";9110152;"European cytokine network";"Mograbi B, Rochet N, Imbert V, Bourget I, Bocciardi R, Emiliozzi C, Rossi B";;"Mar 1997";857174400;;"In the last few years, three new heparin binding growth factors that interact with the Epidermal Growth Factor receptor (EGFR) and/or the related p185erbB-2 tyrosine kinase have been identified. Amphiregulin (AR) and Heparin-Binding EGF-like growth factor (HB-EGF) bind and activate the EGFR while Heregulin (HRG) acts through the p185erbB-2 and p180erbB-4 tyrosine kinases. Recently, activated macrophages were reported to secrete a p185erbB-2- and a heparin binding EGFR-stimulatory activities. We show here that activated monocytes secrete AR, HRG and HB-EGF-like molecules. Indeed, upon activation with Phorbol12, 13-dibutyrate (PDBu), the human monocytic-like THP-1 cells expressed high levels of AR, HRG and HB-EGF transcripts and released heparin binding factors that induced tyrosine phosphorylation of the EGFR in A431 cells and a protein of 185 kDa in MDA MB 453 cells. Similarly, activation of peripheral blood monocytes induces a dramatic increase of these three genes. Since EGFR, cerbB-2, c-erbB-4 transcripts are not or hardly detected upon activation, the occurrence of autocrine loops in these cells is unlikely. Therefore, secretion of these factors by activated monocytes may be implicated in the paracrine activation of the erb receptors thereby contributing to the epithelial and connective tissue proliferation." 4926;"Duration of STAT5 activation influences the response of interleukin-2 receptor alpha gene to different cytokines.";"V. Imbert";"Equipe 04, Team 04";10210776;"European cytokine network";"Imbert V, Renauld PR";;"Mar 1999";920246400;;"Cytokines and growth factors regulate expression of their target genes via the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) signaling pathway. One of the best characterized targets of STAT is the interleukin-2 receptor-alpha (IL-2Ralpha) gene. Its transcription is controlled by interleukin 2 (IL-2) through STAT5 activation. Using the PC60 cell line, in which the role of STAT5 in the regulation of the murine IL-2Ralpha gene by IL-2 has been elucidated, we have compared the response of this gene to IL-2, interleukin-9 (IL-9) and erythropoietin (Epo). IL-2 and IL-9, but not Epo, stimulate cell surface expression of IL-2Ralpha. This correlates with the fact that IL-2 and IL-9 support long-term STAT5 activation whereas Epo only induces transient activation. In cells treated with vanadate, a protein tyrosine phosphatase (PTP) inhibitor, Epo induces prolonged STAT5 activation and strongly stimulates IL-2Ralpha expression. Our study suggests that by controlling the duration of the STAT activation signal, PTP influences the specificity of cytokine signaling." 4924;"Engagement of CD11b and CD11c beta2 integrin by antibodies or soluble CD23 induces IL-1beta production on primary human monocytes through mitogen-activated protein kinase-dependent pathways.";"V. Imbert";"Equipe 04, Team 04";10845922;Blood;"Rezzonico R, Chicheportiche R, Imbert V, Dayer JM";;"Jun 2000";959817600;;"beta2 integrins are involved in the recruitment of leukocytes to inflammatory sites and in cellular activation. We demonstrate that ligation of CD11b (Mac-1, CR3) or CD11c (p150, CR4) alpha chains of beta2 integrins by mAbs or soluble chimeric CD23 (sCD23) on human freshly isolated monocytes rapidly stimulates high levels of interleukin-1beta production. This induction takes place at the transcriptional level and is regulated by members of the mitogen-activated protein kinase (MAPK) family. Indeed, stimulation of monocytes through engagement of CD11b or CD11c results in the phosphorylation and activation of ERK1, ERK2, and p38/SAPK2 MAP kinases. U0126, a potent inhibitor of the upstream activator of ERK1/2, ie, MEK1/2, suppresses IL-1beta messenger RNA (mRNA) expression in a dose-dependent fashion, showing the implication of this pathway in the transcriptional control of IL-1beta production. On the other hand, inhibition of p38 by SB203580 indicates that this MAPK is involved in the control of IL-1beta production at both transcriptional and translational levels. Together these data demonstrate that ligation of CD11b and CD11c beta2 integrins by mAbs or sCD23 fusion proteins triggers the activation of 2 distinct MAPK signaling pathways that cooperate in controlling IL-1beta synthesis at different levels. (Blood. 2000;95:3868-3877)" 4922;"Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";11231305;"European journal of biochemistry";"Livolsi A, Busuttil V, Imbert V, Abraham RT, Peyron JF";;"Mar 2001";983404800;;"Phosphorylation of the N-terminal domain of I kappa B inhibitory subunits induces activation of the transcription factor NF-kappa B. Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome-mediated degradation of I kappa B-alpha, little is known about the mechanisms that lead to release of active NF-kappa B in T cells as a consequence of tyrosine phosphorylation of I kappa B-alpha [Imbert, V., Rupec, R.A., Livolsi, A., Pahl, H.L., Traenckner, B.M., Mueller-Dieckmann, C., Farahifar, D., Rossi, B., Auberger, P., Baeuerle, P. & Peyron, J.F. (1996) Cell 86, 787--798]. The involvement of the tyrosine kinases p56(lck) and ZAP-70 in this reaction is demonstrated here using specific pharmacological inhibitors and Jurkat mutants unable to express these kinases. Although the inhibitors prevented both pervanadate-induced phosphorylation of I kappa B-alpha on Tyr42 and NF-kappa B activation, we observed that, in p56(lck)-deficient Jurkat mutants, NF-kappa B could still associate with I kappa B-alpha despite phosphorylation on Tyr42. Furthermore, the SH2 domain of p56(lck) appeared to be required for pervanadate-induced NF-kappa B activation but not for Tyr42 phosphorylation. These results show that p56(lck) and ZAP-70 are key components of the signaling pathway that leads to phosphotyrosine-dependent NF-kappa B activation in T cells and confirm that tyrosine kinases must control at least two different steps to induce activation of NF-kappa B. Finally, we show that H(2)O(2), which stimulates p56(lck) and ZAP-70 in T cells, is an activator of NF-kappa B through tyrosine phosphorylation of I kappa B-alpha." 4920;"Ligation of CD11b and CD11c beta(2) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta production in primary human monocytes through a pathway dependent on nuclear factor-kappaB.";"V. Imbert";"Equipe 04, Team 04";11342414;Blood;"Rezzonico R, Imbert V, Chicheportiche R, Dayer JM";;"May 2001";988675200;;"Chemokines and adhesion molecules such as integrins play a major part in the trafficking, extravasation, and recruitment of leukocytes to inflammatory sites. This study investigated the effects of beta(2) integrin engagement on chemokine production by freshly isolated human monocytes. We found that ligation of CD11b or CD11c but not CD11a alpha chains of beta(2) integrins by antibodies or soluble CD23 (sCD23) fusion proteins rapidly induced transcription and secretion of interleukin 8, macrophage inflammatory protein (MIP) 1alpha, and MIP-1beta. Because the promoters of these chemokine genes contain kappaB binding sites, we assessed the possible role of nuclear factor-kappaB (NF-kappaB) in controlling induction of the genes through beta(2) integrin engagement. Electrophoretic mobility shift assays showed that sCD23 or antibodies to CD11b or to CD11c up-regulated DNA-binding activity of NF-kappaB. Activation of NF-kappaB was accompanied by degradation of its cytosolic inhibitor IkappaB-alpha. Blockade of depletion of IkappaB-alpha by proteasome inhibitors (proteasome inhibitor I or acetyl-leucinyl-leucinyl-norleucinal) led to concomitant inhibition of NF-kappaB DNA-binding activity and expression of MIP-1alpha and MIP-1beta messenger RNA induced by beta(2) integrin ligation. These results suggest that triggering of CD11b or CD11c beta(2) integrin on primary human monocytes provides activation signals leading to nuclear translocation of NF-kappaB and subsequent secretion of MIP-1alpha and MIP-1beta that may have an important role in recruitment of other inflammatory cells during initiation of an inflammatory response." 4918;"AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";17330097;Leukemia;"Griessinger E, Imbert V, Lagadec P, Gonthier N, Dubreuil P, Romanelli A, Dreano M, Peyron JF";;"May 2007";1177977600;;"Acute myeloid leukemia (AML) cells carry molecular defects that promote their leukemic proliferation, resistance to apoptosis and defect in differentiation. Pharmacological targeting of the nuclear factor kappaB (NF-kappaB) pathway has been shown to promote apoptosis of primary AML cells and to sensitize blasts to neoplastic drugs (Frelin, Blood 2005, 105, 804). The Fms-like tyrosine kinase 3 (FLT3), which sustains proliferation of normal hematopoietic progenitors is frequently overexpressed or mutated in AML patients. Using Ba/F3 murine pre-B cells transfected with various mutants of FLT3 (ITD, D835V, D835Y) and the MV4-11 human AML line, we show that normal or oncogenic stimulation of FLT3 led to activation of NF-kappaB. Pharmacological inhibition of either FLT3 with AG1296 or NF-kappaB with the small molecule inhibitor of IkappaB kinase-2 AS602868 reduced viability and triggered cell death. Moreover, AS602868 was also found to interfere directly with FLT3 kinase activation. AS602868 thus appears to target two different kinases that play a crucial role in the pathogenesis of AML, making it particularly attractive as a new therapeutical approach for AML." 4916;"Inhibition of the NF-kappaB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-kappaB essential modulator NEMO.";"JF. PEYRON, P. Auberger, V. Imbert";"Equipe 04, Team 04, Equipe 02, Team 02";17932497;"Cell death and differentiation";"Frelin C, Imbert V, Bottero V, Gonthier N, Samraj AK, Schulze-Osthoff K, Auberger P, Courtois G, Peyron JF";;"Jan 2008";1199145600;;"Apoptosis is mediated by cysteine-dependent, aspartate-directed proteases of the caspase family that proteolyse strategic intracellular substrates to induce cell suicide. We describe here that engagement of apoptotic processes by Fas triggering or by staurosporine stimulation leads to the caspase-dependent inactivation of the nuclear factor kappa B (NF-kappaB) pathway after cleavage of IKK1 (IkappaB kinase 1) and NEMO (NF-kappaB essential modulator), which are needed to transduce NF-kappaB activation signals. In this study, we have analyzed in more detail, the role of NEMO cleavage, as NEMO, but not IKK1, is important for the pro-survival actions of NF-kappaB. We demonstrate that NEMO is cleaved after Asp355 to remove the last 64 C-terminal amino acids. This short form was unable to rescue NF-kappaB activation by tumor necrosis factor-alpha (TNF-alpha) when transfected in NEMO-deficient cells. Consequently, inactivation of NEMO resulted in an inhibition of the expression of antiapoptotic NF-kappaB-target genes coding for caspase inhibitors (cIAP-1, cIAP-2) or adaptors of the TNF receptor family. NEMO-deficient Jurkat cells transiently expressing a non-cleavable mutant of NEMO were less sensitive to TNF-alpha-induced apoptosis. Therefore, downmodulation of NF-kappaB activation via the proteolytic cleavage of NEMO could represent an amplification loop for apoptosis." 4914;"Preclinical targeting of NF-kappaB and FLT3 pathways in AML cells.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";18239622;Leukemia;"Griessinger E, Frelin C, Cuburu N, Imbert V, Dageville C, Hummelsberger M, Sirvent N, Dreano M, Peyron JF";;"Jul 2008";1214870400;; 4912;"GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin's B lymphomas via NF-κB-dependent induction of HIF-1α.";"V. Imbert";"Equipe 04, Team 04";25394713;Leukemia;"Chiche J, Pommier S, Beneteau M, Mondragón L, Meynet O, Zunino B, Mouchotte A, Verhoeyen E, Guyot M, Pagès G, Mounier N, Imbert V, Colosetti P, Goncalvès D, Marchetti S, Brière J, Carles M, Thieblemont C, Ricci JE";;"May 2015";1430438400;;"Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness. " 4906;"Modification of Salmonella Typhimurium motility by the probiotic yeast strain Saccharomyces boulardii.";"JF. PEYRON";"Equipe 04, Team 04";22442723;"PloS one";"Pontier-Bres R, Prodon F, Munro P, Rampal P, Lemichez E, Peyron JF, Czerucka D";;"Jan 2012";1325376000;;"Motility is an important component of Salmonella enterica serovar Typhimurium (ST) pathogenesis allowing the bacteria to move into appropriate niches, across the mucus layer and invade the intestinal epithelium. In vitro, flagellum-associated motility is closely related to the invasive properties of ST. The probiotic yeast Saccharomyces boulardii BIOCODEX (S.b-B) is widely prescribed for the prophylaxis and treatment of diarrheal diseases caused by bacteria or antibiotics. In case of Salmonella infection, S.b-B has been shown to decrease ST invasion of T84 colon cell line. The present study was designed to investigate the impact of S.b-B on ST motility." 4904;"The Saccharomyces boulardii CNCM I-745 strain shows protective effects against the B. anthracis LT toxin.";"JF. PEYRON";;26529015;Toxins;"Pontier-Bres R, Rampal P, Peyron JF, Munro P, Lemichez E, Czerucka D";;"Oct 2015";1443657600;;"The probiotic yeast Saccharomyces boulardii (S. boulardii) has been prescribed for the prophylaxis and treatment of several infectious diarrheal diseases. Gastrointestinal anthrax causes fatal systemic disease. In the present study, we investigated the protective effects conferred by Saccharomyces boulardii CNCM I-745 strain on polarized T84 columnar epithelial cells intoxicated by the lethal toxin (LT) of Bacillus anthracis. Exposure of polarized T84 cells to LT affected cell monolayer integrity, modified the morphology of tight junctions and induced the formation of actin stress fibers. Overnight treatment of cells with S. boulardii before incubation with LT maintained the integrity of the monolayers, prevented morphological modification of tight junctions, restricted the effects of LT on actin remodeling and delayed LT-induced MEK-2 cleavage. Mechanistically, we demonstrated that in the presence of S. boulardii, the medium is depleted of both LF and PA sub-units of LT and the appearance of a cleaved form of PA. Our study highlights the potential of the S. boulardii CNCM I-745 strain as a prophylactic agent against the gastrointestinal form of anthrax. " 4902;"Nuclear factor-κB regulates βAPP and β- and γ-secretases differently at physiological and supraphysiological Aβ concentrations.";"JF. PEYRON";"Equipe 04, Team 04";26657754;"The Journal of biological chemistry";"Chami L, Buggia-Prévot V, Duplan E, Del Prete D, Chami M, Peyron JF, Checler F";;"Dec 2015";1448928000;; 4900;"Mitochondrial Transfer in the Leukemia Microenvironment.";"JF. PEYRON";"Equipe 04, Team 04";29198439;"Trends in cancer";"Griessinger E, Moschoi R, Biondani G, Peyron JF";;"12 2017";1512086400;;"The bone marrow microenvironment (BMME) is a complex ecosystem that instructs and protects hematopoietic stem cells (HSCs) and their malignant counterparts, the leukemia-initiating cells (LICs). Within the physical and functional crosstalk that takes place between HSCs, LICs, and the BMME, the transfer of organelles and of mitochondria in particular is an important new intercellular communication mode in addition to adhesion molecules, tunneling nanotubes (TNTs), and the paracrine secretion of cytokines, (onco)metabolites, and extracellular vesicles (EVs). In this review we discuss the functional roles of mitochondrial transfer between BMME and leukemic cells, and give insights into this new mechanism of drug resistance whose understanding will open the way to innovative anticancer adjuvant treatments." 4898;"Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA.";"JF. PEYRON";"Equipe 04";29541451;"Cancer & metabolism";"Thongon N, Zucal C, D'Agostino VG, Tebaldi T, Ravera S, Zamporlini F, Piacente F, Moschoi R, Raffaelli N, Quattrone A, Nencioni A, Peyron JF, Provenzani A";;"Jan 2018";1514764800;;"Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance." 4896;"Metformin, an Anti-diabetic Drug to Target Leukemia.";"JF. PEYRON";"Equipe 04, Team 04";30147674;"Frontiers in endocrinology";"Biondani G, Peyron JF";;"Jan 2018";1514764800;;"Metformin, a widely used anti-diabetic molecule, has attracted a strong interest in the last 10 years as a possible new anti-cancer molecule. Metformin acts by interfering with mitochondrial respiration, leading to an activation of the AMPK tumor-suppressive pathway to promote catabolic-energy saving reactions and block anabolic ones that are associated with abnormal cell proliferation. Metformin also acts at the organism level. In type 2 diabetes patients, metformin reduces hyperglycemia and increases insulin sensitivity by enhancing insulin-stimulated glucose uptake in muscles, liver, and adipose tissue and by reducing glucose output by the liver. Lowering insulin and insulin-like growth factor 1 (IGF-1) levels that stimulate cancer growth could be important features of metformin's mode of action. Despite continuous progress in treatments with the use of targeted therapies and now immunotherapies, acute leukemias are still of very poor prognosis for relapse patients, demonstrating an important need for new treatments deriving from the identification of their pathological supportive mechanisms. In the last decade, it has been realized that if cancer cells modify and reprogram their metabolism to feed their intense biochemical needs associated with their runaway proliferation, they develop metabolic addictions that could represent attractive targets for new therapeutic strategies that intend to starve and kill cancer cells. This Mini Review explores the anti-leukemic potential of metformin and its mode of action on leukemia metabolism." 4894;"Combination of PKCδ Inhibition with Conventional TKI Treatment to Target CML Models.";"D. MARY, JF. PEYRON, M. NEBOUT";"Equipe 04, Team 04";33918475;Cancers;"Muselli F, Mourgues L, Morcos R, Rochet N, Nebout M, Guerci-Bresler A, Faller DV, William RM, Mhaidly R, Verhoeyen E, Legros L, Peyron JF, Mary D";;"Apr 2021";1617235200;;"Numerous combinations of signaling pathway blockades in association with tyrosine kinase inhibitor (TKI) treatment have been proposed for eradicating leukemic stem cells (LSCs) in chronic myeloid leukemia (CML), but none are currently clinically available. Because targeting protein kinase Cδ (PKCδ) was demonstrated to eliminate cancer stem cells (CSCs) in solid tumors, we evaluated the efficacy of PKCδ inhibition in combination with TKIs for CML cells. We observed that inhibition of PKCδ by a pharmacological inhibitor, by gene silencing, or by using K562 CML cells expressing dominant-negative (DN) or constitutively active (CA) PKCδ isoforms clearly points to PKCδ as a regulator of the expression of the stemness regulator BMI1. As a consequence, inhibition of PKCδ impaired clonogenicity and cell proliferation for leukemic cells. PKCδ targeting in K562 and LAMA-84 CML cell lines clearly enhanced the apoptotic response triggered by any TKI. A strong synergism was observed for apoptosis induction through an increase in caspase-9 and caspase-3 activation and significantly decreased expression of the Bcl-xL Bcl-2 family member. Inhibition of PKCδ did not modify BCR-ABL phosphorylation but acted downstream of the oncogene by downregulating BMI1 expression, decreasing clonogenicity. PKCδ inhibition interfered with the clonogenicity of primary CML CD34 and BCR-ABL-transduced healthy CD34 cells as efficiently as any TKI while it did not affect differentiation of healthy CD34 cells. LTC-IC experiments pinpointed that PKCδ inhibition strongly decreased the progenitors/LSCs frequency. All together, these results demonstrate that targeting of PKCδ in combination with a conventional TKI could be a new therapeutic opportunity to affect for CML cells." 4892;"Blocking RiBi to suppress MYC lymphomagenesis.";"JF. PEYRON";"Equipe 04, Team 04";34137847;Blood;"Peyron JF";;"06 2021";1622505600;; 4890;"Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies.";"JF. PEYRON, N. Mazure";"Equipe 04, Equipe 05, Team 05, Team 04";34858421;"Frontiers in immunology";"Mancini SJC, Balabanian K, Corre I, Gavard J, Lazennec G, Le Bousse-Kerdilès MC, Louache F, Maguer-Satta V, Mazure NM, Mechta-Grigoriou F, Peyron JF, Trichet V, Herault O";;"Jan 2021";1609459200;;"Knowledge about the hematopoietic niche has evolved considerably in recent years, in particular through analyzes, mouse models and the use of xenografts. Its complexity in the human bone marrow, in particular in a context of hematological malignancy, is more difficult to decipher by these strategies and could benefit from the knowledge acquired on the niches of solid tumors. Indeed, some common features can be suspected, since the bone marrow is a frequent site of solid tumor metastases. Recent research on solid tumors has provided very interesting information on the interactions between tumoral cells and their microenvironment, composed notably of mesenchymal, endothelial and immune cells. This review thus focuses on recent discoveries on tumor niches that could help in understanding hematopoietic niches, with special attention to 4 particular points: i) the heterogeneity of carcinoma/cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs), ii) niche cytokines and chemokines, iii) the energy/oxidative metabolism and communication, especially mitochondrial transfer, and iv) the vascular niche through angiogenesis and endothelial plasticity. This review highlights actors and/or pathways of the microenvironment broadly involved in cancer processes. This opens avenues for innovative therapeutic opportunities targeting not only cancer stem cells but also their regulatory tumor niche(s), in order to improve current antitumor therapies." 4888;"Induction of interleukin-2 receptor alpha (IL-2Ralpha) expression by interleukin-2: important role of the interleukin-2 receptor beta chain region between the two Stat5 docking sites.";"V. Imbert";"Team 04";12231477;"European cytokine network";"Imbert V, Rezzonico R, Reichenbach P, Nabholz M";;"Sep Jul 2002";1026172800;;"The interleukin-2 receptor alpha (IL-2Ralpha) forms, together with IL-2Rbeta and gammac chains, a high affinity IL-2 receptor that is important for IL-2 responsiveness and normal T cell function. Expression of the IL-2Ralpha gene by T cells is regulated mainly at the transcription level which is transiently activated by antigen and upregulated and then prolonged by stimulation with IL-2. The effect of IL-2 on the IL-2Ralpha gene depends on the activation of the transcription factor Stat5, which acts on an IL-2- responsive enhancer that consists of two Stat5 and an Elf1 binding site. To identify the functional domains of the IL-2 receptor required for the stimulation of IL-2Ralpha gene expression, we introduced, into the CTL44 T cell line, receptor chimeras between the extracellular domain of the IL-9 receptor and the cytoplasmic region of IL-2Rbeta. Analyzing the effect of mutations in the intracellular IL-2Rbeta segment, we found that a minimal receptor containing the Jak boxes and one intact Stat5 docking site (i.e. tyrosine 392 or 510) can, as expected, mediate Stat5 activation, but is unable to stimulate IL-2Ralpha expression. However, when this minimal receptor includes the region between the two tyrosines, its capacity to mediate IL-2Ralpha cell surface expression is restored. These data suggest that the segment between the two Stat5 docking sites of the IL-2Rbeta chain mediates signaling events that, together with Stat5 activation, are essential for the stimulation of IL-2Ralpha gene transcription." 4886;"Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival.";"JF. PEYRON, V. Imbert";"Equipe 04";15967637;"Cellular signalling";"Cochet O, Frelin C, Peyron JF, Imbert V";;"Apr 2006";1143849600;;"Survival and proliferation of Hodgkin lymphoma (HL) cells are influenced by many cytokines produced by different cell types in the lymph node microenvironment. STAT, family of transcription factors, are key mediators of cytokine signaling and their perturbation contributes to various human diseases. Electrophoretic mobility shift and phosphoprotein immunoblotting analyses were used to study STAT activation in HL cell lines. We thus observed high levels of constitutively activated STAT1, 3, 5 and 6 in HDLM-2 and L540 cells, which could be correlated with JAK kinase activation. In contrast KM-H2 cells did not display STAT activation. Preventing constitutive STAT activation by specific JAK kinases inhibitors induced apoptosis of HL cell lines and was associated with a strong decrease in the expression of the anti-apoptotic genes IAP-1, IAP-2, Bcl-xL, Bfl1 and Traf1. Silencing of JAKs by specific siRNAs also induced apoptosis of HL cells. Altogether, these results suggest that aberrant STAT activation in Hodgkin cells may promote cell survival and as a consequence facilitate oncogenic transformation." 4884;"Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";17087945;Gastroenterology;"Dalmasso G, Cottrez F, Imbert V, Lagadec P, Peyron JF, Rampal P, Czerucka D, Groux H, Foussat A, Brun V";;"Dec 2006";1164931200;;"Saccharomyces boulardii is a nonpathogenic yeast used for treatment of diarrhea. We used a mice model of inflammatory bowel disease (IBD) to analyze the effects of S boulardii on inflammation." 4882;"miR-483-3p controls proliferation in wounded epithelial cells.";"V. Imbert";"Equipe 04";21676945;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Bertero T, Gastaldi C, Bourget-Ponzio I, Imbert V, Loubat A, Selva E, Busca R, Mari B, Hofman P, Barbry P, Meneguzzi G, Ponzio G, Rezzonico R";;"Sep 2011";1314835200;;"The mechanisms that regulate keratinocyte migration and proliferation in wound healing remain largely unraveled, notably regarding possible involvements of microRNAs (miRNAs). Here we disclose up-regulation of miR-483-3p in 2 distinct models of wound healing: scratch-injured cultures of human keratinocytes and wounded skin in mice. miR-483-3p accumulation peaks at the final stage of the wound closure process, consistent with a role in the arrest of ""healing"" progression. Using an in vitro wound-healing model, videomicroscopy, and 5-bromo-2'-uridine incorporation, we observed that overexpression of miR-483-3p inhibits keratinocyte migration and proliferation, whereas delivery of anti-miR-483-3p oligonucleotides sustains keratinocyte proliferation beyond the closure of the wound, compared with irrelevant anti-miR treatment. Expression profiling of keratinocytes transfected with miR-483-3p identified 39 transcripts that were both predicted targets of miR-483-3p and down-regulated after miR-483-3p overexpression. Luciferase reporter assays, Western blot analyses, and silencing by specific siRNAs finally established that kinase MK2, cell proliferation marker MKI67, and transcription factor YAP1 are direct targets of miR-483-3p that control keratinocyte proliferation. miR-483-3p-mediated down-regulation of MK2, MKI67, and YAP1 thus represents a novel mechanism controlling keratinocyte growth arrest at the final steps of reepithelialization." 4880;"Pharmacological inhibition of carbonic anhydrase XII interferes with cell proliferation and induces cell apoptosis in T-cell lymphomas.";"D. MARY, JF. PEYRON, M. NEBOUT, V. Imbert";"Equipe 04, Team 04";23348702;"Cancer letters";"Lounnas N, Rosilio C, Nebout M, Mary D, Griessinger E, Neffati Z, Chiche J, Spits H, Hagenbeek TJ, Asnafi V, Poulsen SA, Supuran CT, Peyron JF, Imbert V";;"Jun 2013";1370044800;;"The membrane-bound carbonic anhydrase isoforms CAIX and CAXII, underpin a pH-regulating system that enables hypoxic tumor cell survival. Here, we observed for the first time an upregulation of CAXII in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LL) cells. First we showed that CAXII is overexpressed in thymocytes from tPTEN-/- mice suffering of T lymphoma and that its pharmacological inhibition decreased cell proliferation and induced apoptosis. The same results were observed with the SupT1 human T cell lymphoma line. In addition we observed an upregulation of CAXII in human T-ALL samples supporting the case that CAXII may represent a new therapeutic target for T-ALL/LL." 4876;"Structure-function insights reveal the human ribosome as a cancer target for antibiotics.";"JF. PEYRON, M. NEBOUT, V. Imbert";"Team 04, Equipe 04";27665925;"Nature communications";"Myasnikov AG, Kundhavai Natchiar S, Nebout M, Hazemann I, Imbert V, Khatter H, Peyron JF, Klaholz BP";;"Sep 2016";1472688000;;"Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis deregulations such as in highly proliferating cancer cells has not been investigated at the molecular level up to now. Here we report the structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on several cancer cell lines. The structure provides insights into the detailed interactions in a ligand-binding pocket of the human ribosome that are required for structure-assisted drug design. Furthermore, anti-proliferative dose response in leukaemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of eukaryote-specific antibiotics towards cytosolic rather than mitochondrial ribosomes, uncovering the human ribosome as a promising cancer target." 4873;"Iron chelation: an adjuvant therapy to target metabolism, growth and survival of murine PTEN-deficient T lymphoma and human T lymphoblastic leukemia/lymphoma.";"D. MARY, JF. PEYRON, J. BENADIBA, M. NEBOUT, V. Imbert";"Team 04, Equipe 04";27736268;"Leukemia & lymphoma";"Benadiba J, Rosilio C, Nebout M, Heimeroth V, Neffati Z, Popa A, Mary D, Griessinger E, Imbert V, Sirvent N, Peyron JF";;"06 2017";1496275200;;"Iron is an essential nutrient, acting as a catalyst for metabolic reactions that are fundamental to cell survival and proliferation. Iron complexed to transferrin is delivered to the metabolism after endocytosis via the CD71 surface receptor. We found that transformed cells from a murine PTEN-deficient T-cell lymphoma model and from T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) cell lines overexpress CD71. As a consequence, the cells developed an addiction toward iron whose chelation by deferoxamine (DFO) dramatically affected their survival to induce apoptosis. Interestingly, DFO displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase. DFO appeared to act through a reactive oxygen species-dependent DNA damage response and potentiated the action of an inhibitor of the PARP pathway of DNA repair. Our results demonstrate that targeting iron metabolism could be an interesting adjuvant therapy for acute lymphoblastic leukemia." 4871;"Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5.";"M. Ohanna, V. Imbert";"Equipe 11, Team 11, Team 04, Equipe 04";30867824;Theranostics;"Giuliano S, Dufies M, Ndiaye PD, Viotti J, Borchiellini D, Parola J, Vial V, Cormerais Y, Ohanna M, Imbert V, Chamorey E, Rioux-Leclercq N, Savina A, Ferrero JM, Mograbi B, Pagès G";;"Jan 2019";1546300800;;"Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa. : Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839). : We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab. : This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine." 4867;"New Drug Repositioning Candidates for T-ALL Identified Human/Murine Gene Signature Comparison.";"JF. PEYRON, M. NEBOUT, PS. ROHRLICH, V. Imbert";"Team 04, Equipe 04";33240808;"Frontiers in oncology";"Bonnet R, Nebout M, Brousse C, Reinier F, Imbert V, Rohrlich PS, Peyron JF";;"Jan 2020";1577836800;;"T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive subtype of leukemia for which important progress in treatment efficiency have been made in the past decades to reach a cure rate of 75%-80% nowadays. It is nevertheless mandatory to find new targets and active molecules for innovative therapeutic strategies as relapse is associated with a very dismal outcome. We designed an experimental workflow to highlight the conserved core pathways associated with leukemogenesis by confronting the gene expression profiles (GEPs) of human T-ALL cases to the GEP of a murine T-ALL representative model, generated by the conditional deletion of the tumor suppressor gene in T cell precursors (tPTEN-/-). We identified 844 differentially expressed genes, common GEPs (cGEP) that were conserved between human T-ALL and murine signatures, and also similarly differentially expressed, compared to normal T cells. Using bioinformatic tools we highlighted in cGEPan upregulation of E2F, MYC and mTORC1. Next, using Connectivity Map (CMAP) and CMAPViz a visualization procedure for CMAP data that we developed, we selected three FDA-approved, bioactive molecule candidates: α-estradiol (α-E), nordihydroguaiaretic acid (NDGA) and prochlorperazine dimaleate (PCZ). At a biological level, we showed that the three drugs triggered an apoptotic cell death in a panel of T-ALL cell lines, activated a DNA damage response and interfered with constitutive mTORC1 activation and c-MYC expression. This analysis shows that the investigation of conserved leukemogenesis pathways could be a strategy to reveal new avenues for pharmacological intervention." 4865;"The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";34065348;Cancers;"Chargui A, Belaid A, Ndiaye PD, Imbert V, Samson M, Guigonis JM, Tauc M, Peyron JF, Poujeol P, Brest P, Hofman P, Mograbi B";;"May 2021";1619827200;;"Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination-conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy-SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis." 4861;"Enterohemorrhagic Escherichia coli infection induces interleukin-8 production via activation of mitogen-activated protein kinases and the transcription factors NF-kappaB and AP-1 in T84 cells.";"JF. PEYRON, V. Imbert";"Team 04, Equipe 04";11953364;"Infection and immunity";"Dahan S, Busuttil V, Imbert V, Peyron JF, Rampal P, Czerucka D";;"May 2002";1020211200;;"Enterohemorrhagic Escherichia coli (EHEC) infections are associated with hemorrhagic colitis and the hemolytic-uremic syndrome (HUS). In vivo, elevated plasma levels of the proinflammatory cytokine interleukin-8 (IL-8) in EHEC-infected children are correlated with a high risk of developing HUS. As IL-8 gene transcription is regulated by the transcription factors NF-kappaB and AP-1, we analyzed the role of these factors in the regulation of IL-8 production after infection of the epithelial intestinal T84 cell line by EHEC. By 6 h of infection, EHEC had induced significant secretion of IL-8 (35.84 +/- 6.76 ng/ml versus 0.44 +/- 0.04 ng/ml in control cells). EHEC induced AP-1 and NF-kappaB activation by 3 h of infection. Moreover, the three mitogen-activated protein kinases (MAPK) (ERK1/2, p38, and JNK) were phosphorylated in EHEC-infected T84 cells concomitant with induction of AP-1 DNA binding activity, and IkappaB-alpha was phosphorylated and then degraded concomitant with induction of NF-kappaB DNA binding activity. Pretreatment of cells with the highly specific MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and/or the proteasome inhibitor ALLN led to inhibition of the IL-8 secretion induced in EHEC-infected T84 cells. These findings demonstrate that (i) EHEC can induce in vitro a potent proinflammatory response by secretion of IL-8 and (ii) the secretion of IL-8 is due to the involvement of MAPK, AP-1, and NF-kappaB signaling pathways." 4859;"Saccharomyces boulardii interferes with enterohemorrhagic Escherichia coli-induced signaling pathways in T84 cells.";"JF. PEYRON, V. Imbert";"Team 04, Equipe 04";12540556;"Infection and immunity";"Dahan S, Dalmasso G, Imbert V, Peyron JF, Rampal P, Czerucka D";;"Feb 2003";1044057600;;"Enterohemorrhagic Escherichia coli (EHEC) infections are associated with the modification of tight-junction permeability and synthesis of proinflammatory cytokine interleukin-8 (IL-8). In a previous study, it was demonstrated that EHEC-induced IL-8 secretion is due to the involvement of the mitogen-activated protein kinase (MAPK), AP-1, and NF-kappaB pathways. In this study, we investigated the effect of the yeast Saccharomyces boulardii on EHEC infection in T84 cells. For this purpose, cells were (i) incubated with bacteria and yeast at the same time or (ii) incubated overnight with yeast cells that were maintained during infection or eliminated by several washes before infection. Coincubation is sufficient to maintain the transmonolayer electrical resistance (TER) of EHEC-infected cells, whereas the preincubation of cells with the yeast without elimination of the yeast during infection is necessary to significantly decrease IL-8 secretion. We thus analyzed the mechanisms of S. boulardii action. We showed that S. boulardii has no effect on EHEC growth or on EHEC adhesion. Kinetics studies revealed that EHEC-induced myosin light chain (MLC) phosphorylation precedes the decrease of TER. ML-7, an MLC kinase inhibitor, abolishes the EHEC-induced MLC phosphorylation and decrease of TER. Studies show that S. boulardii also abolishes EHEC-induced MLC phosphorylation. We demonstrated that the preincubation of cells with S. boulardii without washes before EHEC infection inhibits NF-kappaB DNA binding activity, phosphorylation and degradation of IkappaB-alpha, and activation of the three members of a MAPK group (extracellular signal-regulated protein kinases 1 and 2, p38, and c-jun N-terminal kinase). These findings demonstrate that S. boulardii exerts a preventive effect on EHEC infection by (i) interfering with one of the transduction pathways implicated in the control of tight-junction structure and (ii) decreasing IL-8 proinflammatory secretion via inhibition of the NF-kappaB and MAPK signaling pathways in infected T84 cells." 4855;"Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells.";"JF. PEYRON, V. Imbert";"Team 04, Equipe 04";15454494;Blood;"Frelin C, Imbert V, Griessinger E, Peyron AC, Rochet N, Philip P, Dageville C, Sirvent A, Hummelsberger M, Bérard E, Dreano M, Sirvent N, Peyron JF";;"Jan 2005";1104537600;;"Acute myeloid leukemia (AML) cells are characterized by a constitutive and abnormal activation of the nuclear factor-kappaB (NF-kappaB) transcription factor. This study, conducted in vitro on 18 patients, shows that targeting the IKB kinase 2 (IKK2) kinase with the specific pharmacologic inhibitor AS602868 to block NF-kappaB activation led to apoptosis of human primary AML cells. Moreover, AS602868 potentiated the apoptotic response induced by the current chemotherapeutic drugs doxorubicin, cytarabine, or etoposide (VP16). AS602868-induced cell death was associated with rupture of the mitochondrial transmembrane potential and activation of cellular caspases. NF-kappaB inhibition did not affect normal CD34+ hematopoietic precursors, suggesting that it could represent a new adjuvant strategy for AML treatment." 4853;"The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells.";"JF. PEYRON, M. NEBOUT, V. Imbert";"Equipe 04, Team 04";23612073;"Cancer letters";"Rosilio C, Lounnas N, Nebout M, Imbert V, Hagenbeek T, Spits H, Asnafi V, Pontier-Bres R, Reverso J, Michiels JF, Sahra IB, Bost F, Peyron JF";;"Aug 2013";1375315200;;"We show here that the antidiabetic agents metformin and phenformin and the AMPK activator AICAR exert strong anti-tumoural effects on tPTEN-/- lymphoma cells and on human T-ALL cell lines and primary samples. The compounds act by inhibiting tumour metabolism and proliferation and by inducing apoptosis in parallel with an activation of AMPK and an inhibition of constitutive mTOR. In tPTEN-/- cells, the drugs potentiated the anti-leukaemic effects of dexamethasone, and metformin and phenformin synergised with 2-deoxyglucose (2DG) to impair tumour cell survival. In vivo, metformin and AICAR strongly decreased the growth of luciferase-expressing tPTEN-/- cells xenografted in Nude mice, demonstrating that metabolism targeting could be a potent adjuvant strategy for lymphoma/leukaemia treatment." 4851;"Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia.";"JF. PEYRON";"Equipe 04, Team 04";24462823;"Cancer letters";"Rosilio C, Ben-Sahra I, Bost F, Peyron JF";;"May 2014";1398902400;;"There is a global and urgent need for expanding our current therapeutical arsenal against leukemia in order to improve their actual cure rates and fight relapse. Targeting the reprogrammed, altered cancer metabolism is an emerging strategy which should profoundly affect cancer cells in their intimate and irrepressible needs and addictions for nutrients uptake and incorporation into the biomass during malignant proliferation. We present here how metformin, an anti-diabetic drug that has attracted a strong interest for its recently discovered anti-cancer properties, can be envisioned as a new adjuvant approach to treat leukemia. Metformin may have a double-edged sword effect (i) by acting on the organism to decrease hyperglycaemia and hyperinsulinemia in diabetic patients and (ii) at the cellular level, by inhibiting the mTORC1-cancer supporting pathway through AMPK-dependent and independent mechanisms. " 4849;"Saccharomyces boulardii modifies Salmonella typhimurium traffic and host immune responses along the intestinal tract.";"JF. PEYRON, V. Imbert";"Team 04, Equipe 04";25118595;"PloS one";"Pontier-Bres R, Munro P, Boyer L, Anty R, Imbert V, Terciolo C, André F, Rampal P, Lemichez E, Peyron JF, Czerucka D";;"Jan 2014";1388534400;;"Salmonella enterica serovar Typhimurium (ST) is an enteropathogenic Gram-negative bacterium that causes infection following oral ingestion. ST spreads rapidly along the gastrointestinal tract (GIT) and invades the intestinal epithelium to ultimately reach internal body organs. The probiotic yeast Saccharomyces boulardii BIOCODEX (S.b-B) is prescribed for prophylaxis of diarrheal infectious diseases. We previously showed that S.b-B prevents weight loss in ST-infected mice and significantly decreases bacterial translocation to the spleen and liver. This study was designed to investigate the effect of S.b-B on ST migration along the GIT and the impact of the yeast on the host's early innate immune responses. Bioluminescent imaging (BLI) was used to evaluate the effect of S.b-B on the progression of luminescent Salmonella Typhimurium (ST-lux) in the GIT of mice pretreated with streptomycin. Photonic emission (PE) was measured in GIT extracts (stomach, small intestine, cecum and colon) at various time periods post-infection (PI). PE analysis revealed that, 45 min PI, ST-lux had migrated slightly faster in the mice treated with S.b-B than in the untreated infected animals. At 90 min PI, ST-lux had reached the cecum in both groups of mice. Adhesion of ST to S.b-B was visualized in the intestines of the mice and probably accounts for (1) the faster elimination of ST-lux in the feces, and (2) reduced translocation of ST to the spleen and liver. In the early phase of infection, S.b-B also modifies the host's immune responses by (1) increasing IFN-γ gene expression and decreasing IL-10 gene expression in the small intestine, and (2) elevating both IFN-γ, and IL-10 mRNA levels in the cecum. BLI revealed that S.b-B modifies ST migration and the host immune response along the GIT. Study findings shed new light on the protective mechanisms of S.b-B during the early phase of Salmonella pathogenesis. " 4847;"Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy.";"D. MARY, JF. PEYRON, M. NEBOUT, V. Imbert";"Equipe 04, Team 04";27257182;Blood;"Moschoi R, Imbert V, Nebout M, Chiche J, Mary D, Prebet T, Saland E, Castellano R, Pouyet L, Collette Y, Vey N, Chabannon C, Recher C, Sarry JE, Alcor D, Peyron JF, Griessinger E";;"07 2016";1467331200;;"Here we demonstrate that in a niche-like coculture system, cells from both primary and cultured acute myeloid leukemia (AML) sources take up functional mitochondria from murine or human bone marrow stromal cells. Using different molecular and imaging approaches, we show that AML cells can increase their mitochondrial mass up to 14%. After coculture, recipient AML cells showed a 1.5-fold increase in mitochondrial adenosine triphosphate production and were less prone to mitochondrial depolarization after chemotherapy, displaying a higher survival. This unidirectional transfer enhanced by some chemotherapeutic agents required cell-cell contacts and proceeded through an endocytic pathway. Transfer was greater in AML blasts compared with normal cord blood CD34(+) cells. Finally, we demonstrate that mitochondrial transfer was observed in vivo in an NSG immunodeficient mouse xenograft model and also occurred in human leukemia initiating cells and progenitors. As mitochondrial transfer provides a clear survival advantage following chemotherapy and a higher leukemic long-term culture initiating cell potential, targeting mitochondrial transfer could represent a future therapeutic target for AML treatment." 4845;"NF-κB in Hematological Malignancies.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";28561798;Biomedicines;"Imbert V, Peyron JF";;"May 2017";1493596800;;"NF-κB (Nuclear Factor Κ-light-chain-enhancer of activated B cells) transcription factors are critical regulators of immunity, stress response, apoptosis, and differentiation. Molecular defects promoting the constitutive activation of canonical and non-canonical NF-κB signaling pathways contribute to many diseases, including cancer, diabetes, chronic inflammation, and autoimmunity. In the present review, we focus our attention on the mechanisms of NF-κB deregulation in hematological malignancies. Key positive regulators of NF-κB signaling can act as oncogenes that are often prone to chromosomal translocation, amplifications, or activating mutations. Negative regulators of NF-κB have tumor suppressor functions, and are frequently inactivated either by genomic deletions or point mutations. NF-κB activation in tumoral cells is also driven by the microenvironment or chronic signaling that does not rely on genetic alterations." 4843;"Co-targeting intracellular pH and essential amino acid uptake cooperates to induce cell death of T-ALL/LL cells.";"D. MARY, JF. PEYRON, M. NEBOUT, V. Imbert";"Equipe 04, Team 04";28641473;"Leukemia & lymphoma";"Imbert V, Nebout M, Mary D, Endou H, Wempe MF, Supuran CT, Winum JY, Peyron JF";;"02 2018";1517443200;;"Cancer cells reprogram their metabolism to optimize their growth and proliferation in the host microenvironment. For this purpose, they enhance the uptake of extracellular nutrients and deal with the metabolic waste products through the overexpression of numerous membrane proteins including amino-acid transporters (LAT1) and acid-base regulating enzymes, such as carbonic anhydrases (CAs). Here we describe the anti-tumoral effects of a new class of CAXII inhibitors, the glycosyl coumarins on T-ALL/LL cells. These effects appeared to be mediated through inhibition of mTOR/Akt pathway and c-myc downregulation. Interestingly, we show that the combined targeting of amino acid fluxes and pH regulators provides a promising therapeutic strategy in the future of T-ALL/LL management." 4837;"The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells.";"F. BOST, JF. PEYRON, M. NEBOUT, V. Imbert";"Equipe 04, Team 04";23612073;"Cancer letters";"Rosilio C, Lounnas N, Nebout M, Imbert V, Hagenbeek T, Spits H, Asnafi V, Pontier-Bres R, Reverso J, Michiels JF, Sahra IB, Bost F, Peyron JF";;"Apr 2013";1366848000;;"We show here that the antidiabetic agents metformin and phenformin and the AMPK activator AICAR exert strong anti-tumoural effects on tPTEN-/- lymphoma cells and on human T-ALL cell lines and primary samples. The compounds act by inhibiting tumour metabolism and proliferation and by inducing apoptosis in parallel with an activation of AMPK and an inhibition of constitutive mTOR. In tPTEN-/- cells, the drugs potentiated the anti-leukaemic effects of dexamethasone, and metformin and phenformin synergised with 2-deoxyglucose (2DG) to impair tumour cell survival. In vivo, metformin and AICAR strongly decreased the growth of luciferase-expressing tPTEN-/- cells xenografted in Nude mice, demonstrating that metabolism targeting could be a potent adjuvant strategy for lymphoma/leukaemia treatment." 4838;"NF-kappaB modulation and ionizing radiation: mechanisms and future directions for cancer treatment.";"JF. PEYRON";"Team 04";16399220;"Cancer letters";"Magné N, Toillon RA, Bottero V, Didelot C, Houtte PV, Gérard JP, Peyron JF";;"Jan 2006";1136073600;;"NF-kappaB transcription factor regulates important cellular processes ranging from establishment of the immune and inflammatory responses to regulation of cell proliferation or apoptosis, through the induction of a large array of target genes. NF-kappaB is now considered as an important actor in the tumorigenic process mainly because it exerts strong anti-apoptotic functions in cancer cells. NF-kappaB is triggered by chimio- and radio-therapeutic strategies that are intended to eliminate cancerous cells through induction of apoptosis. Numerous studies have demonstrated that inhibition of NF-kappaB by different means increased sensitivity of cancer cells to the apoptotic action of diverses effectors such as TNFalpha or chemo- or radio-therapies. From these studies as emerged the concept that NF-kappaB blockade could be associated to conventional therapies in order to increase their efficiency. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy." 4835;"Blocking NF-kappaB activation in Jurkat leukemic T cells converts the survival agent and tumor promoter PMA into an apoptotic effector.";"JF. PEYRON, P. Auberger, V. Imbert";"Equipe 04, Team 04, Equipe 02, Team 02";12082637;Oncogene;"Busuttil V, Bottero V, Frelin C, Imbert V, Ricci JE, Auberger P, Peyron JF";;"Jun 2002";1025049600;;"The transcription factor NF-kappaB promotes cell survival. Using a variant of Jurkat leukemic T cells expressing IkappaB-alphaDeltaN, a super-repressor of NF-kappaB activation we first show that the tumor promoter PMA could prevent Fas-induced apoptosis via activation of NF-kappaB. Moreover, we demonstrate that in the absence of NF-kappaB activation, PMA became a strong inducer of apoptosis through stimulation of the upstream caspases 8 and 9 as well as of the effector caspase 3. A RNase-protection analysis showed that PMA stimulated the expression of several known anti-apoptotic genes (TRAF1, TRAF4, c-IAP-1, c-IAP-2, Bfl-1, Bcl-xl). In the absence of NF-kappaB activation, these survival influences were strongly lowered revealing the apoptotic effect of PMA. These results suggest that NF-kappaB activation could be an important step in the tumor promoting effect of PMA." 4832;"NF-kappaB inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";19378338;"International journal of cancer";"Lounnas N, Frelin C, Gonthier N, Colosetti P, Sirvent A, Cassuto JP, Berthier F, Sirvent N, Rousselot P, Dreano M, Peyron JF, Imbert V";;"Apr 2009";1240272000;;"The Bcr-Abl inhibitor imatinib is the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Nevertheless, resistance to imatinib emerges as CML progresses to an acute deadly phase implying that physiopathologically relevant cellular targets should be validated to develop alternative therapeutic strategies. The NF-kappaB transcription factor that exerts pro-survival actions is found abnormally active in numerous hematologic malignancies. In the present study, using Bcr-Abl-transfected BaF murine cells, LAMA84 human CML cell line and primary CML, we show that NF-kappaB is active downstream of Bcr-Abl. Pharmacological blockade of NF-kappaB by the IKK2 inhibitor AS602868 prevented survival of BaF cells expressing either wild-type, M351T or T315I imatinib-resistant mutant forms of Bcr-Abl both in vitro and in vivo using a mouse xenograft model. AS602868 also affected the survival of LAMA84 cells and of an imatinib-resistant variant. Importantly, the IKK2 inhibitor strongly decreased in vitro survival and ability to form hematopoietic colonies of primary imatinib resistant CML cells including T315I cells. Our data strongly support the targeting of NF-kappaB as a promising new therapeutic opportunity for the treatment of imatinib resistant CML patients in particular in the case of T315I patients. The T315I mutation escapes all currently used Bcr-Abl inhibitors and is likely to become a major clinical problem as it is associated with a poor clinical outcome." 4827;"Frequency and Dynamics of Leukemia-Initiating Cells during Short-term Ex Vivo Culture Informs Outcomes in Acute Myeloid Leukemia Patients.";"JF. PEYRON, M. NEBOUT, V. Imbert";"Equipe 04, Team 04";26960976;"Cancer research";"Griessinger E, Anjos-Afonso F, Vargaftig J, Taussig DC, Lassailly F, Prebet T, Imbert V, Nebout M, Vey N, Chabannon C, Filby A, Bollet-Quivogne F, Gribben JG, Peyron JF, Bonnet D";;"Mar 2016";1457654400;;"Acute myeloid leukemia (AML) is sustained by a subpopulation of rare leukemia-initiating cells (LIC) detected in the xenograft assay by their capacity to self-renew and to generate non-LICs in vivo The xenotransplantation model captures functional properties of LICs that have clinical prognostic value. However, the long duration of this in vivo assay has hampered its use as a prognostic tool. Here, we show, using an ex vivo coculture system, that intermediate and poor risk AML patient samples at diagnosis have a 5 to 7 times higher frequency of leukemic long-term culture-initiating cells (L-LTC-IC) compared with the good risk group. We defined a fluorescence dilution factor (FDF) parameter that monitors sample proliferation over 1 week and established a strong correlation of this parameter with the L-LTC-IC frequency. A higher FDF was found for poor prognostic AMLs or for samples capable of engrafting NSG mice compared with good risk AMLs or nonengrafters. Importantly, FDF could classify normal karyotype intermediate risk patients into two groups with a significant difference in their overall survival, thus making this nongenetic and non-in vivo approach a new clinically relevant tool for better diagnosis of AML patients. Cancer Res; 76(8); 2082-6. ©2016 AACR." 4823;"Druggable Biochemical Pathways and Potential Therapeutic Alternatives to Target Leukemic Stem Cells and Eliminate the Residual Disease in Chronic Myeloid Leukemia.";"D. MARY, JF. PEYRON";"Equipe 04, Team 04";31717629;"International journal of molecular sciences";"Muselli F, Peyron JF, Mary D";;"Nov 2019";1573689600;;"Chronic Myeloid Leukemia (CML) is a disease arising in stem cells expressing the BCR-ABL oncogenic tyrosine kinase that transforms one Hematopoietic stem/progenitor Cell into a Leukemic Stem Cell (LSC) at the origin of differentiated and proliferating leukemic cells in the bone marrow (BM). CML-LSCs are recognized as being responsible for resistances and relapses that occur despite the advent of BCR-ABL-targeting therapies with Tyrosine Kinase Inhibitors (TKIs). LSCs share a lot of functional properties with Hematopoietic Stem Cells (HSCs) although some phenotypical and functional differences have been described during the last two decades. Subverted mechanisms affecting epigenetic processes, apoptosis, autophagy and more recently metabolism and immunology in the bone marrow microenvironment (BMM) have been reported. The aim of this review is to bring together the modifications and molecular mechanisms that are known to account for TKI resistance in primary CML-LSCs and to focus on the potential solutions that can circumvent these resistances, in particular those that have been, or will be tested in clinical trials." 4824;"Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies.";"JF. PEYRON";"Equipe 04, Team 04";32151059;Cells;"Gilles A, Frechin L, Natchiar K, Biondani G, Loeffelholz OV, Holvec S, Malaval JL, Winum JY, Klaholz BP, Peyron JF";;"Mar 2020";1583884800;;"The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor." 4819;"Altered sialylation of CD45 in HIV-1-infected T lymphocytes.";"JF. PEYRON";"Team 04, Equipe 04";8122360;Virology;"Lefebvre JC, Giordanengo V, Doglio A, Cagnon L, Breittmayer JP, Peyron JF, Lesimple J";;"Mar 1994";762480000;;"Immunodeficiency caused by HIV infection probably results from profound dysregulation of normal T lymphocyte properties by the virus. Despite description of the virus cytopathicity and numerous modifications in T cell functions, such as perturbation of antigen receptor signaling, CD4 downregulation, and induction of apoptosis, the precise mechanisms underlying the disruption of normal immune responses have not yet been elucidated. In the present study, we show that HIV-1-infected lymphocytes of the CEM cell line (either latent or virus-producing) and HIV-1-infected CD4+ lymphocytes have several membrane proteins with altered glycosylation patterns. Using lectins with specificity for different carbohydrate moieties, we could demonstrate the presence of two exposed nonsialylated disaccharides: a terminal Gal beta 1-->3GalNAc and a terminal Gal beta 1-->4GlcNAc. In particular, CD45, one of the major T cell glycoproteins, appeared to be partially sialylated on N- and O-linked carbohydrate moieties. Concerning the latter, PNA lectin which recognizes nonsialylated terminal Gal beta 1-->3GalNAc might precipitate up to 75% of the total tyrosine phosphatase activity displayed by CD45 molecules from one latently HIV-1-infected CEM cell line. Since CD45 glycoproteins are thought to play an important regulatory role in cell-to-cell interactions owing to their variable extracellular region and because they may regulate membrane signaling through their intracellular phosphatase domains, we suggest that these altered CD45 molecules may present an abnormal signal for natural ligands such as the B-cell-specific surface receptor CD22, thus perturbing the normal immune response in HIV-1-infected individuals." 4813;"[Biomodulation of transcriptional factor NF-kappa B by ionizing radiation].";"JF. PEYRON";"Team 04, Equipe 04";15561597;"Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique";"Magné N, Didelot C, Toillon RA, Van Houtte P, Peyron JF";;"Oct 2004";1096588800;;"NF-kappaB (Nuclear Factor-kappaB) was described for the first time in 1986 as a nuclear protein binding to the kappa immunoglobulin-light chain enhancer. Since then, NF-kappaB has emerged as an ubiquitous factor involved in the regulation of numerous important processes as diverse as immune and inflammatory responses, apoptosis and cell proliferation. These last two properties explain the implication of NF-kappaB in the tumorigenic process as well as the promise of a targeted therapeutic intervention. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy." 4814;"[Fighting cancer via NF-kappa B inhibition].";"V. Imbert, JF. PEYRON";"Team 04, Equipe 04";12907074;"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie";"Sirvent N, Imbert V, Frelin C, Griessinger E, Peyron JF";;"Jul 2003";1057017600;; 4809;"Interaction of Saccharomyces boulardii with Salmonella enterica serovar Typhimurium protects mice and modifies T84 cell response to the infection.";"V. Imbert, JF. PEYRON";"Team 04, Equipe 04";20111723;"PloS one";"Martins FS, Dalmasso G, Arantes RM, Doye A, Lemichez E, Lagadec P, Imbert V, Peyron JF, Rampal P, Nicoli JR, Czerucka D";;"Jan 2010";1262304000;;"Salmonella pathogenesis engages host cells in two-way biochemical interactions: phagocytosis of bacteria by recruitment of cellular small GTP-binding proteins induced by the bacteria, and by triggering a pro-inflammatory response through activation of MAPKs and nuclear translocation of NF-kappaB. Worldwide interest in the use of functional foods containing probiotic bacteria for health promotion and disease prevention has increased significantly. Saccharomyces boulardii is a non-pathogenic yeast used as a probiotic in infectious diarrhea." 4811;"Pharmacological targeting of NF-kappaB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells.";"JF. PEYRON, V. Imbert";"Equipe 04, Team 04";18182997;"British journal of cancer";"Lagadec P, Griessinger E, Nawrot MP, Fenouille N, Colosetti P, Imbert V, Mari M, Hofman P, Czerucka D, Rousseau D, Berard E, Dreano M, Peyron JF";;"Jan 2008";1199923200;;"NF-kappaB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kappaB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kappaB activation. In human colon cancer cells, inhibition of NF-kappaB using 10 microM AS602868 induced a 30-50% growth inhibitory effect and strongly enhanced the action of SN-38, the topoisomerase I inhibitor and CPT-11 active metabolite. AS602868 also potentiated the cytotoxic effect of two other antineoplasic drugs: 5-fluorouracil and etoposide. In xenografts experiments, inhibition of NF-kappaB potentiated the antitumoural effect of CPT-11 in a dose-dependent manner. Eighty-five and 75% decreases in tumour size were observed when mice were treated with, respectively, 20 or 5 mg kg(-1) AS602868 associated with 30 mg kg(-1) CPT-11 compared to 47% with CPT-11 alone. Ex vivo tumour analyses as well as in vitro studies showed that AS602868 impaired CPT-11-induced NF-kappaB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFalpha on HT-29 cells. This study is the first demonstration that a pharmacological inhibitor of the IKK2 kinase can potentiate the therapeutic efficiency of antineoplasic drugs on solid tumours." 4799;"Co-culture of human fibroblasts, smooth muscle and endothelial cells promotes osteopontin induction in hypoxia.";"JF. PEYRON";"Equipe 04, Team 04";32032472;"Journal of cellular and molecular medicine";"Sadaghianloo N, Contenti J, Dufies M, Parola J, Rouleau M, Lee S, Peyron JF, Fabbri L, Hassen-Khodja R, Pouysségur J, Bost F, Jean-Baptiste E, Dardik A, Mazure NM";;"03 2020";1583020800;;"Arteriovenous fistulas (AVFs) are the preferred vascular access for haemodialysis of patients suffering from end-stage renal disease, a worldwide public health problem. However, they are prone to a high rate of failure due to neointimal hyperplasia and stenosis. This study aimed to determine if osteopontin (OPN) was induced in hypoxia and if OPN could be responsible for driving AVF failure. Identification of new factors that participate in remodelling of AVFs is a challenge. Three cell lines representing the cells of the three layers of the walls of arteries and veins, fibroblasts, smooth muscle cells and endothelial cells, were tested in mono- and co-culture in vitro for OPN expression and secretion in normoxia compared to hypoxia after silencing the hypoxia-inducible factors (HIF-1α, HIF-2α and HIF-1/2α) with siRNA or after treatment with an inhibitor of NF-kB. None of the cells in mono-culture showed OPN induction in hypoxia, whereas cells in co-culture secreted OPN in hypoxia. The changes in oxygenation that occur during AVF maturation up-regulate secretion of OPN through cell-cell interactions between the different cell layers that form AVF, and in turn, these promote endothelial cell proliferation and could participate in neointimal hyperplasia." 4796;"Lymphocytic CD43 and CD45 bear sulfate residues potentially implicated in cell to cell interactions.";"JF. PEYRON";"Equipe 04, Team 04";7843243;"European journal of immunology";"Giordanengo V, Limouse M, Peyron JF, Lefebvre JC";;"Jan 1995";788918400;;"CD43 is a major heavily glycosylated lymphocyte surface molecule. It has been shown to play an important role in lymphocyte activation and cell-cell interactions. Here we demonstrate that in human activated lymphocytes and CEM T cells, CD43 is a sulfated molecule. We also observed that CD45, another lymphocyte surface glycoprotein, is a sulfated molecule. 35SO4(2-) incorporation would thus appear to be an appropriate labeling method for CD43 and CD45 visualization. Moreover, we show that the level of cell surface protein sulfation can modulate CD43-mediated homotypic aggregation induced by CD43 monoclonal antibodies. It is well known that glycoprotein sulfation is required for various recognition phenomena. Since there are numerous potential sulfation sites on CD43 and CD45, these residues could play an important role in regulating cell-cell interactions." 4793;"Comitogenic effects of very late activation antigens on CD3-stimulated human thymocytes. Involvement of various tyrosine kinase pathways.";"V. Imbert, JF. PEYRON";"Equipe 04, Team 04";7529794;"Journal of immunology (Baltimore, Md. : 1950)";"Ticchioni M, Deckert M, Bernard G, Calandra D, Breittmeyer JP, Imbert V, Peyron JF, Bernard A";;"Feb 1995";791596800;;"Thymocytes display several integrins that are involved in cell-extracellular matrix interactions and differentiation processes. We have examined the role of very late activation Ag (VLA) on human thymocyte stimulation. VLA-4, VLA-5, and VLA-6 activated with either mAbs or their natural ligands (fibronectin, laminin, and vascular cell adhesion molecule-1) are able to transduce costimulatory signals in thymocytes activated via the CD3 pathway, i.e., enhancement of thymocyte proliferation, CD25 and CD69 expression, and IL-2 secretion. In contrast, activation of thymocytes with a mitogenic pair of CD2 mAb was not modified by VLA molecules. Cross-linking of both beta 1- and alpha 5-chains induced tyrosine phosphorylation of several proteins, whereas the cross-linking of the alpha 4- and alpha 6-chains did not. Moreover, a different pattern of tyrosine phosphorylation was observed when thymocytes were activated via either beta 1- or alpha 5-chains. These results suggest that VLA molecules activate tyrosine kinase pathways in thymocytes, and that different pathways would be implicated during thymocyte interactions with extracellular matrix or accessory cells, which are likely to play a role in thymocyte differentiation." 4789;"Endopeptidase 24.11 (CD10/NEP) is required for phorbol ester-induced growth arrest in Jurkat T cells.";"V. Imbert, JF. PEYRON";"Team 04, Equipe 04";9285485;"FASEB journal : official publication of the Federation of American Societies for Experimental Biology";"Mari B, Guerin S, Maulon L, Belhacene N, Farahi Far D, Imbert V, Rossi B, Peyron JF, Auberger P";;"Sep 1997";873072000;;"Jurkat T cells express a functional endopeptidase 24.11 that is involved in the regulation of T cell activation. We have analyzed the effect of ectopic CD10 expression in mutant Jurkat cell clones that fail to express CD10 and, unlike wild-type cells, are resistant to the growth-inhibitory effects of the protein kinase C activator, PMA. No differences in the expression of the mRNA encoding the alpha, beta, gamma, delta, epsilon, and zeta isoforms of PKC were found in parental vs. PMA-resistant Jurkat cells, ruling out the possibility that the defect could be accounted for by an altered expression of one of these isoforms. Phorbol ester-induced growth arrest was not due to apoptosis since PMA failed to trigger DNA fragmentation in parental and mutant Jurkat T cells. CD10 mRNA expression and activity were abrogated in four independent PMA-resistant Jurkat T cell clones compared to parental cells, whereas the activities of several other peptidases were unaffected. Transfection of one mutant clone with a functional endopeptidase 24.11 restored in a significant manner PMA-induced growth arrest in all the clones selected and tested, whereas transfection of an inactive form of endopeptidase 24.11 had no effect, demonstrating that the enzymatic activity of CD10 is critical in the mediation of the PMA growth arrest. The data presented here demonstrate that a functional CD10 is required for PMA-induced growth arrest in Jurkat cells and provide further evidence for a role of endopeptidase 24.11 in the regulation of tumor cell proliferation." 4787;"Structural analysis, expression, and chromosomal localization of the mouse ikba gene.";"JF. PEYRON";"Team 04, Equipe 04";10199915;Immunogenetics;"Rupec RA, Poujol D, Grosgeorge J, Carle GF, Livolsi A, Peyron JF, Schmid RM, Baeuerle PA, Messer G";;"Apr 1999";923961600;;"The pleiotropic transcription factor NF-kappaB is localized in the cytoplasm bound to its inhibitory subunit IkappaB. The predominant form of NF-kappaB is a p50/p65 heterodimer which can be released from IkappaB-alpha and migrate to the nucleus. Previous studies have shown that IkappaB-alpha-/- mice die 8 to 10 days postnatally, showing runting and a severe dermatitis. However, the organ distribution of mouse IkappaB-alpha, the exon-intron structure, and the chromosomal localization of ikba have not been determined so far. A mouse Sv129 genomic DNA library was screened with a human IkappaB-alpha/MAD-3 cDNA probe. One clone (P1) was isolated, spanning the complete ikba gene and the promoter/enhancer region. We show that the exon-intron structure between mouse and pig ikba is completely conserved. In contrast to human ikba, the ankyrin repeat 5 is not interrupted by an intron. Furthermore, the mouse ikba promoter contains 6 putative NF-kappaB binding sequences, which are conserved in mouse, pig, and human, underlining the importance of NF-kappaB as a key regulator of ikba transcription. The deduced amino acid sequence shows >90% similarity between mouse, pig, and human ikba. Chromosome mapping localized the mouse ikba gene to chromosome 12. Northern blot analysis demonstrated predominant expression in lymphoid tissue (lymph node and thymus). However, IkappaB-alpha mRNA was detected as well in liver tissue, the gastrointestinal tract, and the reproductive tract. The cloning and determination of the structure are a prerequisite for the construction of vectors for conditional gene targeting experiments." 4783;"AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-alpha in Jurkat leukemic cells.";"V. Imbert, JF. PEYRON";"Equipe 04, Team 04";14603259;Oncogene;"Frelin C, Imbert V, Griessinger E, Loubat A, Dreano M, Peyron JF";;"Nov 2003";1068163200;;"NF-kappaB transcription factors promote survival in numerous cell types via induction of antiapoptotic genes. Pharmacological blockade of the IKK2 kinase with AS602868, a specific inhibitor that competes with ATP binding, prevented TNF-alpha-induced NF-kappaB activation in Jurkat leukemic T cells. While TNF-alpha by itself had no effect on Jurkat survival, the addition of AS602868 induced cell death, visualized by DNA fragmentation and sub-G1 analysis. A disruption of the mitochondrial potential followed by activation of caspases 9 and 3 was observed in cells treated by the combination TNF-alpha+AS602868. Quantitative real-time PCR demonstrated that AS602868 prevented TNF-alpha induction of the antiapoptotic genes coding for c-IAP-2, Bclx, Bfl-1/A1 and Traf-1. The use of a specific IKK2 inhibitor appears, therefore, as an interesting pharmaceutical strategy to increase the cell's sensitivity towards apoptotic effectors." 4784;"Monitoring NF-kappa B transactivation potential via real-time PCR quantification of I kappa B-alpha gene expression.";"V. Imbert, JF. PEYRON";"Equipe 04, Team 04";15068390;"Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology";"Bottero V, Imbert V, Frelin C, Formento JL, Peyron JF";;"Jan 2003";1041379200;;"Nuclear factor-kappa B (NF-kappa B) is an important transcription factor involved in the regulation of immune responses as well as in cell proliferation and survival. An abnormal and constitutive activation of NF-kappa B is observed in many pathological states as diverse as inflammation, neurological diseases, and cancer." 4779;"Calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance in colorectal cancer xenografts.";"V. Imbert, D. MARY, JF. PEYRON";"Equipe 04, Equipe 04";22069124;"The Journal of pathology";"Fenouille N, Grosso S, Yunchao S, Mary D, Pontier-Bres R, Imbert V, Czerucka D, Caroli-Bosc FX, Peyron JF, Lagadec P";;"May 2012";1335830400;;"CPT-11 (irinotecan), the first-line chemotherapy for advanced stage colorectal cancer, remains inactive in about half of patients (primary chemoresistance) and almost all initial responders develop secondary resistance after several courses of treatment (8 months on average). Nude mice bearing HT-29 colon cancer xenografts were treated with CPT-11 and/or an NF-κB inhibitor for two courses. We confirm that NF-κB inhibition potentiated CPT-11 anti-tumoural effect after the first course of treatment. However, tumours grew again at the end of the second course of treatment, generating resistant tumours. We observed an increase in the basal NF-κB activation in resistant tumours and in two resistant sublines, either obtained from resistant HT-29 tumours (HT-29R cells) or generated in vitro (RSN cells). The decrease of NF-κB activation in HT-29R and RSN cells by stable transfections with the super-repressor form of IκBα augmented their sensitivity to CPT-11. Comparing gene expression profiles of HT-29 and HT-29R cells, we identified the S100A10/Annexin A2 complex and calpain 2 as over-expressed potential NF-κB inducers. SiRNA silencing of calpain 2 but not of S100A10 and/or annexin A2, resulted in a decrease in NF-κB activation, an increase in cellular levels of IκBα and a partial restoration of the CPT-11 sensitivity in both HT-29R and RSN cells, suggesting that calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance. Thus, targeted therapies directed against calpain 2 may represent a novel strategy to enhance the anti-cancer efficacy of CPT-11." 4780;"L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.";"V. Imbert, JF. PEYRON, J. BENADIBA, M. NEBOUT";"Team 04, Equipe 04, Team 08";25482130;Leukemia;"Rosilio C, Nebout M, Imbert V, Griessinger E, Neffati Z, Benadiba J, Hagenbeek T, Spits H, Reverso J, Ambrosetti D, Michiels JF, Bailly-Maitre B, Endou H, Wempe MF, Peyron JF";;"Dec 2014";1418083200;;"The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability. " 4772;"Identification of a cellular 110 000-Da protein substrate for the insulin-receptor kinase.";"JF. PEYRON";"Equipe 04, Team 04";2988507;"The Biochemical journal";"Sadoul JL, Peyron JF, Ballotti R, Debant A, Fehlmann M, Van Obberghen E";;"May 1985";483753600;;"Addition of insulin to wheat-germ-lectin-purified glycoproteins derived from rat hepatocytes or rabbit brown adipose tissue results in the increased phosphorylation of a Mr-110 000 protein. This naturally occurring glycoprotein appears as a monomeric structure and is not part of the insulin receptor itself, since it is not immunoprecipitated by highly specific antibodies to insulin receptor. Phosphorylation of the Mr-110 000 protein and autophosphorylation of the receptor beta-subunit (Mr 95 000) are stimulated by insulin in a remarkably similar dose-dependent fasion, with half-maximal stimulation at 1 nM-insulin. Further, kinetic studies suggest that the phosphorylation of the Mr-110 000 protein occurs after autophosphorylation of the insulin-receptor kinase. In conclusion, the present identification of an endogenous substrate for the insulin-receptor kinase could suggest that some, if not all, effects of insulin may be mediated through activation of this kinase." 4773;"Inhibition and activation of interleukin 2 synthesis by direct modification of guanosine triphosphate-binding proteins.";"D. MARY, JF. PEYRON";"Equipe 04, Team 04";2826588;"Journal of immunology (Baltimore, Md. : 1950)";"Aussel C, Mary D, Peyron JF, Pelassy C, Ferrua B, Fehlmann M";;"Jan 1988";567993600;;"To investigate whether guanosine triphosphate-binding proteins (G proteins) are involved in T cell activation, tests were made of the effect of pertussis toxin, cholera toxin, guanosine 5'-(3-O-thio)-triphosphate, and fluoride ions on interleukin 2 (IL-2) synthesis in Jurkat cells. It was found: 1) that pertussis toxin interferes with the first pathway of T cell activation insofar as it can substitute for phytohemagglutinin or monoclonal antibodies directed against the CD3 surface proteins, suggesting that a G protein serves as transducer for signals via the T cell receptor-CD3 complex; and 2) that fluoride ions induce the release of diacylglycerol (DAG) from [3H] arachidonic acid or [3H]oleic acid-prelabeled cells. In [3H]inositol or 32P-prelabeled cells, the increase in DAG production was also found to be accompanied by a 280% increase of intracellular inositol phosphate (IP), without significant modification of IP2 and IP3. These results suggest that a G protein controls the activity of a phospholipase C in Jurkat cells that upon stimulation releases DAG but not IP3. Inasmuch as DAG, like the phorbol ester tetradecanoyl phorbol acetate, activates protein kinase C, it suggests that a G protein is also involved in the transduction of the second signal for lymphocyte activation. Fluoride ions were found to be as effective as tetradecanoyl phorbol acetate to stimulate IL-2 synthesis in Jurkat cells when used in combination with phytohemagglutinin. Finally, cholera toxin and guanosine 5'-(3-O-thio)-triphosphate were found to increase intracellular cyclic adenosine triphosphate and to inhibit IL-2 synthesis. All together these results suggest that several G proteins are involved in the transduction of the two signals necessary for T cell activation as well as in the negative regulation of IL-2 synthesis." 4758;"The CD45 protein tyrosine phosphatase is required for the completion of the activation program leading to lymphokine production in the Jurkat human T cell line.";"JF. PEYRON";"Team 04, Equipe 04";1838006;"International immunology";"Peyron JF, Verma S, de Waal Malefyt R, Sancho J, Terhorst C, Spits H";;"Dec 1991";691545600;;"Stimulation of the T cell antigen receptor, TCR-CD3, induces tyrosine phosphorylation of specific cellular proteins through activation of a tyrosine kinase. The possible regulatory role of the CD45 protein tyrosine phosphatase in this process was explored by studying the functional properties of cellular variants of the Jurkat T cell line which have been selected to have normal levels of the TCR-CD3 complex, but low or negative expression of CD45. These variants had less than 20% of the normal membrane tyrosine phosphatase activity. Triggering the TCR-CD3 receptor on the CD45 variants with anti-CD3 mAb induced the activation of a tyrosine kinase. Tyrosine phosphorylation of cellular substrates as well as of the CD3 zeta chain was qualitatively comparable to normal cells although the extent of stimulation was lower. No differences were observed between the variants and the normal cells in the duration of the tyrosine phosphorylation signal. The increase in intracellular calcium concentration following receptor stimulation was also less efficient, suggesting that CD45 is necessary for optimal generation of the second messengers of the activation. The CD45 deficient cells secreted highly reduced levels of lymphokines (IL-2, IL-3 or GM-CSF) after activation by anti-CD3 mAb combined with the phorbol ester TPA. This impaired lymphokines production is related to the absence of CD45 since a CD45+ revertant subclone, isolated from one CD45- clone, produced normal levels of cytokines upon activation via CD3, while CD45- subclones were unable to secrete cytokines following activation via CD3. However, upon activation with Ca2+ ionophore and PMA, all CD45- (sub)clones secreted cytokines at levels comparable to those produced by CD45+ cells. These results show that CD45 is required for cytokine production after activation via the TCR-CD3 complex." 4755;"Two distinct regions of the CD28 intracytoplasmic domain are involved in the tyrosine phosphorylation of Vav and GTPase activating protein-associated p62 protein.";"JF. PEYRON";"Equipe 04, Team 04";9620604;"International immunology";"Klasen S, Pages F, Peyron JF, Cantrell DA, Olive D";;"Jun 1998";897436800;;"The T cell-associated CD28 molecule plays a key role in T cell co-stimulation. Its ligation induces the tyrosine phosphorylation of numerous proteins including CD28 itself as well as a restricted set of substrates of 97 and 62-68 kDa which are poorly phosphorylated by the tyrosine kinases induced by CD3-TCR triggering. In this study, we identify these substrates as the product of the vav proto-oncogene and as a 62 kDa protein that could correspond at least in part to p62dok, the 62 kDa adaptor molecule associated to p120 Ras-GTPase activating protein. Both p97vav and p62 are tyrosine phosphorylated upon CD28 ligation by mAb or by its counter-receptor B7-1/CD80. Using CD28 mutants, we also show that Vav and p62 tyrosine phosphorylation is regulated by distinct domains within the CD28 cytoplasmic tail: residues 173-181 for Vav and residues 182-202 for p62. Finally, the phosphorylation of Vav and p62 does not require an intact binding site for Grb-2 or p85 SH2 domains. We thus demonstrate that the CD28 cytoplasmic domain contains at least three functionally independent regions involved in CD28-induced signal transduction, since in addition to the Grb-2 and p85 SH2 domain binding site (Tyr173), residues 173-181 and 182-202 are associated with Vav and p62 tyrosine phosphorylation respectively." 4753;"High levels of functional endopeptidase 24.11 (CD10) activity on human thymocytes: preferential expression on immature subsets.";"JF. PEYRON";"Equipe 04, Team 04";7959879;Immunology;"Mari B, Breittmayer JP, Guerin S, Belhacene N, Peyron JF, Deckert M, Rossi B, Auberger P";;"Jul 1994";773020800;;"Although it is now well established that cells of the immune system express most of the exopeptidases described so far, little information is available concerning the identification and the characterization of the peptidases associated with the surface of human thymocytes. In the present study we have focused on CD10 expression on thymocytes using both FACS and enzymatic analysis. Unfractionated intact human thymocytes were shown to express significant levels of CD10-specific enzymatic activity, as assessed by the hydrolysis of the neutral endopeptidase (NEP) substrate Suc-Ala-Ala-Phe-pNA and of D-Ala2-Leu-enkephalin, a typical NEP substrate. CD10 activity was abolished by specific NEP inhibitors, including thiorphan, retrothiorphan and phosphoramidon. Moreover, high performance liquid chromatography (HPLC) analysis showed that intact thymocytes and purified NEP hydrolysed thymopentin, a thymic factor known to induce the maturation of prothymocytes into thymocytes. Finally, CD 10/NEP was preferentially associated with CD3- CD3low and immature CD4- CD8- thymocytes. The data demonstrate for the first time that human thymocytes express functional NEP and suggest a role for this enzyme in the maturation of human thymocytes." 4748;"CD10 (endopeptidase 24.11) is a thymic peptide-degrading enzyme possibly involved in the regulation of thymocyte functions.";"JF. PEYRON";"Equipe 04, Team 04";9015192;"Cellular immunology";"Guerin S, Mari B, Belhacene N, Rossi B, Peyron JF, Auberger P";;"Jan 1997";852854400;;"Human immature thymocytes express significant levels of the CD10 (endopeptidase 24.11) cell surface antigen. We report here that IOB5, an anti-CD10 mAb, as well as the phorbol ester PMA down-regulate CD10 activity at the surface of human thymocytes. The kinetics of CD10 modulation were drastically different for both effectors, indicating different regulatory mechanisms. We also demonstrated that intact human thymocytes hydrolyze thymopentin and that CD10 significantly participates in this process. Finally, we found that thymopentin and to a lesser extent phosphoramidon, a specific endopeptidase 24.11 inhibitor, induced up-regulation of CD4 and CD8 molecules at the thymocyte cell surface. In view of these results, we suggest that down-regulation of endopeptidase 24.11 at the thymocyte cell surface might reduce its activity toward thymic factors possibly involved in the regulation of thymocyte functions." 4747;"A chymotryptic-type serine protease is required for IL-2 production by Jurkat T cells.";"JF. PEYRON, P. Auberger";"Equipe 04, Team 04, Equipe 02, Team 02";2394468;Immunology;"Auberger P, Sonthonnax S, Peyron JF, Mari B, Fehlmann M";;"Aug 1990";649468800;;"Interleukin-2 (IL-2) production by activated Jurkat T cells was markedly delayed when these cells were treated with low concentrations of the chymotryptic-type protease inhibitor N-alpha-p-tosyl-L-phenylalanine chloromethylketone (TPCK). This increased lag time observed in the presence of TPCK directly correlates with the interaction of the inhibitor with a unique 42,000 molecular weight (MW) serine protease, which can be labelled with [3H]DFP, and was not due to an intracellular accumulation of a non-mature form of IL-2 nor to a non-specific inhibition of overall protein synthesis. The results presented in this report indicate that a 42,000 MW chymotryptic-like serine protease is required for IL-2 production by activated Jurkat T cells." 4743;"NF-kappaB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death.";"V. Imbert, JF. PEYRON";"Team 04, Equipe 04";15616591;"The EMBO journal";"Thyss R, Virolle V, Imbert V, Peyron JF, Aberdam D, Virolle T";;"Jan 2005";1104537600;;"Chronic sun exposure can lead to severe skin disorders such as carcinogenesis. The cell death process triggered by ultraviolet B (UVB) irradiation is crucial because it protects the surrounding tissue from the emergence and the accumulation of cells that bear the risk of becoming transformed. Here, we show that repression of NF-kappaB and Egr-1 expression drastically inhibits UVB-mediated cell death. Furthermore, we demonstrate that Egr-1 is induced upon UVB irradiation through NF-kappaB activation and the binding of p65/RelA within the Egr-1 promoter. We show that Egr-1 contributes to the regulation of the Gadd45a and Gadd45b genes, which are involved in the control of cell cycle, DNA repair and apoptosis, by direct binding to their promoter. Our study demonstrates for the first time a signaling cascade involving sequential activation of NF-kappaB, Egr-1 and Gadd45 to induce UVB-mediated cell death. Failure in the induction of each protagonist of this pathway alters the UVB-mediated cell death process. Therefore, impairment of the cascade could be at the onset of skin carcinogenesis mediated by genotoxic stress." 4717;"Molecular association between major histocompatibility complex class I antigens and insulin receptors in mouse liver membranes.";"JF. PEYRON";"Equipe 04, Team 04";3866245;"Proceedings of the National Academy of Sciences of the United States of America";"Fehlmann M, Peyron JF, Samson M, Van Obberghen E, Brandenburg D, Brossette N";;"Dec 1985";502243200;;"Molecular association between major histocompatibility complex (MHC) antigens and cellular proteins are thought to be involved in various immunological and nonimmunological functions of MHC antigens, including hormone signaling. The existence of physical interactions between insulin receptors and MHC class I antigens was investigated in liver plasma membranes from congenic H-2k mice. Insulin receptors were specifically labeled with a 125I-labeled photoreactive insulin analogue, and cellular proteins were solubilized and incubated with various monoclonal antibodies. Immunoprecipitates were analyzed by polyacrylamide gel electrophoresis followed by autoradiography. Antibodies reacting with distinct epitopes on H-2k class I antigens were all able to precipitate up to 25% of the labeled insulin receptors in H-2k mouse liver membranes, whereas no insulin receptors were precipitated in H-2b mouse liver membranes. Sequential immunoprecipitations showed that insulin receptors and H-2 antigens were coprecipitated and that no cross-reactivity occurred. The specificity of the interaction between insulin receptors and H-2 antigens was demonstrated after double labeling of membrane proteins by photoreactive insulin and lactoperoxidase-catalyzed iodination. These results thus show that, in mouse liver membranes, insulin receptors are physically associated to class I antigens of the MHC." 4702;"[Does sleep preserve blood vessels?]";"L. Yvan-Charvet";"Equipe 13";31625894;"Medecine sciences : M/S";"Yvan-Charvet L, Merlin J";;"Oct 2019";1569888000;; 4698;"ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms.";"A. Jacquel, L. Yvan-Charvet, P. Auberger";"Equipe 02, Team 02, Equipe 13";32160545;"Cell reports";"Viaud M, Abdel-Wahab O, Gall J, Ivanov S, Guinamard R, Sore S, Merlin J, Ayrault M, Guilbaud E, Jacquel A, Auberger P, Wang N, Levine RL, Tall AR, Yvan-Charvet L";;"03 2020";1583020800;;"Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis." 4696;"Interplay between Clonal Hematopoiesis of Indeterminate Potential and Metabolism.";"L. Yvan-Charvet";"Equipe 13";32521236;"Trends in endocrinology and metabolism: TEM";"Lee MKS, Dragoljevic D, Bertuzzo Veiga C, Wang N, Yvan-Charvet L, Murphy AJ";;"07 2020";1593561600;;"Clonal hematopoiesis of indeterminate potential (CHIP), defined as a clone of hematopoietic cells consisting of a single acquired mutation during a lifetime, has recently been discovered to be a major risk factor for atherosclerotic cardiovascular disease (CVD). As such, this phenomenon has sparked interest into the role that these single mutations may play in CVD. Atherosclerotic CVD is a complex disease and we have previously shown that atherosclerosis can be accelerated by metabolic- or autoimmune-related risk factors such as diabetes, obesity, and rheumatoid arthritis. In this review, we discuss the role of CHIP, the interplay between CHIP and metabolic diseases, as well as how metabolism of hematopoietic stem cells (HSCs) could regulate CHIP-related HSC fate." 4694;"Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis.";"L. Yvan-Charvet";"Equipe 13";32562600;Immunity;"Tran S, Baba I, Poupel L, Dussaud S, Moreau M, Gélineau A, Marcelin G, Magréau-Davy E, Ouhachi M, Lesnik P, Boissonnas A, Le Goff W, Clausen BE, Yvan-Charvet L, Sennlaub F, Huby T, Gautier EL";;"09 2020";1598918400;;"Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny." 4692;"Liver X receptors are required for thymic resilience and T cell output.";"L. Yvan-Charvet";"Equipe 13";32716519;"The Journal of experimental medicine";"Chan CT, Fenn AM, Harder NK, Mindur JE, McAlpine CS, Patel J, Valet C, Rattik S, Iwamoto Y, He S, Anzai A, Kahles F, Poller WC, Janssen H, Wong LP, Fernandez-Hernando C, Koolbergen DR, van der Laan AM, Yvan-Charvet L, Sadreyev RI, Nahrendorf M, Westerterp M, Tall AR, Gustafsson JA, Swirski FK";;"10 2020";1601510400;;"The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ's indispensable roles in adaptive immunity." 4690;"Metabolic Inflammation in Obesity-At the Crossroads between Fatty Acid and Cholesterol Metabolism.";"L. Yvan-Charvet";"Equipe 13";32754976;"Molecular nutrition & food research";"Curley S, Gall J, Byrne R, Yvan-Charvet L, McGillicuddy FC";;"01 2021";1609459200;;"Metabolic inflammation is a classic hallmark of obesity that is associated with numerous cardiometabolic complications. Disturbances in fatty acid and cholesterol metabolism are evident in obesity and likely intricately linked to the development and/or sustainment of metabolic inflammation and insulin resistance. Elevations in triglyceride-rich lipoproteins and reductions in high-density lipoprotein-cholesterol in turn are two major disturbances that accompany obesity. How metabolic dyslipidemia may contribute to metabolic inflammation is discussed. How aberrant cholesterol homeostasis coupled with excessive fatty acid accumulation prime pro-IL-1β and the evidence to support a synergistic partnership between cholesterol and fatty acids in driving metabolic inflammation are also discussed. Further, pharmaceutical and nutraceutical strategies aimed at attenuating low-grade inflammation and implications for cardiometabolic complications of obesity are reviewed. The current literature on the importance of the local tissue microenvironment in activating adipose tissue macrophages within obese adipose tissue and the contribution of these local immune cells to metabolic inflammation is reviewed. Finally, the limitations to current biomarkers of metabolic inflammation and the importance of novel sensitive biomarkers in driving obesity sub-type characterization to direct personalized medicine approaches to obesity treatment in the future are discussed." 4688;"Metabolic Reprogramming of Macrophages in Atherosclerosis: Is It All about Cholesterol?";"L. Yvan-Charvet";"Equipe 13";32821733;"Journal of lipid and atherosclerosis";"Yvan-Charvet L, Ivanov S";;"May 2020";1588291200;;"Hypercholesterolemia contributes to the chronic inflammatory response during the progression of atherosclerosis, in part by favoring cholesterol loading in macrophages and other immune cells. However, macrophages encounter a substantial amount of other lipids and nutrients after ingesting atherogenic lipoprotein particles or clearing apoptotic cells, increasing their metabolic load and impacting their behavior during atherosclerosis plaque progression. This review examines whether and how fatty acids and glucose shape the cellular metabolic reprogramming of macrophages in atherosclerosis to modulate the onset phase of inflammation and the later resolution stage, in which the balance is tipped toward tissue repair." 4686;"Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy.";"L. Yvan-Charvet";"Equipe 13";33139329;Diabetes;"Gamblin C, Rouault C, Lacombe A, Langa-Vives F, Farabos D, Lamaziere A, Clément K, Gautier EL, Yvan-Charvet L, Dugail I";;"01 2021";1609459200;;"Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes, is unclear. We show that the isolated adipocyte fraction, but not the total undigested adipose tissue (ATs), from obese patients has decreased LAL expression compared with that from nonobese people. Lentiviral-mediated LAL knockdown in the 3T3L1 mouse cell line to mimic the obese adipocytes condition did not affect lysosome density or autophagic flux, but it did increase triglyceride storage and disrupt endoplasmic reticulum cholesterol, as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than did control mice fed a high-fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol level in the former was lower than that of control mice, although triglyceridemia in the two groups of mice was similar. The adipose-specific LAL-overexpressing mouse phenotype depends on the housing temperature and develops only under mild hypothermic stress (e.g., room temperature) but not at thermoneutrality (30°C), demonstrating the prominent contribution of brown AT (BAT) thermogenesis. LAL overexpression increased levels of BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue-cholesterol homeostasis and affects BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure." 4684;"Mitochondria orchestrate macrophage effector functions in atherosclerosis.";"L. Yvan-Charvet, T. Barouillet";"Equipe 13";33162108;"Molecular aspects of medicine";"Dumont A, Lee M, Barouillet T, Murphy A, Yvan-Charvet L";;"02 2021";1612137600;;"Macrophages are pivotal in the initiation and development of atherosclerotic cardiovascular diseases. Recent studies have reinforced the importance of mitochondria in metabolic and signaling pathways to maintain macrophage effector functions. In this review, we discuss the past and emerging roles of macrophage mitochondria metabolic diversity in atherosclerosis and the potential avenue as biomarker. Beyond metabolic functions, mitochondria are also a signaling platform integrating epigenetic, redox, efferocytic and apoptotic regulations, which are exquisitely linked to their dynamics. Indeed, mitochondria functions depend on their density and shape perpetually controlled by mitochondria fusion/fission and biogenesis/mitophagy balances. Mitochondria can also communicate with other organelles such as the endoplasmic reticulum through mitochondria-associated membrane (MAM) or be secreted for paracrine actions. All these functions are perturbed in macrophages from mouse or human atherosclerotic plaques. A better understanding and integration of how these metabolic and signaling processes are integrated and dictate macrophage effector functions in atherosclerosis may ultimately help the development of novel therapeutic approaches." 4682;"Arterial Delivery of VEGF-C Stabilizes Atherosclerotic Lesions.";"L. Yvan-Charvet";"Equipe 13";33210556;"Circulation research";"Silvestre-Roig C, Lemnitzer P, Gall J, Schwager S, Toska A, Yvan-Charvet L, Detmar M, Soehnlein O";;"01 2021";1609459200;; 4680;"Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID-19 severity.";"A. Jacquel, L. Yvan-Charvet, P. Auberger";"Equipe 02, Team 02, Equipe 13";33683342;"Blood advances";"Courjon J, Dufies O, Robert A, Bailly L, Torre C, Chirio D, Contenti J, Vitale S, Loubatier C, Doye A, Pomares-Estran C, Gonfrier G, Lotte R, Munro P, Visvikis O, Dellamonica J, Giordanengo V, Carles M, Yvan-Charvet L, Ivanov S, Auberger P, Jacquel A, Boyer L";;"03 2021";1614556800;;"Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient's evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017." 4678;"Macrophage ontogeny and functional diversity in cardiometabolic diseases.";"F. Murcy, L. Yvan-Charvet";"Equipe 13";34229949;"Seminars in cell & developmental biology";"Gautier EL, Askia H, Murcy F, Yvan-Charvet L";;"11 2021";1635724800;;"Macrophages are the dominant immune cell types in the adipose tissue, the liver or the aortic wall and they were originally believed to mainly derived from monocytes to fuel tissue inflammation in cardiometabolic diseases. However, over the last decade the identification of tissue resident macrophages (trMacs) from embryonic origin in these metabolic tissues has provided a breakthrough in the field forcing to better comprehend macrophage diversity during pathological states. Infiltrated monocyte-derived macrophages (moMacs), similar to trMacs, adapt to the local metabolic environment that eventually shapes their functions. In this review, we will summarize the emerging versatility of macrophages in cardiometabolic diseases with a focus in the control of adipose tissue, liver and large vessels homeostasis." 4676;"Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis.";"L. Yvan-Charvet";"Equipe 13";34279540;"The Journal of experimental medicine";"Nakamizo S, Dutertre CA, Khalilnezhad A, Zhang XM, Lim S, Lum J, Koh G, Foong C, Yong PJA, Tan KJ, Sato R, Tomari K, Yvan-Charvet L, He H, Guttman-Yassky E, Malleret B, Shibuya R, Iwata M, Janela B, Goto T, Lucinda TS, Tang MBY, Theng C, Julia V, Hacini-Rachinel F, Kabashima K, Ginhoux F";;"09 2021";1630454400;;"Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)-mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO." 4674;"A subset of Kupffer cells regulates metabolism through the expression of CD36.";"L. Yvan-Charvet";"Equipe 13";34469775;Immunity;"Blériot C, Barreby E, Dunsmore G, Ballaire R, Chakarov S, Ficht X, De Simone G, Andreata F, Fumagalli V, Guo W, Wan G, Gessain G, Khalilnezhad A, Zhang XM, Ang N, Chen P, Morgantini C, Azzimato V, Kong WT, Liu Z, Pai R, Lum J, Shihui F, Low I, Xu C, Malleret B, Kairi MFM, Balachander A, Cexus O, Larbi A, Lee B, Newell EW, Ng LG, Phoo WW, Sobota RM, Sharma A, Howland SW, Chen J, Bajenoff M, Yvan-Charvet L, Venteclef N, Iannacone M, Aouadi M, Ginhoux F";;"09 2021";1630454400;;"Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206ESAM population (KC1) and a minor CD206ESAM population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions." 4672;"Brown adipose tissue monocytes support tissue expansion.";"J. GILLERON, L. Yvan-Charvet, N. Vaillant";"Equipe 13";34489438;"Nature communications";"Gallerand A, Stunault MI, Merlin J, Luehmann HP, Sultan DH, Firulyova MM, Magnone V, Khedher N, Jalil A, Dolfi B, Castiglione A, Dumont A, Ayrault M, Vaillant N, Gilleron J, Barbry P, Dombrowicz D, Mack M, Masson D, Bertero T, Becher B, Williams JW, Zaitsev K, Liu Y, Guinamard RR, Yvan-Charvet L, Ivanov S";;"09 2021";1630454400;;"Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling." 4670;"LDL-cholesterol drives reversible myelomonocytic skewing in human bone marrow.";"L. Yvan-Charvet";"Equipe 13, Team 13";34508568;"European heart journal";"Yvan-Charvet L, Westerterp M";;"11 2021";1635724800;; 4668;"Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation.";"L. Yvan-Charvet, N. Vaillant";"Equipe 13";34650273;"Nature metabolism";"Merlin J, Ivanov S, Dumont A, Sergushichev A, Gall J, Stunault M, Ayrault M, Vaillant N, Castiglione A, Swain A, Orange F, Gallerand A, Berton T, Martin JC, Carobbio S, Masson J, Gaisler-Salomon I, Maechler P, Rayport S, Sluimer JC, Biessen EAL, Guinamard RR, Gautier EL, Thorp EB, Artyomov MN, Yvan-Charvet L";;"10 2021";1633046400;;"Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans." 4666;"Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.";"L. Yvan-Charvet";"Equipe 13";34731632;"Cell reports";"Matias MI, Yong CS, Foroushani A, Goldsmith C, Mongellaz C, Sezgin E, Levental KR, Talebi A, Perrault J, Rivière A, Dehairs J, Delos O, Bertand-Michel J, Portais JC, Wong M, Marie JC, Kelekar A, Kinet S, Zimmermann VS, Levental I, Yvan-Charvet L, Swinnen JV, Muljo SA, Hernandez-Vargas H, Tardito S, Taylor N, Dardalhon V";;"Nov 2021";1635724800;;"Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate." 4493;"Generation of cytomegalovirus-specific human T-lymphocyte clones by using autologous B-lymphoblastoid cells with stable expression of pp65 or IE1 proteins: a tool to study the fine specificity of the antiviral response.";"V. PROD'HOMME";"Equipe 11, Team 11";10756006;"Journal of virology";"Retière C, Prod'homme V, Imbert-Marcille BM, Bonneville M, Vié H, Hallet MM";;"May 2000";957139200;;"Cytotoxic T lymphocytes (CTLs) play a central role in the control of persistent human cytomegalovirus (HCMV) infection in healthy virus carriers. Previous analyses of the specificity of HCMV-reactive CD8(+) CTLs drawn from in vitro models in which antigen-presenting cells were autologous fibroblasts infected with laboratory HCMV strains have shown focusing of CTL responses against the major tegument protein, pp65. By contrast, the 72-kDa major immediate-early protein (IE1) was identified as a minor target for this response. Here we have studied the fine specificity and T-cell-receptor features of T-cell clones generated against autologous B lymphoblastoid cell lines stably transfected with HCMV cDNA coding for either pp65 or a natural variant of IE1. This strategy allowed efficient generation of T-cell clones against IE1 and pp65 and led to the identification of several new IE1 and pp65 epitopes, including some located in polymorphic regions of IE1. Such an approach may provide relevant information about the characteristics of the CTL response to IE1 and the effect of viral polymorphism on the immune response against HCMV." 4491;"Modulation of HLA-A*0201-restricted T cell responses by natural polymorphism in the IE1(315-324) epitope of human cytomegalovirus.";"V. PROD'HOMME";"Equipe 11, Team 11";12574373;"Journal of immunology (Baltimore, Md. : 1950)";"Prod'homme V, Retière C, Imbert-Marcille BM, Bonneville M, Hallet MM";;"Feb 2003";1044057600;;"Cytotoxic T lymphocytes play a central role in the control of persistent human CMV (HCMV) infection and reactivation. In healthy virus carriers, the specific CD8(+) CTL response is almost entirely directed against the virion tegument protein pp65 and/or the 72-kDa major immediate early protein, IE1. Studies that included a large panel of HCMV(+) donors suggested that immunorelevance of pp65 and IE1 was directly related with individual HLA haplotype difference. Nevertheless, there are no data on the incidence of HCMV natural polymorphism on virus-specific CTL responses. To assess the impact of IE1 polymorphism on CTL response, we have sequenced in 103 clinical isolates the DNA region corresponding to IE1(315-324), an immunodominant epitope presented by HLA-A*0201 molecules. Seven peptidic variants were found with extensive difference in their frequencies. The response of four HLA-A*0201-restricted anti-IE1 T lymphocyte clones, which were previously generated from one donor against autologous B lymphoblastoid cells expressing a recombinant clinical variant of IE1, was then evaluated using target cells loaded with mutant synthetic peptides or expressing rIE1 variants. One of four clones, which have been sorted 19 times among 22 clones targeted against IE1(315-324), recognized six of the seven tested variant epitopes. All three other clones showed distinct reactivity patterns to target cells loaded with the different mutant peptides or expressing IE1 variants. Therefore, in the HLA-A2 context, clonal expansions of anti-IE1 memory CTLs may confer a protection against HCMV successive infections and reactivations by killing cells presenting most of the naturally occurring IE1(315-324) epitope variants." 4489;"Cross-reactivity of HLA-B*1801-restricted T-lymphocyte clones with target cells expressing variants of the human cytomegalovirus 72kDa-IE1 protein.";"V. PROD'HOMME";"Equipe 11, Team 11";12768035;"Journal of virology";"Prod'homme V, Retière C, Valtcheva R, Bonneville M, Hallet MM";;"Jun 2003";1054425600;;"The impact of natural polymorphism in a cytomegalovirus-dominant HLA-B(*)1801-restricted epitope, IE1(199-206), on the specific responses of T-cell clones was assessed by measuring their cytolytic activity against target cells expressing mutated recombinant IE1 proteins. Our results suggest an in vivo selection of T lymphocytes that cross-react with multiple IE1 variants." 4434;"Use of a lentiviral vector encoding a HCMV-chimeric IE1-pp65 protein for epitope identification in HLA-Transgenic mice and for ex vivo stimulation and expansion of CD8(+) cytotoxic T cells from human peripheral blood cells.";"V. PROD'HOMME";"Equipe 11, Team 11";15172452;"Human immunology";"Rohrlich PS, Cardinaud S, Lulè J, Montero-Julian FA, Prodhomme V, Firat H, Davignon JL, Perret E, Monseaux S, Necker A, Michelson S, Lemonnier FA, Charneau P, Davrinche C";;"May 2004";1083369600;;"H2-deleted, HLA-A2, or HLA-B7 transgenic mice were used to identify new human cytomegalovirus (HCMV)-derived major histocompatibility complex class I-restricted epitopes. Three different approaches for mice immunization were compared for their ability to induce a cytotoxic CD8(+) T cell (CTL) response: (1). inoculation of infectious HCMV, (2). injection of immunogenic synthetic peptides, and (3). infection with a newly designed HIV-derived central DNA flap positive lentiviral vector encoding the chimeric IE1-pp65 protein (Trip-IE1-pp65). Targets pulsed with either known immunogenic peptides or computer predicted ones were used to characterize CTL. Most of the mice immunized with the pp65 (495-NLVPMVATV-503) immunodominant peptide responded after one injection whereas only two of six mice responded to two successive inoculations with HCMV. Infection of mice with Trip-IE1-pp65 induced activation and expansion of CTL directed against peptides from both pp65 and IE1 and allowed identification of new epitopes. We further demonstrated the high capacity of monocyte-macrophage cells transduced with Trip-IE1-pp65 to activate and expand CTL directed against pp65 from peripheral blood mononuclear cells of HCMV-seropositive donors. Altogether these results suggest that Trip-IE1-pp65 is a powerful construct both to characterize new epitopes in combination with human leukocyte antigen-transgenic mice immunization and to provide an alternative to the use of known infectious and noninfectious approaches to expand effector T cells for adoptive immunotherapy." 4426;"Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor.";"V. PROD'HOMME";"Equipe 11, Team 11";16339512;"Journal of immunology (Baltimore, Md. : 1950)";"Aldemir H, Prod'homme V, Dumaurier MJ, Retiere C, Poupon G, Cazareth J, Bihl F, Braud VM";;"Dec 2005";1133395200;;"Human NK cells and subsets of T cells or NKT cells express the orphan C-type lectin receptor CD161 (NKR-P1A) of unknown function. In contrast to rodents that possess several NKR-P1 genes coding for either activating or inhibitory receptors, the nature of signals delivered by the single human NKR-P1A receptor is still to be clarified. In this article, we show that the lectin-like transcript 1 (LLT1) molecule is a ligand for the CD161 receptor. Engagement of CD161 on NK cells with LLT1 expressed on target cells inhibited NK cell-mediated cytotoxicity and IFN-gamma secretion. Conversely, LLT1/CD161 interaction in the presence of a TCR signal enhanced IFN-gamma production by T cells. These findings identify a novel ligand/receptor pair that differentially regulate NK and T cell functions." 4424;"The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells.";"V. PROD'HOMME";"Equipe 11, Team 11";17372005;"Journal of immunology (Baltimore, Md. : 1950)";"Prod'homme V, Griffin C, Aicheler RJ, Wang EC, McSharry BP, Rickards CR, Stanton RJ, Borysiewicz LK, López-Botet M, Wilkinson GW, Tomasec P";;"Apr 2007";1175385600;;"The inhibitory leukocyte Ig-like receptor 1 (LIR-1, also known as ILT2, CD85j, or LILRB1) was identified by its high affinity for the human CMV (HCMV) MHC class I homolog gpUL18. The role of this LIR-1-gpUL18 interaction in modulating NK recognition during HCMV infection has previously not been clearly defined. In this study, LIR-1(+) NKL cell-mediated cytotoxicity was shown to be inhibited by transduction of targets with a replication-deficient adenovirus vector encoding UL18 (RAd-UL18). Fibroblasts infected with an HCMV UL18 mutant (DeltaUL18) also exhibited enhanced susceptibility to NKL killing relative to cells infected with the parental virus. In additional cytolysis assays, UL18-mediated protection was also evident in the context of adenovirus vector transduction and HCMV infection of autologous fibroblast targets using IFN-alpha-activated NK bulk cultures derived from a donor with a high frequency of LIR-1(+) NK cells. A single LIR-1(high) NK clone derived from this donor was inhibited by UL18, while 3 of 24 clones were activated. CD107 mobilization assays revealed that LIR-1(+) NK cells were consistently inhibited by UL18 in all tested donors, but this effect was often masked in the global response by UL18-mediated activation of a subset of LIR-1(-) NK cells. Although Ab-blocking experiments support UL18 inhibition being induced by a direct interaction with LIR-1, the UL18-mediated activation is LIR-1 independent." 4422;"Modulation of natural killer cells by human cytomegalovirus.";"V. PROD'HOMME";"Equipe 11, Team 11";18069056;"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology";"Wilkinson GW, Tomasec P, Stanton RJ, Armstrong M, Prod'homme V, Aicheler R, McSharry BP, Rickards CR, Cochrane D, Llewellyn-Lacey S, Wang EC, Griffin CA, Davison AJ";;"Mar 2008";1204329600;;"Human cytomegalovirus (HCMV) causes lifelong, persistent infections and its survival is under intense, continuous selective pressure from the immune system. A key aspect of HCMV's capacity for survival lies in immune avoidance. In this context, cells undergoing productive infection exhibit remarkable resistance to natural killer (NK) cell-mediated cytolysis in vitro. To date, six genes encoding proteins (UL16, UL18, UL40, UL83, UL141 and UL142) and one encoding a microRNA (miR-UL112) have been identified as capable of suppressing NK cell recognition. Even though HCMV infection efficiently activates expression of ligands for the NK cell activating receptor NKG2D, at least three functions (UL16, UL142 and miR-UL112) act in concert to suppress presentation of these ligands on the cell surface. Although HCMV downregulates expression of endogenous MHC-I, it encodes an MHC-I homologue (UL18) and also upregulates the expression of cellular HLA-E through the action of UL40. The disruption of normal intercellular connections exposes ligands for NK cell activating receptors on the cell surface, notably CD155. HCMV overcomes this vulnerability by encoding a function (UL141) that acts post-translationally to suppress cell surface expression of CD155. The mechanisms by which HCMV systematically evades (or, more properly, modulates) NK cell recognition constitutes an area of growing understanding that is enhancing our appreciation of the basic mechanisms of NK cell function in humans." 4420;"Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B.";"V. PROD'HOMME";"Equipe 11, Team 11";18287244;"Journal of virology";"McSharry BP, Burgert HG, Owen DP, Stanton RJ, Prod'homme V, Sester M, Koebernick K, Groh V, Spies T, Cox S, Little AM, Wang EC, Tomasec P, Wilkinson GW";;"May 2008";1209600000;;"The adenovirus (Ad) early transcription unit 3 (E3) encodes multiple immunosubversive functions that are presumed to facilitate the establishment and persistence of infection. Indeed, the capacity of E3/19K to inhibit transport of HLA class I (HLA-I) to the cell surface, thereby preventing peptide presentation to CD8(+) T cells, has long been recognized as a paradigm for viral immune evasion. However, HLA-I downregulation has the potential to render Ad-infected cells vulnerable to natural killer (NK) cell recognition. Furthermore, expression of the immediate-early Ad gene E1A is associated with efficient induction of ligands for the key NK cell-activating receptor NKG2D. Here we show that while infection with wild-type Ad enhances synthesis of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B (MICA and MICB), their expression on the cell surface is actively suppressed. Both MICA and MICB are retained within the endoplasmic reticulum as immature endoglycosidase H-sensitive forms. By analyzing a range of cell lines and viruses carrying mutated versions of the E3 gene region, E3/19K was identified as the gene responsible for this activity. The structural requirements within E3/19K necessary to sequester MICA/B and HLA-I are similar. In functional assays, deletion of E3/19K rendered Ad-infected cells more sensitive to NK cell recognition. We report the first NK evasion function in the Adenoviridae and describe a novel function for E3/19K. Thus, E3/19K has a dual function: inhibition of T-cell recognition and NK cell activation." 4418;"Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112.";"V. PROD'HOMME";"Equipe 11, Team 11";20410314;"The Journal of general virology";"Prod'homme V, Sugrue DM, Stanton RJ, Nomoto A, Davies J, Rickards CR, Cochrane D, Moore M, Wilkinson GWG, Tomasec P";;"Aug 2010";1280620800;;"Human cytomegalovirus (HCMV) UL141 induces protection against natural killer cell-mediated cytolysis by downregulating cell surface expression of CD155 (nectin-like molecule 5; poliovirus receptor), a ligand for the activating receptor DNAM-1 (CD226). However, DNAM-1 is also recognized to bind a second ligand, CD112 (nectin-2). We now show that HCMV targets CD112 for proteasome-mediated degradation by 48 h post-infection, thus removing both activating ligands for DNAM-1 from the cell surface during productive infection. Significantly, cell surface expression of both CD112 and CD155 was restored when UL141 was deleted from the HCMV genome. While gpUL141 alone is sufficient to mediate retention of CD155 in the endoplasmic reticulum, UL141 requires assistance from additional HCMV-encoded functions to suppress expression of CD112." 4416;"3BP2 adapter protein is required for receptor activator of NFκB ligand (RANKL)-induced osteoclast differentiation of RAW264.7 cells.";"M. Deckert, V. PROD'HOMME";"Equipe 11, Team 11";20439986;"The Journal of biological chemistry";"GuezGuez A, Prod'homme V, Mouska X, Baudot A, Blin-Wakkach C, Rottapel R, Deckert M";;"Jul 2010";1277942400;;"The adapter protein 3BP2 (also known as SH3BP2 and Abl SH3-binding protein 2) has been involved in leukocyte signaling and activation downstream immunoreceptors. Genetic studies have further associated 3BP2 mutations to the human disease cherubism and to inflammation and bone dysfunction in mouse. However, how wild type 3BP2 functions in macrophage differentiation remains poorly understood. In this study, using small interfering RNA-mediated silencing of 3BP2 in the RAW264.7 monocytic cell line, we show that 3BP2 was required for receptor activator of NFkappaB ligand (RANKL)-induced differentiation of RAW264.7 cells into multinucleated mature osteoclasts but not for granulocyte macrophage-colony stimulating factor/interleukin-4-induced differentiation into dendritic cells. 3BP2 silencing was associated with impaired activation of multiple signaling events downstream of RANK, including actin reorganization; Src, ERK, and JNK phosphorylation; and up-regulation of osteoclastogenic factors. In addition, 3BP2 knockdown cells induced to osteoclast by RANKL displayed a reduced increase of Src and nuclear factor of activated T cells (NFATc1) mRNA and protein expression. Importantly, 3BP2 interacted with Src, Syk, Vav, and Cbl in monocytic cells, and the introduction of constitutively active mutants of Src and NFATc1 in 3BP2-deficient cells restored osteoclast differentiation. Finally, the expression of a 3BP2 cherubism mutant was found to promote increased Src activity and NFAT-dependent osteoclast formation. Together, this study demonstrates that wild type 3BP2 is a key regulator of RANK-mediated macrophage differentiation into osteoclast through Src and NFATc1 activation." 4414;"Human cytomegalovirus UL40 signal peptide regulates cell surface expression of the NK cell ligands HLA-E and gpUL18.";"V. PROD'HOMME";"Equipe 11, Team 11";22345649;"Journal of immunology (Baltimore, Md. : 1950)";"Prod'homme V, Tomasec P, Cunningham C, Lemberg MK, Stanton RJ, McSharry BP, Wang EC, Cuff S, Martoglio B, Davison AJ, Braud VM, Wilkinson GW";;"Mar 2012";1330560000;;"Human CMV (HCMV)-encoded NK cell-evasion functions include an MHC class I homolog (UL18) with high affinity for the leukocyte inhibitory receptor-1 (CD85j, ILT2, or LILRB1) and a signal peptide (SP(UL40)) that acts by upregulating cell surface expression of HLA-E. Detailed characterization of SP(UL40) revealed that the N-terminal 14 aa residues bestowed TAP-independent upregulation of HLA-E, whereas C region sequences delayed processing of SP(UL40) by a signal peptide peptidase-type intramembrane protease. Most significantly, the consensus HLA-E-binding epitope within SP(UL40) was shown to promote cell surface expression of both HLA-E and gpUL18. UL40 was found to possess two transcription start sites, with utilization of the downstream site resulting in translation being initiated within the HLA-E-binding epitope (P2). Remarkably, this truncated SP(UL40) was functional and retained the capacity to upregulate gpUL18 but not HLA-E. Thus, our findings identify an elegant mechanism by which an HCMV signal peptide differentially regulates two distinct NK cell-evasion pathways. Moreover, we describe a natural SP(UL40) mutant that provides a clear example of an HCMV clinical virus with a defect in an NK cell-evasion function and exemplifies issues that confront the virus when adapting to immunogenetic diversity in the host." 4412;"Human cytomegalovirus suppresses Fas expression and function.";"V. PROD'HOMME";"Equipe 11, Team 11";24394698;"The Journal of general virology";"Seirafian S, Prod'homme V, Sugrue D, Davies J, Fielding C, Tomasec P, Wilkinson GWG";;"Apr 2014";1396310400;;"Human cytomegalovirus (HCMV) is known to evade extrinsic pro-apoptotic pathways not only by downregulating cell surface expression of the death receptors TNFR1, TRAIL receptor 1 (TNFRSF10A) and TRAIL receptor 2 (TNFRSF10B), but also by impeding downstream signalling events. Fas (CD95/APO-1/TNFRSF6) also plays a prominent role in apoptotic clearance of virus-infected cells, so its fate in HCMV-infected cells needs to be addressed. Here, we show that cell surface expression of Fas was suppressed in HCMV-infected fibroblasts from 24 h onwards through the late phase of productive infection, and was dependent on de novo virus-encoded gene expression but not virus DNA replication. Significant levels of the fully glycosylated (endoglycosidase-H-resistant) Fas were retained within HCMV-infected cells throughout the infection within intracellular membranous structures. HCMV infection provided cells with a high level of protection against Fas-mediated apoptosis. Downregulation of Fas was observed with HCMV strains AD169, FIX, Merlin and TB40." 4410;"Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation.";"V. PROD'HOMME";"Equipe 11, Team 11";24787765;"PLoS pathogens";"Fielding CA, Aicheler R, Stanton RJ, Wang EC, Han S, Seirafian S, Davies J, McSharry BP, Weekes MP, Antrobus PR, Prod'homme V, Blanchet FP, Sugrue D, Cuff S, Roberts D, Davison AJ, Lehner PJ, Wilkinson GW, Tomasec P";;"May 2014";1398902400;;"NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1-6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12-US21; a genetic arrangement, which is suggestive of an 'accordion' expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family." 4408;"HCMV pUL135 remodels the actin cytoskeleton to impair immune recognition of infected cells.";"V. PROD'HOMME";"Equipe 11, Team 11";25121749;"Cell host & microbe";"Stanton RJ, Prod'homme V, Purbhoo MA, Moore M, Aicheler RJ, Heinzmann M, Bailer SM, Haas J, Antrobus R, Weekes MP, Lehner PJ, Vojtesek B, Miners KL, Man S, Wilkie GS, Davison AJ, Wang ECY, Tomasec P, Wilkinson GWG";;"Aug 2014";1406851200;;"Immune evasion genes help human cytomegalovirus (HCMV) establish lifelong persistence. Without immune pressure, laboratory-adapted HCMV strains have undergone genetic alterations. Among these, the deletion of the UL/b' domain is associated with loss of virulence. In a screen of UL/b', we identified pUL135 as a protein responsible for the characteristic cytopathic effect of clinical HCMV strains that also protected from natural killer (NK) and T cell attack. pUL135 interacted directly with abl interactor 1 (ABI1) and ABI2 to recruit the WAVE2 regulatory complex to the plasma membrane, remodel the actin cytoskeleton and dramatically reduce the efficiency of immune synapse (IS) formation. An intimate association between F-actin filaments in target cells and the IS was dispelled by pUL135 expression. Thus, F-actin in target cells plays a critical role in synaptogenesis, and this can be exploited by pathogens to protect against cytotoxic immune effector cells. An independent interaction between pUL135 and talin disrupted cell contacts with the extracellular matrix." 4406;"Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages.";"M. Deckert, S. Tartare-Deckert, V. PROD'HOMME";"Equipe 11, Team 11";25705883;"The Journal of clinical investigation";"Prod'Homme V, Boyer L, Dubois N, Mallavialle A, Munro P, Mouska X, Coste I, Rottapel R, Tartare-Deckert S, Deckert M";;"Apr 2015";1427846400;;"Cherubism is a rare autoinflammatory bone disorder that is associated with point mutations in the SH3-domain binding protein 2 (SH3BP2) gene, which encodes the adapter protein 3BP2. Individuals with cherubism present with symmetrical fibro-osseous lesions of the jaw, which are attributed to exacerbated osteoclast activation and defective osteoblast differentiation. Although it is a dominant trait in humans, cherubism appears to be recessively transmitted in mice, suggesting the existence of additional factors in the pathogenesis of cherubism. Here, we report that macrophages from 3BP2-deficient mice exhibited dramatically reduced inflammatory responses to microbial challenge and reduced phagocytosis. 3BP2 was necessary for LPS-induced activation of signaling pathways involved in macrophage function, including SRC, VAV1, p38MAPK, IKKα/β, RAC, and actin polymerization pathways. Conversely, we demonstrated that the presence of a single Sh3bp2 cherubic allele and pathogen-associated molecular pattern (PAMP) stimulation had a strong cooperative effect on macrophage activation and inflammatory responses in mice. Together, the results from our study in murine genetic models support the notion that infection may represent a driver event in the etiology of cherubism in humans and suggest limiting inflammation in affected individuals may reduce manifestation of cherubic lesions." 4404;"Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis.";"M. Deckert, M. Ohanna, S. Tartare-Deckert, V. PROD'HOMME";"Equipe 11, Team 11";25925867;"Nature communications";"Tichet M, Prod'Homme V, Fenouille N, Ambrosetti D, Mallavialle A, Cerezo M, Ohanna M, Audebert S, Rocchi S, Giacchero D, Boukari F, Allegra M, Chambard JC, Lacour JP, Michiels JF, Borg JP, Deckert M, Tartare-Deckert S";;"Apr 2015";1427846400;;"Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis. " 4398;"A Feed-Forward Mechanosignaling Loop Confers Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutant Melanoma.";"F. LARBRET, M. Deckert, S. Tartare-Deckert, V. PROD'HOMME, C. Girard";"Equipe 11, Team 11";32179513;"Cancer research";"Girard CA, Lecacheur M, Ben Jouira R, Berestjuk I, Diazzi S, Prod'homme V, Mallavialle A, Larbret F, Gesson M, Schaub S, Pisano S, Audebert S, Mari B, Gaggioli C, Leucci E, Marine JC, Deckert M, Tartare-Deckert S";;"05 2020";1588291200;;"Aberrant extracellular matrix (ECM) deposition and stiffening is a physical hallmark of several solid cancers and is associated with therapy failure. BRAF-mutant melanomas treated with BRAF and MEK inhibitors almost invariably develop resistance that is frequently associated with transcriptional reprogramming and a de-differentiated cell state. Melanoma cells secrete their own ECM proteins, an event that is promoted by oncogenic BRAF inhibition. Yet, the contribution of cancer cell-derived ECM and tumor mechanics to drug adaptation and therapy resistance remains poorly understood. Here, we show that melanoma cells can adapt to targeted therapies through a mechanosignaling loop involving the autocrine remodeling of a drug-protective ECM. Analyses revealed that therapy-resistant cells associated with a mesenchymal dedifferentiated state displayed elevated responsiveness to collagen stiffening and force-mediated ECM remodeling through activation of actin-dependent mechanosensors Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF). Short-term inhibition of MAPK pathway also induced mechanosignaling associated with deposition and remodeling of an aligned fibrillar matrix. This provided a favored ECM reorganization that promoted tolerance to BRAF inhibition in a YAP- and MRTF-dependent manner. Matrix remodeling and tumor stiffening were also observed upon exposure of BRAF-mutant melanoma cell lines or patient-derived xenograft models to MAPK pathway inhibition. Importantly, pharmacologic targeting of YAP reversed treatment-induced excessive collagen deposition, leading to enhancement of BRAF inhibitor efficacy. We conclude that MAPK pathway targeting therapies mechanically reprogram melanoma cells to confer a drug-protective matrix environment. Preventing melanoma cell mechanical reprogramming might be a promising therapeutic strategy for patients on targeted therapies. SIGNIFICANCE: These findings reveal a biomechanical adaptation of melanoma cells to oncogenic BRAF pathway inhibition, which fuels a YAP/MRTF-dependent feed-forward loop associated with tumor stiffening, mechanosensing, and therapy resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/1927/F1.large.jpg." 4396;"Downregulation of HLA-I by the molluscum contagiosum virus mc080 impacts NK-cell recognition and promotes CD8 T-cell evasion.";"V. PROD'HOMME";"Equipe 11, Team 11";32510303;"The Journal of general virology";"Elasifer H, Wang ECY, Prod'homme V, Davies J, Forbes S, Stanton RJ, Patel M, Fielding CA, Roberts D, Traherne JA, Gruber N, Bugert JJ, Aicheler RJ, Wilkinson GWG";;"08 2020";1596240000;;"Molluscum contagiosum virus (MCV) is a common cause of benign skin lesions in young children and currently the only endemic human poxvirus. Following the infection of primary keratinocytes in the epidermis, MCV induces the proliferation of infected cells and this results in the production of wart-like growths. Full productive infection is observed only after the infected cells differentiate. During this prolonged replication cycle the virus must avoid elimination by the host immune system. We therefore sought to investigate the function of the two major histocompatibility complex class-I-related genes encoded by the MCV genes mc033 and mc080. Following insertion into a replication-deficient adenovirus vector, codon-optimized versions of mc033 and mc080 were expressed as endoglycosidase-sensitive glycoproteins that localized primarily in the endoplasmic reticulum. MC080, but not MC033, downregulated cell-surface expression of endogenous classical human leucocyte antigen (HLA) class I and non-classical HLA-E by a transporter associated with antigen processing (TAP)-independent mechanism. MC080 exhibited a capacity to inhibit or activate NK cells in autologous assays in a donor-specific manner. MC080 consistently inhibited antigen-specific T cells being activated by peptide-pulsed targets. We therefore propose that MC080 acts to promote evasion of HLA-I-restricted cytotoxic T cells." 4394;"SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic Steatohepatitis.";"C. LUCI, F. LARBRET, M. Deckert, P. GUAL, V. PROD'HOMME";"Equipe 08, Team 08, Equipe 11, Team 11";34411785;"Cellular and molecular gastroenterology and hepatology";"Luci C, Vieira E, Bourinet M, Rousseau D, Bonnafous S, Patouraux S, Lefevre L, Larbret F, Prod'homme V, Iannelli A, Tran A, Anty R, Bailly-Maitre B, Deckert M, Gual P";;"Jan 2022";1640995200;;"Spleen tyrosine kinase (SYK) signaling pathway regulates critical processes in innate immunity, but its role in parenchymal cells remains elusive in chronic liver diseases. We investigate the relative contribution of SYK and its substrate c-Abl Src homology 3 domain-binding protein-2 (3BP2) in both myeloid cells and hepatocytes in the onset of metabolic steatohepatitis."