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1. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

Author: Ruth Dobson, P. Kleinova, Tessel F. Runia, H.-P. Hartung, Maria Trojano, A.D. Martinez, Viviana Annibali, Sreeram V. Ramagopalan, Florian Deisenhammer, Mohsen Khademi, Jens Kuhle, Jan Lycke, Mar Tintoré, Ludwig Kappos, Pietro Iaffaldano, Antonio Uccelli, Dana Horakova, Kjell-Morten Myhr, Cecilia Rajda, Konrad Rejdak, Stig Wergeland, Monica Marta, Roberto Furlan, Florian Lauda, Jean Pelletier, Romain Marignier, G. Comi, Giulio Disanto, Romy Roesler, Vita Direnzo, Özgür Yaldizli, N. Moll, Silvia Romano, Sergey V. Lapin, Sylvain Lehmann, Irena Dujmovic, Elio Scarpini, Tomas Olsson, Rogier Q. Hintzen, Raija L.P. Lindberg, E. P. Evdoshenko, Siegrid Fuchs, B. C. Kieseier, Henrik Larsson, Eric Thouvenot, Jonathan P. Bestwick, Maurizio Leone, László Vécsei, S. Saip, Pablo Villoslada, Roberto Bergamaschi, Xavier Montalban, Øivind Torkildsen, José C. Álvarez-Cermeño, Joanne Topping, Albert Saiz, Isabel Bosca, Hayrettin Tumani, Adriana Carrá, Joep Killestein, Sara Llufriu, N. Barizzone, Ute-Christiane Meier, Diego Franciotta, David Brassat, Christian Enzinger, Michael Khalil, Gavin Giovannoni, Timucin Avsar, Scott L. Rauch, Aksel Siva, N. Lazareva, Clas Malmeström, Jette L. Frederiksen, Harald Hegen, Ugur Uygunoglu, Luisa M. Villar, Lucia Bianchi, Marco Salvetti, Tobias Derfuss, Giovanni Castelnovo, Ayse Altintas, Rocco Adiutori, E. Colombo, G. Dalla Costa, Daniela Galimberti, Madeleine H. Sombekke, Vittorio Martinelli, Sandra D'Alfonso, Manuel Comabella, Eva Havrdova, Fredrik Piehl, Charlotte E. Teunissen, Til Menge, Jelena Drulovic, C. Picard, Alice Laroni, Christian Confavreux, Chiara Fenoglio, Neurology, Laboratory Medicine, NCA - Neuroinflamation, Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), National Oceanography Centre (NOC), Department of Anatomy and Structural Biology Albert Einstein College of Medicine, Albert Einstein College of Medicine [New York], Department of public health, University of Turin, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Water Environment Technology, Chalmers University of Technology [Göteborg], Department of Neurology, A.O.U. Maggiore della Carità, and IRCAD, Novara, Leibniz-Institut für Gewässerökologie und Binnenfischerei (IGB), Leibniz Association, Department of Neurology, University of California [San Francisco] (UCSF), University of California-University of California, Center for Neuroimmunology, Service of Neurology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Université européenne de Bretagne - European University of Brittany (UEB), Laboratoire de l'intégration, du matériau au système (IMS), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Azm Center for Biotechnology Research, Agence universitaire de la Francophonie (Beyrouth, Lebanon)-Lebanese University [Beirut] (LU), FOI, Linköping University (LIU), Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, IRMP-Louvain, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Dipartimento Ingegneria Aerospaziale 'Lucio Lazzarino' (DIA), University of Pisa - Università di Pisa, International Centre for Hydrology 'Dino Tonini' and Dipartimento IMAGE, Universita degli Studi di Padova, Dept. of Neurology, University Hospital Rigshospitalet, University of California [Berkeley], University of California, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, The Weizmann Institute, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Laboratory of Neuroimmunology, IRCCS, Neurological Institute 'C. Mondino', University of Pavia, Pa, University of Pavia, Department of Neurology, Albert Szent-Gyorgyi Clinical Centre, University of Szeged [Szeged], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Universitat de Barcelona (UB)-Hospital Clinic, University of Ulm, Department of Neurology, Service Anesthésie et Réanimation [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], University of Eastern Piedmont, Department of Medical Sciences, IRCAD, Novara, Vall d'Hebron University Hospital [Barcelona], Department of Public Health and Clinical Medicine, Umeå University, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Universitaire de Bâle, Laboratory of Molecular Virology, Université libre de Bruxelles (ULB), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Department of Atmospheric, Oceanic and Planetary Physics [Oxford] (AOPP), University of Oxford [Oxford], Blizard Institute of Cell and Molecular Science, Università degli studi di Torino = University of Turin (UNITO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Padova = University of Padua (Unipd), University of California [Berkeley] (UC Berkeley), University of California (UC), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia = University of Pavia (UNIPV), University of Oxford, Direction des Applications Militaires ( DAM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), National Oceanography Centre, University of Southampton [Southampton], Albert Einstein College of Medicine, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Neuropsychiatrie : recherche épidémiologique et clinique, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Leibniz-Institute, University of California [San Francisco] ( UCSF ), Université européenne de Bretagne ( UEB ), Laboratoire de l'intégration, du matériau au système ( IMS ), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique ( CNRS ), Agence universitaire de la Francophonie (Beyrouth, Lebanon)-Lebanese University [Beirut], Linköping University ( LIU ), Department of Neurological Sciences, Dino Ferrari Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy, Università di Bologna [Bologna] ( UNIBO ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Dipartimento Ingegneria Aerospaziale 'Lucio Lazzarino' ( DIA ), Università di Pisa, Universita degli Studi di Padova = University of Padua = Université de Padoue, Educational Testing Service, Graduate School of Education, University of California at Berkeley, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Universitat de Barcelona ( UB ) -Hospital Clinic, Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Department of Atmospheric, Oceanic and Planetary Physics [Oxford] ( AOPP ), Kuhle, J., Disanto, G., Dobson, R., Adiutori, R., Bianchi, L., Topping, J., Bestwick, J. P., Meier, U. -C., Marta, M., Dalla Costa, G, Runia, T., Evdoshenko, E., Lazareva, N., Thouvenot, E., Iaffaldano, P., Direnzo, V., Khademi, M., Piehl, F., Comabella, M., Sombekke, M., Killestein, J., Hegen, H., Rauch, S., Dalfonso, S., Alvarez-Cermeno, J. C., Kleinova, P., Horakova, D., Roesler, R., Lauda, F., Llufriu, S., Avsar, T., Uygunoglu, U., Altintas, A., Saip, S., Menge, T., Rajda, C., Bergamaschi, R., Moll, N., Khalil, M., Marignier, R., Dujmovic, I., Larsson, H., Malmestrom, C., Scarpini, E., Fenoglio, C., Wergeland, S., Laroni, A., Annibali, V., Romano, S., Martinez, A. D., Carra, A., Salvetti, M., Uccelli, A., Torkildsen, O., Myhr, K. M., Galimberti, D., Rejdak, K., Lycke, J., Frederiksen, J. L., Drulovic, J., Confavreux, C., Brassat, D., Enzinger, C., Fuchs, S., Bosca, I., Pelletier, J., Picard, C., Colombo, E., Franciotta, D., Derfuss, T., Lindberg, R. L. P., Yaldizli, O., Vecsei, L., Kieseier, B. C., Hartung, H. P., Villoslada, P., Siva, A., Saiz, A., Tumani, H., Havrdova, E., Villar, L. M., Leone, M., Barizzone, N., Deisenhammer, F., Teunissen, C., Montalban, X., Tintore, M., Olsson, T., Trojano, M., Lehmann, S., Castelnovo, G., Lapin, S., Hintzen, R., Kappos, L., Furlan, R., Martinelli, V., Comi, G., Ramagopalan, S. V., and Giovannoni, G.
Subjects: Male, Pathology, serum 25-hydroxyvitamin D3 (25-OH-D), [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Gastroenterology, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, sclerosis, clinically isolated syndrome (CIS), Vitamin D, 0303 health sciences, Clinically isolated syndrome, Nuclear Proteins, Prognosis, Magnetic Resonance Imaging, Neurology, Clinically definite multiple sclerosis (CDMS), Epstein-Barr nuclear antigen 1 (EBNA-1), oligoclonal bands (OCBs), Predictive value of tests, Cohort, Disease Progression, Female, Cohort study, Adult, medicine.medical_specialty, Multiple Sclerosis, clinic study, Risk Assessment, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Vitamin D and neurology, Humans, Survival analysis, 030304 developmental biology, business.industry, Multiple sclerosis, Oligoclonal Bands, Endonucleases, medicine.disease, Survival Analysis, chemistry, Immunoglobulin G, [ SHS.ANTHRO-BIO ] Humanities and Social Sciences/Biological anthropology, Neurology (clinical), business, Cotinine, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
Published: 2015

2. Chemical Metabolic Inhibitors For The Treatment Of Blood-Borne Cancers

Author: Houda Haouas, Martin Villalba, Moeez Ghani Rathore, Nuria Lopez-Royuela, Ewelina Krzywinska, Robert A. Hipskind, Nerea Allende-Vega, Cellules souches normales et cancéreuses, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Biological and Chemical Engineering, National Institute of Applied Sciences and Technology Tunis, Chercheur d'Avenir, Région Languedoc Roussillon, France, Communauté de Travail des Pyrénées, France, Association pour la Recherche sur le Cancer, ARC, Paris, France, Fondation pour la Recherche Médicale, Paris, France. ligue Nationale Contre le Cancer, Paris, France, Higher Education Commission, Pakistan, European Project, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de recherche en biothérapie, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Biological and Chemical Engineering [Tunis, Tunisia], National Institute of Applied Sciences and Technology [Tunis, Tunisia], Frei, Monique, CLINK, SUDOE, SOE2/P1/E341 - INCOMING, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: Cancer Research, Cell Transplantation, medicine.medical_treatment, Glutamine, Cell, Oxidative Phosphorylation, 0302 clinical medicine, Sirtuins, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Glycolysis, DCA, 0303 health sciences, Leukemia, Warburg effect, Combined Modality Therapy, OXPHOS, 3. Good health, Metformin, Killer Cells, Natural, medicine.anatomical_structure, cancer immunosurveillance, 030220 oncology & carcinogenesis, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Biology, Article, Histone Deacetylases, Immunomodulation, 03 medical and health sciences, Immune system, medicine, MHC-I, Animals, Humans, 030304 developmental biology, Pharmacology, Chemotherapy, Histocompatibility Antigens Class I, glutamine MHC-1, medicine.disease, Anaerobic glycolysis, Immunology, Cancer research, metformin, T-Lymphocytes, Cytotoxic
Abstract: International audience; : Tumor cells, including leukemic cells, remodel their bioenergetic system in favor of aerobic glycolysis. This process is called "the Warburg effect" and offers an attractive pharmacological target to preferentially eliminate malignant cells. In addition, recent results show that metabolic changes can be linked to tumor immune evasion. Mouse models demonstrate the importance of this metabolic remodeling in leukemogenesis. Some leukemias, although treatable, remain incurable and resistance to chemotherapy produces an elevated percentage of relapse in most leukemia cases. Several groups have targeted the specific metabolism of leukemia cells in preclinical and clinical studies to improve the prognosis of these patients, i.e. using L-asparaginase to treat pediatric acute lymphocytic leukemia (ALL). Additional metabolic drugs that are currently being used to treat other diseases or tumors could also be exploited for leukemia, based on preclinical studies. Finally, we discuss the potential use of several metabolic drugs in combination therapies, including immunomodulatory drugs (IMiDs) or immune cell-based therapies, to increase their efficacy and reduce side effects in the treatment of hematological cancers.
Published: 2014

3. 1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma

Author: Stéphanie Chauvelier, Alexandra Debernardi, Katia Delaval, Robert Feil, Remy Gressin, Alexandra Fournier, Martin Figeac, Alicia Lajmanovich, Aurélie Granjon, Christine Lefebvre, Mary Callanan, Yves Usson, Claire Vourc'h, Kassambara Alboukadel, Sophie Rousseaux, John De Vos, Alexei Grichine, Juliana Bruder Ribeyron, Florence de Fraipont, Jean-Pierre Kerckaert, Leila Barki, Thierry Bonnefoix, Anne McLeer-Florin, Saadi Khochbin, Sieme Hamaidia, Samuel Duley, Dominique Leroux, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité de Cancérologie Biologique et biothérapies, Génomique (Plate-Forme) - Genomics Platform, Institut Pasteur [Paris] (IP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), RFMQ, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), INSERM U823, équipe 10 (Stress et Dynamique de l'Organisation du Génome), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 6 (Epigénétique et Signalisation Cellulaire), INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, Funding was from the Fondation de France, the Institut National du Cancer (EpiPro network, the programme 'Developpement de plateformes hospitalières de génétique moléculaire des cancers', the P.A.I.R 'Mantle Cell Lymphoma network' and the INCa-DHOS translational research programme 'CT-Lymph'). Additional funding was obtained from the Région Rhone-Alpes programme 'Thématique prioritaire--Cancer', the canceropôle CLARA (EpiMed), the Ligue Nationale Contre le Cancer (LNCC)--Comités de l'Isère/Savoie, the Délegation Régionale de la Recherche Clinique--CHU de Grenoble, the French GOELAMS clinical trials group and the ARAMIS association. AD and JBR have been recruited through the INCa-DHOS 'CT-Lymph' program. AF has been the recipient of doctoral funding from the Ministère de l'Enseignement Supérieur et de la Recherche, the Association pour la Recherche sur le Cancer (ARC) and the Société Française d'Hématologie (SFH), AMLF of post-doctoral funding from the ARC-ARECA network 'epigenetic profiling in breast and haematological tumours', LB of doctoral funding from the Ministère de l'Enseignement Supérieur et de la Recherche and the LNCC, MC of a Contrat d'Interface INSERM/Grenoble University Hospital Centre (2006-2011). Affymetrix microarrays were processed in the Microarray Core Facility of the Institute of Research on Biotherapy, CHRU-INSERM-UM1 Montpellier, http://irb.chu-montpellier.fr, Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Unité de Cancérologie Biologique et biothérapies, Génomique (Plate-Forme), Institut Pasteur [Paris], Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Département de cancérologie et d'hématologie, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Duley, Samuel
Subjects: Genome instability, Chromosomal translocation, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Chromosomes, Human, Pair 2, MESH : Chromosomes, Human, Pair 1, Translocation, Genetic, 0302 clinical medicine, MESH : Lymphoma, B-Cell, MESH : Translocation, Genetic, Heterochromatin, B-cell lymphoma, 0303 health sciences, MESH : Cell Nucleus, GMCL1, MESH: Gene Expression Regulation, Neoplastic, MESH: Translocation, Genetic, Gene Expression Regulation, Neoplastic, MESH: Heterochromatin, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 2, heterochromatic foci, Molecular Medicine, MESH: Cell Nucleus, Lymphoma, B-Cell, MESH : Gene Expression Regulation, Neoplastic, MESH: Chromosomes, Human, Pair 1, MESH: Chromosomes, Human, Pair 2, Biology, 1q12 pericentric heterochromatin, 03 medical and health sciences, medicine, Constitutive heterochromatin, Humans, Epigenetics, 030304 developmental biology, MESH: Lymphoma, B-Cell, Cell Nucleus, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Heterochromatin, MESH : Humans, medicine.disease, B cell lymphoma, nuclear architecture, Cancer research, Heterochromatin protein 1, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Diffuse large B-cell lymphoma, Reports
Abstract: International audience; Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence that a distinct category of chromosomal translocations observed in human tumours--those targeting 1q12 satellite DNA--can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localized to the nuclear periphery and to arise as a consequence of long range 'pairing' between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms.
Published: 2010

4. Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription

Author: John De Vos, Laure Crabbe, Anna Jauch, Véronique Pantesco, Yves Pommier, Aubin Thomas, Heidi Holtgreve-Grez, Charles Theillet, Philippe Pasero, Sandie Tuduri, Arnaud Coquelle, Jamal Tazi, Hélène Tourrière, Chiara Conti, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 - UFR de Médecine (UM1 Médecine), Université Montpellier 1 (UM1), Unité de thérapie cellulaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Montpellier 1 - UFR de Médecine ( UM1 Médecine ), Université Montpellier 1 ( UM1 ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, and Institut de Génétique Moléculaire de Montpellier ( IGMM )
Subjects: DNA re-replication, DNA Replication, Chromatin Immunoprecipitation, Transcription, Genetic, Eukaryotic DNA replication, Biology, Pre-replication complex, Article, Genomic Instability, S Phase, DNA replication factor CDT1, 03 medical and health sciences, 0302 clinical medicine, Replication factor C, Minichromosome maintenance, Control of chromosome duplication, Animals, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cell Biology, Molecular biology, Cell biology, DNA Topoisomerases, Type I, 030220 oncology & carcinogenesis, biology.protein, Origin recognition complex, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: Topoisomerase I (Top1) is a key enzyme in functioning at the interface between DNA replication, transcription and mRNA maturation. Here, we show that Top1 suppresses genomic instability in mammalian cells by preventing a conflict between transcription and DNA replication. Using DNA combing and ChIP (chromatin immunoprecipitation)-on-chip, we found that Top1-deficient cells accumulate stalled replication forks and chromosome breaks in S phase, and that breaks occur preferentially at gene-rich regions of the genome. Notably, these phenotypes were suppressed by preventing the formation of RNA-DNA hybrids (R-loops) during transcription. Moreover, these defects could be mimicked by depletion of the splicing factor ASF/SF2 (alternative splicing factor/splicing factor 2), which interacts functionally with Top1. Taken together, these data indicate that Top1 prevents replication fork collapse by suppressing the formation of R-loops in an ASF/SF2-dependent manner. We propose that interference between replication and transcription represents a major source of spontaneous replication stress, which could drive genomic instability during the early stages of tumorigenesis.
Published: 2010

5. Topoisomerase 1 suppresses replication stress and genomic instability by preventing interference between replication and transcription

Author: Tuduri, Sandie, Crabbé, Laure, Conti, Chiara, Tourrière, Hélène, Holtgreve-Grez, Heidi, Jauch, Anna, Pantesco, Véronique, De Vos, John, Thomas, Aubin, Theillet, Charles, Pommier, Yves, Tazi, Jamal, Coquelle, Arnaud, Pasero, Philippe, Larose, Catherine, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratory of Molecular Pharmacology, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institute of Human Genetics, Heidelberg University Hospital [Heidelberg], Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Work in the PP lab is supported by FRM (Equipe FRM), ANR, INCa and the EMBO Young Investigator Programme. AC is supported by the Ligue contre le cancer (Comité de l'Hérault), ARC (Association pour la Recherche contre le Cancer) and INCa. ST, LC and HT were recipients of fellowships from ARC, EMBO and CNRS, respectively., Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer
Abstract: International audience; Topoisomerase I (Top1) is a key enzyme acting at the interface between DNA replication, transcription and mRNA maturation. Here, we show that Top1 suppresses genomic instability in mammalian cells by preventing conflicts between transcription and DNA replication. Using DNA combing and ChIP-on-chip, we found that Top1-deficient cells accumulate stalled replication forks and chromosome breaks in S phase and that breaks occur preferentially at gene-rich regions of the genome. Strikingly, these phenotypes were suppressed by preventing the formation of RNA-DNA hybrids (R-loops) during transcription. Moreover, these defects could be mimicked by depletion of the splicing factor ASF/SF2, which interacts functionally with Top1. Taken together, these data indicate that Top1 prevents replication fork collapse by suppressing the formation of R-loops in an ASF/SF2-dependent manner. We propose that interference between replication and transcription represents a major source of spontaneous replication stress, which could drive genomic instability during early stages of tumorigenesis.
Published: 2009

6. The CDK4-pRB-E2F1 pathway controls insulin secretion

Author: Stéphane Dalle, Lluis Fajas, Safia Costes, Emilie Blanchet, Said Assou, Jean-Sébastien Annicotte, Irena Iankova, Claude Sardet, Carine Chavey, Jacques Teyssier, INSERM, U834, Montpellier, F-34298, France, Métabolisme et cancer, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Arnaud de Villeuneuve Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), INSERM-Association Française des Diabétiques (PNR-Diabète), Association pour la Recherche contre le Cancer, and Fondation pour la Recherche Médicale. E.B. is supported by a grant form the Ministère de l'Enseignement Supérieur et de la Recherche, C.C. is supported by a grant from the Agence Nationale pour la Recherche., Agence Nationale pour la Recherche (ANR physio2006),Agence Nationale pour la Recherche (ANR physio2006), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Agence Nationale pour la Recherche (ANR physio2006), Le Ster, Yves, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine.medical_treatment, MESH : Blotting, Western, MESH : RNA, Small Interfering, MESH : E2F1 Transcription Factor, MESH : Phosphorylation, Mice, 0302 clinical medicine, Insulin Secretion, Glucose homeostasis, Insulin, MESH: Animals, ComputingMilieux_MISCELLANEOUS, MESH: Chromatin Immunoprecipitation, 0303 health sciences, Retinoblastoma protein, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH : Protein Binding, Transfection, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Immunohistochemistry, Cell biology, MESH: COS Cells, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, COS Cells, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], endocrine system, Blotting, Western, MESH: Insulin, Article, 03 medical and health sciences, MESH: Gene Expression Profiling, Islets of Langerhans, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Blotting, Western, MESH: Protein Binding, MESH : Islets of Langerhans, Potassium Channels, Inwardly Rectifying, neoplasms, MESH: Phosphorylation, MESH : Glucose, MESH: Islets of Langerhans, MESH : Gene Expression Profiling, MESH: Cercopithecus aethiops, MESH: Cell Line, Mice, Inbred C57BL, Insulin receptor, Glucose, MESH : Cercopithecus aethiops, Chromatin immunoprecipitation, MESH: Signal Transduction, MESH : Cell Line, MESH : Immunohistochemistry, MESH : Insulin, [SDV]Life Sciences [q-bio], MESH : Models, Biological, MESH: Mice, Knockout, Retinoblastoma Protein, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: RNA, Small Interfering, Chlorocebus aethiops, Phosphorylation, RNA, Small Interfering, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mice, Knockout, biology, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Reverse Transcriptase Polymerase Chain Reaction, MESH: Potassium Channels, Inwardly Rectifying, MESH: E2F1 Transcription Factor, MESH: Glucose, MESH : Cyclin-Dependent Kinase 4, Regulatory Pathway, Signal transduction, MESH : Transfection, biological phenomena, cell phenomena, and immunity, MESH : COS Cells, Protein Binding, Signal Transduction, Chromatin Immunoprecipitation, MESH: Cyclin-Dependent Kinase 4, MESH : Mice, Inbred C57BL, Models, Biological, Cell Line, MESH : Chromatin Immunoprecipitation, MESH: Mice, Inbred C57BL, MESH : Mice, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, MESH: Mice, 030304 developmental biology, MESH : Signal Transduction, MESH: Transfection, Gene Expression Profiling, MESH: Models, Biological, Cyclin-Dependent Kinase 4, MESH: Immunohistochemistry, Cell Biology, MESH: Retinoblastoma Protein, MESH : Potassium Channels, Inwardly Rectifying, biology.protein, MESH : Mice, Knockout, MESH : Animals, MESH : Retinoblastoma Protein, E2F1 Transcription Factor
Abstract: International audience; CDK4-pRB-E2F1 cell-cycle regulators are robustly expressed in non-proliferating beta cells, suggesting that besides the control of beta-cell number the CDK4-pRB-E2F1 pathway has a role in beta-cell function. We show here that E2F1 directly regulates expression of Kir6.2, which is a key component of the K(ATP) channel involved in the regulation of glucose-induced insulin secretion. We demonstrate, through chromatin immunoprecipitation analysis from tissues, that Kir6.2 expression is regulated at the promoter level by the CDK4-pRB-E2F1 pathway. Consistently, inhibition of CDK4, or genetic inactivation of E2F1, results in decreased expression of Kir6.2, impaired insulin secretion and glucose intolerance in mice. Furthermore we show that rescue of Kir6.2 expression restores insulin secretion in E2f1(-/-) beta cells. Finally, we demonstrate that CDK4 is activated by glucose through the insulin pathway, ultimately resulting in E2F1 activation and, consequently, increased expression of Kir6.2. In summary we provide evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in glucose homeostasis, defining a new link between cell proliferation and metabolism.
Published: 2008

7. In vivo and in vitro functional characterization of Andersen's syndrome mutations

Author: Bendahhou, Saïd, Fournier, Emmanuel, Sternberg, Damien, Bassez, Guillaume, Furby, Alain, Sereni, Carole, Donaldson, Matthew R, Larroque, Marie-Madeleine, Fontaine, Bertrand, Barhanin, Jacques, Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Fédération de Neurophysiologie Clinique and Centre de Référence des Canalopathies Musculaires, CHU Pitié-Salpêtrière [APHP], Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de recherche biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Hôpital Henri Mondor, Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Centre de Recherches de Climatologie ( CRC ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'étude des environnements terrestre et planétaires ( CETP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Lasers, Plasmas et Procédés photoniques ( LP3 ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre de Recherches de Climatologie (CRC), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Centre d'étude des environnements terrestre et planétaires (CETP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Lasers, Plasmas et Procédés photoniques (LP3), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Muscle Cells, Patch-Clamp Techniques, MESH : Molecular Sequence Data, Action Potentials, Molecular and Genomic Physiology, MESH: Amino Acid Sequence, Kidney, Mice, Chlorocebus aethiops, MESH: Animals, MESH : Muscle, Skeletal, MESH : Patch-Clamp Techniques, MESH: Action Potentials, MESH: Muscle, Skeletal, MESH : Amino Acid Sequence, MESH: Potassium Channels, Inwardly Rectifying, MESH : Adult, MESH : Kidney, Pedigree, MESH: COS Cells, COS Cells, MESH : Electromyography, MESH : COS Cells, Adult, MESH: Pedigree, MESH : Male, Molecular Sequence Data, Mutation, Missense, Paralyses, Familial Periodic, MESH: Electromyography, MESH: Paralyses, Familial Periodic, MESH : Action Potentials, MESH: Patch-Clamp Techniques, MESH : Mice, Animals, Humans, Amino Acid Sequence, Potassium Channels, Inwardly Rectifying, Muscle, Skeletal, MESH: Mice, Muscle Cells, MESH: Mutation, Missense, MESH: Molecular Sequence Data, MESH: Humans, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, MESH : Muscle Cells, Electromyography, MESH : Humans, MESH: Adult, MESH: Kidney, MESH: Cercopithecus aethiops, MESH: Male, MESH : Paralyses, Familial Periodic, MESH : Pedigree, MESH : Potassium Channels, Inwardly Rectifying, MESH : Animals, MESH : Cercopithecus aethiops, [ SDV.BA.MVSA ] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, MESH : Mutation, Missense
Abstract: The inward rectifier K(+) channel Kir2.1 carries all Andersen's syndrome mutations identified to date. Patients exhibit symptoms of periodic paralysis, cardiac dysrhythmia and multiple dysmorphic features. Here, we report the clinical manifestations found in three families with Andersen's syndrome. Molecular genetics analysis identified two novel missense mutations in the KCNJ2 gene leading to amino acid changes C154F and T309I of the Kir2.1 open reading frame. Patch clamp experiments showed that the two mutations produced a loss of channel function. When co-expressed with Kir2.1 wild-type (WT) channels, both mutations exerted a dominant-negative effect leading to a loss of the inward rectifying K(+) current. Confocal microscopy imaging in HEK293 cells is consistent with a co-assembly of the EGFP-fused mutant proteins with WT channels and proper traffick to the plasma membrane to produce silent channels alone or as hetero-tetramers with WT. Functional expression in C2C12 muscle cell line of newly as well as previously reported Andersen's syndrome mutations confirmed that these mutations act through a dominant-negative effect by altering channel gating or trafficking. Finally, in vivo electromyographic evaluation showed a decrease in muscle excitability in Andersen's syndrome patients. We hypothesize that Andersen's syndrome-associated mutations and hypokalaemic periodic paralysis-associated calcium channel mutations may lead to muscle membrane hypoexcitability via a common mechanism.
Published: 2005

8. Kinome expression profiling to target new therapeutic avenues in multiple myeloma

Author: Jérôme Moreaux, Claire Gourzones, Nicolas Robert, Anke Maes, Michel Jourdan, Philippe Pasero, Elke De Bruyne, Guillaume Cartron, Angelique Bruyer, Anja Seckinger, Alboukadel Kassambara, Laure Vincent, Dirk Hose, Hugues de Boussac, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Vrije Universiteit Brussel (VUB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Interactions moléculaires et cancer (IMC (UMR 8126)), Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Heidelberg University Hospital [Heidelberg], Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE15-0024,TIE-Skip,Impact des immunoglobulines tronquées produites par saut d'exon dans les plasmocytes : vers des approches thérapeutiques utilisant des oligonucléotides antisens(2017), Vrije Universiteit Brussel, Clinical sciences, Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, and Hematology
Subjects: Melphalan, CHK1, SRPK1, Cell Cycle Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Article, Plasma Cell Disorders, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, MELK, medicine, Humans, Immunologic Factors, Kinome, CHEK1, Multiple myeloma (MM), Lenalidomide, Multiple myeloma, 030304 developmental biology, 0303 health sciences, Kinase, business.industry, MPS1/TTK), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, 3. Good health, Gene expression profiling, 030220 oncology & carcinogenesis, Cancer research, CDC7-DBF4, PLK4, Neoplasm Recurrence, Local, Multiple Myeloma, business, medicine.drug, Protein kinas-es (PBK
Abstract: International audience; Multiple myeloma (MM) account for approximately 10% of hematological malignancies and is the second most common hematological disorder. Kinases inhibitors are widely used and their efficiency for the treatment of cancers has been demonstrated. Here, in order to identify kinases of potential therapeutic interest for the treatment of MM, we investigated the prognostic impact of the kinome expression profile in large cohorts of patients. We identified 36 kinome-related genes significantly linked with a prognostic value to MM, and built a kinome index based on their expression. The Kinome Index (KI) is linked to prognosis, proliferation, differentiation, and relapse in MM. We then tested inhibitors targeting seven of the identified protein kinas-es (PBK, SRPK1, CDC7-DBF4, MELK, CHK1, PLK4, MPS1/TTK) in human myeloma cell lines. All tested inhibitors significantly reduced the viability of myeloma cell lines, and we confirmed the potential clinical interest of three of them on primary myeloma cells from patients. In addition, we demonstrated their ability to potentialize the toxicity of conventional treatments, including Melphalan and Lenalidomide. This highlights their potential beneficial effect in myeloma therapy. Three kinases inhibitors (CHK1i, MELKi and PBKi) overcome resistance to Lenalidomide, while CHK1, PBK and DBF4 inhibitors re-sensitize Melphalan resistant cell line to this conventional therapeutic agent. Altogether, we demonstrate that kinase inhibitors could be of therapeutic interest especially in high-risk myeloma patients defined by the KI. CHEK1, MELK, PLK4, SRPK1, CDC7-DBF4, MPS1/TTK and PBK inhibitors could represent new treatment options either alone or in combination with Melphalan or IMiD for refractory/relapsing myeloma patients.
Published: 2020

9. Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related ( ATR ) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer

Author: Maguy Del Rio, Nathalie Bonnefoy, Nadia Vezzio-Vie, D. Tosi, Arnaud Coquelle, Flavie Coquel, Jérôme Moreaux, Marta Jarlier, Delphine Desigaud, Roderick L. Beijersbergen, Céline Gongora, Augusto Faria Andrade, Pierre Martineau, Philippe Pasero, Eve Combes, Henri-Alexandre Michaud, Véronique Garambois, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut de Recherche en Infectiologie de Montpellier (IRIM)
Subjects: 0301 basic medicine, Cancer Research, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, medicine, Gene silencing, Kinome, ComputingMilieux_MISCELLANEOUS, Chemotherapy, business.industry, Gene signature, medicine.disease, 3. Good health, Oxaliplatin, 030104 developmental biology, Oncology, Apoptosis, 030220 oncology & carcinogenesis, Cancer research, Immunogenic cell death, business, medicine.drug
Abstract: Although many patients with colorectal cancer initially respond to the chemotherapeutic agent oxaliplatin, acquired resistance to this treatment remains a major challenge to the long-term management of this disease. To identify molecular targets of oxaliplatin resistance in colorectal cancer, we performed an shRNA-based loss-of-function genetic screen using a kinome library. We found that silencing of ataxia-telangiectasia mutated and RAD3-related (ATR), a serine/threonine protein kinase involved in the response to DNA stress, restored oxaliplatin sensitivity in a cellular model of oxaliplatin resistance. Combined application of the ATR inhibitor VE-822 and oxaliplatin resulted in strong synergistic effects in six different colorectal cancer cell lines and their oxaliplatin-resistant subclones, promoted DNA single- and double-strand break formation, growth arrest, and apoptosis. This treatment also increased replicative stress, cytoplasmic DNA, and signals related to immunogenic cell death such as calreticulin exposure and HMGB1 and ATP release. In a syngeneic colorectal cancer mouse model, combined administration of VE-822 and oxaliplatin significantly increased survival by promoting antitumor T-cell responses. Finally, a DNA repair gene signature discriminated sensitive from drug-resistant patients with colorectal cancer. Overall, our results highlight the potential of ATR inhibition combined with oxaliplatin to sensitize cells to chemotherapy as a therapeutic option for patients with colorectal cancer. Significance: These findings demonstrate that resistance to oxaliplatin in colorectal cancer cells can be overcome with inhibitors of ATR and that combined treatment with both agents exerts synergistic antitumor effects.
Published: 2019

10. Coprs inactivation leads to a derepression of LINE1 transposons in spermatocytes

Author: Paul, Conception, Delpech, Hélène, Haouzi, Delphine, Hamamah, Samir, Sardet, Claude, Fabbrizio, Eric, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: endocrine system, Miwi, testis Correspondence, spermatocyte, urogenital system, coprs, teratozoospermia, piRNA, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Abstract: International audience; Repression of retrotransposons is essential for genome integrity during germ cell development and is tightly controlled through epigenetic mechanisms. In primordial germ cells, protein arginine N-methyltransferase (Prmt5) is involved in retrotransposon repression by methylating Piwi proteins , which is part of the piRNA pathway. Here, we show that in mice, genetic inactivation of coprs (which is highly expressed in testis and encodes a histone-binding protein required for the targeting of Prmt5 activity) affects the maturation of spermatogonia to spermatids. Mass spectrom-etry analysis revealed the presence of Miwi in testis protein lysates immunoprecipitated with an anti-Coprs antibody. The observed deregulation of Miwi and pachytene pre-piRNAs levels and the derepression of LINE1 repetitive sequences observed in coprs-/-mice suggest that Coprs is implicated in genome surveillance mechanisms. Spermatogenesis is a multistep process that takes place in the seminiferous tubules whereby mature spermato-zoa are continuously produced during adulthood reproduction lifetime. Specifically, primordial germ cells (PGCs) generate spermatogonia that either self-renew to maintain a pool of stem cells or undergo differentiation. After two meiotic divisions, secondary spermato-cytes are produced. Then, during spermiogenesis, they differentiate into elongating spermatids and finally spermatozoa [1-5]. Importantly, these changes are associated with chromatin compaction, transcription arrest, and specific epigenetic modifications that contribute to the production of mature sperm. Concomi-tantly, to maintain genome integrity, PGCs need to repress repetitive DNA elements because their spread can lead to inherited diseases. These repetitive sequences [for instance, long interspersed nuclear elements 1 (LINEs), short interspersed nuclear element (SINEs), and intracisternal A-particle (IAP) sequences] derive mostly from transposable elements and represent Abbreviations Coprs, coordinator of Prmt5 and differentiation stimulator; IAP, intracisternal A-particle; LINE1, long interspersed nuclear element 1; piRNA, Piwi-interacting RNA; Prmt5, protein arginine N-methyltransferase; SINE, short interspersed nuclear element. 159 FEBS Open Bio 9 (2019) 159-168 ª
Published: 2019

11. MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue

Author: Corinne Vigouroux, Philippe Froguel, Olivier Lascols, Emmanuel Disse, Sara Barraud, Emilie Capel, Anne Miquel, J.J. Robert, Martine Laville, Héléna Mosbah, Isabelle Jéru, Pierre Gourdy, Brigitte Delemer, Martine Auclair, Florence Tenenbaum, Camille Vatier, Tanya Stojkovic, Amélie Bonnefond, Marie Christine Verpont, Stephan Züchner, Pascale Cervera, Anne-Ségolène Cottereau, Sophie Christin-Maitre, Bruno Fève, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Pathologie de l'Adipocyte et des Cellules Hepatiques, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institute of Cardiometabolism and Nutrition,Institut National de la Sante et de la Recherche MedicaleSorbonne UniversiteAFERO (Association Francaise d’Etude et de Recherche sur l’Obesite)
Subjects: Adult, Male, Leptin, 0301 basic medicine, medicine.medical_specialty, FGF21, Lipodystrophy, Endocrinology, Diabetes and Metabolism, Lipomatosis, Adipose tissue, GTP Phosphohydrolases, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Internal medicine, Genetics, Mitofusin 2, Internal Medicine, medicine, Humans, RNA, Messenger, Lipoatrophy, ComputingMilieux_MISCELLANEOUS, Aged, Nutrition and Dietetics, Adiponectin, business.industry, Thermogenic markers, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Mitochondria, Neuropathy, 3. Good health, 030104 developmental biology, Endocrinology, Adipose Tissue, Dyslipidemia, Positron-Emission Tomography, Lipomatosis, Multiple Symmetrical, Female, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Background Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. Objective To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. Methods We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. Results Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. Conclusion MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.
Published: 2018

12. Physiological and druggable skipping of immunoglobulin variable exons in plasma cells

Author: Michel Cogné, Nivine Srour, Mohamad Omar Ashi, Eric Pinaud, Sandrine Le Noir, Ophélie Martin, Christophe Sirac, Jérôme Saulière, Anne Marchalot, Maria Victoria Ayala, Jérôme Moreaux, Jean-Marie Lambert, Laurent Delpy, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Lady Davis Institute for Medical Research, McGill University, 3755 Cote Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada., Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France, Université de Limoges, Limoges, France., Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en biothérapie (IRB), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Plasma cell, Mice, Exon, 0302 clinical medicine, Transcription (biology), [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Immunology and Allergy, Antisense Oligonucleotides, ComputingMilieux_MISCELLANEOUS, B-Lymphocytes, Plasma cells, biology, Chemistry, Cell Differentiation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Exons, Endoplasmic Reticulum Stress, Chromatin, Cell biology, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, RNA splicing, Antibody, Immunoglobulin Heavy Chains, Exon skipping, RNA Splicing, Immunology, Nonsense-associated altered splicing, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Immunoglobulin, Animals, Gene, Alleles, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic Variation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Introns, V(D)J Recombination, Nonsense Mediated mRNA Decay, Mice, Inbred C57BL, 030104 developmental biology, biology.protein, 030215 immunology
Abstract: International audience; The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin (Ig) pre-mRNAs. We recently demonstrated that aberrant Ig chains lacking variable (V) domains can be produced after nonsense-associated altered splicing (NAS) events. Remarkably, the expression of these truncated Ig polypeptides heightens endoplasmic reticulum stress and shortens plasma cell (PC) lifespan. Many questions remain regarding the molecular mechanisms underlying this new truncated Ig exclusion (TIE-) checkpoint and its restriction to the ultimate stage of B-cell differentiation. To address these issues, we evaluated the extent of NAS of Ig pre-mRNAs using an Ig heavy chain (IgH) knock-in model that allows for uncoupling of V exon skipping from TIE-induced apoptosis. We found high levels of V exon skipping in PCs compared with B cells, and this skipping was correlated with a biallelic boost in IgH transcription during PC differentiation. Chromatin analysis further revealed that the skipped V exon turned into a pseudo-intron. Finally, we showed that hypertranscription of Ig genes facilitated V exon skipping upon passive administration of splice-switching antisense oligonucleotides (ASOs). Thus, V exon skipping is coupled to transcription and increases as PC differentiation proceeds, likely explaining the late occurrence of the TIE-checkpoint and opening new avenues for ASO-mediated strategies in PC disorders.
Published: 2018

13. Infusion of in vivo expanded cord blood lymphocytes: A new strategy to control residual disease?

Author: Nathalie Fegueux, J. De Vos, Guillaume Cartron, L. Zhao-Yang, Sylvain Lamure, Laure Vincent, J. Delage, Patrice Ceballos, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), KARLI, Mélanie, European Society for Blood and Marrow Transplantation ( EBMT ), Techniques of Informatics and Microelectronics for integrated systems Architecture ( TIMA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -Institut National Polytechnique de Grenoble ( INPG ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: 0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Pathology, medicine.medical_specialty, MESH: Remission Induction, Cord blood transplantation, [SDV]Life Sciences [q-bio], MESH: Multiple Myeloma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, General Biochemistry, Genetics and Molecular Biology, Donor lymphocyte infusion, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Multiple myeloma, MESH: Cell Proliferation, medicine, MESH: Fetal Blood, ComputingMilieux_MISCELLANEOUS, MESH: Neoplasm, Residual, MESH: Humans, MESH: Middle Aged, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, medicine.disease, MESH: Male, 3. Good health, MESH: Recurrence, 030104 developmental biology, Cord blood, MESH: Lymphocyte Transfusion, MESH: Lymphocytes, MESH: Cord Blood Stem Cell Transplantation, business
Abstract: International audience
Published: 2018

14. Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort

Author: Dufouil , Carole, Dubois , Bruno, Vellas , Bruno, Pasquier , Florence, Blanc , Frédéric, Hugon , Hugo, Hanon , Olivier, Dartigues , Jean-François, Harston , Sandrine, Gabelle , Audrey, Ceccaldi , Mathieu, Beauchet , Olivier, Krolak-Salmon , Pierre, David , David, Rouaud , Olivier, Godefroy , Olivier, Belin , Catherine, Rouch , Isabelle, Auguste , Nicolas, Wallon , David, Benetos , Athanase, Pariente , Jeremie, Paccalin , Marc, Moreaud , Olivier, Hommet , Caroline, Sellal , François, Boutoleau-Bretonnière , Claire, Jalenques , Isabelle, Gentric , Armelle, Vandel , Pierre, Azouani , Chabha, Fillon , Ludovic, Fischer , Clara, Savarieau , Helen, Operto , Grégory, Bertin , Hugo, Chupin , Marie, Bouteloup , Vincent, Habert , Marie-Odile, Mangin , Jean-François, Chêne , Geneviève, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Laboratoire de physique de la matière condensée (LPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Groupe hospitalier Broca, CHU Bordeaux [Bordeaux], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN), Hospices Civils de Lyon (HCL), Centre Mémoire de Ressources et de Recherche [Nice] (CMRR Nice), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de génie des procédés - environnement - agroalimentaire (GEPEA), Mines Nantes (Mines Nantes)-Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Système Nerveux Autonome - Epidémiologie, Physiologie, Ingénierie, Santé (SNA-EPIS), Université Jean Monnet [Saint-Étienne] (UJM)-Centre Hospitalier Universitaire de Saint-Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Rouen, Normandie Université (NU), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de Psychologie et NeuroCognition (LPNC), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux - Clermont Auvergne (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne (UCA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CATI Multicenter Neuroimaging Platform (CATI), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuroimagerie Assistée par Ordinateur (LNAO), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Bordeaux (UB), Pôle de Santé publique [CHU Bordeaux], CHU de bordeaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fédération des Centres Mémoire de Ressource et de Recherche du Sud de la France [CHU Toulouse] (F-CMRR-SF), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre Mémoire de Ressources et de Recherches [Bordeaux], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Mémoire de Ressources et de Recherche [Paris Nord], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologies (EA 4468), Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca, Centre de Mémoire de Ressources et de Recherche [Paris Broca], AP-HP - Hôpital Broca [Paris], Centre de Mémoire de Ressources et de Recherche [Hôpital Pellegrin, Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin [Bordeaux], Centre de Mémoire de Ressources et de Recherche [Hôpital Xavier Arnozan, Bordeaux], Hôpital Xavier Arnozan - CHU de Bordeaux, Centres Mémoire de Ressources et de Recherche [Hôpital Gui de Chauliac, Montpellier] (CMRR), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac, Centre de Mémoire de Ressources et de Recherche [Hôpital La Timone, Marseille], Hôpital de la Timone [CHU - APHM] (TIMONE)-CHU Marseille, Centre Mémoire de Ressources et de Recherche [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Mémoire de Ressources et de Recherche [Lyon] (CMRR), Hospices Civils de Lyon (HCL)-Hôpital des Charpennes [CHU - HCL], Cognition Behaviour Technology (CobTek), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Centre Mémoire Ressources et Recherche [Dijon] (CMRR Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Mémoire de Ressources et de Recherche [CHU Amiens], Clinique de la Mémoire [Hôpitaux Universitaires Paris-Seine-Saint-Denis], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Mémoire de Ressources et de Recherche [CHU de Saint-Etienne Hôpital Nord], CHU de Saint-Étienne Hôpital Nord [Saint Etienne], Centre Mémoire de Ressources et de Recherche [CHU de Saint-Etienne Hôpital de la Charité], CHU de Saint-Étienne Hôpital la Charite, Service de neurologie [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre Mémoire de Ressources et de Recherche [CHU de Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Mémoire [CHU de Toulouse], Centre Mémoire de Ressources et de Recherche [CHRU de Poitiers La Miletrie], CHRU de Poitiers La Miletrie [Poitiers], Centre Mémoire de Ressources et de Recherche [CHU Grenoble Alpes-Site NORD, La Tronche], CHU Grenoble Alpes - Site NORD [La Tronche], Centre Mémoire de Ressources et de Recherche [CHRU de Tours Hôpital Bretonneau], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau [Tours], Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire de Ressources et de Recherche [Hôpitaux Civils de Colmar, Strasbourg], Hôpitaux Civils de Colmar, Centre Mémoire de Ressources et de Recherche [CHU de Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Mémoire de Ressources et de Recherche [CHU Clermont-Ferrand] (CMRR), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Mémoire de Ressources et de Recherche [CHRU de Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Mémoire de Ressources et de Recherche [CHRU de Besançon] (CMRR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques [CHRU de Besançon], Centre pour l’Acquisition et le Traitement des Images [Saclay] (CATI), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut d'imagerie biomédicale (I²BM), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, The MEMENTO cohort was sponsored by the Fondation Plan Alzheimer (Alzheimer Plan 2008–2012). This work was also supported by the following : CIC 1401-EC, Bordeaux University Hospital, Inserm and the University of Bordeaux., on behalf of the MEMENTO cohort Study Group, BMC, BMC, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Mémoire de Ressources et de Recherche [CHU de Saint-Etienne] (CMRR 42), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), Mines Nantes (Mines Nantes)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Laboratoire de Psychologie et NeuroCognition (LPNC ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut d'imagerie biomédicale (I²BM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Toulouse - CHU Toulouse-Hôpital La Grave-Casselardit [Toulouse], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Gui de Chauliac-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice), Centre Mémoire de Ressources et de Recherche [CHU de Toulouse, Hôpital Purpan], Hôpital Purpan [Toulouse], Hôpital Bretonneau [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), INSERM Unit 708-Neuroepidemiology, Paris, France, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] ( IM2A ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Epidémiologie et anlyses en santé publique: risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Neurologie [Lille], Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Kalray, Service de gériatrie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Epidémiologie, santé publique et développement, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR99-ISPED, Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Département de Médecine Interne et Gérontologie clinique, CHU Angers, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de génie des procédés - environnement - agroalimentaire ( GEPEA ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Nantes ( UN ) -IMT Atlantique Bretagne-Pays de la Loire ( IMT Atlantique ) -Université Bretagne Loire ( UBL ) -Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique ( ONIRIS ), Laboratoire de Neurosciences Fonctionnelles et Pathologies ( LNFP ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), AP-HP Hôpital Avicenne [Bobigny], Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Risque cardiovasculaire, rigidité-fibrose et hypercoagulabilité ( RCV ), Université Henri Poincaré - Nancy 1 ( UHP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie cérébrale et handicaps neurologiques, Centre Mémoire de Ressources et de Recherche ( CM2R ), CHU de Poitiers-Hôpital Jean Bernard, Unité de Neuropsychologie, CHU Grenoble, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôpital Nord Laënnec, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux - Clermont Auvergne ( NPsy-Sydo ), CHU Clermont-Ferrand-Université Clermont Auvergne ( UCA ), Service de Médecine Interne Gériatrique ( BREST - SMIG ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Acquisition et de Traitement des Images [Paris], Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Bordeaux population health ( BPH ), Université de Bordeaux ( UB ) -Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Jacques-Louis Lions ( LJLL ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Epidemiologie-Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bordeaux Ségalen [Bordeaux 2], Service de médecine nucléaire [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Neuroimagerie Assistée par Ordinateur ( LNAO ), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université de Bordeaux (UB), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Hôpital Bretonneau [Tours], Centre Mémoire de Ressources et de Recherche [CHU de Clermont-Ferrand], CHU Clermont-Ferrand, Centre Mémoire de Ressources et de Recherche [CHRU de Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Hôpital Saint-Jacques [CHRU de Besançon], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut d'imagerie biomédicale (I²BM), Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut d'imagerie biomédicale (I²BM), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA), Groupe hospitalier Pellegrin [Bordeaux] -CHU Bordeaux [Bordeaux], COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice)-Université Côte d'Azur (UCA), CHU Lille, CNRS, Inserm, Université de Lille, Troubles cognitifs dégénératifs et vasculaires - U1171, Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Fédération des Centres Mémoire de Ressource et de Recherche du Sud de la France [CHU Toulouse] ( F-CMRR-SF ), Troubles cognitifs dégénératifs et vasculaires ( DN2M ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -INSERM, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] ( CMRR ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Roger Salengro [Lille], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie ( ICube ), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg ( ENGEES ) -Université de Strasbourg ( UNISTRA ) -Institut National des Sciences Appliquées - Strasbourg ( INSA Strasbourg ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Sorbonne Paris Cité ( USPC ), Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologie ( EA 4468 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Groupe hospitalier Broca, Centre Hospitalier Universitaire de Bordeaux-Groupe hospitalier Pellegrin [Bordeaux], Centres Mémoire de Ressources et de Recherche [Hôpital Gui de Chauliac, Montpellier] ( CMRR ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui de Chauliac, Hôpital de la Timone [CHU - APHM] ( TIMONE ) -CHU Marseille, Centre Mémoire de Ressources et de Recherche [Lyon] ( CMRR ), Hospices Civils de Lyon ( HCL ) -Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon ( HCL ), Cognition Behaviour Technology ( CobTek ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -CHU Nice-Institut Claude Pompidou [Nice] ( ICP - Nice ), Centre Mémoire de Ressources et de Recherche [Nice] ( CMRR Nice ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -CHU Nice, Centre Mémoire Ressources et Recherche [Dijon] ( CMRR Dijon ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), CHU Amiens Picardie - Site Nord (Hôpital Nord) [Amiens], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre Hospitalier Régional Universitaire de Tours ( CHRU TOURS ) -Hôpital Bretonneau [Tours], Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean-Minjoz [CHRU de Besançon]-Hôpital Saint-Jacques [CHRU de Besançon], Centre pour l’Acquisition et le Traitement des Images [Saclay] ( CATI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -NeuroSpin-Institut d'imagerie biomédicale (I²BM), Sorbonne Universités, Département de Médecine Nucléaire [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Laboratoire d'Imagerie Biomédicale ( LIB ), and Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC )
Subjects: Male, [SDV]Life Sciences [q-bio], Neuroimaging, Neuropsychological Tests, Spinal Puncture, Pattern Recognition, Automated, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Diagnostic Self Evaluation, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cognitive aging, Fluorodeoxyglucose F18, Image Processing, Computer-Assisted, Humans, Cognitive Dysfunction, Longitudinal Studies, ComputingMilieux_MISCELLANEOUS, Aged, [ SDV ] Life Sciences [q-bio], Cohort studies, Natural history studies (prognosis), Alzheimer''s disease, Research, Brain, Organ Size, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Research Design, Positron-Emission Tomography, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Female, France, Radiopharmaceuticals, Alzheimer’s disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: Background The natural history and disease mechanisms of Alzheimer’s disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements. Methods In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR]
Published: 2017

15. Loss of HIF-1 alpha in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis

Author: Krzywinska, Ewelina, Kantari-Mimoun, Chahrazade, Kerdiles, Yann, Sobecki, Michal, Isagawa, Takayuki, Gotthardt, Dagmar, Castells, Magali, Haubold, Johannes, Millien, Corinne, Viel, Thomas, Tavitian, Bertrand, Takeda, Norihiko, Fandrey, Joachim, Vivier, Eric, Sexl, Veronika, Stockmann, Christian, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Department of Medicinal Chemistry and Microbiology, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Physiology, Essen, Unviersité Essen, Medizinische Universität Wien = Medical University of Vienna, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: International audience; Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1 alpha in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1 alpha in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels.
Published: 2017

16. Effect of Azithromycin on Airflow Decline–Free Survival After Allogeneic Hematopoietic Stem Cell Transplant

Author: Bergeron, Anne, Chevret, Sylvie, Granata, Angela, Chevallier, Patrice, Vincent, Laure, Huynh, Anne, Tabrizi, Reza, Labussière-Wallet, Hélène, Bernard, Marc, Chantepie, Sylvain, Bay, Jacques-Olivier, Thiebaut-Bertrand, Anne, Thépot, Sylvain, Contentin, Nathalie, Fornecker, Luc-Matthieu, Maillard, Natacha, Risso, Karine, Berceanu, Ana, Blaise, Didier, Peffault de la Tour, Régis, Chien, Jason W., Coiteux, Valérie, Socié, Gérard, Service de pneumologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Psychiatry Department and Clinics for Adolescent Medicine, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Dpt hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Léon Bérard [Lyon], Laboratoire Hubert Curien [Saint Etienne] (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Clinique Universitaire d'Hématologie [La Tronche, Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Service des maladies du sang [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Service Hématologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Hôpital Jean Bernard, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service greffe de moelle osseuse, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Hubert Curien (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2017

17. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Author: Schmidt, A.F., Swerdlow, D.I., Holmes, M.V., Patel, R.S., Fairhurst-Hunter, Z., Lyall, D.M., Hartwig, F.P., Horta, B.L., Hypponen, E., Power, C., Moldovan, M., Iperen, E. van, Hovingh, G.K., Demuth, I., Norman, K., Steinhagen-Thiessen, E., Demuth, J., Bertram, L., Liu, T., Coassin, S., Willeit, J., Kiechl, S., Willeit, K., Mason, D., Wright, J., Morris, R., Wanamethee, G., Whincup, P., Ben-Shlomo, Y., McLachlan, S., Price, J.F., Kivimaki, M., Welch, C., Sanchez-Galvez, A., Marques-Vidal, P., Nicolaides, A., Panayiotou, A.G., Onland-Moret, N.C., Schouw, Y.T. van der, Matullo, G., Fiorito, G., Guarrera, S., Sacerdote, C., Wareham, N.J., Langenberg, C., Scott, R., Luan, J.A., Bobak, M., Malyutina, S.A., Pajak, A., Kubinova, R., Tamosiunas, A., Pikhart, H., Husemoen, L.L.N., Grarup, N., Pedersen, O., Hansen, T., Linneberg, A., Simonsen, K.S., Cooper, J., Humphries, S.E., Brilliant, M., Kitchner, T., Hakonarson, H., Carrell, D.S., McCarty, C.A., Kirchner, H.L., Larson, E.B., Crosslin, D.R., Andrade, M. de, Roden, D.M., Denny, J.C., Carty, C., Hancock, S., Attia, J., Holliday, E., Donnell, M.O., Yusuf, S., Chong, M., Pare, G., Harst, P. van der, Said, M.A., Eppinga, R.N., Verweij, N., Snieder, H., Christen, T., Mook-Kanamori, D.O., Gustafsson, S., Lind, L., Ingelsson, E., Pazoki, R., Franco, O., Hofman, A., Uitterlinden, A., Dehghan, A., Teumer, A., Baumeister, S., Dorr, M., Lerch, M.M., Volker, U., Volzke, H., Ward, J., Pell, J.P., Smith, D.J., Meade, T., Maitland-van der Zee, A.H., Baranova, E.V., Young, R., Ford, I., Campbell, A., Padmanabhan, S., Bots, M.L., Grobbee, D.E., Froguel, P., Thuillier, D., Balkau, B., Bonnefond, A., Cariou, B., Smart, M., Bao, Y., Kumari, M., Mahajan, A., Ridker, P.M., Chasman, D.I., Reiner, A.P., Lange, L.A., Ritchie, M.D., Asselbergs, F.W., Casas, J.P., Keating, B.J., Preiss, D., Hingorani, A.D., Sattar, N., LifeLines Cohort Study Grp, UCLEB Consortium, Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dept. of Gastroenterology, Hepatology and Endocrinology, Neuroepidemiology of Ageing Research Unit, Imperial College London, Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Division of Community Health Sciences, St George's University of London, Department of Social Medicine, University of Bristol [Bristol], Finnish Institute of Occupational Health of Helsinki, Department of Epidemiology and Public Health, Institute of Social and Preventive Medicine, Lausanne university hospital, Computer Science Department, University of Cyprus, Cyprus Institute of Neurology and Genetics, University Medical Center [Utrecht], Department of Genetics, Biology and Biochemistry, University of Turin, Institute for Scientific Interchange Foundation, Center for Cancer Prevention, CPO-Piemonte, Unità di epidemiologia dei tumori, Università degli studi di Torino (UNITO)-HuGeF Foundation, Medical Research Council Epidemiology Unit, University of Cambridge [UK] (CAM), Serono Genetics Institute S.A.[Evry], Serono Genetics Institute, Institute of Internal and Preventive Medicine Sibe rian Branch, Russian Academy of Medical Sciences, Institute of Internal Medicine, Novosibirsk State Medical University, Centre for Environmental Health, National Institute of Public Health [Prague], Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), University of Copenhagen = Københavns Universitet (KU), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, Rigshospitalet [Copenhagen], Copenhagen University Hospital, BHF Laboratories, Rayne building, Department of Medicine, 5 University Street, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Population Health Research Institute, Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen [Groningen], Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Limnology, Ecology, Uppsala Universitet [Uppsala], Metacohorts Consortium, Erasmus University Medical Center [Rotterdam] (Erasmus MC), King‘s College London, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Institute for Community Medicine, Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], European Associated Laboratory [Sheffield, UK] (Sarcoma Research Unit), Robertson Centre for Biostatistics, University of Glasgow, Faculty of Medicine, University of Glasgow, Julius Center for Health Sciences and Primary Care, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), INSERM UMRS 1178, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Department of Pathological Biochemistry, Royal Infirmary, Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], and Apollo - University of Cambridge Repository
Subjects: Blood Glucose, Cohort Studies, Diabetes Mellitus, Type 2, Case-Control Studies, [SDV]Life Sciences [q-bio], Genetic Variation, Humans, Genetic Predisposition to Disease, Cholesterol, LDL, Mendelian Randomization Analysis, Proprotein Convertase 9, Randomized Controlled Trials as Topic
Abstract: BACKGROUND:Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.METHODS:In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FINDINGS:Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).INTERPRETATION:PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FUNDING:British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
Published: 2016

18. Differential effects of lenalidomide during plasma cell differentiation

Author: Maïlys Cren, Jean-François Rossi, Michel Jourdan, Rajesh Chopra, Peter H. Schafer, Laure Vincent, Nicolas Robert, Jérôme Moreaux, Patrice Ceballos, Bernard Klein, Guillaume Cartron, Christophe Duperray, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Celgene Corporation, Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Montpellier 1 (UM1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Neoplasm, Residual, plasma cell, [SDV]Life Sciences [q-bio], Plasma Cells, lenalidomide, Antineoplastic Agents, Plasma cell, 03 medical and health sciences, 0302 clinical medicine, Plasma cell differentiation, medicine, Humans, Multiple myeloma, Cells, Cultured, Lenalidomide, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Hematopoietic Stem Cell Transplantation, Cell Differentiation, IKZF3, differentiation, medicine.disease, Pomalidomide, IKZF1, 3. Good health, Thalidomide, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Immunology, Bone marrow, business, Multiple Myeloma, 030215 immunology, medicine.drug, Research Paper
Abstract: International audience; Thalidomide, lenalidomide and pomalidomide have greatly improved the outcome of patients with multiple myeloma. However, their effects on plasma cells, the healthy counterpart of myeloma cells, are unknown. Here, we investigated lenalidomide effects on normal human plasma cell generation using an in vitro model. Lenalidomide inhibited the generation of pre-plasmablasts and early plasma cells, while it moderately affected plasmablast production. It also reduced the expression level of Ikaros, Aiolos, and IRF4 transcription factors, in plasmablasts and early plasma cells. This suggests that their differential sensitivity to lenalidomide is not due to a difference in Ikaros or Aiolos degradation. Lenalidomide also inhibited long-lived plasma cell generation, but did not impair their long-term survival once generated. This last observation is in agreement with the finding that lenalidomide treatment for 3-18 months did not affect the bone marrow healthy plasma cell count in allografted patients with multiple myeloma. Our findings should prompt to investigate whether lenalidomide resistance in patients with multiple myeloma could be associated with the emergence of malignant plasmablasts or long-lived plasma cells that are less sensitive to lenalidomide.
Published: 2016

19. Dissecting the First Transcriptional Divergence During Human Embryonic Development

Author: John De Vos, Qiang Bai, Said Assou, Sabine Gerbal-Chaloin, Samir Hamamah, Fabienne Becker, Jean-Marie Ramirez, C. Monzo, Delphine Haouzi, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Montpellier 1 - UFR de Médecine (UM1 Médecine), Université Montpellier 1 (UM1), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Service de biologie de la reproduction, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-UAM : AMP/DPI, Unité de thérapie cellulaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Association Française contre les Myopathies (AFM), Région Languedoc-Roussillon: Chercheur d'Avenir 09-13198-01, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Frei, Monique, Service de gynécologie-obstétrique et médecine de la reproduction, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Cancer Research, Cellular differentiation, Embryonic Development, Biology, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Antigens, Neoplasm, Ectoderm, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Human embryogenesis, Inner cell mass, Gene Regulatory Networks, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA (Cytosine-5-)-Methyltransferases, Blastocyst, Induced pluripotent stem cell, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, Cells, Cultured, transcription factor, reproductive and urinary physiology, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, 0303 health sciences, urogenital system, Gene Expression Profiling, Gene Expression Regulation, Developmental, Trophoblast, Cell Differentiation, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Molecular biology, Trophoblasts, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, transcriptional network, pluripotent stem cells, trophectoderm, Stem cell, transcriptome, Developmental Biology
Abstract: The trophoblast cell lineage is specified early at the blastocyst stage, leading to the emergence of the trophectoderm and the pluripotent cells of the inner cell mass. Using a double mRNA amplification technique and a comparison with transcriptome data on pluripotent stem cells, placenta, germinal and adult tissues, we report here some essential molecular features of the human mural trophectoderm. In addition to genes known for their role in placenta (CGA, PGF, ALPPL2 and ABCG2), human trophectoderm also strongly expressed Laminins, such as LAMA1, and the GAGE Cancer/Testis genes. The very high level of ABCG2 expression in trophectoderm, 7.9-fold higher than in placenta, suggests a major role of this gene in shielding the very early embryo from xenobiotics. Several genes, including CCKBR and DNMT3L, were specifically up-regulated only in trophectoderm, indicating that the trophoblast cell lineage shares with the germinal lineage a transient burst of DNMT3L expression. A trophectoderm core transcriptional regulatory circuitry formed by 13 tightly interconnected transcription factors (CEBPA, GATA2, GATA3, GCM1, KLF5, MAFK, MSX2, MXD1, PPARD, PPARG, PPP1R13L, TFAP2C and TP63), was found to be induced in trophectoderm and maintained in placenta. The induction of this network could be recapitulated in an in vitro trophoblast differentiation model. Electronic supplementary material The online version of this article (doi:10.1007/s12015-011-9301-3) contains supplementary material, which is available to authorized users.
Published: 2011

20. Targeting NF-κB pathway with an IKK2 inhibitor induces inhibition of multiple myeloma cell growth

Author: Karène Mahtouk, Thierry Rème, Angela Romanelli, Dirk Hose, Michel Jourdan, Jean-François Rossi, Bernard Klein, Marion Baudard, Nicolas Robert, Jérôme Moreaux, Michel Dreano, Matthieu Abouladze, John De Vos, Hartmut Goldschmidt, Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Montpellier 1 - UFR de Médecine (UM1 Médecine), Université Montpellier 1 (UM1), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Hematology and Clinical Oncology, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Serono Research Institute, Serono, Serono International SA (SERONO INTERNATIONAL SA), Serono International SA, and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Cell Survival, Antineoplastic Agents, Biology, Article, Bortezomib, cell cycle, 03 medical and health sciences, Paracrine signalling, chemistry.chemical_compound, 0302 clinical medicine, Multiple myeloma, Cell Line, Tumor, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enzyme Inhibitors, Antineoplastic Agents, Alkylating, Melphalan, 030304 developmental biology, 0303 health sciences, Cell growth, NF-kappa B, apoptosis, IKK2 inhibitor, Hematology, Cell cycle, Boronic Acids, I-kappa B Kinase, Haematopoiesis, Pyrimidines, chemistry, Cell culture, Pyrazines, 030220 oncology & carcinogenesis, Cancer research, Stem cell, Growth inhibition, Cell Division, medicine.drug
Abstract: The pathophysiologic basis for multiple myeloma (MM) has been attributed to the dysregulation of various paracrine or autocrine growth factor loops and to perturbations in several signal transduction pathways including IkappaB kinase/nuclear factor-kappaB (IKK/NF-kappaB). The present study aimed at investigating the effect of a pharmaceutical IKK2 inhibitor, the anilinopyrimidine derivative AS602868, on the in vitro growth of 14 human MM cell lines (HMCL) and primary cells from 13 patients. AS602868 induced a clear dose-dependent inhibition of MM cell growth on both HMCL and primary MM cells, which was the result of a simultaneous induction of apoptosis and inhibition of the cell cycle progression. Combination of AS602868 with suboptimal doses of melphalan or Velcade showed an additive effect in growth inhibition of HMCL. AS602868 also induced apoptosis of primary myeloma cells. Importantly, AS602868 did not alter the survival of other bone marrow mononuclear cells (CD138(-)) co-cultured with primary MM (CD138(+)) cells, except for CD34(+) haematopoietic stem cells. The results demonstrate the important role of NF-kappaB in maintaining the survival of MM cells and suggest that a pharmacological inhibition of the NF-kappaB pathway by the IKK2 inhibitor AS602868 can efficiently kill HMCL and primary myeloma cells and therefore might represent an innovative approach for treating MM patients.
Published: 2007

21. T-Cell Activation and Malnutrition Adversely Impact on Endothelial Progenitor Cell Mobilization in Patients on Extracorporeal Maintenance Dialysis Therapy

Author: Jean-Pierre Vendrell, Bernard Canaud, Isabelle Jaussent, Jean-Paul Cristol, Annie Rodrigez, Edouard Tuaillon, Marion Morena, Nils Kuster, Leila Chenine, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: T-Lymphocytes, T cell, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Nutritional Status, Cell Count, 030204 cardiovascular system & hematology, Lymphocyte Activation, Endothelial progenitor cell, Extracorporeal, Immunophenotyping, End stage renal disease, 03 medical and health sciences, 0302 clinical medicine, Renal Dialysis, medicine, Humans, Progenitor cell, ComputingMilieux_MISCELLANEOUS, Endothelial Progenitor Cells, 2. Zero hunger, Mobilization, business.industry, Malnutrition, Hematology, General Medicine, medicine.disease, medicine.anatomical_structure, Nephrology, Immunology, Leukocytes, Mononuclear, Kidney Failure, Chronic, Female, business, Biomarkers, Kidney disease
Abstract: Background: The number of circulating endothelial progenitor cells (EPCs) decreases on account of chronic kidney disease (CKD). Methods: Twenty patients were enrolled in this prospective and randomised study in two parallel arms: conventional haemodialysis versus online haemodiafiltration. EPCs number and T-cell activation were analysed at baseline and monthly during a 4-month period of follow-up. Results: CD38bright and HLA-DR+ expression among CD8 memory T cells were negatively associated with both CD34+ (r = -0.70, p = 0.0006) and CD34+ CD133+ (r = -0.62, p = 0.004) cell numbers. Conversely, a positive correlation was observed between CD34+ and CD34+ CD133+ cells with transferrin (r = 0.75, p = 0.0001 and r = 0.47, p = 0.04, respectively), and CD34+ CD133+ cells with transthyretin (r = 0.51, p = 0.02). No significant association was observed between dialysis modality and the evolution of the EPC number. Conclusions: Chronic T-cell activation may be a component of the malnutrition inflammation complex syndrome that adversely influences EPC mobilization in CKD patients.
Published: 2015

22. Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

Author: Fabienne Proamer, Karène Mahtouk, Emmanuelle Meugnier, Maurizio Aricò, Christine Delprat, Cyrille Debard, Daniel Hanau, Nathalie Bernoud-Hubac, Nathalie Bissay, Giulia Salvatore, Patricia Daira, Hubert Vidal, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), (France) CNRS, INSERM, Universite de Lyon 1, Institut Universitaire de France, Fondation pour l'Innovation et la Valorisation en Infectiologie, ANR Microbiologie-Immunologie-Environnement, LyonBiopole, Etablissement Francais du Sang EFS-Alsace, ARMESA (Association de Recherche et de Developpement en Medecine et Sante Publique), (Italy) Associazione Italiana Ricerca Istiocitosi (AIRI), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Analyses de Biologie Médicale (LABM), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS Alsace, Biologie des Cellules Dendritiques Humaines, EFS-Cancéropôle du Grand Est-Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Onco-Hematology, A.Meyer Children's Hospital, Université de Lyon, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Delprat, Christine, and Mahtouk, Karène
Subjects: Macrophages/immunology/metabolism, Cellular differentiation, [SDV]Life Sciences [q-bio], immunology, monocytes, inflammation, microarrays, lipidomics, interleukin 17A, lipid, immunometabolism, Cell Differentiation/genetics, Lipid Droplets/immunology/metabolism, Inflammation, Foam Cells/metabolism, Biology, Biochemistry, Interleukin-17/genetics/immunology/*metabolism, Proinflammatory cytokine, chemistry.chemical_compound, Cell Proliferation/genetics, Endocrinology, Lipid droplet, medicine, Oil Red O, Humans, T-Lymphocytes/immunology/metabolism, cytokine proinflammatoire, pathogénèse, Liver X receptor, maladie inflammatoire, ComputingMilieux_MISCELLANEOUS, Monocytes/immunology/metabolism, Atherosclerosis/immunology/*metabolism/pathology, Fatty Acids/*metabolism, Lipid metabolism, Cell Biology, Dendritic Cells/immunology/*metabolism, 3. Good health, Cell biology, chemistry, Gene Expression Regulation, Immunology, Orphan Nuclear Receptors/biosynthesis/metabolism, lipids (amino acids, peptides, and proteins), Interleukin 17, medicine.symptom, Lipid Metabolism/immunology
Abstract: International audience; Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2-12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-alpha, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells "foamy DCs" and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A.
Published: 2015

23. CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy

Author: Karine Charton, Bjarne Udd, H. Luque, Per Harald Jonson, Laurence Suel, Jaakko Sarparanta, Anna Vihola, Imène Boumela, Isabelle Richard, Astrid Milic, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Folkhälsan Research Center, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurology Department, Laboratoire Analyse, Modélisation et Matériaux pour la Biologie et l'Environnement (LAMBE - UMR 8587), Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, and École Pratique des Hautes Études (EPHE)
Subjects: Male, MESH: Connectin, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Calpain, Mutant, Amino Acid Motifs, Muscle Proteins, Plasma protein binding, MESH: Amino Acid Motifs, Mice, 0302 clinical medicine, Myotilin, MESH: Animals, Connectin, Muscular dystrophy, Genetics (clinical), 0303 health sciences, MESH: Muscle, Skeletal, biology, Calpain, MESH: Distal Myopathies, General Medicine, musculoskeletal system, Actinin, alpha 2, Titin, Female, Protein Binding, animal structures, MESH: Muscular Dystrophies, Limb-Girdle, Obscurin, MESH: Proteolysis, 03 medical and health sciences, MESH: Muscle Proteins, MESH: Mice, Inbred C57BL, Genetics, medicine, MESH: Protein Binding, Animals, Humans, Muscle, Skeletal, Molecular Biology, MESH: Protein Kinases, MESH: Mice, 030304 developmental biology, MESH: Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Molecular biology, MESH: Male, Distal Myopathies, Mice, Inbred C57BL, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Muscular Dystrophies, Limb-Girdle, MESH: Protein Processing, Post-Translational, Proteolysis, biology.protein, MESH: Female, Protein Kinases, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract: International audience; Mutations in the extreme C-terminus of titin (TTN), situated in the sarcomeric M-band, cause tibial muscular dystrophy (TMD) and limb-girdle muscular dystrophy 2J (LGMD2J). The mutations ultimately cause a loss of C-terminal titin, including a binding site for the protease calpain 3 (CAPN3), and lead to a secondary CAPN3 deficiency in LGMD2J muscle. CAPN3 has been previously shown to bind C-terminal titin and to use it as a substrate in vitro. Interestingly, mutations in CAPN3 underlie limb-girdle muscular dystrophy 2A (LGMD2A). Here, we aimed to clarify the relationship of CAPN3 and M-band titin in normal and pathological muscle. In vitro analyses identified several CAPN3 cleavage sites in C-terminal titin that were defined by protein sequencing. Furthermore, cleavage products were detected in normal muscle extracts by western blotting and in situ by immunofluorescence microscopy. The TMD/LGMD2J mutation FINmaj proved to alter this processing in vitro, while binding of CAPN3 to mutant titin was preserved. Unexpectedly, the pathological loss of M-band titin due to TMD/LGMD2J mutations was found to be independent of CAPN3, whereas the involvement of ubiquitous calpains is likely. We conclude that proteolytic processing of C-terminal titin by CAPN3 may have an important role in normal muscle, and that this process is disrupted in LGMD2A and in TMD/LGMD2J due to CAPN3 deficiency and to the loss of C-terminal titin, respectively.
Published: 2015

24. DNA repair in diffuse large B-cell lymphoma: a molecular portrait

Author: Caroline Bret, Bernard Klein, Guillaume Cartron, Angelos Constantinou, Philippe Pasero, Jean-François Schved, Jérôme Moreaux, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, DNA Repair, DNA repair, Hematology, Biology, Prognosis, medicine.disease, BCL10, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols, Cancer research, medicine, Humans, Lymphoma, Large B-Cell, Diffuse, Diffuse large B-cell lymphoma, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2015

25. Insulin like growth factor binding protein 7 (IGFBP7) expression is linked to poor prognosis but may protect from bone disease in multiple myeloma

Author: Bernard Klein, Dirk Hose, Daniel Heintel, Arnold Bolomsky, Anja Seckinger, Heinz Ludwig, Martin Schreder, Susanne Lipp, Niklas Zojer, Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Hematology, and Basic (bio-) Medical Sciences
Subjects: Male, Cancer Research, Stromal cell, Microenvironment, IGFBP7, Survival, medicine.medical_treatment, Myeloma bone disease, Bone Diseases/etiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Multiple Myeloma/genetics, Biology, Insulin-like growth factor, Multiple myeloma, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Internal Medicine, Humans, Molecular Biology, In Situ Hybridization, Fluorescence, Regulation of gene expression, DNA methylation, Reverse Transcriptase Polymerase Chain Reaction, hematology, Research, Insulin-Like Growth Factor Binding Proteins/biosynthesis, Osteoblast, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, Flow Cytometry, Prognosis, Molecular biology, Survival Analysis, 3. Good health, Insulin-Like Growth Factor Binding Proteins, Gene Expression Regulation, Neoplastic, Vascular endothelial growth factor A, medicine.anatomical_structure, Oncology, Cancer research, Female, Bone marrow, Bone Diseases, Transcriptome
Abstract: Background Insulin like growth factor binding protein 7 (IGFBP7) is a secreted protein binding insulin like growth factor 1 (IGF-1), insulin, vascular endothelial growth factor A (VEGFA), and activin A. It antagonizes bone morphogenetic proteins and is involved in the tumour propagation of solid as well as haematological malignancies. Its role in multiple myeloma (MM) is not defined so far. We therefore aim here to investigate its prognostic and pathophysiological role in MM. Methods The clinical significance of IGFBP7 gene expression was investigated by gene expression profiling in two independent cohorts (n = 948) of newly-diagnosed MM patients. Methylation of the IGFBP7 promoter was analysed by pyrosequencing and treatment of MM cell lines with 5-aza-2-deoxycytidine. The impact of IGFBP7 on MM cells was studied by CCK-8 assay, BrdU assay and flow cytometry, respectively. IGFBP7 expression in bone marrow stromal cells (BMSCs) was studied by quantitative RT-PCR. For osteoblast development, immortalized and primary human BMSCs were cultured in osteogenic differentiation medium for 7–14 days in the presence of recombinant human IGFBP7 and/or activin A. Results Median IGFBP7 expression is significantly lower in CD138-purified plasma cells from individuals with MGUS and MM, compared to normal bone marrow plasma cells. IGFBP7 gene expression in MM cells is regulated by methylation, shown by pyrosequencing and exposure to demethylating agents (5-aza-2-deoxycytidine). High expression of IGFBP7 in MM cells is associated with adverse survival in two independent cohorts of 247 and 701 newly-diagnosed MM patients treated with high-dose therapy and autologous stem cell transplantation. IGFBP7 is associated with prognostically adverse chromosomal aberrations (t(4;14) and gain of 1q21), MMSET expression, and higher myeloma cell proliferation. In vitro, IGFBP7 overcomes activin A induced osteoblast suppression and promotes osteogenesis. MM cells downregulate IGFBP7 in stromal cells, possibly contributing to the osteoblast suppression found in MM. Conversely, higher IGFBP7 expression is associated with a lower probability of myeloma bone disease. Conclusions Our data indicate that IGFBP7 expression is a marker for a specific methylation pattern in myeloma, linked to translocation t(4;14) associated MMSET expression, showing clinical features of adverse prognosis with absence of myeloma bone disease. Electronic supplementary material The online version of this article (doi:10.1186/s13045-014-0105-1) contains supplementary material, which is available to authorized users.
Published: 2015

26. Functional Regulatory T Cells Are Collected in Stem Cell Autografts by Mobilization with High-Dose Cyclophosphamide and Granulocyte Colony-Stimulating Factor

Author: Bernard Klein, Marion Baudard, Philippe Quittet, Maud Condomines, Jean-François Rossi, Jean-François Schved, Zhao-Yang Lu, Ernesto Lopez, Pascal Latry, L Nadal, Karin Tarte, Christophe Duperray, Guilhem Requirand, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Hematology and Clinical Oncology, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de thérapie cellulaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Frei, Monique
Subjects: CD4-Positive T-Lymphocytes, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Lymphocyte, CD8-Positive T-Lymphocytes, Lymphocyte Activation, T-Lymphocytes, Regulatory, Interleukin 21, 0302 clinical medicine, MESH: Immunologic Memor, T-Lymphocyte Subsets, Granulocyte Colony-Stimulating Factor, Immunology and Allergy, Cytotoxic T cell, IL-2 receptor, MESH: CD4-Positive T-Lymphocytes, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, MESH: CD8-Positive T-Lymphocytes, Hematopoietic Stem Cell Mobilization, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Stem cell, Multiple Myeloma, MESH: Dose-Response Relationship, Immunologic, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, Dose-Response Relationship, Immunologic, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Drug Administration Schedule, Biology, Transplantation, Autologous, Drug Administration Schedule, Immunophenotyping, MESH: Hematopoietic Stem Cell Mobilization, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Leukapheresis, Cyclophosphamide, Interleukin 3, MESH: Humans, MESH: Cyclophosphamide, MESH: Granulocyte Colony-Stimulating Factor, Immunologic Memory, MESH: Female, CD8, 030215 immunology, Stem Cell Transplantation
Abstract: High-dose cyclophosphamide (Cy) and G-CSF are widely used to mobilize hemopoietic stem cells for treating patients with high-dose chemotherapy and autologous stem cell transplantation (ASCT). Because lymphocyte count in the graft collected after Cy-G-CSF treatment is an independent survival factor after ASCT for patients with multiple myeloma, our purpose was to study how Cy-G-CSF treatment affects the phenotype and function of T cells in patients with multiple myeloma. Cy induced a 3-fold decrease of T cell counts with a slow and partial T cell recovery of one-third at the time of hemopoietic stem cell collection. Cy-G-CSF treatment did not affect the relative ratios of central memory, effector memory, and late effector CD4+ or CD8+ T cells, but a decrease in the percentage of naive CD4+ cells was observed. The percentages of CD25+ cells increased 2- to 3-fold in CD4+ and CD8+ T cells, the former including both activated CD25low and CD25high cells. CD4+CD25high cells were regulatory T cells (Treg) that expressed high levels of FOXP3, CTLA-4, and GITR and displayed in vitro suppressive properties. The recovery of Treg absolute counts after Cy-G-CSF treatment was higher than the recovery of other lymphocyte subpopulations. In conclusion, Cy-G-CSF treatment induces a severe T cell count decrease without deleting Treg, which are potent inhibitors of antitumor response. The present data encourage novel therapeutic strategies to improve T cell recovery following ASCT while limiting Treg expansion.
Published: 2006

27. IFNα signaling through PKC-θ is essential for antitumor NK cell function

Author: Johan Garaude, Javier Naval, Martin Villalba, Natalia R Comet, Juan Ignacio Aguilo, Elena Catalán, Moeez Ghani Rathore, Julián Pardo, Gilles Uzé, Alberto Anel, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cell Immunity in Cancer, Inflammation and infection Group [Zaragoza, Spain] (Biomedical Research Center), University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID)-Nanoscience Institute of Aragon - INA [Zaragoza, Spain], Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Departamento de Bioquimica y Biologia Molecular y Celular, Universidat de Zaragoza, Spain, Bioquímica y Biología Molecular y Celular, University of Zaragoza - Universidad de Zaragoza [Zaragoza]-University of Zaragoza - Universidad de Zaragoza [Zaragoza], This work was supported by the collaborative projects CliNK SOE2/P1/E341 from Sudoe/Interreg IV B (EU) and Grant CTPP5/12 from 'Communauté de Travail des Pyrénées', by grant SAF2010–15341 to AA and grant SAF2011–25390 to JP, both from Ministerio de Economía y Competitividad (Spain), by Fondo Social Europeo and by the association CIEL, the association L'Un pour l'Autre and the federation Ensangble to MV, and by one AOI from the CHU Montpellier and fellowships from the ARC and Higher Education Commission, Pakistan to MGR., European Project, Hennaut, Odile, CLINK, SUDOE, SOE2/P1/E341 - INCOMING, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), LPHI - Laboratory of Pathogen Host Interactions (LPHI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Nanoscience Institute of Aragon - INA [Zaragoza, Spain]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo - ARAID [Zaragoza, Spain]
Subjects: Poly I:C, [SDV]Life Sciences [q-bio], real-time polymerase chain reaction, NK cells, PI3K, Interleukin 21, poly-inosinic:cytidilic acid, Interferon, Immunology and Allergy, major histocompability complex class I/MHC-I, phosphatidylinositol-3-kinase, Original Research, IFN-α, MEF, CXCL10, Degranulation, cyclin-dependent kinase 8, FCS, murine embryonic fibroblast, IFNA1, signal transducer and activator of transcription-1/STAT1, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, IL-15, PRKCQ, PLC, medicine.drug, NK, Immunology, CDK8, RT-PCR, Biology, PKC-θ, protein kinase C-θ, interferon-α, interferon-γ, medicine, Splenocyte, MHC-I, interleukin-15/IL15, Lymphokine-activated killer cell, phospholipase-C, natural killer, IFNG, Molecular biology, Granzyme B, (C-X-C motif) ligand 10/CXCL10, Cancer research, fetal calf serum, MACS, STAT-1, magnetic cell separation, IFNα, Ex vivo, IFNγ
Abstract: International audience; We have previously shown that the development of a major histocompatibility complex class I (MHC-I)-deficient tumor was favored in protein kinase C-θ knockout (PKC-θ-/-) mice compared to that occurring in wild-type mice. This phenomenon was associated with scarce recruitment of natural killer (NK) cells to the tumor site, as well as impaired NK cell activation and reduced cytotoxicity ex vivo. Poly-inosinic:cytidylic acid (poly I:C) treatment activated PKC-θ in NK cells depending on the presence of a soluble factor produced by a different splenocyte subset. In the present work, we sought to analyze whether interleukin-15 (IL-15) and/or interferon-α (IFNα) mediate PKC-θ-dependent antitumor NK cell function. We found that IL-15 improves NK cell viability, granzyme B expression, degranulation capacity and interferon-γ (IFNγ) secretion independently of PKC-θ. In contrast, we found that IFNα improves the degranulation capability of NK cells against target cancer cells in a PKC-θ-dependent fashion both ex vivo and in vivo. Furthermore, IFNα induces PKC-θ auto-phosphorylation in NK cells, in a signal transduction pathway involving both phosphatidylinositol-3-kinase (PI3K) and phospholipase-C (PLC) activation. PKC-θ dependence was further implicated in IFNα-induced transcriptional upregulation of chemokine (C-X-C motif) ligand 10 (CXCL10), a signal transducer and activator of transcription-1 (STAT-1)-dependent target of IFNα. The absence of PKC-θ did not affect IFNα-induced STAT-1 Tyr701 phosphorylation but affected the increase in STAT-1 phosphorylation on Ser727, attenuating CXCL10 secretion. This connection between IFNα and PKC-θ in NK cells may be exploited in NK cell-based tumor immunotherapy.
Published: 2014

28. Proteomic consequences of expression and pathological conversion of the prion protein in inducible neuroblastoma N2a cells

Author: Stéphane Roche, Manuela Pastore, Monique Provansal, Sandrine Alais, Maxime Belondrade, Danielle Casanova, Pascal Leblanc, Sylvain Lehmann, Otto Windl, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme de Protéomique Clinique, CHU Saint-Eloi, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), EFS, Oncogenèse rétrovirale – Retroviral Oncogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup (VAS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup (VAS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle Protéome de Montpellier (PPM), Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), European Project, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Larose, Catherine, and Food CT 2004 506579, European Netword of Excellence of Neuroprion - INCOMING
Subjects: Cell Extracts, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, PrPSc Proteins, animal diseases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Vimentin, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Proteomics, Biochemistry, Mice, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Cell Extracts, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Electrophoresis, Gel, Two-Dimensional, MESH: Animals, Peptide-mass fingerprint, Endoplasmic Reticulum Chaperone BiP, ComputingMilieux_MISCELLANEOUS, mass spectrometry, 0303 health sciences, biology, MESH: Proteomics, MESH: PrPSc Proteins, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Infectious Diseases, 2D-PAGE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Protein folding, HSP60, Signal transduction, Research Paper, Gene isoform, MESH: Cell Line, Tumor, Blotting, Western, Models, Biological, prion, 03 medical and health sciences, Cellular and Molecular Neuroscience, neuroblastoma, proteomics, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, chaperones, MESH: Blotting, Western, PrPC Proteins, MESH: PrPC Proteins, MESH: Mice, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Models, Biological, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: Electrophoresis, Gel, Two-Dimensional, Molecular biology, MESH: Neuroblastoma, nervous system diseases, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Calreticulin, 030217 neurology & neurosurgery
Abstract: International audience; Neurodegenerative diseases are often associated with misfolding and deposition of specific proteins in the nervous system. The prion protein, which is associated with transmissible spongiform encephalopathies (TSEs), is one of them. The normal function of the cellular form of the prion protein (PrP(C)) is mediated through specific signal transduction pathways and is linked to resistance to oxidative stress, neuronal outgrowth and cell survival. In TSEs, PrP(C) is converted into an abnormally folded isoform, called PrP(Sc), that may impair the normal function of the protein and/or generate toxic aggregates. To investigate these molecular events we performed a two-dimensional gel electrophoresis comparison of neuroblastoma N2a cells expressing different amounts of PrP(C) and eventually infected with the 22L prion strain. Mass spectrometry and peptide mass fingerprint analysis identified a series of proteins with modified expression. They included the chaperones Grp78/BiP, protein disulfide-isomerase A6, Grp75 and Hsp60 which had an opposite expression upon PrPC expression and PrP(Sc) production. The detection of these proteins was coherent with the idea that protein misfolding plays an important role in TSEs. Other proteins, such as calreticulin, tubulin, vimentin or the laminin receptor had their expression modified in infected cells, which was reminiscent of previous results. Altogether our data provide molecular information linking PrP expression and misfolding, which could be the basis of further therapeutic and pathophysiological research in this field.
Published: 2014

29. Extracellular-signal-regulated kinase 5 modulates the antioxidant response by transcriptionally controlling Sirtuin 1 expression in leukemic cells

Author: Nuria Lopez-Royuela, Lluis Fajas, Nerea Allende-Vega, Martin Villalba, Tod Gulick, Moeez Ghani Rathore, Jean-Sébastien Annicotte, Bindu Ramachandran, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Physiology [Lausanne, Switzerland], Université de Lausanne = University of Lausanne (UNIL), Diabetes and Obesity Research Center [Orlando, FL, USA], Sanford-Burnham Medical Research Institute [Orlando, FL, USA], Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), This work was supported by the program 'Chercheur d’avenir' from the Region Languedoc-Rousillon (MV), a scientific program from the 'Communauté de Travail des Pyrénées' (CTPP10/09 to MV), the Association pour la Recherche contre le Cancer (MV), the Fondation pour la Recherche Medicale (MV), l’association CIEL, l’association L’Un pour l’Autre et la fédération Ensangble (MV), a grant FEDER (Fonds européen de développement régional) Objectif competitivite (MV), a grant CliNK SOE2/P1/E341 from Sudoe/Interreg IV B (EU to MV) and fellowships from La Ligue Contre le Cancer (NL-R) and from the ARC and the Higher Education Commission, Pakistan (MGR)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Université de Lausanne (UNIL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), and villalba, martin
Subjects: T cell, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Major histocompatibility complex, Biochemistry, Jurkat cells, Antioxidants, Jurkat Cells, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Sirtuin 1, medicine, Humans, Oxidative phosphorylation, Transcription factor, Mitogen-Activated Protein Kinase 7, 030304 developmental biology, 0303 health sciences, Sirt1, Leukemia, Gene Expression Regulation, Leukemic, Myeloid leukemia, Cell Biology, Molecular biology, Antioxidant Response Elements, Cell biology, Mitochondria, Anti-oxidant response elements (ARE), medicine.anatomical_structure, ERK5, 030220 oncology & carcinogenesis, Sirtuin, Cancer cell, biology.protein, Signal Transduction
Abstract: International audience; Cancer cell metabolism differs from that of non-transformed cells in the same tissue. This specific metabolism gives tumor cells growing advantages besides the effect in increasing anabolism. One of these advantages is immune evasion mediated by a lower expression of the mayor histocompatibility complex class I molecules. The extracellular-signal-regulated kinase-5 regulates both mayor histocom-patibility complex class I expression and metabolic activity. However, the mechanisms underlying are largely unknown. We show here that extracellular-signal-regulated kinase-5 regulates the transcription of the NADH +-dependent histone deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin 1) in leukemic Jurkat T cells. This involves the activation of the transcription factor myocyte enhancer factor-2 and its binding to the sirt1 promoter. In addition, extracellular-signal-regulated kinase-5 is required for T cell receptor-induced and oxidative stress-induced full Sirtuin 1 expression. Extracellular-signal-regulated kinase-5 induces the expression of promoters containing the antioxi-dant response elements through a Sirtuin 1-dependent pathway. On the other hand, down modulation of extracellular-signal-regulated kinase-5 expression impairs the anti-oxidant response. Notably, the extracellular-signal-regulated kinase-5 inhibitor BIX02189 induces apoptosis in acute myeloid leukemia tumor cells without affecting T cells from healthy donors. Our results unveil a new pathway that modulates metabolism in tumor cells. This pathway represents a promising therapeutic target in cancers with deep metabolic layouts such as acute myeloid leukemia.
Published: 2014

30. All-trans retinoic acid (ATRA) induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity

Author: Luis Martínez-Lostao, Julián Pardo, Amélie Cornillon, Ewelina Krzywinska, Alberto Anel, Diego Sánchez-Martínez, Martin Villalba, Zhao Yang Lu, Jean François Rossi, Dietmar Fernández-Orth, Anne Saumet, Nuria Lopez-Royuela, Ariel Ramirez-Labrada, Sergio Escorza, Moeez Ghani Rathore, Charles-Henri Lecellier, Cell Immunity in Cancer, Inflammation and infection Group [Zaragoza, Spain] (Biomedical Research Center), University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID)-Nanoscience Institute of Aragon - INA [Zaragoza, Spain], Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Apoptosis, Immunity and Cancer Group [Zaragoza, Spain] ( Department Biochemistry and Molecular and Cell Biology), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Progenika Biopharma SA [Bizkaia, Spain], Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), This work was supported by the program 'Chercheur d’avenir' from the Region Languedoc-Rousillon (MV), a scientific program from the 'Communauté de Travail des Pyrénées' (CTPP10/09 to MV, SE and AA), the CliNK project (SOE2/P1/E341) from Sudoe/EU (AA, J-FR and MV), the Association pour la Recherche contre le Cancer (MV), the Fondation pour la Recherche Medicale (MV), a grant FEDER Objectif competitivite (MV), l’association CIEL, l’association L’Un pour l’Autre et la fédération Ensangble (MV), Fondo Social Europeo (FSE), grants SAF2010-15341 (AA) and SAF2011-25390 (JP) Ministerio de Economía y Competitividad, Spain and fellowships from Gobierno de Aragon (DS) the ARC (MGR and EK) and Higher Education Commission, Pakistan (MGR) and La Ligue contre le Cancer (NL-R)., villalba, martin, University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Nanoscience Institute of Aragon - INA [Zaragoza, Spain]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo - ARAID [Zaragoza, Spain], CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: Cytotoxicity, Immunologic, C–C motif chemokine, Lymphocyte, Cell, Retinoic acid, C–C chemokine receptor, NK cells, Biochemistry, Granzymes, Cathepsin C, Epstein–Barr virus, chemistry.chemical_compound, Interleukin 21, Jurkat Cells, CXCL, polyinosinic:polycytidylic acid, Cluster Analysis, ATRA, Cytotoxicity, CXCR, Cells, Cultured, C–X–C motif chemokine, miR-23a, Oligonucleotide Array Sequence Analysis, Principal Component Analysis, PCA, Reverse Transcriptase Polymerase Chain Reaction, chemokine receptor, Cell biology, Killer Cells, Natural, all-trans retinoic acid, medicine.anatomical_structure, Female, Blotting, Western, Tretinoin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, poly I:C, Cell Line, FDR, [SDV.CAN] Life Sciences [q-bio]/Cancer, EBV, principal components analysis, medicine, Animals, Humans, Transcriptomics, miRNA, Innate immune system, CCL, Cell Biology, CCRC, Mice, Inbred C57BL, MicroRNAs, chemistry, Granzyme, biology.protein, Interleukin-2, false discovery rate, CTSC, K562 Cells, Transcriptome
Abstract: International audience; NK cell is an innate immune system lymphocyte lineage with natural cytotoxicity. Its optimal use in the clinic requires in vitro expansion and activation. Cytokines and encounter with target cells activate NK cells and induce proliferation, and this could depend on the presence of other immune cells. Here we activated PBMCs during 5 days with IL-2, with IL-2 plus the tumor cell line K562 and with the lymphoblastoid cell line R69 and perform integrated analyses of microRNA and mRNA expression profiles of purified NK cells. The samples cluster depending on the stimuli and not on the donor, indicating that the pattern of NK cell stimulation is acutely well conserved between individuals. Regulation of mRNA expression is tighter than that of miRNA expression. All stimuli induce a common preserved genetic remodeling. In addition, encounter with target cells mainly activates pathways related to metabolism. Different target cells induce different NK cell remodeling which affects cytokine response and cytotoxicity, supporting the notion that encounter with different target cells significantly changing the activation pattern. We validate our analysis by showing that activation down regulates miR-23a, which is a negative regulator of cathepsin C (CTSC) mRNA, a gene up regulated by all stimuli. The peptidase CTSC activates the granzymes, the main effector proteases involved in NK cell cytotoxicity. All-trans retinoic acid (ATRA), which induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity in an in vivo mouse model.
Published: 2014

31. DNA methylation score is predictive of myeloma cell sensitivity to 5-azacitidine

Author: Angelique Bruyer, Hartmut Goldschmidt, Dirk Hose, Bernard Klein, Jean-Luc Veyrune, Jérôme Moreaux, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], National Center for Tumor Diseases (NCTD), Association pour la Recherche sur le Cancer, ARC SL220-110603450, Paris, France, B Klein, INCa-Canceropole GSO 2012-E11, J Moreaux, FEDER 141786 & 42667, B Klein et J Moreaux, Montpellier, France, The Hopp-Foundation, Germany, The National Centre for Tumor Diseases, Heidelberg, Germany, The Tumorsentrum Heidelberg/Mannheim, Germany, European Project, Frei, Monique, FP7-OVERMYR, B Klein - INCOMING, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Heidelberg [Heidelberg] = Heidelberg University, Hematology, and Basic (bio-) Medical Sciences
Subjects: Epigenomics, Antimetabolites, Antineoplastic, [SDV.IMM] Life Sciences [q-bio]/Immunology, Azacitidine, Multiple Myeloma/drug therapy, gene arrays, Article, 03 medical and health sciences, 0302 clinical medicine, Antimetabolites, Antineoplastic/pharmacology, Predictive Value of Tests, Gene expression, medicine, Humans, Sensitivity (control systems), Epigenetics, Multiple myeloma, ComputingMilieux_MISCELLANEOUS, drug sensitivity prediction, 030304 developmental biology, 0303 health sciences, epigenetics, business.industry, hematology, DNA Methylation, medicine.disease, Azacitidine/pharmacology, myeloma, 030220 oncology & carcinogenesis, Predictive value of tests, DNA methylation, Cancer research, gene expression, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Screening Assays, Antitumor, business, Multiple Myeloma, medicine.drug
Abstract: International audience;
Published: 2014

32. Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing

Author: Christelle Brégnard, Jihane Basbous, Marion Larroque, Ahmad Yatim, Pauline Hue, Frank Kirchhoff, Bijan Sobhian, Monsef Benkirane, Nadine Laguette, Angelos Constantinou, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Virology, Universitätsklinikum Ulm - University Hospital of Ulm, CHU Necker - Enfants Malades [AP-HP], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institute of Molecular Virology [Ulm, Allemagne]
Subjects: Cell cycle checkpoint, [SDV]Life Sciences [q-bio], viruses, Regulator, PLK1, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Endonuclease, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, biology, Biochemistry, Genetics and Molecular Biology(all), virus diseases, Cell cycle, biochemical phenomena, metabolism, and nutrition, Virology, MUS81, 3. Good health, Cell biology, Proteasome, 030220 oncology & carcinogenesis, biology.protein
Abstract: International audience; The HIV auxiliary protein Vpr potently blocks the cell cycle at the G2/M transition. Here, we show that G2/M arrest results from untimely activation of the structure-specific endonuclease (SSE) regulator SLX4 complex (SLX4com) by Vpr, a process that requires VPRBP-DDB1-CUL4 E3-ligase complex. Direct interaction of Vpr with SLX4 induced the recruitment of VPRBP and kinase-active PLK1, enhancing the cleavage of DNA by SLX4-associated MUS81-EME1 endonucleases. G2/M arrest-deficient Vpr alleles failed to interact with SLX4 or to induce recruitment of MUS81 and PLK1. Furthermore, knockdown of SLX4, MUS81, or EME1 inhibited Vpr-induced G2/M arrest. In addition, we show that the SLX4com is involved in suppressing spontaneous and HIV-1-mediated induction of type 1 interferon and establishment of antiviral responses. Thus, our work not only reveals the identity of the cellular factors required for Vpr-mediated G2/M arrest but also identifies the SLX4com as a regulator of innate immunity.
Published: 2014

33. Process for identifying rare events

Author: Renaud Cezar, Dino Ienco, André Mas, Florent Masseglia, Pascal Poncelet, Pierre Pudlo, Enikö Székely, Maguelonne Teisseire, Jean-Pierre Vendrell, Laboratoire de Virologie - CHRU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), ADVanced Analytics for data SciencE (ADVANSE), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Mathématiques et de Modélisation de Montpellier (I3M), Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Scientific Data Management (ZENITH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Territoires, Environnement, Télédétection et Information Spatiale (UMR TETIS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-AgroParisTech-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Virologie [CHRU Montpellier], Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Inria Sophia Antipolis - Méditerranée (CRISAM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM), Masseglia, Florent, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-AgroParisTech-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), and Irstea Publications, Migration
Subjects: [SDE] Environmental Sciences, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], [SDE]Environmental Sciences, [INFO.INFO-DB] Computer Science [cs]/Databases [cs.DB]
Abstract: The invention relates to a method for identifying a subpopulation of specific cells among a large population of cells, comprising - a step of exposing the cells of said large population to n- reagents, - a step of detecting said n- reagents, - a step of grouping the cells by clusterisation into k different clusters, and - a step of eliminating cells that are not rare cells., L'invention concerne un procédé d'identification d'une sous-population de cellules spécifiques parmi une grande population de cellules, comprenant - une étape consistant à exposer les cellules de ladite grande population à n réactifs, - une étape consistant à détecter lesdits n réactifs, - une étape consistant à regrouper les cellules par agrégation en k groupes différents, et - une étape consistant à éliminer les cellules qui ne sont pas des cellules rares.
Published: 2014

34. The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast

Author: Ismael Padioleau, Kazumasa Yoshida, Philippe Pasero, Olga Tsaponina, Krzysztof Ginalski, Damien Desmarais, Andrei Chabes, Armelle Lengronne, Magdalena Skrzypczak, Julien Bacal, Véronique Pantesco, Hugues Parrinello, Emeric Dubois, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Biochemistry and Biophysics, Umeå University, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Bioinformatics and Systems Biology, and Medical University of Warsaw - Poland
Subjects: DNA re-replication, DNA Replication, Saccharomyces cerevisiae Proteins, Applied Microbiology, Cell Cycle Proteins, Replication Origin, Saccharomyces cerevisiae, Biology, Origin of replication, Pre-replication complex, Biochemistry, Genetics and Molecular Biology (miscellaneous), Applied Microbiology and Biotechnology, Microbiology, DNA, Ribosomal, Histone Deacetylases, Epigenesis, Genetic, Sirtuin 2, Control of chromosome duplication, Virology, Genetics, Initiation factor, budding yeast, Epigenetics, Repeated sequence, DNA, Fungal, Ribosomal DNA, lcsh:QH301-705.5, Molecular Biology, Silent Information Regulator Proteins, Saccharomyces cerevisiae, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Replication timing, [SDV.GEN]Life Sciences [q-bio]/Genetics, epigenetics, DNA replication, Cell Biology, enzymes and coenzymes (carbohydrates), Checkpoint Kinase 2, Histone, Licensing factor, lcsh:Biology (General), Mutation, biology.protein, Origin recognition complex, Parasitology, Gene Deletion
Abstract: In eukaryotes, duplication of genomic information depends on the sequential activation of multiple replication origins distributed along the chromosomes. Replication origins differ in initiation time, chromatin structure and three-dimensional position in the nucleus. Recently, we have performed a systematic analysis of the role of histone deacetylases (HDACs) in the regulation of origin activity in budding yeast. We have found that the epigenetic regulation of repetitive sequences is a key determinant of the DNA replication program. Indeed, our study revealed that two histone deacetylases, Rpd3 and Sir2, have opposite effects on the replication timing program. Rpd3 delays initiation at late origins, whereas Sir2 promotes efficient activation of early origins. Remarkably, we also found that Rpd3 and Sir2 regulate initiation at ~200 replication origins located within the ribosomal DNA (rDNA) array. We propose that this epigenetic regulation of repetitive origins controls the replication timing program by modulating the availability of limiting initiation factors. Faithful replication of chromosomal DNA is essential for the maintenance of genome integrity. The timing and the efficiency of origin firing is flexible and is finely tuned during development and differentiation. Although the physiological significance of the replication timing program remains unclear, it is generally believed that it coordinates DNA replication with transcription, repair and other cellular functions. A large body of evidence indicates that the replication timing program is determined by a combination of local and global mechanisms that affect the structure of chromatin and the three-dimensional organization of the nucleus. These epigenetic modifications modulate the licensing of origins and/or their accessibility to initiation factors. The abundance of initiation factors restricts the number of origins that can be activated simultaneously. These factors are recycled from early to late origins during S phase. The histone deacetylase Rpd3 has been implicated in the formation of inhibitory chromatin structures that delay initiation at a large fraction of origins. Whether Rpd3 acts specifically on late origins or whether it also represses early origins is currently unclear. Besides Rpd3, it has been reported that the Sir2 and Hst1 sirtuins regulate initiation at a subset of origins in an opposite manner. However, the mechanism by which HDACs modulate the execution of the replication timing program in budding yeast remains poorly
Published: 2014

35. Homo erectus at Trinil on Java used shells for tool production and engraving

Author: Herman J. Mücher, Tony Reimann, Vincent Prié, Jan R. Wijbrans, Michel Panuel, Wil Roebroeks, Stephen Munro, John de Vos, Victoria van der Haas, Christina Ankjærgaard, Anne S. Schulp, Jakob Wallinga, Ineke Joosten, Bertil van Os, John J. G. Reijmer, Josephine C.A. Joordens, Hélène Coqueugniot, Francesco d'Errico, Klaudia F. Kuiper, Wim Lustenhouwer, Frank P. Wesselingh, Sedimentology, Geology and Geochemistry, Earth and Climate, Earth Sciences, Dynamic Earth and Resources, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Netherland Center for Luminescence Dating, Delft University of Technology (TU Delft), De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN), Rijksdienst voor Archeologie, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Hôpital Nord [CHU - APHM], and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, rates, quartz osl ages, 01 natural sciences, INDONESIA, Animal Shells, Assemblage (archaeology), 0601 history and archaeology, History, Ancient, Multidisciplinary, 060102 archaeology, biology, Fossils, south-africa, sediments, Hominidae, 06 humanities and the arts, RECORD, PE&RC, SOUTH-AFRICA, RELIABILITY, Soil Geography and Landscape, Homo erectus, LUMINESCENCE SIGNALS, SEDIMENTS, sangiran, 010506 paleontology, Engraving and Engravings, QUARTZ OSL AGES, indonesia, record, Animals, RATES, SDG 14 - Life Below Water, luminescence signals, 0105 earth and related environmental sciences, reliability, Thermoluminescence dating, Tool Use Behavior, SANGIRAN, biology.organism_classification, Archaeology, Bodemgeografie en Landschap, Homo sapiens, Mollusca, Paleoanthropology, Type locality
Abstract: Argon and luminescence dating of fossil shell infills from Trinil in Java, where Homo erectus lived, reveals that the hominin-bearing deposits are younger than previously thought; perforated shells, a shell tool and an engraved shell indicate that Homo erectus ate freshwater mussels, used their shells as tools and was able to create abstract engravings. Homo erectus made tools from shells, and even decorated some of them with what look like intentional incisions. The fossils of the hominid that came to be known as Homo erectus were discovered at Trinil in central Java by Eugene Dubois in 1891. Josephine Joordens and colleagues have been looking over the historic Dubois collections, now in Leiden in the Netherlands, concentrating on the freshwater shells. They find evidence for shellfish consumption by hominins, a shell tool and other shells showing signs of intentional modification. Age determination on the sediment directly associated with the shells show that they were used sometime between 380,000 and 640,000 years ago, well within the time during which Homo erectus lived in Java, and pre-dating the oldest geometric engravings described previously by more than 300,000 years. The manufacture of geometric engravings is generally interpreted as indicative of modern cognition and behaviour1. Key questions in the debate on the origin of such behaviour are whether this innovation is restricted to Homo sapiens, and whether it has a uniquely African origin1. Here we report on a fossil freshwater shell assemblage from the Hauptknochenschicht (‘main bone layer’) of Trinil (Java, Indonesia), the type locality of Homo erectus discovered by Eugene Dubois in 1891 (refs 2 and 3). In the Dubois collection (in the Naturalis museum, Leiden, The Netherlands) we found evidence for freshwater shellfish consumption by hominins, one unambiguous shell tool, and a shell with a geometric engraving. We dated sediment contained in the shells with 40Ar/39Ar and luminescence dating methods, obtaining a maximum age of 0.54 ± 0.10 million years and a minimum age of 0.43 ± 0.05 million years. This implies that the Trinil Hauptknochenschicht is younger than previously estimated. Together, our data indicate that the engraving was made by Homo erectus, and that it is considerably older than the oldest geometric engravings described so far4,5. Although it is at present not possible to assess the function or meaning of the engraved shell, this discovery suggests that engraving abstract patterns was in the realm of Asian Homo erectus cognition and neuromotor control.
Published: 2014

36. Proof of concept for AAV2/5-mediated gene therapy in iPSC-derived retinal pigment epithelium of a choroideremia patient

Author: Lorenne Robert, John De Vos, Valérie Rigau, Marie O. Pequignot, Nicolas Cereso, Valerie De Luca, Nicolas Nabholz, Vasiliki Kalatzis, Fabienne Becker, Christian P. Hamel, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), We are grateful to the animal house staff of the Institute for Neurosciences of Montpellier for animal care and to Chantal Cazevieille (Centre Régionale d’Imagerie Cellulaire) for the processing of electron microscopy sections. This work was funded by France Choroideremia, 'Terre Plurielle,' Retina France, and the 'Association Française contre les Myopathies.' N.C. was funded by the Choroideremia Research Foundation (United States), L.R. by France Choroideremia, V.D.L. by Retina France, and M.P. by the 'Fondation de France.', Institut des Neurosciences de Montpellier (INM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), and Hennaut, Odile
Subjects: Pathology, medicine.medical_specialty, lcsh:QH426-470, Genetic enhancement, [SDV]Life Sciences [q-bio], Biology, Choroideremia, Article, RAB ESCORT PROTEIN 1, Transduction (genetics), Genetics, medicine, lcsh:QH573-671, Induced pluripotent stem cell, Molecular Biology, Retinal pigment epithelium, lcsh:Cytology, medicine.disease, Fluid transport, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], lcsh:Genetics, medicine.anatomical_structure, biology.protein, Molecular Medicine, Retinal Dystrophies
Abstract: International audience; Inherited retinal dystrophies (IRDs) comprise a large group of genetically and clinically heterogeneous diseases that lead to progressive vision loss, for which a paucity of disease-mimicking animal models renders preclinical studies difficult. We sought to develop pertinent human cellular IRD models, beginning with choroideremia, caused by mutations in the CHM gene encoding Rab escort protein 1 (REP1). We reprogrammed REP1-deficient fibroblasts from a CHM (-/y) patient into induced pluripotent stem cells (iPSCs), which we differentiated into retinal pigment epithelium (RPE). This iPSC-derived RPE is a polarized monolayer with a classic morphology, expresses characteristic markers, is functional for fluid transport and phagocytosis, and mimics the biochemical phenotype of patients. We assayed a panel of adeno-associated virus (AAV) vector serotypes and showed that AAV2/5 is the most efficient at transducing the iPSC-derived RPE and that CHM gene transfer normalizes the biochemical phenotype. The high, and unmatched, in vitro transduction efficiency is likely aided by phagocytosis and mimics the scenario that an AAV vector encounters in vivo in the subretinal space. We demonstrate the superiority of AAV2/5 in the human RPE and address the potential of patient iPSC-derived RPE to provide a proof-of-concept model for gene replacement in the absence of an appropriate animal model.
Published: 2014

37. Female Aging Alters Expression of Human Cumulus Cells Genes that Are Essential for Oocyte Quality

Author: A. Ferrières, Sophie Bringer Deutsch, Said Assou, T. Al-Edani, Charles-Henri Lecellier, Ounissa Aït-Ahmed, Samir Hamamah, Anna Gala, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Montpellier 1 - UFR de Médecine (UM1 Médecine), Université Montpellier 1 (UM1), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Biopathologie [CHRU Montpellier], Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), This work was supported by Ferring Pharmaceuticals A/S.The authors thank the direction of the Montpellier 1 Univer-sity and University Hospital of Montpellier for their support.They thank all members of ART team for their assistanceduring this study., CHU Arnaud-de-Villeneuve [Montpellier], Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier, Institut de recherche en biothérapie (IRB), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Aging, Article Subject, IGFBP3, lcsh:Medicine, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, Humans, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, 030219 obstetrics & reproductive medicine, Cumulus Cells, General Immunology and Microbiology, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, lcsh:R, fungi, Gene Expression Regulation, Developmental, Reproducibility of Results, General Medicine, Activin receptor, Transforming growth factor beta, Oocyte, Gene expression profiling, MicroRNAs, medicine.anatomical_structure, biology.protein, Oocytes, Female, Signal Transduction, Research Article
Abstract: Impact of female aging is an important issue in human reproduction. There was a need for an extensive analysis of age impact on transcriptome profile of cumulus cells (CCs) to link oocyte quality and developmental potential with patient’s age. CCs from patients of three age groups were analyzed individually using microarrays. RT-qPCR validation was performed on independent CC cohorts. We focused here on pathways affected by aging in CCs that may explain the decline of oocyte quality with age. In CCs collected from patients >37 years, angiogenic genes includingANGPTL4,LEPR,TGFBR3, andFGF2were significantly overexpressed compared to patients of the two younger groups. In contrast genes implicated in TGF-βsignaling pathway such asAMH,TGFB1, inhibin, and activin receptor were underexpressed. CCs from patients whose ages are between 31 and 36 years showed an overexpression of genes related to insulin signaling pathway such asIGFBP3,PIK3R1, andIGFBP5. A bioinformatic analysis was performed to identify the microRNAs that are potential regulators of the differentially expressed genes of the study. It revealed that the pathways impacted by age were potential targets of specific miRNAs previously identified in our CCs small RNAs sequencing.
Published: 2014

38. Neutrophil role in in vivo anti-lymphoma activity of rituximab: FCGR3B-NA1/NA2 polymorphism does not influence response and survival after rituximab treatment

Author: Philippe Colombat, Marc Ohresser, Philippe Solal-Celigny, Gilles Salles, Hervé Watier, Guillaume Cartron, Dequeant, Evelyne, Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), and Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Neutrophils, [SDV]Life Sciences [q-bio], Follicular lymphoma, Antineoplastic Agents, GPI-Linked Proteins, Antibodies, Monoclonal, Murine-Derived, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, In vivo, hemic and lymphatic diseases, medicine, Humans, Lymphoma, Follicular, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Polymorphism, Genetic, biology, business.industry, Receptors, IgG, Antibodies, Monoclonal, Hematology, Gene rearrangement, medicine.disease, 3. Good health, Lymphoma, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Oncology, Monoclonal, Immunology, biology.protein, Female, Rituximab, Bone marrow, Antibody, business, 030215 immunology, medicine.drug
Abstract: Background Neutrophils could play an important role in in vivo rituximab anti-lymphoma activity. FcγRIIIb is expressed only by neutrophils and FcγRIIIb-neutrophil antigen (NA)1/NA2 polymorphism influenced phagocytosis of immunoglobulin G1-opsonized particles. We formulated the hypothesis that if neutrophils are critical cells for in vivo rituximab activity, FcγRIIIb-NA1/NA2 polymorphism could influence the response to rituximab. Patients and methods FCGR3B-NA1/NA2 genotypes were determined in 46 patients having received rituximab for a previously untreated, follicular, non-Hodgkin's lymphoma. The clinical response and the disappearance of the BCL2-JH gene rearrangement in both peripheral blood and bone marrow were evaluated at 2 months (M2) and each year during 7 years. Results : They were 13% homozygous for FCGR3B-NA1, 61% homozygous for FCGR3B-NA1/NA2 and 26% heterozygous. The objective response rates at M2 were 67% in homozygous FCGR3B-NA1 patients compared with 75% in homozygous FCGR3B-NA2 and 75% in heterozygous patients (not significant). We found no difference for progression-free and overall survival by FCGR3B-NA1/NA2 genotypes. Conclusion : These results indicate no association between FCGR3B-NA1/NA2 polymorphism and response to rituximab indicating no significant role of phagocytosis mediated by neutrophils in in vivo mechanism of rituximab activity.
Published: 2008

39. Cloning and expression of an alternatively spliced mRNA encoding a soluble form of the human interleukin-6 signal transducer gp1301

Author: Morten Svenson, Nadir Mechti, Marcus Diamant, Xue-Guang Zhang, Klaus Bendtzen, Klaus Rieneck, Bernard Klein, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biomonitor A/S, Institut de recherche en biothérapie (IRB), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0303 health sciences, [SDV]Life Sciences [q-bio], Chinese hamster ovary cell, Alternative splicing, Biophysics, Cell Biology, Biology, Biochemistry, Molecular biology, Transmembrane protein, 03 medical and health sciences, Transmembrane domain, Exon, 0302 clinical medicine, Structural Biology, 030220 oncology & carcinogenesis, Complementary DNA, Genetics, Coding region, Molecular Biology, Peptide sequence, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: The membrane-bound gp130 glycoprotein acts as an affinity converting and signal transducing receptor (R) for interleukin-6 and several other cytokines. In this work, we RT-PCR amplified gp130 cDNA using primers flanking the sequence encoding the transmembrane domain of gp130. We observed in blood mononuclear cells, in addition to the expected 333-bp length fragment, a second major band of 418 bp. Sequencing of the 418-bp fragment and its genomic counterpart showed a new 85-bp exon located in the sequence encoding the extracellular region of the gp130 protein. This exon is most likely due to alternative splicing and leads to a frame-shift resulting in a stop-codon 1 bp before the transmembrane coding region. Correspondingly, supernatants from chinese hamster ovary cells transfected with this cDNA contained 4-5 times more soluble (s) gp130 than supernatants from cells transfected with a cDNA encoding the membrane-bound gp130 protein. Both gp130 and alternatively spliced sgp130 were also transcribed by the myeloma cell lines XG-1, XG-2, XG-4, XG-4CNTF XG-6, XG-7, XG-9, XG-10, U266 and RPMI 8226. However, XG-4A cells derived from XG-4 cells, but growing independently of exogenous IL-6, did not transcribe sgp130 mRNA. A possible interference with intracrine stimulatory factors by alternatively spliced sgp130 needs to be further investigated.
Published: 1997

40. Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors

Author: Guilhem Requirand, Hartmut Goldschmidt, Wim Leonard, Dirk Hose, Bernard Klein, Jean-Luc Veyrune, Thierry Rème, Jérôme Moreaux, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Nationales Centrum für Tumorerkrankungen, National Center for Tumor Diseases (NCTD), Association pour la Recherche sur le Cancer, ARC SL220110603450, B Klein, Paris, France, FEDER 141786&42667 B Klein, J Moreaux, France, The Hopp-Foundation, Germany, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Frei, Monique
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, prediction of drug sensitivity, Biology, Hydroxamic Acids, Cohort Studies, Histones, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Predictive Value of Tests, Panobinostat, Internal medicine, medicine, Humans, Vorinostat, Multiple myeloma, 030304 developmental biology, Regulation of gene expression, GEP-based score, 0303 health sciences, HDACi, Histone deacetylase inhibitor, Acetylation, medicine.disease, Up-Regulation, 3. Good health, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Trichostatin A, chemistry, 030220 oncology & carcinogenesis, Immunology, Significance analysis of microarrays, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Histone deacetylase, Gene expression, Neoplasm Grading, Translational Therapeutics, Transcriptome, Multiple Myeloma, medicine.drug
Abstract: International audience; BACKGROUND: Multiple myeloma (MM) is still a fatal plasma cell cancer. Novel compounds are currently clinically tested as a single agent in relapsing patients, but in best cases with partial response of a fraction of patients, emphasising the need to design tools predicting drug efficacy. Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression and are in clinical development in MM. METHODS: To create a score predicting HDACi efficacy, five MM cell lines were treated with trichostatin A (TSA) and gene expression profiles were determined. RESULTS: The expression of 95 genes was found to be upregulated by TSA, using paired supervised analysis with Significance Analysis of Microarrays software. Thirty-seven of these 95 genes had prognostic value for overall survival in a cohort of 206 newly diagnosed MM patients and their prognostic information was summed up in a histone acetylation score (HA Score); patients with the highest HA Score had the shorter overall survival. It is worth noting that MM cell lines or patients' primary MM cells with a high HA Score had a significant higher sensitivity to TSA, valproic acid, panobinostat or vorinostat. CONCLUSION: In conclusion, the HA Score allows identification of MM patients with poor survival, who could benefit from HDACi treatment.
Published: 2013

41. Side scatter intensity is highly heterogeneous in undifferentiated pluripotent stem cells and predicts clonogenic self-renewal.: Side scatter establishes a new PSC hierarchy

Author: Ramirez, Jean-Marie, Bai, Qiang, Péquignot, Marie, Becker, Fabienne, Kassambara, Alboukadel, Bouin, Alexandra, Kalatzis, Vasiliki, Dijon-Grinand, Marilyne, de Vos, John, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Association Française contre les Myopathies (AFM, Paris), The Languedoc-Roussillon Region (Chercheur d'Avenir 09-13198-01), and Frei, Monique
Subjects: side scatter, [SDV.IMM] Life Sciences [q-bio]/Immunology, clonogenic self-renewal, [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.IMM]Life Sciences [q-bio]/Immunology, pluripotent stem cells, heterogeneity, skin and connective tissue diseases, pluripotency, stem cell hierarchies, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract: International audience; In culture, human pluripotent stem cells (PSCs) are phenotypically (for instance, the SSEA3 expression level) and functionally (capacity to survive after single-cell dissociation) heterogeneous. We report here that the side scatter (SSC) signal measured by flow cytometry, a variable correlated with membrane irregularity and cell granularity, is very high in PSCs, even higher than in blood polymorphonuclear cells, and markedly heterogeneous. Moreover, SSC intensity rapidly and strongly decreases upon PSC differentiation into any of the three germ layers. PSCs with high SSC (HSSC cells) or low SSC (LSSC cells) values both express pluripotency markers, but HSSC cells are characterized by more frequent simultaneous expression of the membrane pluripotency factors SSEA3, SSEA4, TRA-1-81, TRA-1-60, and CD24 and by a higher mitochondrial content. Functionally, HSSC cells are more likely to generate colonies upon single-cell passage than LSSC cells. SSC monitoring might provide a simple, but robust and rapid method to estimate pluripotency variations in culture and unveils a new phenotypic and functional heterogeneity in PSCs.
Published: 2013

42. Comparative analysis of protein expression of three stem cell populations: models of cytokine delivery system in vivo

Author: Paul C. Schiller, Sylvain Lehmann, Claudia N. Montero-Menei, Gianluca D'Ippolito, Thomas Bouckenooghe, L. Adriana Gomez, Stéphane Roche, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU) - Assistance Publique - Hôpitaux de Marseille (APHM) - Hôpital de la Timone [CHU - APHM] (TIMONE) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Plateforme de Protéomique Clinique, Hôpital Saint Eloi, Department of Orthopaedics, Tissue Bank, Geriatrics, University of Miami Miller School of Medicine - Interdisciplinary Stem Cell Institutes, Geriatric Research, Education and Clinical Center and Research Services, Bruce W. Carter Veterans Affairs Medical Center, Ingénierie de la vectorisation particulaire, Université d'Angers (UA) - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1) - Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier) - Université de Montpellier (UM), Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine - Geriatrics and Vascular Biology Institutes, Merit Review Award (PCS) by the Department of Veterans Affairs, Roche, Stephane, Adult mesenchymal stem cells engineering for connective tissue disorders. From the bench to the bed side - GENOSTEM - 26809 - OLD, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Pôle Protéome de Montpellier (PPM), Université de Montpellier (UM), Department of Orthopaedics, Tissue Bank, Geriatrics and Interdisciplinary Stem Cell Institutes [Miami, FL, USA], University of Miami Leonard M. Miller School of Medicine (UMMSM), Geriatric Research, Education and Clinical Center and Research Services [Miami, FL, USA], Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Biochemistry & Molecular Biology Geriatrics and Vascular Biology Institutes [Miami, FL, USA], European Project: 26809,GENOSTEM, CHU Saint-Eloi, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: Proteomics, [SDV.IMM] Life Sciences [q-bio]/Immunology, Angiogenesis, medicine.medical_treatment, Pharmaceutical Science, Bone Marrow Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, 0302 clinical medicine, stem cells, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, cytokine, Humans, Progenitor cell, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Delivery system, 030304 developmental biology, Mesenchymal stem cell, 0303 health sciences, Mass spectrometry, Embryonic stem cell, Cell biology, Endothelial stem cell, delivery systems, Cytokine, 2D-PAGE, Cytokines, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokine secretion, Stem cell, 030217 neurology & neurosurgery
Abstract: International audience; Several mechanisms mediate the regenerative and reparative capacity of stem cells, including cytokine secretion; therefore these cells can act as delivery systems of therapeutic molecules. Here we begin to address the molecular and cellular basis of their regenerative potential by characterizing the proteomic profile of human embryonic stem cells (hESCs), mesenchymal stem cells (hMSCs) and marrow isolated adult multilineage inducible (MIAMI) cells, followed by analysis of the secretory profile of the latter stem cell population. Proteomic analysis establishes the closer relationship between hMSCs and MIAMI cells, while hESCs are more divergent. However, MIAMI cells appear to have more proteins in common with hESCs than hMSCs. Proteins characteristic of hMSCs include transgelin-2, phosphatidylethanolamine-binding protein 1 (PEBP1), Heat-Shock 20 kDa protein (HSP20/HSPβ6), and programmed cell death 6-interacting protein (PDC6I) among others. MIAMI cells are characterized by the high level expression of ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCHL1), 14-3-3 zeta, HSP27 (HSPβ1), and tropomyosin 4 and 3. For hESC, elongation factor Tu (EFTu), isocitrate dehydrogenase (IDH1) and the peroxiredoxins 1, 2, and 6 (PRDX1, PRDX2, and PRDX6) were the most characteristic. Secretome analysis indicates that MIAMI cells secrete higher levels of vascular endothelial growth factor (VEGF), Fractalkine, Interleukin-6, interlukin-8, and growth related oncogene (GRO), compared to hMSCs. These soluble mediators are known to play key roles in angiogenesis, arteriogenesis, atheroprotection, immunomodulation, neuroprotection, axonal growth, progenitor cell migration, and prevention of apoptosis. All these roles are consistent with a reparative pro-survival secretory phenotype. We further discuss the potential of these cells as therapeutic vehicles.
Published: 2013

43. Anti-tumour immunotherapy with Vγ9Vδ2 T lymphocytes: from the bench to the bedside

Author: Mounia Sabrina Braza, Bernard Klein, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Montpellier 1 - UFR de Médecine (UM1 Médecine), Université Montpellier 1 (UM1), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Frei, Monique
Subjects: Receptors, Antigen, T-Cell, alpha-beta, medicine.medical_treatment, Lymphocyte, MESH: Antigens, Neoplasm, MESH: Translational Medical Research, MESH: Adjuvants, Immunologic, MESH: T-Lymphocyte Subsets, Adaptive Immunity, CD8-Positive T-Lymphocytes, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, Translational Research, Biomedical, 0302 clinical medicine, Cancer immunotherapy, T-Lymphocyte Subsets, Neoplasms, MESH: Neoplasms, Immunologic Surveillance, Cells, Cultured, Clinical Trials as Topic, 0303 health sciences, MESH: Receptors, Antigen, T-Cell, alpha-beta, Diphosphonates, MESH: Dendritic Cells, Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor, Receptors, Antigen, T-Cell, gamma-delta, Hematology, Acquired immune system, MESH: Gene Rearrangement, delta-Chain T-Cell Antigen Receptor, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, MESH: Immunotherapy, Adoptive, MESH: Tumor Escape, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Immunity, Innate, immunotherapy, monoclonal antibodies, MESH: Cells, Cultured, MESH: Killer Cells, Natural, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Clinical Trials as Topic, MESH: Diphosphonates, T cell, Gene Rearrangement, delta-Chain T-Cell Antigen Receptor, haematological oncology, 03 medical and health sciences, Adjuvants, Immunologic, Antigen, Antigens, Neoplasm, gamma delta T lymphocytes, MESH: Receptors, Antigen, T-Cell, gamma-delta, medicine, Humans, cancer, 030304 developmental biology, MESH: Immunologic Surveillance, MESH: Humans, business.industry, MESH: T-Lymphocytes, Regulatory, Mesenchymal Stem Cells, Dendritic Cells, Immunotherapy, Gene rearrangement, T lymphocyte, Immunity, Innate, MESH: Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor, Immunology, MESH: Mesenchymal Stromal Cells, Tumor Escape, business, MESH: T-Lymphocytes, Cytotoxic, MESH: Adaptive Immunity, T-Lymphocytes, Cytotoxic, 030215 immunology
Abstract: International audience; Gamma delta (γδ) Τ cells are non-conventional T lymphocyte effectors that can interact with and eradicate tumour cells. Several data demonstrate that these T cells, which are implicated in the first line of defence against pathogens, have anti-tumour activity against many cancers and suggest that γδ Τ cell-mediated immunotherapy is feasible and might induce objective tumour responses. Due to the importance of γδ Τ lymphocytes in the induction and control of immunity, a complete understanding of their biology is crucial for the development of a potent cancer immunotherapy. This review discusses recent advances in γδ Τ basic research and data from clinical trials on the use of γδ Τ cells in the treatment of different cancers. It analyses how this knowledge might be applied to develop new strategies for the clinical manipulation and the potentiation of γδ Τ lymphocyte activity in cancer immunotherapy.
Published: 2013

44. Inhibition of DEPDC1A, a bad prognostic marker in multiple myeloma, delays growth and induces mature plasma cell markers in malignant plasma cells

Author: Thierry Rème, Alboukadel Kassambara, Bernard Klein, Dirk Hose, Jean-Luc Veyrune, Matthieu Schoenhals, Hartmut Goldschmidt, Jérôme Moreaux, Hematology, Basic (bio-) Medical Sciences, Frei, Monique, FP7-OVERMYR - INCOMING, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], National Center for Tumor Diseases (NCTD), ARC, Association pour la Recherche sur le Caner, Paris, France, The Tumorzentrum Heidelberg/Mannheim, Germany, The Deutsche Krebshilfe, Bonn, Germany, European Project, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), and Universität Heidelberg [Heidelberg] = Heidelberg University
Subjects: Cellular differentiation, Apoptosis, Cyclin-Dependent Kinase Inhibitor p21/metabolism, Plasma cell, Signal transduction, CXCR4, Plasma Cell Disorders, Hematologic Cancers and Related Disorders, 0302 clinical medicine, RNA interference, Neoplasm Proteins/genetics, Apoptosis/genetics, Molecular Cell Biology, Cluster Analysis, Genetics(clinical), Multiple myeloma, 0303 health sciences, Gene knockdown, Multidisciplinary, phosphorylation, hematology, Plasma Cells/metabolism, Cell Cycle, GTPase-Activating Proteins, Cell Differentiation, Cell cycle, Prognosis, Neoplasm Proteins, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, protein stability, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, oncology, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor Suppressor Protein p53/genetics, Multiple Myeloma, Research Article, Cyclin-Dependent Kinase Inhibitor p21, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, Plasma Cells, Cell Differentiation/genetics, Bone Marrow Cells, Multiple Myeloma/genetics, Biology, Cell Growth, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, Cell Cycle/genetics, Myelomas and Lymphoproliferative Diseases, 030304 developmental biology, Cell growth, Gene Expression Profiling, Bone Marrow Cells/metabolism, Cancers and Neoplasms, medicine.disease, cell proliferation, Cancer research, Tumor Suppressor Protein p53, mutation
Abstract: International audience; High throughput DNA microarray has made it possible to outline genes whose expression in malignant plasma cells is associated with short overall survival of patients with Multiple Myeloma (MM). A further step is to elucidate the mechanisms encoded by these genes yielding to drug resistance and/or patients' short survival. We focus here on the biological role of the DEP (for Disheveled, EGL-10, Pleckstrin) domain contained protein 1A (DEPDC1A), a poorly known protein encoded by DEPDC1A gene, whose high expression in malignant plasma cells is associated with short survival of patients. Using conditional lentiviral vector delivery of DEPDC1A shRNA, we report that DEPDC1A knockdown delayed the growth of human myeloma cell lines (HMCLs), with a block in G2 phase of the cell cycle, p53 phosphorylation and stabilization, and p21(Cip1) accumulation. DEPDC1A knockdown also resulted in increased expression of mature plasma cell markers, including CXCR4, IL6-R and CD38. Thus DEPDC1A could contribute to the plasmablast features of MMCs found in some patients with adverse prognosis, blocking the differentiation of malignant plasma cells and promoting cell cycle.
Published: 2013

45. Prion replication occurs in endogenous adult neural stem cells and alters their neuronal fate: involvement of endogenous neural stem cells in prion diseases

Author: Claire Hamela, Carole Crozet, Danielle Casanova, Maxime Belondrade, Chantal Mourton-Gilles, Aroa Relano-Gines, Sylvain Lehmann, Audrey Gabelle, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Agence Nationale de Sécurité du Médicament et des produits de santé, ANSM, Fondation pour la Recherche Médicale, Paris, France, France Alzheimer Association, Paris, France, CDJ Foundation, Akron, Ohio, USA, European Project, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Frei, Monique, and Food CT 2004 506579, European Netword of Excellence of Neuroprion - INCOMING
Subjects: Male, lcsh:Immunologic diseases. Allergy, [SDV.IMM] Life Sciences [q-bio]/Immunology, Prions, medicine.medical_treatment, Cellular differentiation, Immunology, Subventricular zone, Biology, Microbiology, Prion Diseases, Mice, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Virology, Genetics, medicine, Animals, Molecular Biology, lcsh:QH301-705.5, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Dentate gyrus, Neurogenesis, Stem-cell therapy, Neural stem cell, 3. Good health, nervous system diseases, Neuroepithelial cell, Adult Stem Cells, Infectious Diseases, Mental Health, medicine.anatomical_structure, nervous system, lcsh:Biology (General), Dentate Gyrus, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Parasitology, lcsh:RC581-607, Neuroscience, 030217 neurology & neurosurgery, Research Article, Adult stem cell
Abstract: Prion diseases are irreversible progressive neurodegenerative diseases, leading to severe incapacity and death. They are characterized in the brain by prion amyloid deposits, vacuolisation, astrocytosis, neuronal degeneration, and by cognitive, behavioural and physical impairments. There is no treatment for these disorders and stem cell therapy therefore represents an interesting new approach. Gains could not only result from the cell transplantation, but also from the stimulation of endogenous neural stem cells (NSC) or by the combination of both approaches. However, the development of such strategies requires a detailed knowledge of the pathology, particularly concerning the status of the adult neurogenesis and endogenous NSC during the development of the disease. During the past decade, several studies have consistently shown that NSC reside in the adult mammalian central nervous system (CNS) and that adult neurogenesis occurs throughout the adulthood in the subventricular zone of the lateral ventricle or the Dentate Gyrus of the hippocampus. Adult NSC are believed to constitute a reservoir for neuronal replacement during normal cell turnover or after brain injury. However, the activation of this system does not fully compensate the neuronal loss that occurs during neurodegenerative diseases and could even contribute to the disease progression. We investigated here the status of these cells during the development of prion disorders. We were able to show that NSC accumulate and replicate prions. Importantly, this resulted in the alteration of their neuronal fate which then represents a new pathologic event that might underlie the rapid progression of the disease., Author Summary Prion diseases are irreversible progressive neurodegenerative diseases, leading to severe incapacity and death. They are considered to be caused by an abnormally folded infectious protein named PrPSc. They are characterized in the brain by prion amyloid deposits, vacuolisation, astrocyte proliferation, neuronal degeneration, and by cognitive, behavioural and physical impairments. There is no treatment for these disorders. Transplantation of stem cells, or the stimulation of endogenous neural stem cells (NSC) in the adult brain therefore constitute new interesting and promising strategies. While our first interest was the development of a cell therapy approach, we rapidly realised that there were a lot of questions to address before investigating pre-clinical cell therapy assays. Some of them were: (i) what is the status of endogenous neural stem cells during the development of prion diseases and can they amplify prions, and (ii) can they still proliferate and give rise to new neurons. In this study we definitely demonstrate that PrPSc was not only able to replicate in adult neural stem cells derived from infected brains but also that this results in an impairment of the production of their neuronal derivatives.
Published: 2013

46. Embryonic stem cells or induced pluripotent stem cells? A DNA integrity perspective

Author: Bai, Qiang, Desprat, Romain, Klein, Bernard, Lemaitre, Jean-Marc, de Vos, John, Frei, Monique, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 - UFR de Médecine (UM1 Médecine), Université Montpellier 1 (UM1), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Association Française contre les Myopathies (AFM, Paris, France), and Région Languedoc-Roussillon, France
Subjects: Induced pluripotent stem cells, genome integrity, [SDV.IMM] Life Sciences [q-bio]/Immunology, cell reprogramming, genetic abnormalities, DNA damage, [SDV.IMM]Life Sciences [q-bio]/Immunology, pluripotency
Abstract: International audience; Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are two types of pluripotent stem cells that hold great promise for biomedical research and medical applications. iPSCs were initially favorably compared to ESCs. This view was first based on ethical arguments (the generation of iPSCs does not require the destruction of an embryo) and on immunological reasons (it is easier to derive patient HLA-matched iPSCs than ESCs). However, several reports suggest that iPSCs might be characterized by higher occurrence of epigenetic and genetic aberrations than ESCs as a consequence of the reprogramming process. We focus here on the DNA integrity of pluripotent stem cells and examine the three main sources of genomic abnormalities in iPSCs: (1) genomic variety of the parental cells, (2) cell reprogramming, and (3) in vitro cell culture. Recent reports claim that it is possible to generate mouse or human iPSC lines with a mutation level similar to that of the parental cells, suggesting that "genome-friendly" reprogramming techniques can be developed. The issue of iPSC DNA integrity clearly highlights the crucial need of guidelines to define the acceptable level of genomic integrity of pluripotent stem cells for biomedical applications. We discuss here the main issues that such guidelines should address.
Published: 2013

47. Gene expression-based risk score in diffuse large B-cell lymphoma

Author: Caroline Bret, Jérôme Moreaux, Bernard Klein, Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Université Montpellier 1 - UFR de Médecine (UM1 Médecine), Université Montpellier 1 (UM1), Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Association pourla Recherche sur le Cancer (SL220110603450, Paris, France), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Frei, Monique, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Oncology, Drug resistance, nucleotide excision DNA repair, Kaplan-Meier Estimate, CHOP, Bioinformatics, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, International Prognostic Index, Risk Factors, Prednisone, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Cluster Analysis, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Framingham Risk Score, Hematology, medicine.diagnostic_test, Research Papers, 3. Good health, Phenotype, Treatment Outcome, Vincristine, 030220 oncology & carcinogenesis, gene expression profile, [SDV.IMM]Life Sciences [q-bio]/Immunology, Lymphoma, Large B-Cell, Diffuse, Rituximab, medicine.drug, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Editorials: Cell Cycle Features, Biology, risk score, Risk Assessment, Genomic Instability, 03 medical and health sciences, Internal medicine, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Genetic Testing, Molecular Biology, Gene, Cyclophosphamide, Genetic testing, Proportional Hazards Models, 030304 developmental biology, drug resistance, Gene Expression Profiling, fungi, Cell Biology, DNA Repair Pathway, Gene signature, medicine.disease, Lymphoma, Gene expression profiling, Doxorubicin, DLBCL, Multivariate Analysis, Immunology, prognosis, Diffuse large B-cell lymphoma, Developmental Biology
Abstract: // Caroline Bret 1,2,3 , Bernard Klein 2,3 , and Jerome Moreaux 2 1 Department of Biological Hematology, St Eloi Hospital, Montpellier, France 2 INSERM U1040, Institute of Research in Biotherapy, Montpellier, France 3 University of Montpellier 1, UFR de Medecine, Montpellier, France Correspondence: Jerome Moreaux, email: // Keywords : DLBCL, gene expression profile, risk score, prognosis Received : December 29, 2012, Accepted : December 30, 2012, Published : December 31, 2012 Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and displays heterogeneous clinical and molecular characteristics. In this study, high throughput gene expression profiling of DLBCL tumor samples was used to design a 12-gene expression–based risk score (GERS) predictive for patient’s overall survival. GERS allowed identifying a high-risk group comprising 46,4% of the DLBCL patients in two independent cohorts (n=414 and n=69). GERS was shown to be an independent predictor of survival when compared to the previously published prognostic factors, including the International Prognostic Index (IPI). GERS displayed a prognostic value in germinal-center B-cell–like subgroup (GCB) and activated B cell–like (ABC) molecular subgroups of patients as well as in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or Rituximab-CHOP (R-CHOP) regimens. Combination of GERS and IPI lead to a potent prognostic classification of DLBCL patients. Finally, a genomic instability gene signature was highlighted in gene expression profiles of patients belonging to the high-risk GERS-defined group.
Published: 2012

48. Development of gene expression-based score to predict sensitivity of multiple myeloma cells to DNA methylation inhibitors

Author: Jean Luc Veyrune, Dirk Hose, Guilhem Requirand, Hartmut Goldschmidt, Bernard Klein, Thierry Rème, Jérôme Moreaux, Wim Leonard, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], National Center for Tumor Diseases (NCTD), Frei, Monique, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Cancer Research, MESH: Multiple Myeloma, Plasma cell, Bioinformatics, 0302 clinical medicine, MESH: DNA Methylation, DNA Modification Methylases, Multiple myeloma, MESH: DNA Modification Methylases, Regulation of gene expression, 0303 health sciences, MESH: Antimetabolites, Antineoplastic, DNA methylation inhibitors, MESH: Gene Expression Regulation, Neoplastic, Prognosis, MESH: Predictive Value of Tests, 3. Good health, Gene Expression Regulation, Neoplastic, multiple myeloma, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Azacitidine, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug, Antimetabolites, Antineoplastic, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, Decitabine, MESH: Azacitidine, Biology, DNA methyltransferase, MESH: Prognosis, 03 medical and health sciences, MESH: Gene Expression Profiling, Predictive Value of Tests, Cell Line, Tumor, Biomarkers, Tumor, medicine, Humans, 030304 developmental biology, MESH: Humans, Gene Expression Profiling, Cancer, DNA Methylation, medicine.disease, MESH: Tumor Markers, Biological, Cancer research, Bone marrow, Gene expression
Abstract: Multiple myeloma is a plasma cell cancer with poor survival, characterized by the clonal expansion of multiple myeloma cells (MMC), primarily in the bone marrow. Novel compounds are currently tested in this disease, but partial or minor patients' responses are observed for most compounds used as a single agent. The design of predictors for drug efficacy could be most useful to better understand basic mechanisms targeted by these drugs and design clinical trials. In the current study, we report the building of a DNA methylation score (DM score) predicting the efficacy of decitabine, an inhibitor of DNA methyltransferase (DNMT), targeting methylation-regulated gene expression. DM score was built by identifying 47 genes regulated by decitabine in human myeloma cell lines and the expression of which in primary MMCs of previously untreated patients is predictive for overall survival. A high DM score predicts patients' poor survival, and, of major interest, high sensitivity of primary MMCs or human myeloma cell lines to decitabine in vitro. Thus, DM score could be useful to design novel treatments with DMNT inhibitor in multiple myeloma and has highlighted 47 genes, the gene products of which could be important for multiple myeloma disease development. Mol Cancer Ther; 11(12); 2685–92. ©2012 AACR.
Published: 2012

49. Residual malignant and normal plasma cells shortly after high dose melphalan and stem cell transplantation. Highlight of a putative therapeutic window in Multiple Myeloma?

Author: Jean-François Rossi, Gaëlle Olivier, Anouk Caraux, Laure Vincent, Salahedine Bouhya, Jean-Luc Veyrune, Bernard Klein, Jérôme Moreaux, Guilhem Requirand, Philippe Quittet, Guillaume Cartron, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Service d'hématologie et oncologie médicale, Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Unité de Thérapie Cellulaire et Génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Association pour la Recherche sur le Cancer ARC (SL220110603450, Paris, France) Ligue Nationale Contre le Cancer (fellowship), European Project, Frei, Monique, fp7 OVER-MyR - INCOMING, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Melphalan, Adult, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Transplantation, Autologous, plasma cells, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, parasitic diseases, medicine, Humans, human, Antineoplastic Agents, Alkylating, Multiple myeloma, Dexamethasone, Aged, business.industry, Minimal residual disease, digestive, oral, and skin physiology, High dose melphalan, Middle Aged, medicine.disease, 3. Good health, Transplantation, body regions, multiple myeloma, Oncology, 030220 oncology & carcinogenesis, minimal resigual disease, Immunology, Proteasome inhibitor, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Stem cell, business, 030215 immunology, medicine.drug, Stem Cell Transplantation, Research Paper
Abstract: International audience; Multiple Myeloma (MM) is an incurable malignant plasma cell disorder. We have evaluated the counts of Multiple Myeloma Cells (MMCs) and normal plasma cells (N-PCs), seven days after high-dose melphalan (HDM) and autologous stem transplantation (ASCT). Two third of patients had detectable minimal residual disease (MRD+) (71.7 MMCs/µL) after induction treatment with dexamethasone and proteasome inhibitor. MMC counts were reduced by 92% (P ≤ .05) but not eradicated 7 days after HDM+ASCT. Post-HDM+ASCT MMCs were viable and bathed in a burst of MMC growth factors, linked with post-HDM aplasia. In one third of patients (MRD- patients), MMCs were not detectable after induction treatment and remained undetectable after HDM+ASCT. Major difference between MRD- and MRD+ patients is that N-PC counts were increased 3 fold (P〈.05) by HDM+ASCT in MRD- patients, but were unaffected in MRD+ patients. Possible explanation could be that clearance of MMCs in MRD- patients makes more niches available for N-PCs. Thus, MMCs are not fully eradicated shortly after HDM, are bathed in high concentrations of MMC growth factors in an almost desert BM, are viable in short-term culture, which suggests providing additional therapies shortly after HDM to kill resistant MMCs before full repair of lesions.
Published: 2012

50. Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes

Author: Olivier Fouquet, Gersende Caron, Fabien Guilloton, Joelle Dulong, Thierry Lamy, Patricia Amé-Thomas, Delphine Rossille, Cédric Ménard, John De Vos, Catherine Henry, Ceéline Pangault, Thierry Fest, Karin Tarte, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Modélisation Conceptuelle des Connaissances Biomédicales, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], INCa libre PL06-10, INCa PAIR Lymphome 2008-019, and Ligue Régionale Contre le Cancer
Subjects: Male, Cellular differentiation, Follicular lymphoma, MESH: Monocytes, Biochemistry, Monocytes, MESH: Lymphoma, Follicular, 0302 clinical medicine, Cell Movement, Lymphoma, Follicular, MESH: Cell Movement, Cells, Cultured, Chemokine CCL2, Oligonucleotide Array Sequence Analysis, MESH: Aged, B-Lymphocytes, 0303 health sciences, MESH: Middle Aged, MESH: Real-Time Polymerase Chain Reaction, Cell Polarity, Cell Differentiation, Hematology, Middle Aged, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Monocyte differentiation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Cell Polarity, MESH: Cells, Cultured, Adult, MESH: Cell Differentiation, Stromal cell, Blotting, Western, Immunology, Biology, CCL2, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: B-Lymphocytes, MESH: Cell Proliferation, Biomarkers, Tumor, medicine, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Chemokine CCL2, Aged, Cell Proliferation, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Gene Expression Profiling, Mesenchymal stem cell, Mesenchymal Stem Cells, MESH: Adult, Cell Biology, medicine.disease, MESH: Male, Lymphoma, MESH: Mesenchymal Stem Cells, MESH: Oligonucleotide Array Sequence Analysis, MESH: Tumor Markers, Biological, Cancer research, Bone marrow, Stromal Cells, MESH: Stromal Cells, MESH: Female
Abstract: Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.
Published: 2012

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