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1. Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

Author

Christian Trepo, Michael P. Manns, David Wright, Jose Luis Calleja, Peter W. White, Chan-Loi Yong, Stanislas Pol, George Kukolj, Jerry O. Stern, Marc Bourlière, Maurizio Bonacini, Thomas Berg, Wulf Otto Boecher, Yves Benhamou, Gerhard G. Steinmann, Joe Scherer, Department of Gastroenterology, Hepatology and Endocrinology (MHH), Hannover Medical School [Hannover] (MHH), Hôpital saint joseph, Service d' Hépato-gastroentérologie, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [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), 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), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), California Pacific medical research center institute, Pacific medical center, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, University Clinic, University Clinic, Leipzig, Hospital universitano Puerta de Hierro, hospital universitano puerta de hierro, Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), 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 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), Department of Gastroenterology, Hepatology and Endocrinology ( MHH ), Hannover Medical School [Hannover] ( MHH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut Cochin ( 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], 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 ), IFR Laennec ( IL ), Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Male, Aminoisobutyric Acids, Hepacivirus, MESH : Viral Load, Viral Nonstructural Proteins, medicine.disease_cause, Gastroenterology, MESH : Hepacivirus, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Polyethylene Glycols, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, MESH : Thiazoles, Pegylated interferon, MESH : Female, MESH: Double-Blind Method, MESH: Hepacivirus, MESH : Viral Nonstructural Proteins, 0303 health sciences, MESH: Middle Aged, MESH: Protease Inhibitors, MESH: Drug Resistance, Viral, biology, MESH : Polyethylene Glycols, Intracellular Signaling Peptides and Proteins, MESH : Adult, Middle Aged, Viral Load, Hepatitis C, Recombinant Proteins, MESH : Antiviral Agents, 3. Good health, MESH : Drug Resistance, Viral, MESH: Oligopeptides, Quinolines, MESH : Interferon-alpha, Female, 030211 gastroenterology & hepatology, MESH : Carrier Proteins, MESH: Interferon-alpha, MESH: Viral Load, Oligopeptides, Viral load, medicine.drug, Pegylated Interferon Alfa, MESH : Oligopeptides, Adult, MESH: Antiviral Agents, medicine.medical_specialty, MESH : Protease Inhibitors, Proline, MESH : Recombinant Proteins, MESH : Male, Hepatitis C virus, MESH: Thiazoles, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Interferon alpha-2, Antiviral Agents, 03 medical and health sciences, Double-Blind Method, Leucine, MESH: Ribavirin, Internal medicine, Drug Resistance, Viral, Ribavirin, medicine, MESH : Double-Blind Method, Humans, MESH : Middle Aged, Protease Inhibitors, Protease inhibitor (pharmacology), 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Hepatology, business.industry, MESH : Humans, Interferon-alpha, MESH: Adult, MESH : Hepatitis C, biology.organism_classification, MESH: Male, MESH : Ribavirin, Thiazoles, MESH: Polyethylene Glycols, chemistry, Faldaprevir, Immunology, MESH: Viral Nonstructural Proteins, Carrier Proteins, business, MESH: Female
Abstract

International audience; BACKGROUND & AIMS: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients. METHODS: Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan. RESULTS: In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL

Published
2011

2. Pharmacological exposure to ribavirin: a key player in the complex network of factors implicated in virological response and anaemia in hepatitis C treatment

Author

Loustaud-Ratti, Véronique, Carrier, Paul, Rousseau, Annick, Maynard, Marianne, Babany, Gérard, Alain, Sophie, Trépo, Christian, De Ledinghen, Victor, Bourlière, Marc, Pol, Stanislas, Di Martino, Vincent, Zarski, Jean-Pierre, Pinta, Alexandrina, Sautereau, Denis, Marquet, Pierre, Renseigné, Non, Service d'Hépato-Gastro-Entérologie et Nutrition [CHU Limoges], CHU Limoges, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-enterologie, Hospices Civils de Lyon (HCL), Produits Roche, Roche, Service de Bactériologie, Virologie, Hygiène [CHU Limoges], Equipe 16, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Hôpital saint joseph, Service d' Hépato-gastroentérologie, 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), Service d'hépatologie médicale [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Agents pathogènes et inflammation - UFC (EA 4266) (API), Université de Franche-Comté (UFC), Service d'hépatologie, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), Département d'hépato-gastroentérologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Roche, Laboratoire Roche [Boulogne-Billancourt], Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), CHU Grenoble-Université Grenoble Alpes (UGA), Pharmacologie des Immunosuppresseurs et de la Transplantation ( PIST ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hospices Civils de Lyon ( HCL ), IFR Laennec ( IL ), Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -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 ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Agents pathogènes et inflammation - UFC (EA 4266) ( API ), Université de Franche-Comté ( UFC ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), and Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
MESH: Anemia, MESH: Pyrophosphatases, Hepacivirus, MESH : Viral Load, MESH : Hepacivirus, Polyethylene Glycols, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, Medicine, MESH: Hepacivirus, Pyrophosphatases, media_common, 0303 health sciences, biology, MESH : Polyethylene Glycols, Gastroenterology, virus diseases, Anemia, Hepatitis C, Viral Load, Recombinant Proteins, MESH : Antiviral Agents, 3. Good health, MESH : Interferon-alpha, Drug Therapy, Combination, 030211 gastroenterology & hepatology, MESH: Interferon-alpha, MESH: Viral Load, Viral load, Drug, MESH: Antiviral Agents, MESH: Interleukins, MESH : Recombinant Proteins, MESH : Anemia, media_common.quotation_subject, Alpha interferon, [SDV.CAN]Life Sciences [q-bio]/Cancer, Interferon alpha-2, Antiviral Agents, Virus, 03 medical and health sciences, MESH: Ribavirin, Ribavirin, Humans, MESH : Pyrophosphatases, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Hepatology, business.industry, Interleukins, MESH : Drug Therapy, Combination, MESH : Humans, Interferon-alpha, MESH : Hepatitis C, biology.organism_classification, medicine.disease, Virology, MESH : Ribavirin, MESH: Drug Therapy, Combination, chemistry, MESH: Polyethylene Glycols, Pharmacodynamics, Immunology, Interferons, MESH : Interleukins, business
Abstract

International audience; Ribavirin remains today a pivotal drug in the treatment of hepatitis C; in standard double therapy, as well as in triple combination with direct antiviral agents, ribavirin reduces relapse and can double the sustained virological response obtained with peginterferon alone or in association with direct antiviral agents. In the complex network of interacting factors determining sustained virological response independently of known predictive factors related to host and virus, two modern tools are emerging: polymorphisms in the IL28B gene and very early exposure to ribavirin. The use of a pharmacokinetic-pharmacodynamic model of early ribavirin exposure to adjust the dose individually would help promote a safer ribavirin use and improve sustained virological response. The variability of the influence of ribavirin exposure on anaemia is probably genetically determined; however, the low prevalence of the implicated protective alleles of the inosine triphosphate pyrophosphatase gene could explain their lack of influence on sustained virological response.

Published
2011

3. Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice

Author

Eric Giang, Jacques Belghiti, Serban Morosan, Sophie Berissi, Céline Lamant, Johan Neyts, Eva Wimmer, Gherard Puerstinger, Patrick Soussan, Lucie DaSilva, Olivier Hantz, Marie-Noëlle Brunelle, Laurent Hannoun, Dina Kremsdorf, Hélène Massinet, Nicolas Brezillon, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), neuroscience and barin technology, Service de chirurgie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Microbiology and Immunology, Rega Institute for Medical Research, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), equipe 16, Physiopathologie moléculaire et nouveaux traitements des hépatites virales, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogenèse Hépatique et Virologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénèse des Hépatites Virales B et Immunothérapie (UMR_S 812), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec ( IL ), Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Service de chirurgie digestive et hépato-bilio-pancréatique [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Catholic University of Leuven ( KU Leuven ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche en Cancérologie de Lyon ( 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 ) -Centre Léon Bérard [Lyon]-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 ), Pathogénèse des Hépatites Virales B et Immunothérapie ( UMR_S 812 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (CRCL), and 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)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mouse, Pyridines, Gastroenterology and hepatology, Biopsy, medicine.medical_treatment, MESH : Immunohistochemistry, MESH : Pyrimidines, MESH : Hepatitis B virus, MESH : Viral Load, Mice, SCID, MESH : Hepatocytes, Liver transplantation, medicine.disease_cause, Hepatitis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, MESH: Biopsy, 0302 clinical medicine, MESH : Albumins, MESH: Animals, MESH : DNA, Viral, MESH: Mice, SCID, 0303 health sciences, Multidisciplinary, MESH: Kinetics, virus diseases, Animal Models, Viral Load, Hepatitis B, Antivirals, Immunohistochemistry, 3. Good health, MESH : Antiviral Agents, Infectious hepatitis, MESH: Hepatitis B virus, Real-time polymerase chain reaction, Liver, Capsid, 030220 oncology & carcinogenesis, Infectious diseases, Medicine, MESH : Kinetics, MESH: Viral Load, Viral load, Research Article, MESH: Antiviral Agents, Hepatitis B virus, MESH : Pyridines, Science, Alpha interferon, Viremia, [SDV.CAN]Life Sciences [q-bio]/Cancer, Viral diseases, Biology, Antiviral Agents, Microbiology, 03 medical and health sciences, Model Organisms, Albumins, Virology, MESH : Mice, medicine, Animals, Humans, MESH: Mice, Liver diseases, 030304 developmental biology, MESH: Humans, MESH: Hepatitis B, MESH : Humans, MESH: Pyridines, MESH : Liver, MESH : Hepatitis B, MESH: Immunohistochemistry, medicine.disease, MESH : Mice, SCID, digestive system diseases, MESH: DNA, Viral, Kinetics, Animal Models of Infection, Pyrimidines, Viral replication, MESH : Biopsy, MESH: Pyrimidines, DNA, Viral, Immunology, Hepatocytes, MESH : Animals, MESH: Albumins, MESH: Liver
Abstract

International audience; Current treatments for HBV chronic carriers using interferon alpha or nucleoside analogues are not effective in all patients and may induce the emergence of HBV resistant strains. Bay 41-4109, a member of the heteroaryldihydropyrimidine family, inhibits HBV replication by destabilizing capsid assembly. The aim of this study was to determine the antiviral effect of Bay 41-4109 in a mouse model with humanized liver and the spread of active HBV. Antiviral assays of Bay 41-4109 on HepG2.2.15 cells constitutively expressing HBV, displayed an IC(50) of about 202 nM with no cell toxicity. Alb-uPA/SCID mice were transplanted with human hepatocytes and infected with HBV. Ten days post-infection, the mice were treated with Bay 41-4109 for five days. During the 30 days of follow-up, the HBV load was evaluated by quantitative PCR. At the end of treatment, decreased HBV viremia of about 1 log(10) copies/ml was observed. By contrast, increased HBV viremia of about 0.5 log(10) copies/ml was measured in the control group. Five days after the end of treatment, a rebound of HBV viremia occurred in the treated group. Furthermore, 15 days after treatment discontinuation, a similar expression of the viral capsid was evidenced in liver biopsies. Our findings demonstrate that Bay 41-4109 displayed antiviral properties against HBV in humanized Alb-uPA/SCID mice and confirm the usefulness of Alb-uPA/SCID mice for the evaluation of pharmaceutical compounds. The administration of Bay 41-4109 may constitute a new strategy for the treatment of patients in escape from standard antiviral therapy.

Published
2011

4. First presentation for care of HIV-infected patients with low CD4 cell count in Lyon, France: risk factors and consequences for survival

Author

Jean-Michel Livrozet, Jean-Louis Touraine, D. Baratin, François Bailly, Abdoulaye Touré, Philippe Vanhems, Nagham Khanafer, Dominique Peyramond, Christian Trepo, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie, Hôpital Hôtel Dieu, Service d'Immunologie Clinique, Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Service d'Hygiène, Epidémiologie et Prévention [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Pediatrics, Time Factors, Health (social science), Multivariate analysis, MESH: CD4 Lymphocyte Count, MESH: Transients and Migrants, [SDV]Life Sciences [q-bio], HIV Infections, MESH: Logistic Models, 030312 virology, Logistic regression, Health Services Accessibility, MESH: Antiretroviral Therapy, Highly Active, MESH: Proportional Hazards Models, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Antiretroviral Therapy, Highly Active, Health care, Epidemiology, 030212 general & internal medicine, MESH: Treatment Outcome, Transients and Migrants, 0303 health sciences, MESH: Health Services Accessibility, MESH: AIDS-Related Opportunistic Infections, Age Factors, MESH: Patient Acceptance of Health Care, MESH: Follow-Up Studies, MESH: HIV Infections, Prognosis, 3. Good health, Survival Rate, Treatment Outcome, Female, France, Presentation (obstetrics), Adult, medicine.medical_specialty, Social Psychology, MESH: Survival Rate, MESH: Multivariate Analysis, MESH: Prognosis, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, medicine, Humans, Survival rate, Proportional Hazards Models, MESH: Age Factors, MESH: Humans, AIDS-Related Opportunistic Infections, Proportional hazards model, business.industry, Public health, MESH: Time Factors, Public Health, Environmental and Occupational Health, MESH: Adult, Patient Acceptance of Health Care, MESH: Male, CD4 Lymphocyte Count, MESH: France, Logistic Models, Multivariate Analysis, business, MESH: Female, Follow-Up Studies
Abstract

International audience; To identify the risk factors associated with presentation for care with CD4 cell count ≤ 200 cells/mm(3) and death in HIV-infected patients in Lyon, France. Data were analyzed on participants from mid-1992 to December 2006 in the Lyon section of the French Hospital Database on HIV Infection. Patients were stratified into two categories according to CD4 cell count at first presentation for care in University of Lyon hospitals: Group 1 (Gr1) patients with CD4 ≤ 200 cells/mm(3) and Group 2 (Gr2) patients with CD4 >200 cells/mm(3). Multivariate logistic regression assessed the risk factors associated with first presentation for care with CD4 ≤ 200 cells/mm(3). Survival was analyzed according to the Cox regression model. Among 3569 eligible patients (838 females and 2731 males, mean age: 36.3 ± 10.3 years), 1139 (31.9%) were categorized as Gr1. The factors associated with first presentation for care with CD4 ≤ 200 cells/mm(3) were: older age, male gender, route of HIV transmission, migrant populations, geographical areas other than Rhône-Alpes, and access to care in 1992-1997. Overall mortality was higher in Gr1 than in Gr2 (24.4% [278/1139] vs. 4.1% [101/2430]; p

Published
2012

5. A poxvirus vaccine is safe, induces T-cell responses, and decreases viral load in patients with chronic hepatitis C

Author

Christine Bain, Jean-Pierre Bronowicki, Jean Yves Bonnefoy, Géraldine Honnet, Jean Marc Limacher, François Habersetzer, Christian Trepo, Michel Doffoel, Marianne Maynard–Muet, Martine Baudin, Myew–Ling Toh, Thomas F. Baumert, Cyrille Feray, Vincent Leroy, Delphine Agathon, Geneviève Inchauspé, Jean-Pierre Zarski, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôptaux universitaires de Strasbourg (HUS), CHU Strasbourg, Immunothérapie des maladies infectieuses chroniques (IMIC), BIOMERIEUX-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire d'Énergétique Moléculaire et Macroscopique, Combustion (EM2C), Université Paris Saclay (COmUE)-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec, Département d'hépato-gastroentérologie, CHU Grenoble-Université Grenoble Alpes (UGA), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Plate-forme de R&D - Puces à Cellules Transfectées (PCT), Cancéropôle du Grand-Est (CGE)-Centre Européen de Biologie et de Génomique Structurale (CEBGS), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Equipe 16, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), transgene, Transgene, Hôpital pasteur [Colmar], Scanella, Marie-Pierre, CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Cancéropôle du Grand-Est (CGE)-Centre Européen de Biologie et de Génomique Structurale (CEBGS)-Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes (UGA)-CHU Grenoble, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Poxviridae, Modified vaccinia Ankara, T-Lymphocytes, Hepacivirus, Viral Nonstructural Proteins, Antibodies, Viral, medicine.disease_cause, MESH: Dose-Response Relationship, Drug, MESH: Genotype, chemistry.chemical_compound, 0302 clinical medicine, Interferon, MESH: Hepacivirus, 0303 health sciences, MESH: Middle Aged, Immunogenicity, Gastroenterology, Hepatitis C, Middle Aged, Viral Load, 3. Good health, MESH: Hepatitis C, Chronic, MESH: RNA, Viral, RNA, Viral, Female, 030211 gastroenterology & hepatology, MESH: Viral Load, Viral load, medicine.drug, Adult, Genotype, MESH: Interferon-gamma, Hepatitis C virus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Interferon-gamma, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Viral Vaccines, medicine, Humans, Adverse effect, NS5B, 030304 developmental biology, MESH: Humans, Dose-Response Relationship, Drug, Hepatology, business.industry, Poxviridae, Viral Vaccines, MESH: Adult, Hepatitis C, Chronic, medicine.disease, MESH: Male, MESH: T-Lymphocytes, chemistry, Immunology, MESH: Viral Nonstructural Proteins, business, MESH: Female, MESH: Antibodies, Viral
Abstract

International audience; BACKGROUND & AIMS: Therapy for chronic hepatitis C (CHC) has limited efficacy, adverse effects, and high costs. Cohort and vaccine-based preclinical studies have indicated the importance of T-cell-based immunity in controlling viral infection. TG4040 is a recombinant poxvirus vaccine that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase I clinical trial to assess the safety, immunogenicity, and early antiviral efficacy of TG4040 in patients with CHC. METHODS: In an open-label, dose-escalating study, patients with mild CHC (genotype 1) were assigned to 3 groups of 3 patients each; they received subcutaneous injections of 10⁶, 10⁷, or 10⁸ plaque-forming units of TG4040 on study days 1, 8, and 15. Six additional patients were given the highest dose of vaccine (10⁸ plaque-forming units). Patients were followed for 6 months after the last injection. T-cell-based and antibody responses and levels of HCV RNA were measured. RESULTS: All 3 doses of TG4040 were well tolerated, without serious adverse events. Vaccine-induced HCV-specific cellular immune responses were observed in 5 of the 15 patients (33%). A transient decrease in circulating levels of HCV RNA, from -0.52 log₁₀ to -1.24 log₁₀, was observed in 8 patients; in 5 patients, the lowest level of HCV RNA was observed on day 37, after the first injection. The most pronounced decrease in viral load occurred in 2 patients, who also had marked vaccine-induced T-cell responses. CONCLUSIONS: In patients with CHC, the viral-vector-based vaccine TG4040 had a good safety profile, induced HCV-specific cellular immune responses, and reduced viral load. This vaccine should be investigated in further clinical studies, in combination with standard of care.

Published
2011

6. Evolution of Hepatitis B and C serum markers: a still challenging issue

Author

Chemin, Isabelle, Trépo, Christian, Equipe 16, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-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), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (CRCL), and 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)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Hepatitis C, Hepatitis B Surface Antigens, MESH: Humans, MESH: Hepatitis B, MESH: Serologic Tests, MESH: Biological Markers, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hepatitis C Antibodies, Hepatitis B, Hepatitis C, MESH: Hepatitis B Surface Antigens, MESH: Hepatitis C Antibodies, Humans, Serologic Tests, Biomarkers, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2011

7. Long-term propagation of serum hepatitis C virus (HCV) with production of enveloped HCV particles in human HepaRG hepatocytes

Author

Pascale Berthillon, Marie-Anne Petit, Isabelle Bordes, Elisabeth Errazuriz, Christian Trepo, Sylvie De Sequeira, Ndiémé Ndongo-Thiam, 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), Service d'hépatologie et de gastroentérologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Cell Differentiation, medicine.medical_specialty, Time Factors, Apolipoprotein B, medicine.drug_class, Cellular differentiation, Hepatitis C virus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hepacivirus, MESH: Stem Cells, Monoclonal antibody, medicine.disease_cause, MESH: Hepatocytes, 03 medical and health sciences, 0302 clinical medicine, Viral Envelope Proteins, Antigen, Internal medicine, medicine, Humans, MESH: Hepacivirus, Progenitor cell, Cells, Cultured, 030304 developmental biology, MESH: Hepatitis C, 0303 health sciences, MESH: Humans, Hepatology, biology, Stem Cells, MESH: Time Factors, Virion, Cell Differentiation, Hepatitis C, Virology, In vitro, 3. Good health, MESH: Viral Envelope Proteins, Hepatocytes, biology.protein, MESH: Virion, 030211 gastroenterology & hepatology, MESH: Cells, Cultured
Abstract

International audience; UNLABELLED: HepaRG human liver progenitor cells exhibit morphology and functionality of adult hepatocytes. We investigated the susceptibility of HepaRG hepatocytes to in vitro infection with serum-derived hepatitis C virus (HCV) particles (HCVsp) and the potential neutralizing activity of the E1E2-specific monoclonal antibody (mAb) D32.10. The infection was performed using HCVsp when the cells actively divided at day 3 postplating. HCV RNA, E1E2, and core antigens were quantified in HCV particles recovered from culture supernatants of differentiated cells for up to 66 days. The density distributions of particles were analyzed on iodixanol or sucrose gradients. Electron microscopy (EM) and immune-EM studies were performed for ultrastructural analysis of cells and localization of HCV E1E2 proteins in thin sections. HCV infection of HepaRG cells was documented by increasing production of E1E2-core-RNA(+) HCV particles from day 21 to day 63. Infectious particles sedimented between 1.06 and 1.12 g/mL in iodixanol gradients. E1E2 and core antigens were expressed in 50% of HCV-infected cells at day 31. The D32.10 mAb strongly inhibited HCV RNA production in HepaRG culture supernatants. Infected HepaRG cells frozen at day 56 were reseeded at low density. After only 1-3 subcultures and induction of a cell differentiation process the HepaRG cells produced high titer HCV RNA and thus showed to be sustainably infected. Apolipoprotein B-associated empty E1E2 and complete HCV particles were secreted. Characteristic virus-induced intracellular membrane changes and E1E2 protein-association to vesicles were observed. CONCLUSION: HepaRG progenitor cells permit HCVsp infection. Differentiated HepaRG cells support long-term production of infectious lipoprotein-associated enveloped HCV particles. The E1E2-specific D32.10 mAb neutralizes the infection and this cellular model could be used as a surrogate infection system for the screening of entry inhibitors.

Published
2011

8. Hepatitis B genotypes/subgenotypes and MHR variants among Moroccan chronic carriers

Author

Khadija Rebbani, Soumaya Benjelloun, Omar Derdabi, Hanane Salih Alj, Isabelle Chemin, M. Benazzouz, Younes Cherradi, Abdellah Essaid El Feydi, Christian Trepo, Bouchra Kitab, Ikram Brahim, Fabien Zoulim, Rajaa Afifi, Sayeh Ezzikouri, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), Service d'hépatologie et de gastroentérologie, Hospices Civils de Lyon (HCL)-Hôtel-Dieu, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Hépatites Virales [Casablanca, Maroc] (LHV), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche en Cancérologie de Lyon (CRCL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, HBsAg, medicine.disease_cause, MESH: Genotype, 0302 clinical medicine, MESH: Aged, 80 and over, Gene Frequency, Genotype, MESH: Phylogeny, Phylogeny, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, virus diseases, Hepatitis B, Middle Aged, 3. Good health, MESH: Hepatitis B virus, Morocco, Infectious Diseases, HBeAg, MESH: Young Adult, Carrier State, 030211 gastroenterology & hepatology, Female, MESH: Carrier State, Viral load, Sequence Analysis, Microbiology (medical), MESH: DNA Primers, Adult, Hepatitis B virus, MESH: Mutation, Adolescent, MESH: Hepatitis B, Chronic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, MESH: Sequence Analysis, Young Adult, Hepatitis B, Chronic, Antigen, medicine, MESH: Gene Frequency, Humans, Gene, 030304 developmental biology, Aged, DNA Primers, MESH: Adolescent, MESH: Humans, Hepatitis B Surface Antigens, MESH: Adult, medicine.disease, Virology, digestive system diseases, MESH: Male, MESH: Hepatitis B Surface Antigens, MESH: Morocco, Mutation, MESH: Female
Abstract

International audience; OBJECTIVES: The aim of this study was to determine the prevalence of Hepatitis B Virus (HBV) genotypes, subgenotypes, HBV surface antigen (HBsAg) subtypes and naturally occurring mutations in Major Hydrophilic region (MHR) of HBsAg among Moroccan patients with chronic HBV infection. METHODS: The study included 200 patients chronically infected with HBV. The HBV genotypes, subgenotypes, HBsAg subtypes and MHR variants were determined by direct sequencing of the HBV surface (S) gene and phylogenetic analysis. RESULTS: The S gene was successfully amplified in 134 patients. The mean age was 40.6 ± 12.2 years. Genotype D was predominant (90%, 120/134) and genotype A was less frequent (10%, 14/134). Genotype D strains belonged to subgenotypes D7 (70.8%, 85/120), D1 (25.8%, 31/120) and D2 (0.9%, 1/120). Three strains (2.5%) could not be classified in any subgenotype of genotype D. All genotype A strains belonged to subgenotype A2. HBsAg subtypes found were ayw2 (82.1%, 110/134), adw2 (10.4%, 14/134), ayw3 (3%, 4/134) and ayw4 (3%, 4/134). The global prevalence of MHR variants was 15% (20/134) with substitution P120T/S the most frequent (3.7%, 5/134). The occurrence of MHR variants was significantly associated with advancing age (>40 years) (p = 0.003) and independent of sex, HBeAg status, viral load, genotype, subgenotype and HBsAg subtype. CONCLUSIONS: This study provides the first description of predominance of HBV subgenotype D7/subtype ayw2 among Moroccan HBV chronic carriers. It also showed a significant prevalence of naturally occurring MHR variants in Morocco.

Published
2011

9. Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma

Author

Lydie Lefrancois, Miran Kim, Jack R. Wands, Sarah B. Nambotin, Xavier Sainsily, Michèle Chevallier, Jean-Yves Scoazec, Philippe Merle, Christian Trepo, Pascale Berthillon, Fabien Zoulim, Pierre Jalinot, 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), The Liver Research Center, Brown Medical School, Brown medical school, The liver research center, Biomnis, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Service d'hépatologie et de gastroentérologie, Hospices Civils de Lyon (HCL)-Hôtel-Dieu, Ganivet, Agnès, Institut National de la Santé et de la Recherche Médicale (INSERM), E16, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Anatomie Pathologique, Laboratoires Marcel-Mérieux, Laboratoire Central d'Anatomie et de Cytologie Pathologiques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Equipe 15, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Equipe 16, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Service d'hépatologie et de gastroentérologie, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), equipe 4, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (CRCL), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service d'hépatologie et de gastroentérologie, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Frizzled, Hepatocellular carcinoma, Antigens, Polyomavirus Transforming, MESH: beta Catenin, Dishevelled Proteins, Apoptosis, MESH: Receptors, G-Protein-Coupled, Receptors, G-Protein-Coupled, Dishevelled, Targeted therapy, Mice, 0302 clinical medicine, MESH: Liver Neoplasms, MESH: Animals, MESH: Tumor Suppressor Protein p53, MESH: Carcinoma, Hepatocellular, beta Catenin, chemistry.chemical_classification, 0303 health sciences, MESH: Peptides, Liver Neoplasms, 3. Good health, Protein Kinase C-delta, MESH: Cell Survival, 030220 oncology & carcinogenesis, MESH: Frizzled Receptors, MESH: Protein Kinase C-delta, Genetically modified mouse, Carcinoma, Hepatocellular, MESH: Cell Line, Tumor, Cell Survival, MESH: Mice, Transgenic, PDZ domain, Antineoplastic Agents, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Phosphoproteins, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Cell surface receptor, Cell Line, Tumor, Animals, Humans, Viability assay, MESH: Mice, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Adaptor Proteins, Signal Transducing, MESH: Humans, Hepatology, MESH: Antigens, Polyomavirus Transforming, MESH: Apoptosis, Phosphoproteins, Frizzled Receptors, In vitro, chemistry, Cancer research, MESH: Antineoplastic Agents, Tumor Suppressor Protein p53, Peptides
Abstract

International audience; BACKGROUND & AIMS: We previously reported the frequent overexpression of the FZD7 membrane receptor in hepatocellular carcinoma (HCC) and its role for controlling cancer phenotype. Herein, this study aimed at assessing the anticancer properties of compounds inhibiting FZD7 activity by disrupting its binding with the cytosolic Dishevelled (DVL) adaptator. METHODS: We have designed small interfering peptides (RHPDs) that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL. Their anti-neoplastic properties were assessed in vitro on a panel of human HCC cell lines and in vivo on the SV40-TAg transgenic mouse model of HCC. RESULTS: We have shown that RHPDs decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells. RHPD properties were linked to β-catenin degradation and PKCδ activation. In transgenic mice, intra-tumor injection of RHPDs inhibited HCC progression. CONCLUSIONS: We have completed a proof-of-concept showing that in vitro and in vivo the pharmacological inhibition of FZD7 displays anti-cancerous properties against HCC. The mechanisms can involve β-catenin and PKCδ modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications.

Published
2011

10. Infection with hepatitis B and C viruses and risk of lymphoid malignancies in theEuropean Prospective Investigation into Cancer and Nutrition (EPIC)

Author

Anja Olsen, Signe Borgquist, Rosario Tumino, Carlotta Sacerdote, Pagona Lagiou, Elio Riboli, Kim Overvad, Sara Regnér, Christina Bamia, Laudina Rodríguez, Kay-Tee Khaw, Bas Bueno-de-Mesquita, Paolo Vineis, Carmen Navarro, Nikolaus Becker, Manuela M. Bergmann, Anne Tjønneland, María José Sánchez, Nicholas J. Wareham, Rudolf Kaaks, Salvatore Panico, Pascale Berthillon, Roel Vermeulen, Ruth C. Travis, Mauro Lise, Beatrice Melin, Domenico Palli, Shu Chun Chuang, Göran Hallmans, Sabina Rinaldi, Alexandra Nieters, Leila Luján Barroso, Antonia Trichopoulou, Silvia Franceschi, Christian Trepo, Pierre Hainaut, Miren Dorronsoro, Heiner Boeing, Sabina Sieri, Aurelio Barricarte, Petra H.M. Peeters, Franceschi, S, Lise, M, Trépo, C, Berthillon, P, Chuang, Sc, Nieters, A, Travis, Rc, Vermeulen, R, Overvad, K, Tjønneland, A, Olsen, A, Bergmann, Mm, Boeing, H, Kaaks, R, Becker, N, Trichopoulou, A, Lagiou, P, Bamia, C, Palli, D, Sieri, S, Panico, Salvatore, Tumino, R, Sacerdote, C, Bueno de Mesquita, B, Peeters, Ph, Rodríguez, L, Barroso, Ll, Dorronsoro, M, Sánchez, Mj, Navarro, C, Barricarte, A, Regnér, S, Borgquist, S, Melin, B, Hallmans, G, Khaw, Kt, Wareham, N, Rinaldi, S, Hainaut, P, Riboli, E, Vineis, P., Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), E16, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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)-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), Molecular Epidemiology, Center of Chronic Immunodeficiency, University Medical Center and University of Freiburg, Institute for Medical Biostatistics and Medical Informatics, University Medical Center and University of Freiburg, Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Section of Epidemiology, Aarhus University [Aarhus], Danish Cancer Society Research Center, Cancer Epidemiology Institute, Danish Cancer Society, Epidemiology, Division of Cancer Epidemiology, Deutsches Krebsforschungszentrum, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hellenic Health Foundation, WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene-Epidemiology and Medical Statistics-Athens Medical School, WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Clinical and Experimental Medicine, Università degli studi di Napoli Federico II, Cancer Registry, Azienda Ospedaliera 'Civile M.P.Arezzo', CPO Piemonte, National Institute for Public Health and the Environment [Bilthoven] (RIVM), Department of Gastroenterology and Hepatology, University Medical Centre, Julius Centre for Health Sciences and Primary Care, VU University Medical Center [Amsterdam], Julius Center for Health Sciences and Primary Care, Public Health and Participation Directorate, Health and Health Care Services Council, Epidemiology and Health Information, Public Health Department of Gipuzkoa, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), Granada Cancer Registry, Andalusian School of Public Health [Granada], CIBERESP, CIBER Epidemiologia y Salud Pública, Epidemiology Department, Murcia Health Council, Navarre Public Health Institute, Department of Oncology, Lund University [Lund]-Lund University Hospital, Department of Radiation Sciences and Oncology, Umeå University, Department of Public Health and Clinical Medicine, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Medical Research Council, Addenbrooke's Hospital-Epidemiology Unit, International Agency for Cancer Research (IACR), Sect Mech Carcinogenesis, School of Public Health, Imperial College London, Centre for Environment and Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Human Genetics Foundation (HuGeF), Università degli studi di Torino (UNITO), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Freiburg University Medical Center, Civile - M.P.Arezzo Hospital, and Lund University Hospital-Lund University [Lund]

Subjects
Male, HBsAg, Epidemiology, medicine.disease_cause, Gastroenterology, 0302 clinical medicine, MESH: Lymphoma, Non-Hodgkin, MESH: Risk Factors, Risk Factors, immune system diseases, hemic and lymphatic diseases, Prospective Studies, MESH: Middle Aged, Lymphoma, Non-Hodgkin, virus diseases, Hepatitis C, Hepatitis B, Middle Aged, MESH: Case-Control Studies, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, Oncology, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, medicine.medical_specialty, Hepatitis C virus, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, medicine, Humans, Risk factor, Hepatitis B virus, MESH: Hepatitis C, MESH: Humans, MESH: Hepatitis B, business.industry, Odds ratio, medicine.disease, digestive system diseases, MESH: Male, MESH: Prospective Studies, Case-Control Studies, Immunology, MESH: Europe, business, MESH: Female
Abstract

Background: Case–control studies suggested a moderate, but consistent, association of hepatitis C virus (HCV) infection with lymphoid tissue malignancies, especially non–Hodgkin lymphoma (NHL). More limited data suggested that hepatitis B virus (HBV) infection might also be associated with NHL. However, prospective studies on the topic are few. Methods: A nested case–control study was conducted in eight countries participating in the EPIC prospective study. Seven hundred thirty-nine incident cases of NHL, 238 multiple myeloma (MM), and 46 Hodgkin lymphoma (HL) were matched with 2,028 controls. Seropositivity to anti-HCV, anti-HBc, and HBsAg was evaluated and conditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for NHL, MM, or HL, and their combination. Results: Anti-HCV seropositivity among controls in different countries ranged from 0% to 5.3%; HBsAg from 0% to 2.7%; and anti-HBc from 1.9% to 45.9%. Similar nonsignificant associations were found with seropositivity to HBsAg for NHL (OR = 1.78; 95% CI: 0.78–4.04), MM (OR = 4.00; 95% CI: 1.00–16.0), and HL (OR = 2.00; 95% CI: 0.13–32.0). The association between HBsAg and the combination of NHL, MM, and HL (OR = 2.21; 95% CI: 1.12–4.33) was similar for cancer diagnosed less than 3 and 3 or more years after blood collection. No significant association was found between anti-HCV and NHL, MM, or HL risk, but the corresponding CIs were very broad. Conclusions: Chronic HBV infection may increase the risk of lymphoid malignancies among healthy European volunteers. Impact: Treatment directed at control of HBV infection should be evaluated in HBsAg-seropositive patients with lymphoid tissue malignancies. Cancer Epidemiol Biomarkers Prev; 20(1); 208–14. ©2011 AACR.

Published
2011

11. Mutations in TP53 and CTNNB1 in Relation to Hepatitis B and C Infections in Hepatocellular Carcinomas from Thailand

Author

Olivier Galy, Suleeporn Sangrajrang, Iris Suarez, Christian Trepo, Stephanie Villar, Beatriz Vieco, Michèle Chevallier, Pierre Hainaut, Isabelle Chemin, Doriane Gouas, Emilie Le Roux, María Cristina Navas, Florence Le Calvez-Kelm, Helene Norder, Anant Karalak, Petcharin Srivatanakul, Myriam Lereau, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), E16, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Section Génétique - Groupe Prédispositions génétiques au cancer, Centre International de Recherche contre le Cancer (CIRC), Biomnis, Swedish Institute for Infectious Disease Control, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sect Mech Carcinogenesis, International Agency for Cancer Research (IACR), 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), 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)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (CRCL), and 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)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Hepatitis B virus, endocrine system diseases, Article Subject, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hepacivirus, medicine.disease_cause, Mutually exclusive events, Tp53 mutation, 03 medical and health sciences, 0302 clinical medicine, Genes p53, Genotype, medicine, Pathology, Molecular, neoplasms, 030304 developmental biology, Virus de la Hepatitis B, 0303 health sciences, Mutation, Hepatology, Patología Molecular, business.industry, Mutagenesis, virus diseases, Hepatitis B, Genes, p53, medicine.disease, Virology, digestive system diseases, 3. Good health, Hepatocellular carcinoma, 030211 gastroenterology & hepatology, business, Research Article
Abstract

Hepatocellular carcinoma (HCC) may develop according to two major pathways, one involving HBV infection and TP53 mutation and the other characterized by HCV infection and CTNNB1 mutation. We have investigated HBV/HCV infections and TP53/CTNNB1 mutations in 26 HCC patients from Thailand. HBV DNA (genotype B or C) was detected in 19 (73%) of the cases, including 5 occult infections and 3 coinfections with HCV. TP53 and CTNNB1 mutations were not mutually exclusive, and most of TP53 mutations were R249S, suggesting a significant impact of aflatoxin-induced mutagenesis in HCC development.

Published
2011

12. Expression of E1E2 on hepatitis C RNA-containing particles released from primary cultured human hepatocytes derived from infected cirrhotic livers

Author

Subjini Selliah, Christian Trepo, Valérie-Ann Raymond, Marc Bilodeau, Marie-Anne Petit, Ndiémé Ndongo, Pascale Berthillon, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hopital Saint-Luc, Centre Hospitalier de l'Université de Montréal (CHUM), 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), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montréal (UdeM)-Université de Montréal (UdeM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Liver Cirrhosis, Hepacivirus, Centrifugation, Isopycnic, medicine.disease_cause, Epitope, MESH: Antibodies, Monoclonal, MESH: Hepatocytes, Epitopes, MESH: Gene Expression Regulation, Viral, 0302 clinical medicine, Viral Envelope Proteins, MESH: Hepacivirus, Cells, Cultured, chemistry.chemical_classification, 0303 health sciences, MESH: Peptides, Antibodies, Monoclonal, Hepatitis C, 3. Good health, MESH: Centrifugation, Isopycnic, Infectious Diseases, MESH: RNA, Viral, RNA, Viral, 030211 gastroenterology & hepatology, MESH: Liver Cirrhosis, MESH: Cells, Cultured, Gene Expression Regulation, Viral, MESH: Epitopes, medicine.drug_class, Hepatitis C virus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Monoclonal antibody, 03 medical and health sciences, Antigen, In vivo, Virology, medicine, Humans, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Molecular biology, chemistry, Cytoplasm, MESH: Viral Envelope Proteins, Hepatocytes, Glycoprotein, Peptides, Immunostaining
Abstract

Objective: To determine whether liver-derived hepatitis C RNA-containing particles express the E1E2 discontinuous antigenic determinant defined by unique monoclonal antibody (mAb) D32.10 which recognizes three highly conserved segments in E1 (aa297–306) and E2 (aa480–494 and aa613–621) envelope glycoproteins. Methods: Human hepatocytes were isolated from HCV-infected cirrhotic explanted livers. The liver-derived hepatitis C virus (HCV) particles released from three distinct cultures (genotypes 1b and 2b) were characterized. HCV RNA+ was quantified by real-time RT-PCR. The E1E2 antigenic activity was assessed by indirect ELISA and immunoblotting using D32.10. The density distributions of HCV RNA and E1E2 antigen were determined by isopycnic sucrose density gradients. HCV E1E2, E2 and core antigens were detected in the cells by immunochemical staining. Results: Liver-derived HCV particles contained HCV RNA (106–107 copies/mg of protein) and core proteins and expressed the E1E2/D32.10 epitope. HCV RNA and E1E2 cosedimented between 1.15 and 1.25 g/ml in sucrose gradients. Moreover, the mAb D32.10 detected E1E2 by immunostaining in HCV-infected hepatocytes in parallel with E2 and core antigens. Conclusion: Our results provide evidence that the mAb D32.10 recognizes E1E2 envelope complexes expressed in the cell cytoplasm and on the surface of HCV RNA-containing particles released from short-term cultures of in vivo infected hepatocytes.

Published
2011

13. A p.C217R Mutation in Fibulin-5 from Cutis Laxa Patients Is Associated with Incomplete Extracellular Matrix Formation in a Skin Equivalent Model

Author

Romain Debret, Florence Jobard, Safa Saker, Odile Damour, Judith Fischer, Pascal Sommer, André Mégarbané, Stephanie Claus, Hala Mégarbané, Martine Devillers, Simone Peyrol, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de dermatologie, Saint Georges Hospital, Institut Jérôme Lejeune, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Banque d’ADN et de Cellules, Généthon, Université Paris Descartes - Paris 5 (UPD5), Deleage, Gilbert, Institut de biologie et chimie des protéines [Lyon] (IBCP), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Pathology, medicine.medical_specialty, Collagen Type VII, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Mutation, Missense, Dermatology, Models, Biological, Biochemistry, Basement Membrane, Cutis Laxa, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Dermis, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Skin equivalent, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Skin, 030304 developmental biology, Basement membrane, Extracellular Matrix Proteins, 0303 health sciences, business.industry, Homozygote, Genodermatosis, Cell Biology, Fibroblasts, medicine.disease, Extracellular Matrix, 3. Good health, Fibulin, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Female, business, Elastic fiber, Cutis laxa
Abstract

International audience; Cutis laxa (CL) is a rare genodermatosis, which is clinically and genetically heterogeneous. It is characterized by redundant, loose, sagging, and inelastic skin. In a consanguineous family from Lebanon with autosomal-recessive transmission, we identified a homozygous missense mutation (c.649T --> C; p.C217R) in the fibulin-5 gene (FBLN5), which was, to our knowledge, previously unreported. Small skin biopsies were performed, which permitted isolation of skin fibroblasts harboring this FBLN5 mutation; they exhibited a deficit in cell growth. A CL skin equivalent (CL-SE) model compared with control SE was successfully developed to define the behavior of CL fibroblasts in a three-dimensional model. There was increased cell death and a global extracellular matrix deficiency in the dermis of this CL-SE model, and a low level of the main elastic fiber expression. There was no basement membrane evident at the ultrastructural level, and type-VII collagen could not be detected at the histological level. This model reproduced some defects of the extracellular matrix and highlighted other defects, which occurred at the time of the basement membrane formation, which were not evident in skin from patients. This CL-SE model could be adapted to screen for therapeutically active molecules.Cutis laxa (CL) is a rare genodermatosis, which is clinically and genetically heterogeneous. It is characterized by redundant, loose, sagging, and inelastic skin. In a consanguineous family from Lebanon with autosomal-recessive transmission, we identified a homozygous missense mutation (c.649T --> C; p.C217R) in the fibulin-5 gene (FBLN5), which was, to our knowledge, previously unreported. Small skin biopsies were performed, which permitted isolation of skin fibroblasts harboring this FBLN5 mutation; they exhibited a deficit in cell growth. A CL skin equivalent (CL-SE) model compared with control SE was successfully developed to define the behavior of CL fibroblasts in a three-dimensional model. There was increased cell death and a global extracellular matrix deficiency in the dermis of this CL-SE model, and a low level of the main elastic fiber expression. There was no basement membrane evident at the ultrastructural level, and type-VII collagen could not be detected at the histological level. This model reproduced some defects of the extracellular matrix and highlighted other defects, which occurred at the time of the basement membrane formation, which were not evident in skin from patients. This CL-SE model could be adapted to screen for therapeutically active molecules.

Published
2008

14. Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice

Author

Annie Durand, Jennifer Rieusset, Simone Peyrol, Marie-Agnès Chauvin, Hubert Vidal, C. Bonnard, Béatrice Morio, Emilie Chanseaume, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, This work was supported by grants of INSERM, the French National Research Agency (ANR-05-PCOD-012) and the French National Program on Diabetes Research (to J.R), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vericel, Evelyne, and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, Sucrose, Mitochondrial Diseases, Muscle Fibers, Skeletal, Type 2 diabetes, medicine.disease_cause, Mice, 0302 clinical medicine, Myocyte, MESH: Animals, 2. Zero hunger, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Muscle Fibers, Skeletal, MESH: Oxidative Stress, MESH: Mitochondria, Muscle, MESH: Reactive Oxygen Species, MESH: Mitochondrial Diseases, General Medicine, 3. Good health, MESH: Insulin Resistance, medicine.anatomical_structure, MESH: Dietary Fats, Research Article, MESH: Diabetes Mellitus, Type 2, Muscle tissue, medicine.medical_specialty, Biology, 03 medical and health sciences, Insulin resistance, MESH: Diet, MESH: Mice, Inbred C57BL, Internal medicine, Diabetes mellitus, medicine, Animals, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, MESH: Sucrose, Skeletal muscle, medicine.disease, Dietary Fats, MESH: Male, Diet, Mitochondria, Muscle, Mice, Inbred C57BL, Oxidative Stress, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Diabetes Mellitus, Type 2, Mitochondrial biogenesis, Insulin Resistance, Reactive Oxygen Species, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Oxidative stress
Abstract

International audience; Mitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity. Glucose- or lipid-induced ROS production resulted in mitochondrial alterations in muscle cells in vitro, and these effects were blocked by antioxidant treatment. These data suggest that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice.

Published
2008

15. Transcriptional regulation of the glucose-6-phosphatase gene by cAMP/vasoactive intestinal peptide in the intestine. Role of HNF4alpha, CREM, HNF1alpha, and C/EBPalpha

Author

Fabienne Rajas, Enzo Lalli, Carine Zitoun, Amandine Gautier-Stein, Gilles Mithieux, Mécanisme Moléculaire du Diabète (MMD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations métaboliques, nutrition et diabètes (RMND), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec (IL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Nestlé, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Loudig, Nadine

Subjects
Enzymologic, Male, Glucose uptake, Vasoactive intestinal peptide, MESH: Rats, Sprague-Dawley, MESH: Base Sequence, Biochemistry, Rats, Sprague-Dawley, 0302 clinical medicine, Transcriptional regulation, Cyclic AMP, MESH: CCAAT-Enhancer-Binding Protein-alpha, Glucose homeostasis, MESH: Animals, Hepatocyte Nuclear Factor 1-alpha, Intestinal Mucosa, MESH: Cyclic AMP, Cancer, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Gene Expression Regulation, Enzymologic, MESH: Vasoactive Intestinal Peptide, Intestines, Hepatocyte Nuclear Factor 4, Glucose-6-Phosphatase, MESH: Caco-2 Cells, MESH: Hepatocyte Nuclear Factor 4, Glucose 6-phosphatase, Vasoactive Intestinal Peptide, MESH: Intestines, Gene isoform, medicine.medical_specialty, MESH: Rats, Molecular Sequence Data, Médecine humaine et pathologie, 030209 endocrinology & metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Cyclic AMP Response Element Modulator, Gene Expression Regulation, Enzymologic, Cyclic AMP Response Element Modulator, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, SDV:BBM, medicine, CCAAT-Enhancer-Binding Protein-alpha, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Hepatocyte Nuclear Factor 1-alpha, Protein kinase A, Base Sequence, Caco-2 Cells, Gene Expression Regulation, Rats, Sprague-Dawley, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Cell Biology, MESH: Glucose-6-Phosphatase, MESH: Male, Endocrinology, Gluconeogenesis, biology.protein, Human health and pathology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Gluconeogenesis is induced in both the liver and intestine by increased cAMP levels. However, hepatic and intestinal glucose production can have opposite effects on glucose homeostasis. Glucose release into the portal vein by the intestine increases glucose uptake and reduces food intake. In contrast, glucose production by the liver contributes to hyperglycemia in type II diabetes. Glucose-6-phosphatase (Glc6Pase) is the key enzyme of gluconeogenesis in both the liver and intestine. Here we specify the cAMP/protein kinase A regulation of the Glc6Pase gene in the intestine compared with the liver. Similarly to the liver, the molecular mechanism of cAMP/protein kinase A regulation involves cAMP-response element-binding protein, HNF4alpha, CAAT/enhancer-binding protein, and HNF1. In contrast to the situation in the liver, we find that different isoforms of CAAT/enhancer-binding protein and HNF1 contribute to the specific regulation of the Glc6Pase gene in the intestine. Moreover, we show that cAMP-response element binding modulator specifically contributes to the regulation of the Glc6Pase gene in the intestine but not in the liver. These results allow us to identify intestine-specific regulators of the Glc6Pase gene and to improve the understanding of the differences in the regulation of gluconeogenesis in the intestine compared with the liver.

Published
2006

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