Author: "CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)" / Language: undetermined - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)"' showing total 86 results

Start Over Author "CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)" Language undetermined

86 results on '"CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)"'

1. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia

Author: Sonia Zaghdoudi, Guangli Yang, Lara Gales, Mathilde Cathebas, François Vergez, Héléna Boutzen, François Delhommeau, Isabelle Jouanin, Marion David, Tony Kaoma, Ouathek Ouerfelli, Pierre Hirsch, Jean-Emmanuel Sarry, Lucille Stuani, Clément Larrue, Christophe Junot, Estelle Saland, Laurent Le Cam, Romain Riscal, Laetitia K. Linares, Jean-Charles Portais, Véronique De Mas-Mansat, Eric Delabesse, Laurent Vallar, Fabienne De Toni, Florence Castelli, Christian Recher, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), 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 National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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 National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Luxembourg Institute of Health (LIH), 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), Organic Synthesis Core Facility [New York, NY, USA], Memorial Sloane Kettering Cancer Center [New York], Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de biologie clinique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], CHU Saint-Antoine [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), Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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 Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the French government under the program 'Investissement d'avenir' Cancer Pharmacology of Toulouse-Oncopole and Region (ANR-11-PHUC-001) and the project MET AML (INCA-2012-105), from the Fondation Innabiosante/Toulouse Cancer Santé, the Fondation ARC, the Association Laurette Fugain under the program RES IST AML, and the Association G.A.E.L. H. Boutzen was supported by the Fondation pour la Recherche Médicale (FDT20140930983). F. de Toni had a fellowship from the Fondation de FranceWork at the Organic Synthesis Core is partially funded through National Cancer Institute Core grant P30 CA008748-48. MetaToul is supported by grants from the Région Midi-Pyrénées, the European Regional Development Fund, the SIC OVAL, the Infrastructures en Biologie Sante et Agronomie (France), the Centre National de la Recherche Scientifique (CNRS), and the Institut National de la Recherche Agronomique (INRA)., ANR-11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), MetaToul AXIOM (E20), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), 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)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genomics Research Unit, Ctr Rech Publ Sante, Centre de Recherche Public de la Santé, Institut Régional du Cancer, Organic Synthesis Core Facility, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, Université Pierre et Marie Curie (Paris 6), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), French government under the program 'Investissement d'avenir' Cancer Pharmacology of Toulouse-Oncopole and Region [ANR-11-PHUC-001], project MET AML [INCA-2012-105], Fondation Innabiosante/Toulouse Cancer Sante, Fondation ARC, Association Laurette Fugain under the program RES IST AML, Association G.A.E.L., Fondation pour la Recherche Medicale [FDT20140930983], Fondation de FranceWork at the Organic Synthesis Core through National Cancer Institute [P30 CA008748-48], Region Midi-Pyrenee s, European Regional Development Fund, SIC OVAL, Infrastructures en Biologie Sante et Agronomie (France), Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], CRLCC Henri Becquerel-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Service d'immunologie et hématologies biologiques [Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU)-CHU Saint-Antoine [APHP], 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), ANR-11-PHUC-0001/11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), Linares, Laetitia, Pôle hospitalier Universitaire Cancer (PHUC) - Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région - - CAPTOR2011 - ANR-11-PHUC-0001 - PHUC - VALID, Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-MetaboHUB-MetaToul, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Male, gene set enrichment analysis, IDH, 0301 basic medicine, Myeloid, Abbreviations used: 2-HG, [SDV]Life Sciences [q-bio], Mutant, Retinoic acid, gene set enrich, Mice, chemistry.chemical_compound, 0302 clinical medicine, NBT, AML, hemic and lymphatic diseases, retinoic acid, Immunology and Allergy, L-CFU, promyelocytic leukemia, ATRA, promyelocytic l, Research Articles, transcription factor, all-trans RA, BCL, Myeloid leukemia, Cell Differentiation, Isocitrate Dehydrogenase, Neoplasm Proteins, quantitative Ch, 3. Good health, chromatin immun, Leukemia, Myeloid, Acute, qPCR, Leukemia, Haematopoiesis, qChIP, medicine.anatomical_structure, Isocitrate dehydrogenase, 030220 oncology & carcinogenesis, Female, 2-hydroxyglutar, TF, liquid chromato, α-KG, quantitative ChIP, IDH1, Cell Survival, Immunology, Mutation, Missense, ChIP, Mice, Nude, 2-hydroxyglutarate, HL-60 Cells, Tretinoin, [SDV.CAN]Life Sciences [q-bio]/Cancer, chromatin immunoprecipitation, acute myeloid leukemia, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, nitrotetrazolium blue, quantitative PC, medicine, Animals, Humans, isocitrate de-, neoplasms, liquid chromatography-mass spectrometry, GSEA, nitrotetrazoliu, PML, Brief Definitive Report, LC/MS, transcription f, acute PML, medicine.disease, Xenograft Model Antitumor Assays, B cell lymphoma, APL, α-ketoglutarate, 030104 developmental biology, Amino Acid Substitution, chemistry, isocitrate de- hydrogenase, quantitative PCR, CCAAT-Enhancer-Binding Proteins, Cancer research, acute myeloid l, leukemic CFU, Blast Crisis, Abbreviations u, RA, Granulocytes
Abstract: Boutzen et al. show that the IDH1 mutation and its oncometabolite, (R)-2-hydroxyglutarate, dysregulate downstream target pathways of myeloid-specific TFs, especially CEBPα, priming mutant IDH1-R132H AML blasts to the granulomonocytic lineage., Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD–Scid–IL2rγnull mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies.
Published: 2016

2. Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer

Author: Christel Larbouret, Thierry Chardès, Bruno Robert, Gaëlle Thomas, Pierre-Emmanuel Colombo, Véronique Garambois, Martine Pugnière, Charline Ogier, Pierre Martineau, Marta Jarlier, Céline Gongora, Nelly Pirot, Pierre Sicard, André Pèlegrin, Nadège Gaborit, Nadia Vie, Corinne Bousquet, Lucile Canterel-Thouennon, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), 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 Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale (LPPCE), Université de Bourgogne (UB), 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 Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Immunociblage et radiobiologie en oncologie, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), and Chardès, Thierry
Subjects: 0301 basic medicine, Cancer Research, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Receptor, ErbB-3, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Apoptosis, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Mice, 0302 clinical medicine, Cancer-Associated Fibroblasts, Pancreatic tumor, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Tumor Cells, Cultured, Tumor Microenvironment, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, biology, Chemistry, Antibodies, Monoclonal, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Carcinoma, Pancreatic Ductal, Signal Transduction, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cancer-associated fibroblast, Neuregulin-1, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Stroma, [SDV.CAN] Life Sciences [q-bio]/Cancer, HER3, Pancreatic cancer, mental disorders, Neuregulin 1, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Xenograft Model Antitumor Assays, Coculture Techniques, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Pancreatic Neoplasms, 030104 developmental biology, Tumor progression, Cancer cell, biology.protein, Cancer research
Abstract: International audience; Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation. To do so, we demonstrated the promising tumor growth inhibitory effect of the 7E3, an original antibody directed to NRG1. This antibody promotes antibody dependent cellular cytotoxicity in NRG1-positive PC and CAFs and inhibits NRG1-associated signaling pathway induction, by blocking NRG1-mediated HER3 activation. Moreover, 7E3 inhibits migration and growth of pancreatic cancer cells co-cultured with CAFs, both in vitro and in vivo using orthotopic pancreatic tumor xenografts. Our preclinical results demonstrate that the anti-NRG1 antibody 7E3 could represent a promising approach to target pancreatic stroma and cancer cells, thereby providing novel therapeutic options for PDAC.
Published: 2018

3. BAG6/BAT3 modulates autophagy by affecting EP300/p300 intracellular localization

Author: Guy Berchem, Valeŕie Palissot, Céline Gongora, Salwa Sebti, Laetitia K. Linares, Patrice Codogno, Nelly Pirot, Emmanuelle Liaudet-Coopman, Esther Pérez-Gracia, Sophie Pattingre, Fabienne Desmots, Chantal Bauvy, Anne Sophie Bach, Andrew V. Hubberstey, Christine Prébois, 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 Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Department of Biological Sciences [Windsor], University of Windsor [Ca], Laboratory of Experimental Hemato-Oncology [Luxembourg] (CRP-Santé), Centre de Recherche Public de la Santé, This work is supported by the Institut National de la Santé et de la Recherche Médicale (CG, PC, LKL, EL-C, and SP), by the ARC foundation (SP), La Ligue Régionale contre Le Cancer (Comités du Gard et de l’Hérault, SP), Cancéropole Grand Sud-Ouest (SP), and the CHEMORES consortium (Tumour Chemotherapy Resistance EU FP6 to EL-C). SS has fellowships from the Fond National de la Recherche Luxembourg (FNR Luxembourg) and La Ligue Nationale contre le Cancer., 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), CHU Pontchaillou [Rennes], 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 Recherche en Informatique Fondamentale (IRIF (UMR_8243)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), 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), Signalisation et physiopathologie des cellules épithéliales, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Experimental Hemato-Oncology (CRP-Santé), Centre de Recherche Public-Santé, UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, and Nowak, Cécile
Subjects: p53, [SDV]Life Sciences [q-bio], animal diseases, Intracellular Space, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], E1A-Associated p300 Protein/*metabolism, Mice, Models, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Gene expression, Nuclear protein, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Life Sciences, Nuclear Proteins, Acetylation, Cell biology, Protein Transport, Intracellular Space/*metabolism, ATG5, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, BAG3, Models, Biological, Molecular Chaperones/*metabolism, [SDV.CAN] Life Sciences [q-bio]/Cancer, Nuclear Proteins/*metabolism, BAT3, Autophagy, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Tumor Suppressor Protein p53/metabolism, Cell Biology, Biological, Molecular biology, Autophagic Punctum, ATG, Cytoplasm, Tumor Suppressor Protein p53, E1A-Associated p300 Protein, Nuclear localization sequence, nucleocytoplasmic shuttling, Molecular Chaperones
Abstract: International audience; We recently reported that BAG6/BAT3 (BCL2-associated athanogene 6) is essential for basal and starvation-induced autophagy in E18.5 bag6(-/-) mouse embryos and in mouse embryonic fibroblasts (MEFs) through the modulation of the EP300/p300-dependent acetylation of TRP53 and autophagy-related (ATG) proteins. We observed that BAG6 increases TRP53 acetylation during starvation and pro-autophagic TRP53-target gene expression. BAG6 also decreases the EP300 dependent-acetylation of ATG5, ATG7, and LC3-I, posttranslational modifications that inhibit autophagy. In addition, in the absence of BAG6 or when using a mutant of BAG6 exclusively located in the cytoplasm, autophagy is inhibited, ATG7 is hyperacetylated, TRP53 acetylation is abrogated, and EP300 accumulates in the cytoplasm indicating that BAG6 is involved in the regulation of the nuclear localization of EP300. We also reported that the interaction between BAG6 and EP300 occurs in the cytoplasm rather than the nucleus. Moreover, during starvation, EP300 is transported to the nucleus in a BAG6-dependent manner. We concluded that BAG6 regulates autophagy by controlling the localization of EP300 and its accessibility to nuclear (TRP53) and cytoplasmic (ATGs) substrates.
Published: 2014

4. Estrogen-related receptor γ is an in vivo receptor of bisphenol A

Author: Marie Tohme, Sophie M. Prud'homme, Yann Gibert, William Bourguet, Laure Bernard, Frédéric Brunet, Patrick Balaguer, Abdel Boulahtouf, Vincent Laudet, Eric Samarut, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and 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)
Subjects: medicine.medical_specialty, endocrine system, Bisphenol, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, 010501 environmental sciences, Protein Binding/*drug effects, 01 natural sciences, Biochemistry, 03 medical and health sciences, Estrogen-related receptor, Otolithic Membrane, Phenols, In vivo, Estrogen/*metabolism, Internal medicine, Receptors, Genetics, medicine, Animals, Zebrafish/*metabolism, Benzhydryl Compounds, Receptor, Molecular Biology, Zebrafish, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Otolithic Membrane/drug effects/metabolism, biology, urogenital system, biology.organism_classification, body regions, Endocrinology, Endocrine disruptor, Receptors, Estrogen, Estrogen, Benzhydryl Compounds/*pharmacology, Otic vesicle, sense organs, hormones, hormone substitutes, and hormone antagonists, Phenols/*pharmacology, Biotechnology, Protein Binding
Abstract: Bisphenol A (BPA) is an endocrine disruptor that displays estrogenic activity. Several reports suggest that BPA may have estrogen receptor-independent effects. In zebrafish, 50 muM BPA exposure induces otic vesicle abnormalities, including otolith aggregation. The purpose of this study was to test if BPA action was mediated in vivo during zebrafish development by the orphan nuclear estrogen related receptor (ERR) gamma. Combining pharmacological and functional approaches, we demonstrate that the zebrafish ERRgamma mediates BPA-induced malformations in otoliths. Using different bisphenol derivatives, we show that different compounds can induce a similar otolith phenotype than BPA and that the binding affinity of these derivatives to the zebrafish ERRgamma correlates with their ability to induce otolith malformations. Morpholino knockdown of ERRgamma function suppresses the BPA effect on otoliths whereas overexpression of ERRgamma led to a BPA-like otolith phenotype. Moreover, a subphenotypical dose of BPA (1 muM) combined with ERRgamma overexpression led to a full-dose (50 muM) BPA otolith phenotype. We therefore conclude that ERRgamma mediates the otic vesicle phenotype generated by BPA. Our results suggest that the range of pathways perturbed by this compound and its potential harmful effect are larger than expected.-Tohme, M., Prud'homme, S. M., Boulahtouf, A., Samarut, E., Brunet, F., Bernard, L., Bourguet, W., Gibert, Y., Balaguer, P., Laudet, V. Estrogen-related receptor gamma is an in vivo receptor of bisphenol A.
Published: 2014

5. Circulating Cell-Free DNA from Colorectal Cancer Patients May Reveal High KRAS or BRAF Mutation Load

Author: Anne Sophie Guedj, Maguy Del Rio, Bruno Robert, Alain R. Thierry, Franck Molina, Marc Ychou, Denis Pezet, Evelyne Lopez-Crapez, Muriel Mathonnet, Céline Gongora, Pierre-Jean Lamy, Florent Mouliere, Safia El Messaoudi, 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 Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Public Health Agency of Canada, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, UNICANCER - Institut régional du Cancer [Montpellier] (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Département d'oncologie Médicale, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratoire des Défenses Antivirales et Antitumorales, Université Montpellier 2 - Sciences et Techniques (UM2), 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), Sysdiag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (SysDiag ), BIO-RAD-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, and Pathology
Subjects: Cancer Research, Pathology, medicine.medical_specialty, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Colorectal cancer, [SDV]Life Sciences [q-bio], Mutant, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Medicine, Allele, 030304 developmental biology, 0303 health sciences, Mutation, Cardiovascular diseases [NCEBP 14], business.industry, medicine.disease, Molecular biology, Circulating Cell-Free DNA, 3. Good health, Real-time polymerase chain reaction, Oncology, Cell culture, 030220 oncology & carcinogenesis, KRAS, business, Research Article
Abstract: Contains fulltext : 119240.pdf (Publisher’s version ) (Open Access) We used a novel method based on allele-specific quantitative polymerase chain reaction (Intplex) for the analysis of circulating cell.free DNA (ccfDNA) to compare total ccfDNA and KRAS- or BRAF-mutated ccfDNA concentrations in blood samples from mice xenografted with the human SW620 colorectal cancer (CRC) cell line and from patients with CRC. Intplex enables single-copy detection of variant alleles down to a sensitivity of >/=0.005 mutant to wild-type ratio. The proportion of mutant allele corresponding to the percentage of tumor-derived ccfDNA was elevated in xenografted mice with KRAS homozygous mutation and varied highly from 0.13% to 68.7% in samples from mutation-positive CRC patients (n = 38). Mutant ccfDNA alleles were quantified in the plasma of every patient at stages II/III and IV with a mean of 8.4% (median, 8.4%) and 21.8% (median, 12.4%), respectively. Twelve of 38 (31.6%) and 5 of 38 (13.2%) samples showed a mutation load higher than 25%and 50%, respectively. This suggests that an important part of ccfDNA may originate from tumor cells. In addition, we observed that tumor-derived (mutant) ccfDNA was more fragmented than ccfDNA from normal tissues. This observation suggests that the form of tumor-derived and normal ccfDNA could differ. Our approach revealed that allelic dilution is much less pronounced than previously stated, considerably facilitating the noninvasive molecular analysis of tumors.
Published: 2013

6. RETRACTED: Recommandations françaises du Comité de Cancérologie de l’AFU — Actualisation 2018—2020 : tumeurs de la voie excrétrice supérieure

Author: Géraldine Pignot, Pierre Colin, Evanguelos Xylinas, Mathieu Roumiguié, Arnaud Mejean, Yann Neuzillet, Eva Compérat, Nadine Houede, Stéphane Larré, François Audenet, Morgan Rouprêt, S. Brunelle, Alexandra Masson-Lecomte, CHU Pitié-Salpêtrière [APHP], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpital Privé La Louvière, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], 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), Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'Urologie [CHU Saint-Louis], 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital de Rangueil, CHU Toulouse [Toulouse], Hôpital Foch [Suresnes], 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), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: Cytologie urinaire, medicine.medical_specialty, Survival, Urology, MESH: Societies, Medical, 030232 urology & nephrology, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Uretère, Ureteroscopy, medicine, Urinary cytology, Cancer, MESH: Medical Oncology, Urothelial carcinoma, MESH: Carcinoma, Transitional Cell, Gynecology, Bassinet, MESH: Humans, MESH: Urologic Neoplasms, business.industry, Carcinome urothélial, MESH: Urothelium, 3. Good health, MESH: France, Urétéroscopie, Survie, 030220 oncology & carcinogenesis, MESH: Practice Patterns, Physicians', Renal pelvis, Ureter, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Resume Introduction Proposer une mise a jour des recommandations du comite de cancerologie de l’Association francaise d’urologie pour la prise en charge des tumeurs de la voie excretrice urinaire superieure (TVES). Methodes Une revue systematique de la litterature (Medline) de 2016 a 2018 sur les elements du diagnostic, les options de traitement et la surveillance des TVES en evaluant les references avec leur niveau de preuve. Resultats Le diagnostic de cette pathologie rare repose sur l’uro-TDM avec acquisition au temps excreteur et l’ureteroscopie avec prelevements biopsiques. Le traitement chirurgical de reference est la nephroureterectomie totale (NUT), mais un traitement conservateur peut etre discute pour les lesions dites a bas risque : tumeur unifocale, resection complete potentielle, faible grade et absence d’infiltration sur l’imagerie, necessitant alors une surveillance endoscopique (ureteroscopie souple) rapprochee chez un patient compliant. Une instillation postoperatoire de chimiotherapie est recommandee et permet de diminuer le risque de recidive vesicale apres NUT. La chimiotherapie adjuvante a demontre son benefice clinique comparee a la surveillance apres NUT pour les tumeurs (pT2-T4 N0-3 M0). Conclusion Ces nouvelles recommandations doivent contribuer a ameliorer non seulement la prise en charge des patients, mais aussi le diagnostic et la decision therapeutique des TVES.
Published: 2018

7. Autocrine Adenosine Regulates Tumor Polyfunctional CD73+CD4+ Effector T Cells Devoid of Immune Checkpoints

Author: Pedro Romero, Marion Bossennec, Isabelle Durand, Bertrand Dubois, Christelle Machon, David Bauché, Julien Faget, Nicolas Gourdin, Christophe Caux, Jérôme Guitton, Julien C. Marie, Camilla Jandus, Nicolas Chopin, Olivier Tredan, Christine Ménétrier-Caux, Céline Rodriguez, Selena Vigano, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Université de Lausanne (UNIL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), 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), Department of Medical Oncology [Lyon], Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), and Herrada, Anthony
Subjects: 0301 basic medicine, Cancer Research, T-Lymphocytes, Drug Resistance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, chemical and pharmacologic phenomena, C-C chemokine receptor type 6, CXCR3, GPI-Linked Proteins/metabolism, Helper-Inducer/immunology/metabolism, 5'-Nucleotidase/metabolism, Adenosine/metabolism, Antineoplastic Agents, Immunological/pharmacology, Antineoplastic Agents, Immunological/therapeutic use, Apyrase/metabolism, Breast Neoplasms/drug therapy, Breast Neoplasms/immunology, Breast Neoplasms/pathology, Costimulatory and Inhibitory T-Cell Receptors/antagonists & inhibitors, Costimulatory and Inhibitory T-Cell Receptors/metabolism, Drug Resistance, Neoplasm/immunology, Female, Humans, Interleukin-17/metabolism, Lymphocytes, Tumor-Infiltrating/immunology, Lymphocytes, Tumor-Infiltrating/metabolism, Ovarian Neoplasms/drug therapy, Ovarian Neoplasms/immunology, Ovarian Neoplasms/pathology, T-Lymphocytes, Helper-Inducer/immunology, T-Lymphocytes, Helper-Inducer/metabolism, T-Lymphocytes, Regulatory/immunology, T-Lymphocytes, Regulatory/metabolism, Tumor Escape/immunology, Regulatory/immunology/metabolism, Interleukin 22, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Lymphocytes, Autocrine signalling, Costimulatory and Inhibitory T-Cell Receptors/antagonists & inhibitors/metabolism, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Breast Neoplasms/drug therapy/immunology/pathology, Chemistry, Effector, Neoplasm/immunology, Immunological/pharmacology/therapeutic use, Immune checkpoint, Tumor-Infiltrating/immunology/metabolism, 030104 developmental biology, Oncology, Tumor Escape, Cancer research, Ovarian Neoplasms/drug therapy/immunology/pathology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4 + T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39 + Tregs selectively targeted CD73 + Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73 + Teffs to secrete IL17A. CD73 + Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73 + Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.Significance: Polyfunctional CD73 + T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604-18. ©2018 AACR.
Published: 2018

8. Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects

Author: Jaafar Bennouna, Christophe Borg, Cécile Badoual, Jean-Baptiste Bachet, Julien Taieb, François Ghiringhelli, Florence Castan, Elie Marcheteau, Sophie Gourgou, Aurélie Cazes, Christelle De La Fouchardiere, Simon Pernot, Olivier Bouché, Trevor Stanbury, Eric Francois, Emmanuelle Samalin, Magali Terme, David Malka, Michel Ducreux, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire [AP-HP Hôpital Européen Georges Pompidou] (Service de Biochimie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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), Service d’anatomo‑pathologie [AP-HP Hôpital Européen Georges Pompidou] (Centre de Ressources biologiques), 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 de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Cancérologie de l'Ouest, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre Léon Bérard [Lyon], CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, CHU Pitié-Salpêtrière [APHP], Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Institut Gustave Roussy (IGR), Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire [AP-HP Hôpital Européen Georges Pompidou] ( Service de Biochimie ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service d’anatomo‑pathologie [AP-HP Hôpital Européen Georges Pompidou] ( Centre de Ressources biologiques ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), 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 ), Centre Hospitalier Universitaire de Reims ( CHU Reims ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-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)-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), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM)
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, Pathology, Esophageal Neoplasms, Organoplatinum Compounds, MESH : Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Cell Count, MESH : Leucovorin, Kaplan-Meier Estimate, MESH : Cell Count, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Prostate, Circulating tumour cells, Antineoplastic Combined Chemotherapy Protocols, MESH : Stomach Neoplasms, MESH : Esophagogastric Junction, MESH : Female, MESH: Treatment Outcome, MESH : Prognosis, MESH: Organoplatinum Compounds, MESH: Stomach Neoplasms, Neoplastic Cells, Circulating, Prognosis, 3. Good health, Oxaliplatin, Clinical trial, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Esophageal Neoplasms, Monoclonal, Disease Progression, MESH : Fluorouracil, MESH : Disease-Free Survival, Adenocarcinoma, Female, MESH: Disease Progression, Esophagogastric Junction, Fluorouracil, MESH: Esophagogastric Junction, medicine.drug, medicine.medical_specialty, MESH : Male, Stomach neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, MESH: Neoplastic Cells, Circulating, Antibodies, Monoclonal, Humanized, MESH : Organoplatinum Compounds, Disease-Free Survival, MESH : Antibodies, Monoclonal, Humanized, MESH: Prognosis, MESH : Kaplan-Meier Estimate, 03 medical and health sciences, Internal medicine, medicine, Humans, In patient, Clinical significance, MESH: Kaplan-Meier Estimate, MESH: Humans, MESH: Cell Count, business.industry, MESH : Humans, Therapeutic effect, MESH : Disease Progression, medicine.disease, MESH: Male, 030104 developmental biology, MESH: Antibodies, Monoclonal, Humanized, MESH : Neoplastic Cells, Circulating, MESH: Disease-Free Survival, MESH : Esophageal Neoplasms, MESH: Leucovorin, business, MESH: Female, MESH: Fluorouracil, Biomarkers
Abstract: IF 6.029; International audience; Background: The identification of dynamic biomarkers in advanced gastric and oesogastric junction adenocarcinoma (GOA) could help to tailor strategies for each patient. Enumeration of circulating tumour cells (CTCs) is approved by the US Food and Drug Administration in breast, colon and prostate cancer but is not in advanced GOA. Our study aims to establish the optimal threshold and the clinical significance of CTC count in advanced GOA before and during treatment.Methods: One hundred six patients with untreated advanced GOA were included in the ancillary study of the PRODIGE 17-ACCORD 20 trial. CTCs were detected in the peripheral blood using the CellSearch system on day 0 (D0) and day 28 (D28). The prognostic value of CTCs at D0 and D28 was analysed by testing several thresholds.Results: At baseline, median CTC count was 1 (range, 0-415). While CTCs >= 1, 2 or 3 at D0 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS), CTCs >2 were the optimal threshold, on D0 or D28. CTCs >2 at D28 were also predictive of disease control. Taking into account both D0 and D28 CTC count defined 3 groups (low/low, high/low and low-high/high) with significantly different PFS (p = 0.0002) and OS (p = 0.003).Conclusion: Quantification of CTCs at baseline and during treatment may be a useful prognostic tool in advanced GOA, as it is associated with worse PFS and OS. A threshold >= 2 CTCs seems to have the best discriminant value. Change in CTC count between baseline and D28 could help to tailor treatment to each individual patient. (C) 2017 Elsevier Ltd. All rights reserved.
Published: 2017

9. Atomic Force Microscopy Study of the Topography and Nanomechanics of Casein Micelles Captured by an Antibody

Author: Dominique Chevalier-Lucia, Marta Martin, Sylvie Marchesseau, Asma Bahri, Csilla Gergely, Martine Pugnière, Ingénierie des Agro-polymères et Technologies Émergentes (UMR IATE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Laboratoire Charles Coulomb (L2C), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Carboxylic acid, Analytical chemistry, Ionic bonding, 02 engineering and technology, Microscopy, Atomic Force, Antibodies, 03 medical and health sciences, Colloid, chemistry.chemical_compound, Monolayer, Electrochemistry, General Materials Science, Micelles, health care economics and organizations, Spectroscopy, Carbodiimide, chemistry.chemical_classification, Caseins, Surfaces and Interfaces, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Elasticity, Characterization (materials science), 030104 developmental biology, chemistry, Chemical engineering, Covalent bond, 0210 nano-technology, Nanomechanics
Abstract: International audience; Casein micelles (CMs) are colloidal phospho-protein-mineral complexes naturally present in milk. This study used atomic force microscopy (AFM) in a liquid environment to evaluate the topography and nanomechanics of single native CMs immobilized by a novel capture method. The proposed immobilization method involves weak interactions with theantiphospho-Ser/Thr/Tyr monoclonal antibody covalently bound to a carboxylic acid self-assembled monolayer (SAM)on a gold surface. This capture strategy was compared to the commonly used covalent immobilization method of CMs viacarbodiimide chemistry. With this conventional method, CMs remained mainly mobile during AFM measurements in liquid,disturbing the evaluation of their average size and elastic properties. Conversely, when captured by the specific antibody, they were successfully immobilized and their integrity was preserved during the AFM measurement. The characterization of both CM topography and elastic properties was carried out in a liquid ionic environment at native pH 6.6. The CMs’ capture efficiency via antibody was concurrently proved by surface plasmon resonance. The calculation of casein micelles’ width, height, and contact angle was carried out from the recorded 2D AFM images. CMs were characterized by a mean width of 148 ± 8 nm and a mean height of 42 ± 1 nm. Weak forces were applied to single captured CMs. The obtained force versus indentation curves were fitted using the Hertz model in order to evaluate their elastic properties. The elasticity distribution of native CMs exhibited a unimodal trend with a peak centered at 269 ± 14 kPa.
Published: 2017

10. Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies

Author: Céline Gongora, Janick Selves, Jacques Robert, Nadia Vie, M. Ychou, Caroline Mollevi, Jean-François Emile, P. Roger, M. del Rio, Pierre Martineau, Nicole Tubiana-Mathieu, Frédéric Bibeau, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), CRLCC Val d'Aurelle - Paul Lamarque, CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Hôpital Ambroise Paré, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université de Montpellier (UM), Validation et identification de nouvelles cibles en oncologie (VINCO), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'anatomie pathologique [Ambroise-Paré], Hôpital Ambroise Paré [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service d'Anatomie et Cytologie Pathologiques, CHU Nîmes, Université de Montpellier, Laboratoire Aimé Cotton (LAC), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique, de Modélisation et d'optimisation des Systèmes (LIMOS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Mines de St Etienne, CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré [AP-HP], Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Sigma CLERMONT (Sigma CLERMONT)-Ecole Nationale Supérieure des Mines de St Etienne-Centre National de la Recherche Scientifique (CNRS), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, Organoplatinum Compounds, Colorectal cancer, [SDV]Life Sciences [q-bio], Leucovorin, Cetuximab, FOLFIRI protocol, 0302 clinical medicine, FOLFOX, Antineoplastic Combined Chemotherapy Protocols, Neoplasm Metastasis, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Liver Neoplasms, Middle Aged, Prognosis, Gene expression profiling, 3. Good health, Survival Rate, Bevacizumab, Treatment Outcome, 030220 oncology & carcinogenesis, FOLFIRI, Female, Fluorouracil, medicine.drug, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Irinotecan, Colorectal neoplasms, 03 medical and health sciences, Folfox protocol, Internal medicine, medicine, Humans, Survival rate, Aged, business.industry, medicine.disease, Regimen, 030104 developmental biology, Camptothecin, Transcriptome, business
Abstract: Background Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. Patients and methods We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. Results We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P = 0.003), but not to FOLFOX (P = 0.911) and FOLFIRI + Bevacizumab (P = 0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). Conclusions Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.
Published: 2017

11. The performance of PI-RADSv2 and quantitative apparent diffusion coefficient for predicting confirmatory prostate biopsy findings in patients considered for active surveillance of prostate cancer

Author: Andreas M. Hötker, Behfar Ehdaie, Evis Sala, Nicola L Robertson, Nicolas Molinari, Stephanie Nougaret, Jennifer S. Golia Pernicka, Hedvig Hricak, Hebert Alberto Vargas, 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Institut Montpelliérain Alexander Grothendieck (IMAG), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Memorial Sloane Kettering Cancer Center [New York]
Subjects: Male, PI-RADSv2, Oncology, Prostate biopsy, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], Biopsy, 030232 urology & nephrology, Contrast Media, 0302 clinical medicine, Prostate, Stage (cooking), ComputingMilieux_MISCELLANEOUS, Cancer, Aged, 80 and over, Radiological and Ultrasound Technology, medicine.diagnostic_test, Gastroenterology, Middle Aged, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Radiology, Adult, medicine.medical_specialty, Urology, Active surveillance of prostate cancer, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Sensitivity and Specificity, Article, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, Effective diffusion coefficient, Radiology, Nuclear Medicine and imaging, Aged, Retrospective Studies, business.industry, Prostatic Neoplasms, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Retrospective cohort study, medicine.disease, Confirmatory, body regions, Diffusion Magnetic Resonance Imaging, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neoplasm Grading, business
Abstract: To assess the performance of the updated Prostate Imaging Reporting and Data System (PI-RADSv2) and the apparent diffusion coefficient (ADC) for predicting confirmatory biopsy results in patients considered for active surveillance of prostate cancer (PCA). IRB-approved, retrospective study of 371 consecutive men with clinically low-risk PCA (initial biopsy Gleason score ≤6, prostate-specific antigen
Published: 2017

12. Syringaresinol: A Renewable and Safer Alternative to Bisphenol A for Epoxy-Amine Resins

Author: Florent Allais, Louis Hollande, Marina Grimaldi, Patrick Balaguer, Paul-Henri Ducrot, Miguel Pernes, Johnny Beaugrand, Abdus Samad Jaufurally, Marine Janvier, Raphaël Ménard, Agro-Biotechnologies Industrielles (ABI), AgroParisTech, Institut Jean-Pierre Bourgin (IJPB), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Ingénierie, Procédés, Aliments (GENIAL), Fractionnement des AgroRessources et Environnement (FARE), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Recherche Agronomique (INRA), 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), Region Champagne-Ardenne, Conseil Departemental de la Marne, Reims Metropole, Fractionnement des AgroRessources et Environnement - UMR-A 614 (FARE), Université de Reims Champagne-Ardenne (URCA)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Recherche Agronomique (INRA)-SFR Condorcet, and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Syringaresinol, Bisphenol A, Polymers, Bisphenol, bisphenol A, [SDV]Life Sciences [q-bio], General Chemical Engineering, Thermosetting polymer, bisepoxide, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Lignans, chemistry.chemical_compound, Phenols, Diamine, Environmental Chemistry, Organic chemistry, syringaresinol, General Materials Science, Amines, Benzhydryl Compounds, Furans, Isophorone, Aqueous solution, Epoxy Resins, Green Chemistry Technology, Epoxy, 021001 nanoscience & nanotechnology, 0104 chemical sciences, General Energy, chemistry, DGEBA, visual_art, visual_art.visual_art_medium, resin, 0210 nano-technology
Abstract: A renewable bisepoxide, SYR-EPO, was prepared from syringaresinol, a naturally occurring bisphenol deriving from sinapic acid, by using a chemo-enzymatic synthetic pathway. Estrogenic activity tests revealed no endocrine disruption for syringaresinol. Its glycidylation afforded SYR-EPO with excellent yield and purity. This biobased, safe epoxy precursor was then cured with conventional and renewable diamines for the preparation of epoxy-amine resins. The resulting thermosets were thermally and mechanically characterized. Thermal analyses of these new resins showed excellent thermal stabilities (T-d5%=279-309 degrees C) and T-g ranging from 73 to 126 degrees C, almost reaching the properties of those obtained with the diglycidylether of bisphenol A (DGEBA), extensively used in the polymer industry (T-d5%= 319 degrees C and T-g = 150 degrees C for DGEBA/isophorone diamine resins). Degradation studies in NaOH and HCl aqueous solutions also highlighted the robustness of the syringaresinol-based resins, similar to bisphenol A (BPA). All these results undoubtedly confirmed the potential of syringaresinol as a greener and safer substitute for BPA
Published: 2017

13. Activity of a Synthetic Peptide Targeting MgtC on Pseudomonas aeruginosa Intramacrophage Survival and Biofilm Formation

Author: Malika Moussouni, Pauline Nogaret, Preeti Garai, Bérengère Ize, Eric Vivès, Anne-Béatrice Blanc-Potard, 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), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), 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), Vaincre La Mucoviscidose (RIF20170502042) and Association Gregory Lemarchal, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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: 0301 basic medicine, Microbiology (medical), 030106 microbiology, Immunology, Mutant, Antimicrobial peptides, lcsh:QR1-502, Peptide, macrophage, medicine.disease_cause, Microbiology, lcsh:Microbiology, 03 medical and health sciences, Cellular and Infection Microbiology, medicine, Enzyme Inhibitors, Cation Transport Proteins, Original Research, chemistry.chemical_classification, Mutation, Microbial Viability, biology, MgtC, Pseudomonas aeruginosa, Chemistry, Macrophages, antivirulence strategy, Biofilm, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, peptide, 030104 developmental biology, Infectious Diseases, Biofilms, Heterologous expression, EPS, Peptides, Bacteria
Abstract: International audience; Antivirulence strategies aim to target pathogenicity factors while bypassing the pressure on the bacterium to develop resistance. The MgtC membrane protein has been proposed as an attractive target that is involved in the ability of several major bacterial pathogens, including Pseudomonas aeruginosa, to survive inside macrophages. In liquid culture, P. aeruginosa MgtC acts negatively on biofilm formation. However, a putative link between these two functions of MgtC in P. aeruginosa has not been experimentally addressed. In the present study, we first investigated the contribution of exopolysaccharides (EPS) in the intramacrophage survival defect and biofilm increase of mgtC mutant. Within infected macrophages, expression of EPS genes psl and alg was increased in a P. aeruginosa mgtC mutant strain comparatively to wild-type strain. However, the intramacrophage survival defect of mgtC mutant was not rescued upon introduction of psl or alg mutation, suggesting that MgtC intramacrophage role is unrelated to EPS production, whereas the increased biofilm formation of mgtC mutant was partially suppressed by introduction of psl mutation. We aimed to develop an antivirulence strategy targeting MgtC, by taking advantage of a natural antagonistic peptide, MgtR. Heterologous expression of mgtR in P. aeruginosa PAO1 was shown to reduce its ability to survive within macrophages. We investigated for the first time the biological effect of a synthetic MgtR peptide on P. aeruginosa. Exogenously added synthetic MgtR peptide lowered the intramacrophage survival of wild-type P. aeruginosa PAO1, thus mimicking the phenotype of an mgtC mutant as well as the effect of endogenously produced MgtR peptide. In correlation with this finding, addition of MgtR peptide to bacterial culture strongly reduced MgtC protein level, without reducing bacterial growth or viability, thus differing from classical antimicrobial peptides. On the other hand, the addition of exogenous MgtR peptide did not affect significantly biofilm formation, indicating an action toward EPS-independent phenotype rather than EPS-related phenotype. Cumulatively, our results show an antivirulence action of synthetic MgtR peptide, which may be more potent against acute infection, and provide a proof of concept for further exploitation of anti-Pseudomonas strategies.
Published: 2019

14. Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies

Author: Hélène Rispaud-Blanc, Jean-François Eliaou, Cécile Dejou, Rachel Courtois, Béatrice Amigues, Emilie Narni-Mancinelli, Nathalie Bonnefoy, Jérémy Bastid, Armand Bensussan, Marc Giraudon-Paoli, Aurélie Docquier, François Romagné, O. Becquart, Carine Paturel, Ivan Perrot, Benjamin Rossi, Yannis Morel, Laurent Gauthier, Henri-Alexandre Michaud, Laurent Gros, Eric Vivier, Nicolas Gourdin, Alain Roussel, Diana Jecko, Stéphanie Chanteux, Severine Augier, Innate Pharma, 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Architecture et fonction des macromolécules biologiques (AFMB), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), OREGA Biotech, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et physiopathologie cutanées : expression génique, signalisation et thérapie, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR50, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Faculté de Médecine Nice, Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), AB Science SA, Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Sud - Paris 11 (UP11), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie, Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Recherche & Développement, Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, Adenosine, T-Lymphocytes, medicine.medical_treatment, Mice, Adenosine Triphosphate, 0302 clinical medicine, Tumor Microenvironment, Medicine, Gene Knock-In Techniques, 5'-Nucleotidase, Melanoma, lcsh:QH301-705.5, Mice, Knockout, biology, Apyrase, Immunosuppression, 3. Good health, Oxaliplatin, Survival Rate, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, medicine.drug, medicine.drug_class, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monoclonal antibody, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Antigens, CD, Cell Line, Tumor, Blocking antibody, Animals, Humans, Antibodies, Blocking, business.industry, Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Immune checkpoint, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, lcsh:Biology (General), Leukocytes, Mononuclear, biology.protein, Cancer research, business, 030217 neurology & neurosurgery
Abstract: Summary: Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer. : The production of adenosine via CD39 and CD73 ectoenzymes participates in an immunosuppressive tumor microenvironment. Perrot et al. generated two antibodies, IPH5201 and IPH5301, targeting human CD39 and CD73, respectively. In vitro and in vivo data support the use of anti-CD39 and anti-CD73 mAbs in combination cancer therapies. Keywords: CD39, CD73, cancer immunotherapies, therapeutic antibodies, adenosine pathway, tumor micro-environment, immunosuppression
Published: 2019
Full Text: View/download PDF

15. Nascent DNA Proteomics Reveals a Chromatin Remodeler Required for Topoisomerase I Loading at Replication Forks

Author: Christian Larroque, Cyril Ribeyre, Angelos Constantinou, Massimo Lopes, Maeva Chauvin, Nicole Bec, Ralph Zellweger, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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 recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), 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: DNA Replication, Male, Proteomics, 0301 basic medicine, Transcription, Genetic, Chromosomal Proteins, Non-Histone, Eukaryotic DNA replication, General Biochemistry, Genetics and Molecular Biology, DNA replication factor CDT1, 03 medical and health sciences, Replication factor C, Control of chromosome duplication, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:QH301-705.5, Replication protein A, ComputingMilieux_MISCELLANEOUS, Adenosine Triphosphatases, Genetics, biology, Topoisomerase, DNA replication, DNA, Chromatin Assembly and Disassembly, 3. Good health, Cell biology, 030104 developmental biology, lcsh:Biology (General), DNA Topoisomerases, Type I, biology.protein, Origin recognition complex, Camptothecin, Topoisomerase I Inhibitors, HeLa Cells, Transcription Factors
Abstract: SummaryDuring transcription and DNA replication, the DNA template is overwound ahead of RNA and DNA polymerases and relaxed by DNA topoisomerases. Inhibitors of topoisomerases are potent anti-cancer agents. Camptothecin traps topoisomerase I on DNA and exerts preferential cytotoxicity toward cancer cells by way of its interference with the progression of replication forks. Starting with an unbiased proteomic analysis, we find that the chromatin remodeling complex BAZ1B-SMARCA5 accumulates near replication forks in camptothecin-exposed cells. We report that BAZ1B associates with topoisomerase I and facilitates its access to replication forks. Single-molecule analyses of replication structures show that BAZ1B contributes to replication interference by camptothecin. A lack of BAZ1B confers increased cellular tolerance of camptothecin. These findings reveal BAZ1B as a key facilitator of topoisomerase I function during DNA replication that affects the response of cancer cells to topoisomerase I inhibitors.
Published: 2016

16. Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neurons

Author: Marina Lavigne, Christina Begon-Pescia, Eric J. Kremer, Philippe Lory, Antonella Consiglio, Sara Salinas, Assumpció Bosch, Sophie Creyssels, Ana Maria Cuervo, Daniel Simão, Neus Bayó-Puxan, Florence Bernex, Thierry Levade, Vasiliki Kalatzis, Ana Paula Terrasso, Catarina Brito, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Instituto de Biologia Experimental e Tecnológica (IBET), Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa (NOVA), 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 ), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), BioCampus Montpellier (BCM), 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), Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona [Barcelona] (UAB), 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), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Albert Einstein College of Medicine, 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), Department of Molecular and Translational Medicine, University of Brescia, Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Universitat Autònoma de Barcelona (UAB), and Albert Einstein College of Medicine [New York]
Subjects: Case-Control Studies, Cell Differentiation, Cells, Cultured, Glycosaminoglycans, Humans, Induced Pluripotent Stem Cells, Lysosomes, Mucopolysaccharidosis VII, Neurons, Stem Cells, Neural Pathways, Lysosomal Storage Disorders (LSD), 0301 basic medicine, Cells, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mucopolysaccharidosis, lcsh:Medicine, Mucopolysaccharides, Biology, Article, Lipofuscin, Lysosome-associated Membrane Protein (LAMP1), 03 medical and health sciences, Cognition, SDG 3 - Good Health and Well-being, Downregulation and upregulation, Lysosome, Lysosomal storage disease, medicine, Premovement neuronal activity, GABAergic Neurons, General, lcsh:Science, Cultured, Multidisciplinary, lcsh:R, Enzyme replacement therapy, medicine.disease, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Mucopolisacàrids, EGFR Degradation, Ipsc Clones, Cognició, lcsh:Q, Astrocyte
Abstract: International audience; Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by deficient β-glucuronidase (β-gluc) activity. Significantly reduced β-gluc activity leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. Numerous combinations of mutations in GUSB (the gene that codes for β-gluc) cause a range of neurological features that make disease prognosis and treatment challenging. Currently, there is little understanding of the molecular basis for MPS VII brain anomalies. To identify a neuronal phenotype that could be used to complement genetic analyses, we generated two iPSC clones derived from skin fibroblasts of an MPS VII patient. We found that MPS VII neurons exhibited reduced β-gluc activity and showed previously established disease-associated phenotypes, including GAGs accumulation, expanded endocytic compartments, accumulation of lipofuscin granules, more autophagosomes, and altered lysosome function. Addition of recombinant β-gluc to MPS VII neurons, which mimics enzyme replacement therapy, restored disease-associated phenotypes to levels similar to the healthy control. MPS VII neural cells cultured as 3D neurospheroids showed upregulated GFAP gene expression, which was associated with astrocyte reactivity, and downregulation of GABAergic neuron markers. Spontaneous calcium imaging analysis of MPS VII neurospheroids showed reduced neuronal activity and altered network connectivity in patient-derived neurospheroids compared to a healthy control. These results demonstrate the interplay between reduced β-gluc activity, GAG accumulation and alterations in neuronal activity, and provide a human experimental model for elucidating the bases of MPS VII-associated cognitive defects. Lysosomal storage disorders (LSD) are caused by intra-and extracellular accumulation of undigested macromol-ecules that induce dysfunction of the greater lysosomal system. Among LSD, mucopolysaccharidoses (MPS) are caused by deficiency in enzymatic activities that degrade glycosaminoglycans (GAGs). GAGs are the most abundant polysaccharides of the extracellular matrix (ECM) and, with the exception of hyaluronic acid, are covalently attached to protein moieties to form proteoglycans 1. β-glucuronidase (β-gluc, EC 3.2.1.31), is found in lysosomes
Published: 2018

17. Prognostic relevance of RIP140 and ERβ expression in unifocal versus multifocal breast cancers: a preliminary report

Author: Sven Mahner, Sophie Sixou, Doris Mayr, Nina Ditsch, Christina Kühn, Katharina Müller, Vincent Cavaillès, Tobias Weissenbacher, Udo Jeschke, Stéphan Jalaguier, Nadia Harbeck, Department of Obstetrics and Gynecology [Munich, Germany], University-Hospital Munich-Großhadern [München]-Ludwig Maximilian University [Munich] (LMU), Faculté des Sciences Pharmaceutiques, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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 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), Department of Pathology [Munich, Germany], Ludwig Maximilian University [Munich] (LMU), S.S. salary was supported by the University Paul Sabatier in Toulouse (France). The project wassupported by the 'Centre de Coopération Universitaire Franco-Bavarois' (CCUFB) or 'Bayerisch-FranzösischesHochschulzentrum' (BFHZ), Project funding FK19-15., Cavailles, Vincent, and 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)
Subjects: tumor focality, Estrogen receptor, Gene Expression, Kaplan-Meier Estimate, lcsh:Chemistry, 0302 clinical medicine, Preliminary report, Medicine, lcsh:QH301-705.5, Spectroscopy, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, estrogen receptors, General Medicine, Middle Aged, Prognosis, Immunohistochemistry, Computer Science Applications, Nuclear Receptor Interacting Protein 1, Tumor Burden, 030220 oncology & carcinogenesis, Female, Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Breast cancer, breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, Estrogen Receptor beta, Humans, In patient, ddc:610, Physical and Theoretical Chemistry, Molecular Biology, 030304 developmental biology, Aged, Neoplasm Staging, business.industry, Organic Chemistry, medicine.disease, lcsh:Biology (General), lcsh:QD1-999, Nuclear receptor, RIP140, LCoR, Cancer research, LCOR, Neoplasm Grading, business, Corepressor, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The aim of this study was to investigate the expression of two nuclear receptor transcriptional coregulators, namely RIP140 (receptor-interacting protein of 140 kDa) and LCoR (ligand-dependent corepressor) in unifocal versus multifocal breast cancers. The expression of these two proteins was analyzed by immunohistochemistry in a matched-pair cohort of 21 unifocal and 21 multifocal breast tumors. The expression of the two estrogen receptors (ERα and ERβ) was studied in parallel. RIP140 and LCoR levels appeared lower in unifocal tumors compared to multifocal samples (decreased of immune-reactive scores and reduced number of high expressing cells). In both tumor types, RIP140 and LCoR expression was correlated with each other and with expression of ERβ. Very interestingly, the expression of RIP140, LCoR, and ERβ was inversely correlated with overall survival only for the unifocal group. The negative correlation with overall and recurrence free survival was more pronounced in patients whose unifocal tumors expressed high levels of both RIP140 and ERβ. Altogether, this preliminary report indicates that the ERβ/RIP140 signaling is altered in unifocal breast cancers and correlated with patient outcome. Further investigation is needed to decipher the molecular mechanisms and the biological relevance of this deregulation.
Published: 2018

18. Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence

Author: Caroline Andrique, Laetitia Morardet, Sylvain Provot, Candice Merle, Frédéric Chibon, Madi Y. Cissé, Laetitia K. Linares, Hang-Korng Ea, Dominique Modrowski, Martine Cohen-Solal, Eric Haÿ, Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the Fédération Enfants et Santé (R12118HH), Ligue contre le cancer (R14148HH), and European Calcified Tissue Society (ECTS) (EEE09002HHHA). English was corrected by Laura Smales (BioMedEditing, Toronto, Canada)., CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse]-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), Herrada, Anthony, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Carcinogenesis, [SDV]Life Sciences [q-bio], Mice, 0302 clinical medicine, Neoplasms, Hypoxia, Mice, Inbred BALB C, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Calpain, Sarcoma, Nanog Homeobox Protein, General Medicine, 3. Good health, Oncology, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Stem cell, Microtubule-Associated Proteins, Research Article, Homeobox protein NANOG, Senescence, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Sarcoma, Biology, Cellular senescence, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SOX2, Cancer stem cell, Cell Line, Tumor, Autophagy, medicine, Animals, Humans, education, Gene Expression Profiling, SOXB1 Transcription Factors, Oncogenes, medicine.disease, Xenograft Model Antitumor Assays, Disease Models, Animal, 030104 developmental biology, Cancer research, Octamer Transcription Factor-3, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Sarcomas are still unsolved therapeutic challenges. Cancer stem cells are believed to contribute to sarcoma development, but lack of specific markers prevents their characterization and targeting. Here, we show that calpain-6 expression is associated with cancer stem cell features. In mouse models of bone sarcoma, calpain-6-expressing cells have unique tumor-initiating and metastatic capacities. Calpain-6 levels are especially high in tumors that have been successfully propagated in mouse to establish patient-derived xenografts. We found that calpain-6 levels are increased by hypoxia in vitro and calpain-6 is detected within hypoxic areas in tumors. Furthermore, calpain-6 expression depends on the stem cell transcription network that involves Oct4, Nanog, and Sox2 and is activated by hypoxia. Calpain-6 knockdown blocks tumor development in mouse and induces depletion of the cancer stem cell population. Data from transcriptomic analyses reveal that calpain-6 expression in sarcomas inversely correlates with senescence markers. Calpain-6 knockdown suppresses hypoxia-dependent prevention of senescence entry and also promotion of autophagic flux. Together, our results demonstrate that calpain-6 identifies sarcoma cells with stem-like properties and is a mediator of hypoxia to prevent senescence, promote autophagy, and maintain the tumor-initiating cell population. These findings open what we believe is a novel therapeutic avenue for targeting sarcoma stem cells.
Published: 2018

19. Biosafety of Mesoporous Silica Nanoparticles

Author: Magali Gary-Bobo, Yannick Guari, Jean Charles Gaillard, Joël Chopineau, Jean-Marie Devoisselle, Jean Armengaud, Morgane Daurat, Marcel Garcia, Afitz Da Silva, Jeff L. Nyalosaso, Cédric Pisani, Marie Maynadier, Estelle Rascol, Odette Prat, Clarence Charnay, Christophe Dorandeu, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2), Génétique et Amélioration des Fruits et Légumes (GAFL), Institut National de la Recherche Agronomique (INRA), Institut de Chimie de Clermont-Ferrand - Clermont Auvergne (ICCF), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Sigma CLERMONT (Sigma CLERMONT), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Innovations technologiques pour la Détection et le Diagnostic (LI2D), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), 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 National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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 National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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 Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Larionova, Joulia, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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 National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), NanoMedSyn (NMS), Université de Nîmes (UNIMES), French National Research Agency (BioSiPharm project) : ANR-13-NANO-0007, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), 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), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), and NanoMedSyn
Subjects: safety, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Biomedical Engineering, Nanoparticle, Bioengineering, Protein Corona, Context (language use), Nanotechnology, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Biochemistry, lcsh:Technology, Biomaterials, Biosafety, protein corona, [CHIM]Chemical Sciences, [CHIM.COOR]Chemical Sciences/Coordination chemistry, mesoporous silica, ComputingMilieux_MISCELLANEOUS, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, [CHIM.MATE] Chemical Sciences/Material chemistry, Chemistry, lcsh:T, [CHIM.MATE]Chemical Sciences/Material chemistry, Mesoporous silica, [CHIM.COOR] Chemical Sciences/Coordination chemistry, 021001 nanoscience & nanotechnology, adverse outcome pathways, 3. Good health, 0104 chemical sciences, internalization, nanoparticles, Drug delivery, Perspective, Molecular Medicine, Nanomedicine, 0210 nano-technology, Biotechnology, Potential toxicity
Abstract: International audience; Careful analysis of any new nanomedicine device or disposal should be undertaken to comprehensively characterize the new product before application, so that any unintended side effect is minimized. Because of the increasing number of nanotechnology-based drugs, we can anticipate that regulatory authorities might adapt the approval process for nanomedicine products due to safety concerns, e.g., request a more rigorous testing of the potential toxicity of nanoparticles (NPs). Currently, the use of mesoporous silica nanoparticles (MSN) as drug delivery systems is challenged by a lack of data on the toxicological profile of coated or non-coated MSN. In this context, we have carried out an extensive study documenting the influence of different functionalized MSN on the cellular internalization and in vivo behaviour. In this article, a synthesis of these works is reviewed and the perspectives are drawn. The use of magnetic MSN (Fe3O4@MSN) allows an efficient separation of coated NPs from cell cultures with a simple magnet, leading to results regarding corona formation without experimental bias. Our interest is focused on the mechanism of interaction with model membranes, the adsorption of proteins in biological fluids, the quantification of uptake, and the effect of such NPs on the transcriptomic profile of hepatic cells that are known to be readily concerned by NPs' uptake in vivo, especially in the case of an intravenous injection.
Published: 2018

20. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort

Author: Laurence Vanlemmens, Marc Debled, Christian Cailliot, Elisa Gobbini, Thomas Bachelot, Monia Ezzalfani, Christelle Jouannaud, Suzette Delaloge, Magali Lacroix-Triki, Anne Patsouris, Thierry Petit, Simone Mathoulin-Pélissier, Veronique Lorgis, William Jacot, Marie Ange Mouret-Reynier, Mathieu Robain, C. Lefeuvre-Plesse, Florence Dalenc, Audrey Lardy Cleaud, Etienne Brain, Christelle Levy, David Pérol, C. Courtinard, Véronique Diéras, Marianne Leheurteur, Lionel Uwer, Anthony Gonçalves, Jean Marc Ferrero, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute Curie, Centre Léon Bérard [Lyon], Institut Curie [Saint-Cloud], Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale supérieure d'architecture de Toulouse (ENSA Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CRLCC Jean Godinot, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Département de biologie et pathologie médicales [Gustave Roussy], Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Haute Normandie-CRLCC Henri Becquerel, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Center Oscar Lambret, CRLCC Oscar Lambret, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie - Saint Cloud (ICSC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER
Subjects: Adult, Cancer Research, medicine.medical_specialty, Multivariate analysis, Time Factors, Receptor, ErbB-2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Triple Negative Breast Neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cancer Survivors, Risk Factors, HER2, Internal medicine, polycyclic compounds, Overall survival, Biomarkers, Tumor, Medicine, Humans, 030212 general & internal medicine, Neoplasm Metastasis, skin and connective tissue diseases, Aged, Retrospective Studies, Subtypes, Aged, 80 and over, business.industry, Time trends, Hazard ratio, Middle Aged, Metastatic breast cancer, medicine.disease, Confidence interval, 3. Good health, Treatment Outcome, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cohort, Observational study, Female, France, business, Receptors, Progesterone
Abstract: Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.
Published: 2018

21. Inhibition of CD39 Enzymatic Function at the Surface of Tumor Cells Alleviates Their Immunosuppressive Activity

Author: Nathalie Bonnefoy, Armand Bensussan, Nicole Bec, Jérémy Bastid, Stéphanie Cochaud, Caroline Laheurte, Jean-François Eliaou, Cécile Dejou, Laurent Gros, Anne Regairaz, Jérôme Giustiniani, Christian Larroque, Patrice Hemon, Emilie Laprevotte, Gilles Alberici, Elisa Funck-Brentano, OREGA Biotech, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Immunodermatologie, Cytokines, Cancer - EA 7319 (ICA), Université de Reims Champagne-Ardenne (URCA), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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: Cancer Research, Adenosine, Regulatory T cell, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Biology, T-Lymphocytes, Regulatory, Immune tolerance, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, 0302 clinical medicine, Antigens, CD, Cell Line, Tumor, Immune Tolerance, medicine, Humans, Cytotoxic T cell, 5'-Nucleotidase, 030304 developmental biology, Adenosine Triphosphatases, 0303 health sciences, Lymphokine-activated killer cell, Apyrase, Receptors, Purinergic P1, Adenosine receptor, 3. Good health, Cell biology, Killer Cells, Natural, Adenosine diphosphate, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug
Abstract: The ectonucleotidases CD39 and CD73 hydrolyze extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to generate adenosine, which binds to adenosine receptors and inhibits T-cell and natural killer (NK)–cell responses, thereby suppressing the immune system. The generation of adenosine via the CD39/CD73 pathway is recognized as a major mechanism of regulatory T cell (Treg) immunosuppressive function. The number of CD39+ Tregs is increased in some human cancers, and the importance of CD39+ Tregs in promoting tumor growth and metastasis has been demonstrated using several in vivo models. Here, we addressed whether CD39 is expressed by tumor cells and whether CD39+ tumor cells mediate immunosuppression via the adenosine pathway. Immunohistochemical staining of normal and tumor tissues revealed that CD39 expression is significantly higher in several types of human cancer than in normal tissues. In cancer specimens, CD39 is expressed by infiltrating lymphocytes, the tumor stroma, and tumor cells. Furthermore, the expression of CD39 at the cell surface of tumor cells was directly demonstrated via flow cytometry of human cancer cell lines. CD39 in cancer cells displays ATPase activity and, together with CD73, generates adenosine. CD39+CD73+ cancer cells inhibited the proliferation of CD4 and CD8 T cells and the generation of cytotoxic effector CD8 T cells (CTL) in a CD39- and adenosine-dependent manner. Treatment with a CD39 inhibitor or blocking antibody alleviated the tumor-induced inhibition of CD4 and CD8 T-cell proliferation and increased CTL- and NK cell–mediated cytotoxicity. In conclusion, interfering with the CD39–adenosine pathway may represent a novel immunotherapeutic strategy for inhibiting tumor cell–mediated immunosuppression. Cancer Immunol Res; 3(3); 254–65. ©2014 AACR.
Published: 2015

22. Dexamethasone in hyperleukocytic acute myeloid leukemia

Author: Clément Larrue, Isabelle Luquet, Emmanuel Griessinger, Martin Carroll, Françoise Huguet, Eric Delabesse, Christian Recher, Audrey Sarry, Emilie Bérard, François Vergez, Suzanne Tavitian, Laetitia K. Linares, Jean-Emmanuel Sarry, Sarah Bertoli, Muriel Picard, Estelle Saland, Pierre Luc Mouchel, Jean Ruiz, Edwige Yon, Gwenn Danet-Desnoyers, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation polyvalente [Toulouse], CHU Toulouse [Toulouse], Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), 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 des Maladies Métaboliques et Cardiovasculaires (I2MC), 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, University of Pennsylvania [Philadelphia], This work was supported by grants from the French government under the 'Investissement d'Avenir' program (ANR-11-PHUC-001), the Institut National du Cancer (PLBIO 2015-143), the InnaBioSanté Foundation (RESISTAML project), the Toulouse Cancer Santé Foundation, the Laboratoire d'Excellence TOUCAN and La Ligue Contre le Cancer. EG is supported bya postdoctoral grant from La Fondation de France., ANR-11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-11-PHUC-0001/11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), Linares, Laetitia, Pôle hospitalier Universitaire Cancer (PHUC) - Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région - - CAPTOR2011 - ANR-11-PHUC-0001 - PHUC - VALID, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation polyvalente [CHU Toulouse], Pôle Anesthésie Réanimation [CHU de Toulouse], Université Nice Sophia Antipolis (1965 - 2019) (UNS), and University of Pennsylvania
Subjects: 0301 basic medicine, Oncology, Male, Myeloid, Leukocytosis, medicine.medical_treatment, Kaplan-Meier Estimate, Dexamethasone, 0302 clinical medicine, Recurrence, Gene Expression Regulation, Leukemic, Remission Induction, Myeloid leukemia, Nuclear Proteins, Leukostasis, Hematology, Middle Aged, Prognosis, 3. Good health, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Nucleophosmin, medicine.drug, Adult, Acute Myeloid Leukemia, medicine.medical_specialty, Adolescent, Antineoplastic Agents, Hormonal, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, White blood cell, medicine, Humans, Aged, Chemotherapy, business.industry, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Mutation, Cytarabine, business
Abstract: International audience; Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; P=0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; P=0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; P
Published: 2017

23. Detection of known and novel ALK fusion transcripts in lung cancer patients using next-generation sequencing approaches

Author: David Grand, Peter Coopman, Sylvie Taviaux, Isabelle Rouquette, Beno ⁱt Béganton, Jean-Louis Pujol, Jérôme Solassol, Sylvain Godreuil, Estelle Clermont, Julien Mazieres, Pierre Brousset, Patricia Audran, Isabelle Serre, Julie A. Vendrell, Valérie Costes, Vanessa Szablewski, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), Centre Max Weber (CMW), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Monnet [Saint-Étienne] (UJM), 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), Service de Pneumologie, Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), IUCT Oncopole - Institut Universitaire du Cancer de Toulouse, CHU Toulouse [Toulouse], CHU, Hôpital Larrey, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), 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), Service Pneumologie-Allergologie [CHU Toulouse], Pôle Clinique des Voies respiratoires [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Pathology, Lung Neoplasms, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], lcsh:Medicine, Gene Expression, 0302 clinical medicine, hemic and lymphatic diseases, Carcinoma, Non-Small-Cell Lung, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, lcsh:Science, In Situ Hybridization, Fluorescence, Multidisciplinary, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Dynactin Complex, Amplicon, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Microtubule-Associated Proteins, medicine.drug, medicine.medical_specialty, Adenocarcinoma of Lung, Antineoplastic Agents, Biology, DNA sequencing, Article, 03 medical and health sciences, Crizotinib, medicine, Carcinoma, Humans, RNA, Messenger, Lung cancer, Aged, Neoplasm Staging, lcsh:R, Golgi Matrix Proteins, medicine.disease, 030104 developmental biology, Case-Control Studies, Cancer research, lcsh:Q, Fluorescence in situ hybridization
Abstract: Rearrangements of the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) represent a novel molecular target in a small subset of tumors. Although ALK rearrangements are usually assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), molecular approaches have recently emerged as relevant alternatives in routine laboratories. Here, we evaluated the use of two different amplicon-based next-generation sequencing (NGS) methods (AmpliSeq and Archer®FusionPlex®) to detect ALK rearrangements, and compared these with IHC and FISH. A total of 1128 NSCLC specimens were screened using conventional analyses, and a subset of 37 (15 ALK-positive, and 22 ALK-negative) samples were selected for NGS assays. Although AmpliSeq correctly detected 25/37 (67.6%) samples, 1/37 (2.7%) and 11/37 (29.7%) specimens were discordant and uncertain, respectively, requiring further validation. In contrast, Archer®FusionPlex® accurately classified all samples and allowed the correct identification of one rare DCTN1-ALK fusion, one novel CLIP1-ALK fusion, and one novel GCC2-ALK transcript. Of particular interest, two out of three patients harboring these singular rearrangements were treated with and sensitive to crizotinib. These data show that Archer®FusionPlex® may provide an effective and accurate alternative to FISH testing for the detection of known and novel ALK rearrangements in clinical diagnostic settings.
Published: 2017

24. Multicentric initial experience with the use of the pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the management of unresectable peritoneal carcinomatosis

Author: Denis Pezet, Olivier Glehen, Naoual Bakrin, Mohammad Alyami, Guillaume Passot, Delphine Cabelguenne, Johan Gagnière, Laurent Villeneuve, Olivia Sgarbura, François Quenet, Chirurgie digestive et hépatobiliaire, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), 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), Service de pharmacie - Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), Unité de Méthodologie en Recherche Clinique, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL), Department of Digestive Surgery, University Medical Hospital, Center Val d'Aurel, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Department of Obstetrics and Gynaecology, Ciblage thérapeutique en Oncologie (EA3738), Université de Lyon-Université de Lyon, Centre Hospitalier Universitaire Estaing, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, Constipation, medicine.medical_treatment, Antineoplastic Agents, 03 medical and health sciences, 0302 clinical medicine, Ascites, medicine, Pressure, Pseudomyxoma peritonei, Humans, Mesothelioma, Prospective Studies, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Peritoneal Neoplasms, Aged, Aerosols, Chemotherapy, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Middle Aged, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Surgery, Oxaliplatin, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Conventional PCI, 030211 gastroenterology & hepatology, Female, France, medicine.symptom, business, Injections, Intraperitoneal, medicine.drug
Abstract: Background PIPAC is a recent approach for intraperitoneal chemotherapy with promising results for patients with peritoneal carcinomatosis (PC). We aimed to evaluate the postoperative outcome of PIPAC in patients with non-resectable PC during our initial experience of the technique. Methods All patients who underwent PIPAC for non-resectable PC in three centers were analyzed regarding postoperative outcomes. Results Seventy-three patients underwent 164 PIPAC. PC was from colorectal, gastric, ovarian, malignant mesothelioma, pseudomyxoma peritonei or other origins in 20, 26, 13, 8, 1 and 5 patients respectively. Forty-five (62%), 31 (42%), 8 (11%), 6 (8%), 1 (1%) patients underwent a second, third, fourth, fifth, and sixth PIPAC respectively. At the time of the first PIPAC, the median PCI was 17 (1–39), 57 patients presented with symptomatic PC (pain: 33; ascites: 35; transit disorder like diarrhea and constipation: 11). PCI improved in 64.5% of patients, 63.5% of patients presented with complete disappearance of symptoms. Major complications occurred as the outcome of 16 PIPAC (9.7%) and 5 (6.8%) patients died within 30 days of the PIPAC procedure. Rate of mortality and major complications 40% and 62% respectively occurred in first 20 treated patients. For 64 (88%) patients, systemic chemotherapy was associated with PIPAC and could be administered after PIPAC with a median delay of 14 days (2–28). Conclusions Implementing a PIPAC program in association with systemic chemotherapy is feasible and is associated with a risk of postoperative morbidity, even in teams highly experienced in PC management and requires a learning curve in patient selection.
Published: 2017

25. RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia

Author: Rudy Birsen, Didier Bouscary, Christian Récher, Nathalie Jacque, Pierre Sujobert, M. Le Gall, Estelle Saland, Laury Poulain, Fetta Mazed, V Salnot, Alexa S. Green, Michaela Fontenay, Clément Larrue, Patrick Mayeux, Olivier Kosmider, E.F. Gautier, Arnaud Jacquel, Justine Decroocq, Jerome Tamburini, J-E Sarry, Mireille Lambert, Patrick Auberger, Johanna Mondesir, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Cités, Territoires, Environnement et Sociétés (CITERES), Université de Tours-Centre National de la Recherche Scientifique (CNRS), 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), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), [Institut Cochin] Departement Infection, immunité, inflammation, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Université de Tours, CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Toulouse [Toulouse]-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), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT), Université de Tours (UT), and Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: 0301 basic medicine, FLT3 Internal Tandem Duplication, Cancer Research, Myeloid, Cell Survival, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, Biology, Protein Serine-Threonine Kinases, Ribosomal Protein S6 Kinases, 90-kDa, 03 medical and health sciences, Mice, hemic and lymphatic diseases, Cell Line, Tumor, Gene Duplication, Proto-Oncogene Proteins, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, bcl-2-Associated X Protein, Kinase, Gene Expression Profiling, Myeloid leukemia, Hematology, medicine.disease, 3. Good health, RPS6KA3, Leukemia, Disease Models, Animal, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Oncology, fms-Like Tyrosine Kinase 3, Tandem Repeat Sequences, Ribosomal protein s6, Caspases, Gene Knockdown Techniques, embryonic structures, Cancer research, Transcriptome, Tyrosine kinase, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20–30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.
Published: 2017

26. Case report of the patient source of the Babesia microti R1 reference strain and implications for travelers

Author: Emmanuel Cornillot, Peter J. Krause, Laurence Berry, Vasilica Ciubotaru, Choukri Ben Mamoun, Brinda Emu, Philipp Stahl, Yves Poinsignon, Pascal Pouedras, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), 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 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 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), Centre Hospitalier Bretagne Atlantique [Vannes], CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)
Subjects: 0301 basic medicine, Male, animal diseases, tick-borne disease, MESH: Tick Bites, law.invention, MESH: Babesia microti, 0302 clinical medicine, Ticks, law, MESH: Animals, MESH: Travel, Polymerase chain reaction, MESH: Aged, Tick-borne disease, Travel, biology, medicine.diagnostic_test, Babesiosis, General Medicine, 3. Good health, MESH: Babesiosis, Massachusetts, R1 strain, France, Antibody, MESH: Massachusetts, 030231 tropical medicine, Physical examination, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tick, Babesia microti, 03 medical and health sciences, parasitic diseases, medicine, Animals, Humans, Medical history, MESH: Ticks, Aged, MESH: Humans, Tick Bites, business.industry, Original Articles, medicine.disease, biology.organism_classification, Virology, MESH: Male, MESH: France, 030104 developmental biology, Babesia, biology.protein, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BackgroundIn 2002, a previously healthy 69-year-old man travelled to France from the United States and presented to our hospital with a febrile illness that subsequently was determined to be babesiosis. The blood isolated from this patient served as a source for propagation of the Babesia microti R1 strain with subsequent sequencing and annotation of the parasite genome.MethodsUpon admission, we obtained a medical history, performed a physical examination, and examined his blood for the presence of a blood borne pathogen by microscopy, PCR and indirect immunofluorescence antibody testing. Once the diagnosis of babesiosis was made, we reviewed the literature to assess the distribution of B. microti-associated babesiosis cases in immunocompetent patients from outside the USA.ResultsThe patient recalled a tick bite during the previous month on Cape Cod, Massachusetts. The diagnosis was confirmed by identification of Babesia-infected red blood cells on blood smears, amplification of B. microti DNA in blood by PCR and the presence of B. microti antibody in the serum. This strain was the first isolate of B. microti to be fully sequenced and its annotated genome serves as a reference for molecular and cell biology studies aimed at understanding B. microti pathophysiology and developing diagnostic tests and therapies. A review of babesiosis cases demonstrates a worldwide distribution of B. microti and identifies potential emerging endemic areas where travelers may be at risk of contracting B. microti infection.ConclusionThis case provides clinical information about the patient infected with the R1 isolate and a review of travel risk, diagnosis and treatment of babesiosis in endemic and non-endemic areas.
Published: 2017

27. In vitro and in vivo estrogenic activity of BPA, BPF and BPS in zebrafish-specific assays

Author: Vincent Le Fol, Selim Ait-Aissa, Jean-Marc Porcher, Jean Pierre Cravedi, Manoj Sonavane, Patrick Balaguer, Daniel Zalko, François Brion, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut National de l'Environnement Industriel et des Risques (INERIS), Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université de Montpellier (UM), French Ministry of Ecology (P181-DRC50), FP7-PEOPLE-2011-ITN EDAEMERGE project under the grant agreement number 290100, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Métabolisme et Xénobiotiques (ToxAlim-MeX), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, Embryo, Nonmammalian, Health, Toxicology and Mutagenesis, pertubateur endocrinien, [SDV]Life Sciences [q-bio], brachydanio rerio, toxicologie alimentaire, Estrogen receptor, 010501 environmental sciences, Endocrine Disruptors, human health, 01 natural sciences, Green fluorescent protein, Animals, Genetically Modified, chemistry.chemical_compound, Vitellogenins, Genes, Reporter, Sulfones, Aromatase, Zebrafish, biology, zebrafish, endocrine disruptors, bisphenols, estrogenic activity, MESH: Animals, Genetically Modified, Aromatase/metabolism, Brain/drug effects, Cell Line, Brain, General Medicine, santé humaine, Pollution, Cell biology, Receptors, Estrogen, [SDE]Environmental Sciences, bisphénol s, oestrogénicité, Biological Assay, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, endocrine system, Green Fluorescent Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Vitellogenin, Phenols, In vivo, Internal medicine, medicine, bisphénol a, Animals, Benzhydryl Compounds, 0105 earth and related environmental sciences, urogenital system, Public Health, Environmental and Occupational Health, Estrogens, Zebrafish Proteins, biology.organism_classification, In vitro, 030104 developmental biology, Endocrinology, Bisphenol S, chemistry, biology.protein
Abstract: International audience; Bisphenol A (BPA) is a widely used chemical that has been extensively studied as an endocrine-disrupting chemical (EDC). Other bisphenols sharing close structural features with BPA, are increasingly being used as alternatives, increasing the need to assess associated hazards to the endocrine system. In the present study, the estrogenic activity of BPA, bisphenol S (BPS) and bisphenol F (BPF) was assessed by using a combination of zebrafish-specific mechanism-based in vitro and in vivo assays. The three bisphenols were found to efficiently transactivate all zebrafish estrogen receptor (zfER) subtypes in zebrafish hepatic reporter cell lines (ZELH-zfERs). BPA was selective for zfERα while BPS and BPF were slightly more potent on zfERβ subtypes. We further documented the estrogenic effect in vivo by quantifying the expression of brain aromatase using a transgenic cyp19a1b-GFP zebrafish embryo assay. All three bisphenols induced GFP in a concentration-dependent manner. BPS only partially induced brain aromatase at the highest tested concentrations (>30µM) while BPA and BPF strongly induced GFP, in an ER-dependent manner, at 1-10µM. Furthermore, we show that BPF strongly induced vitellogenin synthesis in adult male zebrafish. Overall, this study demonstrates the estrogenic activity of BPA, BPF and BPS in different cell- and tissue-contexts and at different stages of development. Differences between in vitro and in vivo responses are discussed in light of selective ER activation and the fate of the compounds in the models. This study confirms the relevance of combining cellular and whole-organism bioassays in a unique model species for the hazard assessment of candidate EDCs.
Published: 2017

28. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials)

Author: Manfred B. Lutz, Roberto Labianca, Patrick Pessaux, Bert A. Bonsing, Benoist Chibaudel, David Malka, Claudio Bassi, Sophie Gourgou-Bourgade, Geertjan van Tienhoven, Pascal Hammel, Carine Bellera, Laeticia Dahan, Jean-Luc Van Laethem, Daniela Aust, Emmanuel Chamorey, Jean Robert Delpero, Josep Tabernero, Adelaide Dousseau, Teresa Macarulla, Franck Bonnetain, Julien Taieb, Karin Haustermans, Laurence Collette, Thomas Aparicio, François Lacaine, John P. Neoptolemos, Simone Mathoulin-Pélissier, Bengt Glimelius, Thierry Conroy, Paula Ghaneh, Alain Sauvanet, Erich Gerber, Christos Dervenis, Aurélien Latouche, Murielle Mauer, Michel Ducreux, Valérie Jooste, Virginie Berger, Jocelyn Gal, Alain Hendlisz, Aimery de Gramont, Emmanuel Mitry, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), UNICANCER, Leiden University Medical Center (LUMC), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Université Victor Segalen - Bordeaux 2, CHU Bordeaux [Bordeaux], Uppsala Universitet [Uppsala], University Hospitals Leuven [Leuven], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Service de Gastro-entérologie [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Carl Gustav Carus University (DRESDEN - CGCU), Technische Universität Dresden = Dresden University of Technology (TU Dresden), G.B. Rossi Hospital, Verona University, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cooperator Multidisciplinary Oncology Group (GERCOR), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Agia Olga Hospital [Athènes] (Konstantopoulio ), Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut für Radioonkologie, Royal Liverpool University Hospital, University of Liverpool-Royal Liverpool and Broadgreen University Hospital NHS Trust, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Institut Jules Bordet [Bruxelles], Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Azienda Ospedaleria Ospedali Riuniti di Bergamo, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), CaritasKlinikum Saarbrücken, Vall d'Hebron University Hospital [Barcelona], European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), Institut Curie [Paris], CRLCC René Huguenin, L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Service d’Hépatologie [Hôpital Beaujon], Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Academisch Medisch Centrum bij, Universiteit van Amsterdam (UvA), 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), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Maladies chroniques, santé perçue, et processus d'adaptation. Approches épidémiologiques et psychologiques. ( APEMAC - EA 4360 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), CHU Tenon [APHP], Hôpital Erasme (Bruxelles), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Carl Gustav Carus University ( DRESDEN - CGCU ), Technische Universität Dresden ( TUD ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, CRLCC Antoine Lacassagne, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Cooperator Multidisciplinary Oncology Group ( GERCOR ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut Paoli Calmettes, Agia Olga Hospital [Athènes] ( Konstantopoulio ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Hôpital Beaujon, Institut Jules Bordet, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), European Organisation for Research and Treatment of Cancer [Bruxelles] ( EORTC ), European Cancer Organisation [Bruxelles] ( ECCO ), Institut Curie, L'Institut hospitalo-universitaire de Strasbourg ( IHU Strasbourg ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Service de gastroenterologie [CHU Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Universiteit van Amsterdam ( UvA ), 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 National de la Santé et de la Recherche Médicale ( INSERM ), Institut Bergonié - CRLCC Bordeaux, Universiteit Leiden, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Verona = University of Verona (UNIVR), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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: Oncology, Cancer Research, Pathology, Delphi Technique, MESH : Randomized Controlled Trials as Topic, MESH: Delphi Technique, MESH : Consensus, law.invention, Clinical trials, 0302 clinical medicine, Pancreatic cancer, Time to event end-point, Consensus, Guidelines, Methodology, Clinical trials, Randomized controlled trial, law, 030212 general & internal medicine, Time to event end-point, Randomized Controlled Trials as Topic, Event (probability theory), MESH: Endpoint Determination, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, 16. Peace & justice, 3. Good health, 030220 oncology & carcinogenesis, MESH : Disease-Free Survival, MESH : Endpoint Determination, MESH: Pancreatic Neoplasms, medicine.medical_specialty, Consensus, Endpoint Determination, Guidelines, Disease-Free Survival, 03 medical and health sciences, Internal medicine, Pancreatic cancer, medicine, Overall survival, Humans, MESH: Consensus, Distributed File System, neoplasms, MESH: Humans, End point, business.industry, MESH : Humans, Methodology, Cancer, medicine.disease, Pancreatic Neoplasms, Clinical trial, MESH: Randomized Controlled Trials as Topic, MESH : Delphi Technique, MESH: Disease-Free Survival, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH : Pancreatic Neoplasms
Abstract: International audience; BACKGROUND:Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer.METHODS:Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9).RESULTS:For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items.CONCLUSION:The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.
Published: 2014

29. Combining gemcitabine, cisplatin, and ifosfamide (GIP) is active in patients with relapsed metastatic germ-cell tumors (GCT): a prospective multicenter GETUG phase II trial

Author: Lionnel Geoffrois, Remy Delva, N. Houede, Frederic Rolland, Agnès Laplanche, J.-C. Eymard, B. Laguerre, Aude Flechon, Karim Fizazi, Stéphane Culine, D. Burcoveanu, G. Gravis, Christine Chevreau, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Léon Bérard [Lyon], Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, CRLCC Eugène Marquis (CRLCC), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), CRLCC Jean Godinot, CRLCC René Gauducheau, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Institut Bergonié - CRLCC Bordeaux, 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), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Bergonié [Bordeaux], 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Male, Oncology, 030232 urology & nephrology, Salvage therapy, Kaplan-Meier Estimate, Deoxycytidine, Gastroenterology, Testicular Neoplasms/*drug therapy/mortality/pathology, 0302 clinical medicine, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Ifosfamide, Hematology, Middle Aged, Neoplasms, Germ Cell and Embryonal, Ifosfamide/administration & dosage, Chemotherapy regimen, 3. Good health, Treatment Outcome, Germ Cell and Embryonal/*drug therapy/mortality/secondary, Lymphatic Metastasis, 030220 oncology & carcinogenesis, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug Administration Schedule, Young Adult, 03 medical and health sciences, Testicular Neoplasms, Internal medicine, Deoxycytidine/administration & dosage/analogs & derivatives, medicine, Local/*drug therapy, Humans, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use, Progression-free survival, Survival rate, Salvage Therapy, business.industry, medicine.disease, Gemcitabine, Regimen, Neoplasm Recurrence, Cisplatin, Neoplasm Recurrence, Local, business, Cisplatin/administration & dosage, Febrile neutropenia
Abstract: International audience; BACKGROUND: The standard treatment of patients with metastatic germ-cell tumor (GCT) relapsing after first-line chemotherapy is based on a cisplatin and ifosfamide-containing three-drug regimen, which usually yields a complete response (CR) rate \textless50%. As gemcitabine consistently displayed activity in patients with advanced GCT and as synergy with cisplatin was reported, we integrated this drug into the salvage triplet regimen and assessed its activity in this phase II study. PATIENTS AND METHODS: The GIP regimen consisted in gemcitabine 1000 mg/m(2) day 1 and 5, ifosfamide 1200 mg/m(2)/day day 1-5, cisplatin 20 mg/m(2)/day day 1-5, and granulocyte colony-stimulating factor 263 mug/day day 7-15, repeated every 3 weeks for four cycles. Eligibility criteria were that patients had favorable prognostic factors to conventional-dose salvage chemotherapy including a testis primary tumor and a previous CR to first-line chemotherapy for metastatic disease. The primary end point was the CR rate and a two-stage Simon design was used. RESULTS: Thirty-seven patients were accrued and 29 (78%) achieved a favorable response, including a CR in 20 (54%) and a partial response with normalization of tumor markers (PRm-) in 9 (24%). With a median follow-up of 53 months (13-81), the 2-year overall survival rate is 73% (57%-84%) and the continuous progression-free survival rate is 51% (35%-66%). Myelosuppression was the main toxicity including febrile neutropenia in 8 (22%) patients and 18 (50%) cases required platelet infusion. No grade 3 and 4 peripheral neurotoxicity or renal toxicity occurred. Two patients died of treatment-related toxicity, one of them with cancer progression. CONCLUSION: In a multicenter context, four cycles of the GIP regimen achieved a high CR rate in patients with relapsed testicular GCT. The GIP regimen avoided severe neurotoxicity and yielded a high survival rate. CLINICAL TRIAL NUMBER: NCT00127049.
Published: 2014

30. RIP140 increases APC expression and controls intestinal homeostasis and tumorigenesis

Author: Stéphan Jalaguier, Michela Plateroti, Frédéric Hollande, Caroline Bascoul-Mollevi, Marion Lapierre, Imade Ait-Arsa, Paul Roepman, Maguy Del Rio, Vincent Cavaillès, Marc Ychou, Malcolm G. Parker, Sandrine Bonnet, Julie Pannequin, 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), Unité de biostatistiques, CRLCC Val d'Aurelle - Paul Lamarque, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Agendia NV, Agendia NV, Amsterdam, Agendia Inc, Irvine, 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), Institute of Reproductive and Developmental Biology (IRDB), Imperial College London, and This work was supported by INSERM, Université de Montpellier 1, Fondation Lejeune, INCa (2011-054), SIRIC Montpellier and the Institut régional du Cancer de Montpellier (ICM).
Subjects: Male, Colorectal cancer, Adenomatous Polyposis Coli Protein, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, Biology, medicine.disease_cause, Mice, Intestinal mucosa, Cell Line, Tumor, medicine, Animals, Homeostasis, Humans, Intestinal Mucosa, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Knockout, Regulation of gene expression, Cell growth, Wnt signaling pathway, Nuclear Proteins, Epithelial Cells, General Medicine, medicine.disease, Nuclear Receptor Interacting Protein 1, 3. Good health, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Colonic Neoplasms, Immunology, Cancer research, Heterografts, Female, Signal transduction, Carcinogenesis, Neoplasm Transplantation, Research Article
Abstract: International audience; Deregulation of the Wnt/APC/β-catenin signaling pathway is an important consequence of tumor suppressor APC dysfunction. Genetic and molecular data have established that disruption of this pathway contributes to the development of colorectal cancer. Here, we demonstrate that the transcriptional coregulator RIP140 regulates intestinal homeostasis and tumorigenesis. Using Rip140-null mice and mice overexpressing human RIP140, we found that RIP140 inhibited intestinal epithelial cell proliferation and apoptosis. Interestingly, following whole-body irradiation, mice lacking RIP140 exhibited improved regenerative capacity in the intestine, while mice overexpressing RIP140 displayed reduced recovery. Enhanced RIP140 expression strongly repressed human colon cancer cell proliferation in vitro and after grafting onto nude mice. Moreover, in murine tissues and human cancer cells, RIP140 stimulated APC transcription and inhibited β-catenin activation and target gene expression. Finally, RIP140 mRNA and RIP140 protein levels were decreased in human colon cancers compared with those in normal mucosal tissue, and low levels of RIP140 expression in adenocarcinomas from patients correlated with poor prognosis. Together, these results support a tumor suppressor role for RIP140 in colon cancer.
Published: 2014

31. BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy

Author: Laetitia K. Linares, Andrew V. Hubberstey, Emmanuelle Liaudet-Coopman, Nelly Pirot, Fabienne Desmots, Guy Berchem, Anne-Sophie Bach, Esther Pérez-Gracia, Christine Prébois, Valérie Palissot, Patrice Codogno, Céline Gongora, Salwa Sebti, Sophie Pattingre, Chantal Bauvy, 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 Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire ( HITC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Department of Biological Sciences [Windsor], University of Windsor [Ca], Laboratory of Experimental Hemato-Oncology ( CRP-Santé ), Centre de Recherche Public-Santé, This work is supported by INSERM, ARC (SP), La Ligue Régionale contre Le Cancer (Comités du Gard et de l'Hérault) (SP), Cancéropole GSO (SP) and CHEMORES consortium (EU FP6, ELC). SS has fellowships from the FNR Luxembourg and La Ligue Nationale contre le Cancer., 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 Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratory of Experimental Hemato-Oncology (CRP-Santé), Le Ster, Yves, 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), and Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]
Subjects: p53, Autophagy-Related Protein 7, MESH: Mice, Knockout, Mice, Cytosol, MESH: Cytosol, MESH : Embryo, Mammalian, MESH: Animals, Nuclear protein, MESH: Tumor Suppressor Protein p53, Mice, Knockout, MESH : Cell Nucleus, Multidisciplinary, MESH: Real-Time Polymerase Chain Reaction, MESH : Cytosol, Life Sciences, Nuclear Proteins, Biological Sciences, Cell biology, medicine.anatomical_structure, MESH : Cell Fractionation, MESH: Cell Fractionation, MESH : DNA Primers, MESH: Molecular Chaperones, Microtubule-Associated Proteins, MESH: Acetylation, MESH: Cell Nucleus, MESH: DNA Primers, MESH : Real-Time Polymerase Chain Reaction, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Fractionation, Real-Time Polymerase Chain Reaction, MESH : Acetylation, BAG3, MESH : E1A-Associated p300 Protein, MESH : Immunoprecipitation, BAT3, MESH : Mice, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Autophagy, medicine, Animals, Immunoprecipitation, MESH: Autophagy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA Primers, acetylation, Cell Nucleus, MESH: Immunoprecipitation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Embryo, Mammalian, MESH : Molecular Chaperones, MESH : Nuclear Proteins, Embryo, Mammalian, MESH : Autophagy, Molecular biology, ATG, MESH: Microtubule-Associated Proteins, MESH : Tumor Suppressor Protein p53, Cell nucleus, MESH : Microtubule-Associated Proteins, Acetylation, MESH : Mice, Knockout, MESH: E1A-Associated p300 Protein, MESH : Animals, Tumor Suppressor Protein p53, E1A-Associated p300 Protein, MESH: Nuclear Proteins, Nuclear localization sequence, Molecular Chaperones
Abstract: International audience; Autophagy is regulated by posttranslational modifications, including acetylation. Here we show that HLA-B-associated transcript 3 (BAT3) is essential for basal and starvation-induced autophagy in embryonic day 18.5 BAT3(-/-) mouse embryos and in mouse embryonic fibroblasts (MEFs) through the modulation of p300-dependent acetylation of p53 and ATG7. Specifically, BAT3 increases p53 acetylation and proautophagic p53 target gene expression, while limiting p300-dependent acetylation of ATG7, a mechanism known to inhibit autophagy. In the absence of BAT3 or when BAT3 is located exclusively in the cytosol, autophagy is abrogated, ATG7 is hyperacetylated, p53 acetylation is abolished, and p300 accumulates in the cytosol, indicating that BAT3 regulates the nuclear localization of p300. In addition, the interaction between BAT3 and p300 is stronger in the cytosol than in the nucleus and, during starvation, the level of p300 decreases in the cytosol but increases in the nucleus only in the presence of BAT3. We conclude that BAT3 tightly controls autophagy by modulating p300 intracellular localization, affecting the accessibility of p300 to its substrates, p53 and ATG7.
Published: 2014

32. Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial

Author: Pascal Fenoglietto, Stéphane Culine, Rodolphe Thuret, Simon Thezenas, O. Riou, D. Azria, Damien Pouessel, Xavier Rebillard, 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), Radiothérapie Oncologique, Université de Montpellier (UM), Service d'urologie, Clinique Beausoleil, Unité de biostatistiques, CRLCC Val d'Aurelle - Paul Lamarque, Service Urologie [Lapeyronie], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Service d'oncologie médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Urinary Bladder, Urology, cisplatin, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemo-radiotherapy, Deoxycytidine, Disease-Free Survival, Drug Administration Schedule, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Neoplasm Invasiveness, Radiology, Nuclear Medicine and imaging, Survival rate, Aged, Aged, 80 and over, Radiation, Bladder cancer, Performance status, business.industry, gemcitabine, Chemoradiotherapy, Middle Aged, medicine.disease, Gemcitabine, 3. Good health, Survival Rate, Radiation therapy, Regimen, Urinary Bladder Neoplasms, Concomitant, bladder cancer, Female, organ preservation, business, Organ Sparing Treatments, medicine.drug
Abstract: International audience; PURPOSE: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. METHODS AND MATERIALS: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. RESULTS: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. CONCLUSIONS: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.
Published: 2014

33. Correction to: Surgery in reference centers improves survival of sarcoma patients: a nationwide study

Author: M. Karanian-Philippe, Isabelle Ray-Coquard, A. Di Marco, J.-M. Guilloit, C. Perrin, M. Toulmonde, J.-P. Spano, G. Ferron, C. Le Pechoux, O. Collard, M. Rios, François Sirveaux, J. Guiramand, A. Dufresne, L. Chaigneau, C. Chevreau, S. Causeret, P. Gimbergues, L.R. Le Nail, M. Jafari, J.-C. Ruzic, O. Marco, F. Gouin, G. Vaz, A. Dupré, P. Anract, E. Stoeckle, A. Michot, F. Dujardin, Jean-Yves Blay, Emmanuelle Bompas, F. Guillemin, C. Honore, F. Duffaud, P. Meeus, A. Rochwerger, Nicolas Penel, F. Fiorenza, F. Le Loarer, S. Bonvalot, Mickaël Ropars, A. Le Cesne, F. Ducimetière, D. Pérol, A. Italiano, F. Marchal, P. Soibinet, Sébastien Carrère, J.-C. Machiavello, A. Giraud, François Bertucci, N. Firmin, M. Brahmi, AIRPARIF - Surveillance de la qualité de l'air en Île-de-France, Institut Bergonié - CRLCC Bordeaux, Centre Léon Bérard [Lyon], 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), CHU Pontchaillou [Rennes], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Centre chirurgical Émile-Gallé, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Department of Surgical Oncology, Jean Perrin Comprehensive Cancer Centre, Service de Chirurgie orthopédique et traumatologique [CHU Limoges], CHU Limoges, Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Laboratoire de Chimie et Physique - Approche Multi-échelle des Milieux Complexes (LCP-A2MC), CHU Pitié-Salpêtrière [APHP], Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Département de radiothérapie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire Interdisciplinaire de Recherche Impliquant la Géologie et la Mécanique, Université Joseph Fourier - Grenoble 1 (UJF), Centre Oscar Lambret, Laboratoire des Mécanismes et Transfert en Géologie (LMTG), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, medicine.medical_specialty, Multivariate analysis, [SDV]Life Sciences [q-bio], medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Relapse free survival, 03 medical and health sciences, 0302 clinical medicine, medicine, Neurofibromatosis, Pathological, ComputingMilieux_MISCELLANEOUS, business.industry, Hazard ratio, Cancer, Hematology, medicine.disease, 3. Good health, Surgery, Radiation therapy, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Sarcoma, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. Patients and methods Patients’ characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). Results Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li–Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P
Published: 2019

34. β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice

Author: Magalie A. Ravier, Morgane M. Roussel, Annie Varrault, Joy Richard, Joël Bockaert, Nelly Pirot, Michele Leduc, Nathalie Linck, Gyslaine Bertrand, Stéphane Dalle, 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), 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), Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale (grant DRM20101220453), research allocation from SFD-ALFEDIAM, 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 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 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), and Ravier, Magalie
Subjects: Scaffold protein, medicine.medical_specialty, Arrestins, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Blotting, Western, 030209 endocrinology & metabolism, Pancreatic beta cell mass, Diet, High-Fat, Real-Time Polymerase Chain Reaction, Receptor tyrosine kinase, Diabetes Mellitus, Experimental, Beta-Arrestin-2, Mice, 03 medical and health sciences, 0302 clinical medicine, Glucagon-Like Peptide 1, Insulin-Secreting Cells, Internal medicine, Internal Medicine, medicine, Animals, Insulin, Receptor, Pancreas, Pancreatic islet biology, beta-Arrestins, 030304 developmental biology, Mice, Knockout, 0303 health sciences, biology, Beta-Arrestins, Insulin secretion, β-Arrestin, beta-Arrestin 2, Receptor, Insulin, [SDV] Life Sciences [q-bio], Insulin receptor, High-fat diet, Endocrinology, biology.protein, Beta cell, Signal transduction, GLP-1, Signal Transduction
Abstract: International audience; AIMS/HYPOTHESIS:Beta cell failure due to progressive secretory dysfunction and limited expansion of beta cell mass is a key feature of type 2 diabetes. Beta cell function and mass are controlled by glucose and hormones/neurotransmitters that activate G protein-coupled receptors or receptor tyrosine kinases. We have investigated the role of β-arrestin (ARRB)2, a scaffold protein known to modulate such receptor signalling, in the modulation of beta cell function and mass, with a specific interest in glucagon-like peptide-1 (GLP-1), muscarinic and insulin receptors.METHODS:β-arrestin2-knockout mice and their wild-type littermates were fed a normal or a high-fat diet (HFD). Glucose tolerance, insulin sensitivity and insulin secretion were assessed in vivo. Beta cell mass was evaluated in pancreatic sections. Free cytosolic [Ca(2+)] and insulin secretion were determined using perifused islets. The insulin signalling pathway was evaluated by western blotting.RESULTS:Arrb2-knockout mice exhibited impaired glucose tolerance and insulin secretion in vivo, but normal insulin sensitivity compared with wild type. Surprisingly, the absence of ARRB2 did not affect glucose-stimulated insulin secretion or GLP-1- and acetylcholine-mediated amplifications from perifused islets, but it decreased the islet insulin content and beta cell mass. Additionally, there was no compensatory beta cell mass expansion through proliferation in response to the HFD. Furthermore, Arrb2 deletion altered the islet insulin signalling pathway.CONCLUSIONS/INTERPRETATION:ARRB2 is unlikely to be involved in the regulation of insulin secretion, but it is required for beta cell mass plasticity. Additionally, we provide new insights into the mechanisms involved in insulin signalling in beta cells.
Published: 2013

35. Paracetamol, Aspirin, and Indomethacin Induce Endocrine Disturbances in the Human Fetal Testis Capable of Interfering With Testicular Descent

Author: Isabelle Coiffec, Séverine Mazaud-Guittot, Patrice Poulain, Vincent Lavoué, David Møbjerg Kristensen, Millissia Ben Maamar, Christèle Desdoits-Lethimonier, Nathalie Dejucq-Rainsford, Cécile Chevrier, Bernard Jégou, Patrick Balaguer, Christophe Nicolas Nicolaz, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), 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), Microenvironnement et remodelage, Foie, métabolismes et cancer, 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 )-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 de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Service d'obstétrique, Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes], INSERM, Université de Rennes1, EHESP, Agence Nationale de Sécurité du Médicament et des Produits de Santé, Danish Council for independent Research, Coval, Nathalie, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), 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), and Université de Rennes (UR)-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 )-Université de Rennes (UR)-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 de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes]
Subjects: Male, Endocrinology, Diabetes and Metabolism, Indomethacin, Clinical Biochemistry, Biochemistry, 0302 clinical medicine, Endocrinology, Pregnancy, Cryptorchidism, Testis, Testosterone, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, Anti-Inflammatory Agents, Non-Steroidal, Abnormalities, Drug-Induced, Analgesics, Non-Narcotic, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Paracetamol, Androgens, Gestation, Female, medicine.drug, medicine.medical_specialty, Context (language use), 03 medical and health sciences, Fetus, Organ Culture Techniques, Internal medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Endocrine disturbances, medicine, Humans, Endocrine system, Acetaminophen, 030304 developmental biology, Aspirin, business.industry, Biochemistry (medical), Abortion, Induced, medicine.disease, Pregnancy Trimester, First, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Hormone
Abstract: International audience; Context: Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol or/and to other mild-analgesics is associated with an increased risk of cryptorchidism. Objective:We aimed at determining whether mild analgesics disrupted the morphology and endocrine function of the human testis.Design:We used an in vitro system based on the culture of human fetal testes exposed or not to paracetamol, its metabolite AM404, aspirin, indomethacin, ketoconazole at 10(-4) M to 10(-7) M.Setting:The study was conducted at the University of Rennes I.Patients/Participants:Human fetal testes were from pregnant women following induced abortion, between 7 and 12 weeks of gestation (GW). Main Outcome Measures:Testosterone (radioimmunoassay: RIA), Anti-Müllerian Hormone (AMH; ELISA), insulin-like factor 3 (INSL3; RIA), prostaglandin D2 and E2 (PGD2 and PGE2, respectively; ELISA), were assayed in the media. Testicular cells were counted using histology and image analysis. The possible nuclear receptor-mediated activities of the analgesics were investigated using reporter cell lines expressing estrogen (ERs), androgen (AR) and peroxysome proliferator-activated γ ( PPARγ) receptors.Results:Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8-9 GW vs 10-12 GW). Paracetamol, AM404 and ketoconazole decreased INSL3 levels. Aspirin stimulated, whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol, and aspirin in the 7-12 GW testes, and by indomethacin but only in 7-9.86 GW old testes. The inhibitory trends seen for PGD2 were not statistically significant. Conclusions:Analgesics at concentrations relevant to human exposure cause endocrine disturbances in the fetal testis. We suggest that the fetal human testis displays slight critical age windows for sensitivity to direct exposure to aspirin, indomethacin and paracetamol. The analgesic-induced inhibition of INSL3 may be the mechanism by which analgesics increase the risk of cryptorchidism. Greater caution is required concerning consumption of analgesics during pregnancy.
Published: 2013

36. AhR- and NF-κB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-α in human mammary MCF-7 cells

Author: Noémie Houlbert, Patrick Balaguer, Elise Kolasa, Olivier Fardel, Martin, Clémence, Contaminants Chimiques, immunité et Inflammation, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), 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), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), 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: Transcriptional Activation, medicine.medical_treatment, Toxicology, Benzanthracene, NF-κB, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Benz(a)Anthracenes, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Interleukin 6, Aryl hydrocarbon receptor, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Inflammation, 0303 health sciences, Tumor microenvironment, biology, Interleukin-6, Tumor Necrosis Factor-alpha, Chemistry, Macrophages, NF-kappa B, Interleukin, General Medicine, Phosphoproteins, Polycyclic aromatic hydrocarbon, Tumor necrosis factor-α, Up-Regulation, 3. Good health, Cytokine, Receptors, Aryl Hydrocarbon, 13. Climate action, 030220 oncology & carcinogenesis, Immunology, Cancer cell, MCF-7 Cells, biology.protein, Cancer research, Environmental Pollutants, Tumor necrosis factor alpha
Abstract: International audience; Co-exposure to environmental polycyclic aromatic hydrocarbons (PAHs) and interleukin (IL)-1β induces expression of the tumor-promoting cytokine IL-6 in cancer cells. The present study was designed to determine whether such an IL-6 up-regulation also occurs in response to co-treatment by PAHs and tumor necrosis factor (TNF)-α, an inflammatory cytokine commonly found in tumor microenvironment. Co-exposure to the prototypical PAH benzanthracene (BZA) and TNF-α was found to markedly induce mRNA expression and secretion of IL-6 in human breast cancer cells MCF-7, whereas exposure to either BZA or TNF-α alone was without significant effect. Co-treatment by BZA and TNF-α-containing conditioned media from human inflammatory macrophages similarly up-regulated IL-6 expression in MCF-7 cells. BZA/TNF-α-mediated IL-6 induction in MCF-7 cells was counteracted by silencing aryl hydrocarbon receptor (AhR), known to mediates most of PAH effects. IL-6 up-regulation was moreover associated with NF-κB activation and was abolished by using chemical NF-κB inhibitors or knocking-down expression of the p65/RelA NF-κB subunit. Taken together, these data indicate that co-exposure to BZA/TNF-α induces IL-6 expression by AhR- and NF-κB-dependent pathways in MCF-7 cancer cells. This regulation of IL-6 by environmental PAHs, that is dependent of inflammatory cytokine microenvironment, may contribute to the well-known carcinogenic properties of these organic pollutants.
Published: 2013

37. Nanofluidic Fluorescence Microscopy (NFM) for real-time monitoring of protein binding kinetics and affinity studies

Author: Chia-Fu Chou, Pattamon Teerapanich, Yii-Lih Lin, Thierry Leichle, Corinne Henriquet, Martine Pugnière, Équipe Microsystèmes électromécaniques (LAAS-MEMS), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), 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), Academia Sinica, ANR-13-IS10-0001,DEPSLIT,Système nanofluidique biofonctionnalisé avec pré-concentrateur moléculaire pour la détection ultra-rapide et l'analyse cinétique(2013), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse Capitole (UT Capitole), Université Fédérale Toulouse Midi-Pyrénées, Leichle, Thierry, Blanc – Accords bilatéraux 2013 - Système nanofluidique biofonctionnalisé avec pré-concentrateur moléculaire pour la détection ultra-rapide et l'analyse cinétique - - DEPSLIT2013 - ANR-13-IS10-0001 - Blanc – Accords bilatéraux 2013 - VALID, Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), 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), 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: Streptavidin, Analyte, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Microfluidics, Kinetics, Biomedical Engineering, Biophysics, Analytical chemistry, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Biotin, 02 engineering and technology, Interaction kinetics, 01 natural sciences, chemistry.chemical_compound, Mice, Electrochemistry, Fluorescence microscope, Animals, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Surface plasmon resonance, Fluorescence microscopy, Detection limit, Immunoassay, Chemistry, 010401 analytical chemistry, Nanofluidics, General Medicine, Equipment Design, Microfluidic Analytical Techniques, Surface Plasmon Resonance, 021001 nanoscience & nanotechnology, 0104 chemical sciences, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Biosensors, Microscopy, Fluorescence, Immunoglobulin G, 0210 nano-technology, Biosensor, Antibodies, Immobilized, Biotechnology, Protein Binding
Abstract: International audience; Kinetic monitoring of protein interactions offers insights to their corresponding functions in cellular processes. Surface plasmon resonance (SPR) is the current standard tool used for label-free kinetic assays; however, costly and sophisticated setups are required, decreasing its accessibility to research laboratories. We present a cost-effective nanofluidic-based immunosensor for low-noise real-time kinetic measurement of fluorescent-labeled protein binding. With the combination of fluorescence microscopy and reversed buffer flow operation, association and dissociation kinetics can be accessed in one single experiment without extra buffer loading step, which results in a simplified operation and reduced time of analysis compared to typical microfluidic immunoassays. Kinetic constants of two representative protein-ligand binding pairs (streptavidin/biotin; IgG/anti-IgG) were quantified. The good agreement of extracted rate constants with literature values and analogous SPR measurements indicates that this approach is applicable to study protein interactions of medium- and high-affinities with a limit of detection down to 1 pM, regardless of the analyte size.
Published: 2016

38. Subtelomere organization in the genome of the microsporidian Encephalitozoon cuniculi: patterns of repeated sequences and physicochemical signatures

Author: Emmanuel Cornillot, Ndongo Dia, Christophe Duroure, Mbayame Ndiaye Niang, Edouard Yeramian, Christian P. Vivarès, Guy Méténier, Laurence Lavie, Choukri Ben Mamoun, Roger Frutos, Bhen Sikina Toguebaye, Ngor Faye, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratoire de Parasitologie Générale, Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Département de Biologie Animale, Bioinformatique structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Météorologie Physique - Clermont Auvergne (LaMP), Institut national des sciences de l'Univers (INSU - CNRS)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Internal Medecine, Yale (Department of Internal Medecine), Yale University School of Medicine, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), This work was supported by grants from AUF (Agence Universitaire de la Francophonie, Ngor Faye, invited Professor), EGIDE-Campus France France (Ndongo Dia PhD) and the Medical Research Foundation (FRM: Fondation pour la Recherche Médicale, Laurence Lavie post-doctoral position)., Bioinformatique structurale - Structural Bioinformatics, Laboratoire de Météorologie Physique (LaMP), Institut national des sciences de l'Univers (INSU - CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), BRICHEUX, Genevieve, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: 0301 basic medicine, Nuclear gene, MESH: Repetitive Sequences, Nucleic Acid/genetics, [SDV.MP.PRO] Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, MESH: Encephalitozoon cuniculi/genetics, L73 - Maladies des animaux, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Genome, MESH: Host-Parasite Interactions/genetics, Host-Parasite Interactions, MESH: Multigene Family/genetics, 03 medical and health sciences, MESH: Base Composition, Chromosome ends, parasitic diseases, Genetics, MESH: Genome, Encephalitozoon cuniculi, Gene, Repetitive Sequences, Nucleic Acid, Segmental duplication, Whole genome sequencing, Base Composition, Subtelomere, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, fungi, Chromosome, DNA, Protozoan, Telomere, MESH: DNA, Protozoan/genetics, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Recombination, 030104 developmental biology, MESH: Telomere/genetics, Microsporidia, Multigene family, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, GC-content, Research Article, Biotechnology
Abstract: Background The microsporidian Encephalitozoon cuniculi is an obligate intracellular eukaryotic pathogen with a small nuclear genome (2.9 Mbp) consisting of 11 chromosomes. Although each chromosome end is known to contain a single rDNA unit, the incomplete assembly of subtelomeric regions following sequencing of the genome identified only 3 of the 22 expected rDNA units. While chromosome end assembly remains a difficult process in most eukaryotic genomes, it is of significant importance for pathogens because these regions encode factors important for virulence and host evasion. Results Here we report the first complete assembly of E. cuniculi chromosome ends, and describe a novel mosaic structure of segmental duplications (EXT repeats) in these regions. EXT repeats range in size between 3.5 and 23.8 kbp and contain four multigene families encoding membrane associated proteins. Twenty-one recombination sites were identified in the sub-terminal region of E. cuniculi chromosomes. Our analysis suggests that these sites contribute to the diversity of chromosome ends organization through Double Strand Break repair mechanisms. The region containing EXT repeats at chromosome extremities can be differentiated based on gene composition, GC content, recombination sites density and chromosome landscape. Conclusion Together this study provides the complete structure of the chromosome ends of E. cuniculi GB-M1, and identifies important factors, which could play a major role in parasite diversity and host-parasite interactions. Comparison with other eukaryotic genomes suggests that terminal regions could be distinguished precisely based on gene content, genetic instability and base composition biais. The diversity of processes assciated with chromosome extremities and their biological consequences, as they are presented in the present study, emphasize the fact that great effort will be necessary in the future to characterize more carefully these regions during whole genome sequencing efforts. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1920-7) contains supplementary material, which is available to authorized users.
Published: 2016

39. Genetic Characterization of Plasmodium Putative Pantothenate Kinase Genes Reveals Their Essential Role in Malaria Parasite Transmission to the Mosquito

Author: Choukri Ben Mamoun, Emmanuel Cornillot, Robert J. Hart, Amanah Abraham, Emily Molina, Ahmed S. I. Aly, Catherine S. Nation, Department of Tropical Medicine [New Orleans, LA, USA], Tulane University, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Section of Infectious Diseases [New Haven, CT, USA] (Department of Internal Medicine), Yale University School of Medicine, AA is supported by funds provided by Tulane University School of Public Health and Tropical Medicine and by NIH-NIAID grant (1R21AI111058-01A1). CBM is supported by NIH grants (AI097218, GM110506, AI09486 and AI112938) and the Bill and Melinda Gates Foundation (ID#: 1021571)., CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), ALY, AHMED SAYED IBRAHıM, Herrada, Anthony, and Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: 0301 basic medicine, MESH: Sequence Analysis, DNA, Plasmodium, Erythrocytes, Transcription, Genetic, Genes, Protozoan, Protozoan Proteins, MESH: Amino Acid Sequence, MESH: Sporozoites, chemistry.chemical_compound, MESH: Animals, MESH: Phylogeny, MESH: Protozoan Proteins, Conserved Sequence, Phylogeny, Genetics, Regulation of gene expression, Mice, Inbred BALB C, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Conserved Sequence, biology, MESH: Erythrocytes, Anopheles, MESH: Gene Expression Regulation, 3. Good health, Phosphotransferases (Alcohol Group Acceptor), MESH: Genes, Protozoan, Sporozoites, Pantothenate kinase, MESH: Biosynthetic Pathways, Female, MESH: Oocysts, Coenzyme A, MESH: Malaria, MESH: Mice, Inbred BALB C, Models, Biological, Article, MESH: Anopheles, 03 medical and health sciences, parasitic diseases, medicine, Animals, Parasites, Amino Acid Sequence, Gene, MESH: Life Cycle Stages, MESH: Parasites, Life Cycle Stages, 030102 biochemistry & molecular biology, MESH: Plasmodium, MESH: Transcription, Genetic, MESH: Models, Biological, Oocysts, Plasmodium falciparum, Sequence Analysis, DNA, biology.organism_classification, PANK2, medicine.disease, MESH: Coenzyme A, MESH: Phosphotransferases (Alcohol Group Acceptor), Biosynthetic Pathways, Malaria, 030104 developmental biology, chemistry, Gene Expression Regulation, MESH: Gene Deletion, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Gene Deletion
Abstract: The metabolic machinery for the biosynthesis of Coenzyme A (CoA) from exogenous pantothenic acid (Vitamin B5) has long been considered as an excellent target for the development of selective antimicrobials. Earlier studies in the human malaria parasite Plasmodium falciparum have shown that pantothenate analogs interfere with pantothenate phosphorylation and block asexual blood stage development. Although two eukaryotic-type putative pantothenate kinase genes (PanK1 and PanK2) have been identified in all malaria parasite species, their role in the development of Plasmodium life cycle stages remains unknown. Here we report on the genetic characterization of PanK1 and PanK2 in P. yoelii. We show that P. yoelii parasites lacking either PanK1 or PanK2 undergo normal asexual stages development and sexual stages differentiation, however they are severely deficient in ookinete, oocyst and sporozoite formation inside the mosquito vector. Quantitative transcriptional analyses in wild-type and knockout parasites demonstrate an important role for these genes in the regulation of expression of other CoA biosynthesis genes. Together, our data provide the first genetic evidence for the importance of the early steps of pantothenate utilization in the regulation of CoA biosynthesis and malaria parasite transmission to Anopheles mosquitoes.
Published: 2016

40. Phorbol ester-modulation of estrogenic genomic effects triggered by the environmental contaminant benzanthracene

Author: Elise Kolasa, Noémie Houlbert, Olivier Fardel, Patrick Balaguer, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), 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), Contaminants Chimiques, immunité et Inflammation, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Programme National de Recherche sur les Perturbateurs Endocriniens (PNRPE) from the French Minister of Ecology, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), 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), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), and Le Corre, Morgane
Subjects: MAPK/ERK pathway, Phorbol ester, Estrogen receptor, MESH: Aryl Hydrocarbon Hydroxylases, Toxicology, Benzanthracene, MESH: Estrogens, chemistry.chemical_compound, 0302 clinical medicine, MESH: RNA, Small Interfering, Polycyclic Aromatic Hydrocarbons, RNA, Small Interfering, Modulation, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, 0303 health sciences, pS2, Chemistry, General Medicine, [SDV.EE] Life Sciences [q-bio]/Ecology, environment, MESH: Cytochrome P-450 CYP1A1, Protein Kinase C-delta, MESH: Environmental Pollutants, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, Intercellular Signaling Peptides and Proteins, Tetradecanoylphorbol Acetate, Environmental Pollutants, Trefoil Factor-1, Aryl Hydrocarbon Hydroxylases, MESH: Protein Kinase C-delta, MESH: Chemokine CXCL12, Receptors, Progesterone, MESH: Receptors, Progesterone, EGF Family of Proteins, MESH: Glycoproteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Amphiregulin, Cell Line, MESH: Polycyclic Hydrocarbons, Aromatic, 03 medical and health sciences, Protein kinase C, Cytochrome P-450 CYP1A1, Humans, MESH: Tumor Suppressor Proteins, RNA, Messenger, MESH: Intercellular Signaling Peptides and Proteins, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Tetradecanoylphorbol Acetate, MESH: RNA, Messenger, Glycoproteins, 030304 developmental biology, Hormone response element, MESH: Humans, Interleukin-6, Activator (genetics), Tumor Suppressor Proteins, Estrogens, Estrogen, MESH: Interleukin-6, Chemokine CXCL12, MESH: Cell Line, Phorbol, Cancer research
Abstract: International audience; Aryl hydrocarbon receptor-dependent genomic effects of environmental polycyclic aromatic hydrocarbons (PAHs) have been shown to be modulated by non-genomic protein kinase C (PKC)-related pathways. The present study was designed to determine whether PKC activation may also impair estrogenic genomic response triggered by PAHs. Treatment by the PKC activator phorbol 12-myristate 13-acetate (PMA) was found to markedly and differentially impair the up-regulation of estrogenic markers triggered by the estrogenic PAH benzanthracene (BZA) in cultured human mammary cells; BZA-mediated mRNA up-regulation of pS2 and amphiregulin was thus increased, whereas that of progesterone receptor and CXCL12 was repressed. BZA/PMA cotreatment however failed to alter BZA-mediated increase of activity of a luciferase gene reporter construct driven by an estrogen response element, thus discarding any global effect of PMA toward BZA-triggered estrogen receptor activation. Various chemicals inhibiting PKCs or extracellular signal-regulated kinase (ERK) as well as the knock-down of PKCδ expression counteracted the PMA-mediated increase of pS2 mRNA up-regulation triggered by BZA, demonstrating that it was dependent on PKCs, including PKCδ isoform, and ERKs. This non-genomic modulation of estrogenic effects of PAHs by PKC activation may have to be considered when considering the deleterious effects of these environmental contaminants towards the endocrine system.
Published: 2012

41. The Novel Antibacterial Compound Walrycin A Induces Human PXR Transcriptional Activity

Author: Céline Gheeraert, Alexandre Berthier, Rémy Le Guével, Gilles Salbert, Patrick Balaguer, Philippe Lefebvre, Bart Staels, Abdel Boulahtouf, Frédérik Oger, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique fonctionnelle, agronomie et santé (GFAS), Institut National de la Recherche Agronomique (INRA)-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)-Centre National de la Recherche Scientifique (CNRS), 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 National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Derudas, Marie-Hélène
Subjects: Receptors, Steroid, CYP3A4, Gene Expression, Quantitative Structure-Activity Relationship, Naphthols, Walrycin A, Toxicology, MESH: Hepatocytes, Transactivation, 0302 clinical medicine, MESH: RNA, Small Interfering, Gene expression, Cytochrome P-450 CYP3A, Xenobiotic, RNA, Small Interfering, Cell Line, Transformed, Oligonucleotide Array Sequence Analysis, MESH: Cytochrome P-450 CYP3A, MESH: Quantitative Structure-Activity Relationship, 0303 health sciences, Pregnane X receptor, MESH: Real-Time Polymerase Chain Reaction, Pregnane X Receptor, Transfection, Anti-Bacterial Agents, 3. Good health, MESH: Cell Survival, Biochemistry, 030220 oncology & carcinogenesis, Rifampin, Signal transduction, Protein Binding, MESH: Computational Biology, MESH: Gene Expression, Cell Survival, Biology, Real-Time Polymerase Chain Reaction, digestive system, Article, 03 medical and health sciences, MESH: Computer Simulation, MESH: Anti-Bacterial Agents, Ligand Binding Domain, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: Protein Binding, Computer Simulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Cell Line, Transformed, Transcription factor, 030304 developmental biology, MESH: Humans, MESH: Naphthols, Activator (genetics), MESH: Transfection, Computational Biology, MESH: Rifampin, digestive system diseases, Nuclear receptor, MESH: Oligonucleotide Array Sequence Analysis, Hepatocytes, Nuclear Receptor, MESH: Receptors, Steroid
Abstract: International audience; The human pregnane X receptor (PXR) is a ligand-regulated transcription factor belonging to the nuclear receptor superfamily. PXR is activated by a large, structurally diverse, set of endogenous and xenobiotic compounds and coordinates the expression of genes central to metabolism and excretion of potentially harmful chemicals and therapeutic drugs in humans. Walrycin A is a novel antibacterial compound targeting the WalK/WalR two-component signal transduction system of Gram (+) bacteria. Here, we report that, in hepatoma cells, walrycin A potently activates a gene set known to be regulated by the xenobiotic sensor PXR. Walrycin A was as efficient as the reference PXR agonist rifampicin to activate PXR in a transactivation assay at noncytotoxic concentrations. Using a limited proteolysis assay, we show that walrycin A induces conformational changes at a concentration which correlates with walrycin A ability to enhance the expression of prototypic target genes, suggesting that walrycin A interacts with PXR. The activation of the canonical human PXR target gene CYP3A4 by walrycin A is dose and PXR dependent. Finally, in silico docking experiments suggest that the walrycin A oxidation product Russig's blue is the actual ligand for PXR. Taken together, these results identify walrycin A as a novel human PXR activator.
Published: 2012

42. Peptides for the Biofunctionalization of Silicon for Use in Optical Sensing with Porous Silicon Microcavities

Author: Marie-Belle Saab, Elias Estephan, Christian Larroque, Vivechana Agarwal, Frédéric Cuisinier, Csilla Gergely, Laboratoire Charles Coulomb (L2C), 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), 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: Detection limit, Streptavidin, Materials science, Silicon, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], technology, industry, and agriculture, chemistry.chemical_element, Resonance, Nanotechnology, 02 engineering and technology, 010402 general chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Porous silicon, 01 natural sciences, 0104 chemical sciences, Electronic, Optical and Magnetic Materials, Biomaterials, chemistry.chemical_compound, chemistry, Silanization, Electrochemistry, Surface modification, 0210 nano-technology, Biosensor
Abstract: International audience; Addressing the surface chemistry of silicon is of fundamental scientific and technical significance due to the wide use of this material in electronics and optics. A novel method to functionalize silicon (Si) via short peptides with binding specificity for Si is presented. The peptide presenting the highest affinity for Si is identified via phage display technology, and the 12-mer LLADTTHHRPWT and SPGLSLVSHMQT peptides were found to be specific for the n+-Si and p+-Si surfaces, respectively. In our sensing application, the obtained peptides are used as functionalizing linkers to allow porous silicon microcavities to bind biotin and then capture streptavidin. Molecular detection is monitored via reflectometric interference spectra as shifts in the resonance peaks of the cavity structure. An improved streptavidin sensing (21 times lower detection limit) with peptide-functionalized porous silicon microcavities is demonstrated, compared to sensing performed with devices functionalized with the commonly used silanization method, suggesting that the modification of Si via Si-specific peptides provides better interface layers for molecular detection. High-resolution atomic force microscopy images corroborate this result and reveal the formation of ordered nanometer-sized molecular layers when peptide-route functionalization is performed.
Published: 2011

43. A Family of Protein-Deglutamylating Enzymes Associated with Neurodegeneration

Author: Carsten Janke, Jean-Christophe Deloulme, Annie Andrieux, Max Holzer, Christophe Bosc, Montserrat Bosch Grau, Leticia Peris, Nicole Bec, Nicholas D. Gold, Solange Desagher, Benjamin Lacroix, Christian Larroque, Krzysztof Rogowski, Juliette van Dijk, Marie-Jo Moutin, Anouk Bosson, Maria M. Magiera, Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Grenoble Institut des Neurosciences ( GIN ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Paul-Flechsig-Institute of Brain Research, University of Leipzig, This work was supported by the CNRS, the Universities Montpellier 2 and 1, the Institut Curie, the Association pour la Recherche sur le Cancer (ARC) award 3140 to CJ and 4892 and 7927 to AA, the French National Research Agency (ANR) awards 05-JCJC-0035 and 08- JCJC-0007 to CJ, and 'TyrTips' to AA, the Fondation pour la Recherche Médicale (FRM) research grant DEQ20081213977, the HFSP program grant RGP 23/2008 and the EMBO Young Investigator Program grant to CJ, the La Ligue contre le cancer research grant R07Job to AA and the Alzheimer Forschung Initiative project 06825 to MH. BL was supported by a fellowship from the La Ligue contre le Cancer, and the EMBO short-term fellowship ASTF 157-2007. KR received two postdoctoral fellowships from the La Ligue contre le Cancer and the EMBO long-term fellowship ALTF 546-2006, ANR-05-JCJC-0035,Pgases,The polyglutamylase enzyme family: which enzyme is doing what? ( 2005 ), Dubois, Frederic, Jeunes chercheuses et jeunes chercheurs - The polyglutamylase enzyme family: which enzyme is doing what? - - Pgases2005 - ANR-05-JCJC-0035 - JCJC - VALID, Centre de recherche en Biologie Cellulaire (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-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 Génétique Moléculaire de Montpellier (IGMM), Universität Leipzig [Leipzig], ANR-05-JCJC-0035,Pgases,The polyglutamylase enzyme family: which enzyme is doing what?(2005), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (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), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: HUMDISEASE, Carboxypeptidases, Protein deglutamylation, Mice, 0302 clinical medicine, Tubulin, Cerebellum, Polyglutamylation, deglutamylation, chemistry.chemical_classification, 0303 health sciences, Mice, Inbred BALB C, biology, polyglutamylase, neurodegeneration, Olfactory Bulb, Serine-Type D-Ala-D-Ala Carboxypeptidase, Nna1, Biochemistry, Polyglutamic Acid, Myosin light-chain kinase, Cell Survival, Molecular Sequence Data, General Biochemistry, Genetics and Molecular Biology, MOLNEURO, polyglutamylation, Cell Line, microtubules, 03 medical and health sciences, Microtubule, GTP-Binding Proteins, Detyrosination, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, cytosolic carboxy peptidase, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, pcd mouse, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Polyglutamate, CCP, Biochemistry, Genetics and Molecular Biology(all), TTLL, Enzyme, chemistry, Nerve Degeneration, biology.protein, CELLBIO, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: International audience; Polyglutamylation is a posttranslational modification that generates glutamate side chains on tubulins and other proteins. Although this modification has been shown to be reversible, little is known about the enzymes catalyzing deglutamylation. Here we describe the enzymatic mechanism of protein deglutamylation by members of the cytosolic carboxypeptidase (CCP) family. Three enzymes (CCP1, CCP4, and CCP6) catalyze the shortening of polyglutamate chains and a fourth (CCP5) specifically removes the branching point glutamates. In addition, CCP1, CCP4, and CCP6 also remove gene-encoded glutamates from the carboxyl termini of proteins. Accordingly, we show that these enzymes convert detyrosinated tubulin into Δ2-tubulin and also modify other substrates, including myosin light chain kinase 1. We further analyze Purkinje cell degeneration (pcd) mice that lack functional CCP1 and show that microtubule hyperglutamylation is directly linked to neurodegeneration. Taken together, our results reveal that controlling the length of the polyglutamate side chains on tubulin is critical for neuronal survival.
Published: 2010
Full Text: View/download PDF

44. miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers

Author: Khalil Arar, Christina Laurini, Michèle Sabbah, Laurent Vallar, Michèle Moes, Charles-Henri Lecellier, Evelyne Friederich, A. Le Bechec, Guillaume Vetter, Anne Saumet, Charles Theillet, Le Ster, Yves, Cytoskeleton and Cell Plasticity Lab, Université du Luxembourg (Uni.lu), 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), Centre de Recherche Publique- Santé, 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), Sigma-Aldrich - Evry GENEPOLE, Sigma-Aldrich, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Fond National de la Recherche (FNR) du Luxembourg, (BIOSAN), the Fondation Luxembourgeoise Contre le Cancer, Human Frontier Science Program (RGP0058/2005), INSERM and CNRS, France. A. Saumet is a recipient of a fellowship from the Ministère de la Culture, de l'Enseignement Supérieur et de la Recherche, Luxembourg (BFR 08/046). M. Moes and A. Le Béchec are supported by AFR grants from the Fond National de la Recherche, Luxembourg., 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), Université du Luxembourg ( Uni.lu ), 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 ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), and Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: SNAI1, Cancer Research, MESH : RNA, Messenger, MESH : Transcription Factors, MESH : Cell Dedifferentiation, Gene Expression, MESH : Breast Neoplasms, Biochemistry, biophysics & molecular biology [F05] [Life sciences], Validation Studies as Topic, MESH : RNA, Small Interfering, medicine.disease_cause, Bioinformatics, MESH : Neoplasm Invasiveness, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Metastasis, 0302 clinical medicine, MESH : Tumor Cells, Cultured, MESH : Validation Studies as Topic, EMT/miR-661/ SNAI1/StarD10/Nectin-1/breast cancer cell invasion, MESH: RNA, Small Interfering, Tumor Cells, Cultured, MESH : Female, RNA, Small Interfering, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], Oligonucleotide Array Sequence Analysis, 0303 health sciences, EMT, MESH: Transcription Factors, MESH: Gene Expression Regulation, Neoplastic, MESH : Epithelial Cells, Gene Expression Regulation, Neoplastic, MESH : Oligonucleotide Array Sequence Analysis, MESH: Epithelial Cells, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, Female, Breast disease, StarD10, Nectin-1, MESH: Gene Expression, MESH : Gene Expression Regulation, Neoplastic, Nectins, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Phosphoproteins, MESH : Cell Adhesion Molecules, MESH: Gene Expression Profiling, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, microRNA, Genetics, medicine, Humans, Gene silencing, Neoplasm Invasiveness, RNA, Messenger, MESH: Tumor Cells, Cultured, Epithelial–mesenchymal transition, Molecular Biology, MESH: RNA, Messenger, 030304 developmental biology, breast cancer cell invasion, MESH: Validation Studies as Topic, MESH: Humans, MESH : Gene Expression Profiling, Gene Expression Profiling, MESH : Humans, Cancer, Epithelial Cells, Mesenchymal Stem Cells, MESH: Neoplasm Invasiveness, Cell Dedifferentiation, Phosphoproteins, medicine.disease, MESH: Cell Dedifferentiation, miR-661, MESH : Gene Expression, MESH : MicroRNAs, MicroRNAs, Retraction Note, MESH: Mesenchymal Stem Cells, MESH: Oligonucleotide Array Sequence Analysis, Cancer research, Snail Family Transcription Factors, MESH : Phosphoproteins, MESH : Mesenchymal Stem Cells, Carcinogenesis, Cell Adhesion Molecules, MESH: MicroRNAs, MESH: Female, MESH: Breast Neoplasms, Transcription Factors
Abstract: 4; International audience; Epithelial to mesenchymal transition (EMT) is a key step toward metastasis. MCF7 breast cancer cells conditionally expressing the EMT master regulator SNAI1 were used to identify early expressed microRNAs (miRNAs) and their targets that may contribute to the EMT process. Potential targets of miRNAs were identified by matching lists of in silico predicted targets and of inversely expressed mRNAs. MiRNAs were ranked based on the number of predicted hits, highlighting miR-661, a miRNA with so far no reported role in EMT. MiR-661 was found required for efficient invasion of breast cancer cells by destabilizing two of its predicted mRNA targets, the cell-cell adhesion protein Nectin-1 and the lipid transferase StarD10, resulting, in turn, in the downregulation of epithelial markers. Reexpression of Nectin-1 or StarD10 lacking the 3'-untranslated region counteracted SNAI1-induced invasion. Importantly, analysis of public transcriptomic data from a cohort of 295 well-characterized breast tumor specimen revealed that expression of StarD10 is highly associated with markers of luminal subtypes whereas its loss negatively correlated with the EMT-related, basal-like subtype. Collectively, our non-a priori approach revealed a nonpredicted link between SNAI1-triggered EMT and the down-regulation of Nectin-1 and StarD10 through the up-regulation of miR-661, which may contribute to the invasion of breast cancer cells and poor disease outcome.
Published: 2010

45. Origin and quantification of circulating DNA in mice with human colorectal cancer xenografts

Author: Alain R. Thierry, Maguy Del Rio, Florent Mouliere, Céline Gongora, Marc Ychou, Jeremy Ollier, Bruno Robert, Franck Molina, Sysdiag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (SysDiag ), BIO-RAD-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), Gongora, Céline, 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), and Pathology
Subjects: Serum, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Colorectal cancer, [SDV]Life Sciences [q-bio], Transplantation, Heterologous, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA Fragmentation, Biology, medicine.disease_cause, Polymerase Chain Reaction, Mice, Plasma, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Fragmentation (cell biology), Molecular Biology, ComputingMilieux_MISCELLANEOUS, DNA Primers, 030304 developmental biology, 0303 health sciences, Mutation, DNA, Neoplasm, medicine.disease, Molecular biology, 3. Good health, Transplantation, Apoptosis, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DNA fragmentation, Female, KRAS, Primer (molecular biology), Colorectal Neoplasms, Neoplasm Transplantation
Abstract: International audience; Although circulating DNA (ctDNA) could be an attractive tool for early cancer detection, diagnosis, prognosis, monitoring or prediction of response to therapies, knowledge on its origin, form and rate of release is poor and often contradictory. Here, we describe an experimental system to systematically examine these aspects. Nude mice were xenografted with human HT29 or SW620 colorectal carcinoma (CRC) cells and ctDNA was analyzed by Q–PCR with highly specific and sensitive primer sets at different times post-graft. We could discriminate ctDNA from normal (murine) cells and from mutated and non-mutated tumor (human) cells by using species-specific KRAS or PSAT1 primers and by assessing the presence of the BRAF V600E mutation. The concentration of human (mutated and non-mutated) ctDNA increased significantly with tumor growth. Conversely, and differently from previous studies, low, constant level of mouse ctDNA was observed, thus facilitating the study of mutated and non-mutated tumor derived ctDNA. Finally, analysis of ctDNA fragmentation confirmed the predominance of low-size fragments among tumor ctDNA from mice with bigger tumors. Higher ctDNA fragmentation was also observed in plasma samples from three metastatic CRC patients in comparison to healthy individuals. Our data confirm the predominance of mononucleosome-derived fragments in plasma from xenografted animals and, as a consequence, of apoptosis as a source of ctDNA, in particular for tumor-derived ctDNA. Altogether, our results suggest that ctDNA features vary during CRC tumor development and our experimental system might be a useful tool to follow such variations.
Published: 2010

46. Does interference between replication and transcription contribute to genomic instability in cancer cells?

Author: Sandie Tuduri, Arnaud Coquelle, Philippe Pasero, Laure Crabbe, Hélène Tourrière, 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), Work in the PP lab is supported by Fondation Recherche Médicale (Equipe FRM), ANR and INCa. Work in AC lab is supported by the Ligue contre le Cancer (comité Hérault), ARC and INCa., 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: Genomic instability, Genome instability, DNA re-replication, Chromatin Immunoprecipitation, Transcription, Genetic, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, DNA replication, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Models, Biological, ChIP-chip, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Gene, Cancer, 030304 developmental biology, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, biology, Topoisomerase, Cell Biology, Replication fork arrest, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, biology.protein, Origin recognition complex, Transcription, Chromatin immunoprecipitation, Developmental Biology
Abstract: International audience; We have recently reported that topoisomerase 1 (Top1) cooperates with ASF/SF2, a splicing factor of the SR family, to prevent unscheduled replication fork arrest and genomic instability in human cells. Our results suggest that Top1 execute this function by suppressing the formation of DNA-RNA hybrids during transcription, these so-called R-loops interfering with the progression of replication forks. Using ChIP-chip, we have shown that γ-H2AX, a marker of DNA damage, accumulates at gene-rich regions of the genome in Top1-deficient cells. This is best illustrated at histone genes, which are highly expressed during S phase and display discrete γ-H2AX peaks on ChIP-chip profiles. Here, we show that these γ-H2AX domains are different from those induced by camptothecin, a Top1 inhibitor inducing double-strand DNA breaks throughout the genome. These data support the view that R-loops promote genomic instability at specific sites by blocking fork progression and inducing chromosome breaks. Whether this type of transcription-dependent fork arrest contributes to the replication stress observed in precancerous lesions is an important question that deserves further attention.
Published: 2010

47. Aptamer-Derived Peptides as Potent Inhibitors of the Oncogenic RhoGEF Tgat

Author: Bruno Robert, Sylvie Fromont, Anne Debant, Nathalie Bouquier, Camille Auziol, Mahel Zeghouf, Susanne Schmidt, Jean-Christophe Zeeh, Jacqueline Cherfils, Pauline Larrousse, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Laboratoire d'enzymologie et biochimie structurales (LEBS), 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), This work was supported by grants from the CNRS, the Agence Nationale de la Recherche ANR-PCV (Physique et Chimie du Vivant) (A.D. and J.C.), the Association pour la Recherche contre le Cancer (grant #2736 to A.D., PhD grants to C.A. and J.C.Z). All authors except Bruno Robert are members of the CNRS consortium GDR2823., Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Dubois, Frederic, 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: RHOA, GTP', Aptamer, Clinical Biochemistry, Peptide, Protein Serine-Threonine Kinases, Biology, Biochemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, Peptide Library, Drug Discovery, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Guanine Nucleotide Exchange Factors, Humans, Point Mutation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Peptide library, Molecular Biology, 030304 developmental biology, Pharmacology, Peptide Metabolism, chemistry.chemical_classification, Mice, Inbred BALB C, 0303 health sciences, General Medicine, Molecular biology, In vitro, Protein Structure, Tertiary, 3. Good health, Cell biology, CHEMBIO, Cell Transformation, Neoplastic, chemistry, SIGNALING, 030220 oncology & carcinogenesis, NIH 3T3 Cells, biology.protein, RNA, Molecular Medicine, Female, Guanine nucleotide exchange factor, rhoA GTP-Binding Protein, Aptamers, Peptide
Abstract: International audience; Guanine nucleotide exchange factors (GEFs) activate the Rho GTPases by accelerating their GDP/GTP exchange rate. Some RhoGEFs have been isolated based on their oncogenic potency, and strategies to inhibit their activity are therefore actively being sought. In this study we devise a peptide inhibitor screening strategy to target the GEF activity of Tgat, an oncogenic isoform of the RhoGEF Trio, based on random mutations of the Trio inhibitor TRIP alpha, which we previously isolated using a peptide aptamer screen. This identifies one peptide, TRIP(E32G), which specifically inhibits Tgat GEF activity in vitro and significantly reduces Tgat-induced RhoA activation and foci formation. Furthermore, subcutaneous injection of cells expressing Tgat and TRIP(E32G) into nude mice reduces the formation of Tgat-induced tumors. Our approach thus demonstrates that peptide aptamers are potent inhibitors that can be used to interfere with RhoGEF functions in vivo.
Published: 2009

48. Profiling of benzophenone derivatives using fish and human estrogen receptor-specific in vitro bioassays

Author: José-Manuel Molina-Molina, Vincent Cavaillès, Patrick Balaguer, Elena Gomez, Nicolás Olea, Selim Ait-Aissa, Arnaud Pillon, Aurélie Escande, Farzad Pakdel, 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 Medical Investigations, Universidad de Granada = University of Granada (UGR)-San Cecilio University Hospital, Hydrosciences Montpellier (HSM), Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut National de l'Environnement Industriel et des Risques (INERIS), This research was supported by grants from the European Union Commission (EDEN QLK4-CT-2002-00603 and CASCADE FOOD-CT-2004-506319) and from the French Ministry of Ecology and Sustainable Development (PRG189-07-DRC01) to SA., 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), University of Granada [Granada]-San Cecilio University Hospital, Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Vitellogenins, Estrogen receptor, Estrogenic activity, Endocrine Disruptors, 010501 environmental sciences, Toxicology, 01 natural sciences, MESH: Dose-Response Relationship, Drug, Vitellogenins, MESH: Animals, Receptor, MESH: Estrogen Receptor alpha, Benzophenones (BPs), MESH: Estrogen Receptor beta, 0303 health sciences, Estradiol, Human androgen receptor (hAR), Rainbow trout estrogen receptor alpha (rtERΑ), Biological activity, Vitellogenin (Vtg), MESH: Endocrine Disruptors, 3. Good health, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Reporter gene assay, Cell proliferation assay, MESH: Androgen Antagonists, MESH: Oncorhynchus mykiss, Endocrine disruptor, Oncorhynchus mykiss, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Biological Assay, MESH: Estradiol, Receptor binding assay, medicine.medical_specialty, MESH: Benzophenones, Biology, MESH: Biological Assay, Benzophenones, 03 medical and health sciences, Vitellogenin, MESH: Cell Proliferation, Internal medicine, medicine, Animals, Estrogen Receptor beta, Humans, Cell Proliferation, 030304 developmental biology, 0105 earth and related environmental sciences, Pharmacology, Reporter gene, MESH: Humans, Dose-Response Relationship, Drug, Estrogen Receptor alpha, Androgen Antagonists, Molecular biology, Androgen receptor, Endocrinology, biology.protein, Estrogen receptor alpha, Human estrogen receptor alpha and beta (hERα and hERβ)
Abstract: International audience; Benzophenone (BP) derivatives, BP1 (2,4-dihydroxybenzophenone), BP2 (2,2',4,4'-tetrahydroxybenzophenone), BP3 (2-hydroxy-4-methoxybenzophenone), and THB (2,4,4'-trihydroxybenzophenone) are UV-absorbing chemicals widely used in pharmaceutical, cosmetics, and industrial applications, such as topical sunscreens in lotions and hair sprays to protect skin and hair from UV irradiation. Studies on their endocrine disrupting properties have mostly focused on their interaction with human estrogen receptor alpha (hERalpha), and there has been no comprehensive analysis of their potency in a system allowing comparison between hERalpha and hERbeta activities. The objective of this study was to provide a comprehensive ER activation profile of BP derivatives using ER from human and fish origin in a battery of in vitro tests, i.e., competitive binding, reporter gene based assays, vitellogenin (Vtg) induction in isolated rainbow trout hepatocytes, and proliferation based assays. The ability to induce human androgen receptor (hAR)-mediated reporter gene expression was also examined. All BP derivatives tested except BP3 were full hERalpha and hERbeta agonists (BP2>THB>BP1) and displayed a stronger activation of hERbeta compared with hERalpha, the opposite effect to that of estradiol (E2). Unlike E2, BPs were more active in rainbow trout ERalpha (rtERalpha) than in hERalpha assay. All four BP derivatives showed anti-androgenic activity (THB>BP2>BP1>BP3). Overall, the observed anti-androgenic potencies of BP derivatives, together with their proposed greater effect on ERbeta versus ERalpha activation, support further investigation of their role as endocrine disrupters in humans and wildlife.
Published: 2008

49. Microstructural Correlates of Infant Functional Development: Example of the Visual Pathways

Author: Catherine Soares, Lucie Hertz-Pannier, Ghislaine Dehaene-Lambertz, Y. Cointepas, Denis Le Bihan, Jessica Dubois, 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), Département de radiothérapie, CRLCC Val d'Aurelle - Paul Lamarque, 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, Institut d'imagerie neurofonctionnelle (IIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure des Télécommunications (ENST)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École des hautes études en sciences sociales (EHESS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie cognitive (LCogn), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement et Communication de l'Information (LTCI), Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Human Brain Research Center [Kyoto] (HBRC), Kyoto University [Kyoto], IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service Hospitalier Frédéric Joliot (SHFJ), National Institutes of Health [Bethesda] (NIH), 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), 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-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École des hautes études en sciences sociales (EHESS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Ecole Nationale Supérieure des Télécommunications (ENST)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Kyoto University, and Le Bihan, Denis
Subjects: Physiological significance, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neural Conduction, MESH: Diffusion Magnetic Resonance Imaging, Visual system, 050105 experimental psychology, White matter, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Child Development, 0302 clinical medicine, MESH: Neural Conduction, Fractional anisotropy, medicine, Humans, Visual Pathways, 0501 psychology and cognitive sciences, MESH: Neuronal Plasticity, MESH: Brain Mapping, MESH: Child Development, Brain Mapping, MESH: Visual Pathways, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Neuronal Plasticity, MESH: Humans, [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, MESH: Infant, Newborn, 05 social sciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Infant, Newborn, Infant, Cognition, MESH: Infant, Functional development, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Diffusion Magnetic Resonance Imaging, MESH: Photic Stimulation, medicine.anatomical_structure, nervous system, Brief Communications, Psychology, Neuroscience, Photic Stimulation, 030217 neurology & neurosurgery, Diffusion MRI, Tractography
Abstract: The development of cognitive functions during childhood relies on several neuroanatomical maturation processes. Among these processes is myelination of the white matter pathways, which speeds up electrical conduction. Quantitative indices of such structural processes can be obtainedin vivowith diffusion tensor imaging (DTI), but their physiological significance remains uncertain. Here, we investigated the microstructural correlates of early functional development by combining DTI and visual event-related potentials (VEPs) in 15 one- to 4-month-old healthy infants. Interindividual variations of the apparent conduction speed, computed from the latency of the first positive VEP wave (P1), were significantly correlated with the infants' age and DTI indices measured in the optic radiations. This demonstrates that fractional anisotropy and transverse diffusivity are structural markers of functionally efficient myelination. Moreover, these indices computed along the optic radiations showed an early wave of maturation in the anterior region, with the posterior region catching up later in development, which suggests two asynchronous fronts of myelination in both the geniculocortical and corticogeniculate fibers. Thus, in addition to microstructural information, DTI provides noninvasive exquisite information on the functional development of the brain in human infants.
Published: 2008

50. Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation

Author: Georges Noël, E. Cohen Jonathan Moyal, Danielle Ibarrola, Isabelle Berry, J. Khalifa, Nicolas Magné, Marie-Pierre Sunyach, Paul Walker, M. Charissoux, Gilles Truc, I. Catalaa, Anne Laprie, Léonor Chaltiel, F. Tensaouti, S. Ken, Patrice Péran, Jean-Albert Lotterie, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), 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), Dept Radiat Oncol, Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Dept Biostatistiques, Département Médecine nucléaire, CHU Rangueil, CHU Rangueil, Service de Radiologie [Rangueil / Larrey], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Centre Léon Bérard [Lyon], Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Radiations Oncologie, Centre Paul Strauss, Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Département de Radiation oncologie, CGFL, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, 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], Institut Claudius Regaud, Service de Médecine Nucléaire [Toulouse], Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Pathology, Imaging biomarker, Cerebral Blood-Volume, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, medicine.medical_treatment, Contrast Media, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Adc Histogram Analysis, Prospective Studies, Prospective cohort study, Blood Volume, medicine.diagnostic_test, Brain Neoplasms, rCBV, General Medicine, Chemoradiotherapy, Middle Aged, Magnetic Resonance Imaging, 3. Good health, 030220 oncology & carcinogenesis, Disease Progression, Biomarker (medicine), [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, Radiology, Perfusion, Perfusion weighted magnetic resonance imaging, Bevacizumab Treatment, Adult, medicine.medical_specialty, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Apparent Diffusion-Coefficient, 03 medical and health sciences, Contrast-Enhanced Mr, Radiation-Injury, medicine, Effective diffusion coefficient, Humans, Radiology, Nuclear Medicine and imaging, Aged, Radiotherapy, business.industry, Surrogate endpoint, High-Grade Gliomas, Magnetic resonance imaging, Biomarker, Imaging Biomarker, Radiation therapy, Brain-Tumor Recurrence, ROC Curve, True Progression, Neoplasm Recurrence, Local, business, Nuclear medicine, Glioblastoma, Biomarkers
Abstract: International audience; To identify relevant relative cerebral blood volume biomarkers from T2* dynamic-susceptibility contrast magnetic resonance imaging to anticipate glioblastoma progression after chemoradiation. Twenty-five patients from a prospective study with glioblastoma, primarily treated by chemoradiation, were included. According to the last follow-up MRI confirmed status, patients were divided into: relapse group (n = 13) and control group (n = 12). The time of last MR acquisition was t(end); MR acquisitions performed at t(end-2M), t(end-4M) and t(end-6M) (respectively 2, 4 and 6 months before t(end)) were analyzed to extract relevant variations among eleven perfusion biomarkers (B). These variations were assessed through R(B), as the absolute value of the ratio between a dagger B from t(end-4M) to t(end-2M) and a dagger B from t(end-6M) to t(end-4M). The optimal cut-off for R(B) was determined using receiver-operating-characteristic curve analysis. The fraction of hypoperfused tumor volume (F_hP(g)) was a relevant biomarker. A ratio R(F_hP(g)) aeyenaEuroe0.61 would have been able to anticipate relapse at the next follow-up with a sensitivity/specificity/accuracy of 92.3 %/63.6 %/79.2 %. High R(F_hPg) (aeyen0.61) was associated with more relapse at t(end) compared to low R(F_hPg) (75 % vs 12.5 %, p = 0.008). Iterative analysis of F_hP(g) from consecutive examinations could provide surrogate markers to predict progression at the next follow-up. aEuro cent Related rCBV biomarkers from DSC were assessed to anticipate GBM progression. aEuro cent Biomarkers were assessed through their patterns of variation during the follow-up. aEuro cent The fraction of hypoperfused tumour volume (F_hP (g) ) seemed to be a relevant biomarker. aEuro cent An innovative ratio R(F_hP (g) ) could be an early surrogate marker of relapse. aEuro cent A significant time gain could be achieved in the management of GBM patients.
Published: 2015

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Journal

Database

Publisher

86 results on '"CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources