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201. Intoxication au paracétamol

Author

Marc Bardou

Subjects
Pharmacology, business.industry, Medicine, Pharmacology (medical), business
Published
2008

203. W1904 Proton Pump Inhibitors Versus Histamine 2 Receptor Antagonists or Sucralfate for Stress Related Mucosal Bleeding Prophylaxis in Critically Ill Patients: A Follow-Up Meta-Analysis

Author

C Q D Pham, Marc Bardou, Myriam Martel, and Alan N. Barkun

Subjects
medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, Lansoprazole, Rabeprazole, Placebo, law.invention, Ranitidine, Sucralfate, Randomized controlled trial, law, Meta-analysis, Internal medicine, Anesthesia, medicine, business, Omeprazole, medicine.drug
Abstract

Background: Stress-relatedmucosal bleeding (SRMB) causes significantmorbidity andmortality. H2-receptor receptor antagonists (H2RA) have been shown to reduce SRMB rates, yet randomized trials (RCTs) assessing proton pump inhibitors (PPIs) have yielded conflicting results. Objective: To evaluate the efficacy of PPIs versus H2RAs and/or sucralfate in the prophylaxis of SRMB in critically ill adults with risk factors for bleeding. Methods: Searches of the past 4 decades in MEDLINE, EMBASE, CENTRAL (Q4-2006), and ISI WEB OF KNOWLEDGE were conducted. Both abstracts and full publications of RCTs in English were included if the required data could be extracted. We reviewed all RCTs comparing the efficacy of PPIs to controls (H2RAs, sucralfate, or placebo). Outcomes measured were the decreases in rates of clinically significant bleeding (B, primary outcome of the metaanalysis), nosocomial pneumonia (P), and mortality (M) (secondary outcomes). Study heterogeneity was sought and quantified. Results are reported as odd-ratios (OR) with 95% confidence intervals using a random effect model (Review Manager 4.1). Results: Three fully published RCTs and four abstracts met the inclusion criteria; of the 17 arms contained in these studies, the meta-analysis assessed the 12 treatments arms that compared PPIs to H2RAs (omeprazole (n=5), rabeprazole (n=1), lansoprazole (n=1), cimetidine (n=1), ranitidine (n= 3), and famotidine (n=2)). PPI compared to sucralfate was assessed in 3 treatments arms. Prophylactic PPI administration significantly decreased the incidence of bleeding (N=996 patients, OR 0.36, [0.20;0.65]) with no observed statistical heterogeneity amongst the relevant comparisons (p=0.59, I^2=0.0%). No statistical differences were noted for mortality (n=2, N= 643 pts, OR=1.26, [0.82;1.93]) or the development of nosocomial pneumonia (n=6, N=966 pts, OR=1.09, [0.72;1.64]) (and no heterogeneity was found for either: p=0.87, I^2= 0%, and p=0.73 I^2=0.0%, respectively). Conclusion: In critically ill patients at risk for the development of SRMB, when including both full manuscripts and the literature published only in abstract form to date, PPI prophylaxis significantly decreased rates of clinically significant bleeding, but did not affect mortality rates or the development of nosocomial pneumonia.

Published
2008

204. Combination of Hemoclipping and Epinephrine Injection Decrease Re-Bleeding and Surgery in High-Risk Patients with Acute Peptic Ulcer Bleeding: A Meta-Analysis

Author

Myriam Martel, Elham Rahme, Youssef Toubouti, Alan N. Barkun, and Marc Bardou

Subjects
Re bleeding, medicine.medical_specialty, Epinephrine, High risk patients, business.industry, Meta-analysis, Gastroenterology, Medicine, Radiology, Nuclear Medicine and imaging, business, Acute peptic ulcer, medicine.drug, Surgery
Published
2007

205. [Untitled]

Author

Yaseen M. Arabi, Marc Bardou, Bandar Al Knawy, and Alan N. Barkun

Subjects
medicine.medical_specialty, Gastrointestinal bleeding, medicine.diagnostic_test, business.industry, Octreotide, Critical Care and Intensive Care Medicine, medicine.disease, Intensive care unit, law.invention, Endoscopy, law, Critical illness, medicine, In patient, Upper gastrointestinal bleeding, Intensive care medicine, Complication, business, medicine.drug
Abstract

Whether it is the primary reason for admission or a complication of critical illness, upper gastrointestinal bleeding is commonly encountered in the intensive care unit. In this setting, in the absence of endoscopy, intensivists generally provide supportive care (transfusion of blood products) and acid suppression (such as proton pump inhibitors). More recently, octreotide (a somatostatin analogue) has been used in such patients. However, its precise role in patients with upper gastrointestinal bleeding is not necessarily clear and the drug is associated with significant costs. In this issue of Critical Care, two expert teams debate the merits of using octreotide in non-variceal upper gastrointestinal bleeding.

Published
2006

207. Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding

Author

Alan N. Barkun, Marc Bardou, and John Marshall

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Mortality rate, Hemostasis, Internal Medicine, medicine, General Medicine, Upper gastrointestinal bleeding, medicine.disease, business, Endoscopy, Surgery
Published
2004

208. Magnetic Resonance Cholangiopancreatography

Author

Marc Bardou, Caroline Reinhold, Joseph Romagnuolo, Alan N. Barkun, Lawrence Joseph, and Elham Rahme

Subjects
medicine.medical_specialty, Context (language use), Sensitivity and Specificity, Gastroenterology, Diagnosis, Differential, Biliary disease, Cholelithiasis, Internal medicine, Internal Medicine, medicine, Humans, Magnetic resonance cholangiopancreatography, Cholestasis, medicine.diagnostic_test, business.industry, Pancreatic Ducts, Confounding Factors, Epidemiologic, Magnetic resonance imaging, General Medicine, Gold standard (test), Odds ratio, medicine.disease, Magnetic Resonance Imaging, Bile Duct Neoplasms, ROC Curve, Meta-analysis, Radiology, Differential diagnosis, business, Cholangiography
Abstract

Background: Magnetic resonance cholangiopancreatography (MRCP) is one of many newer noninvasive tests that can image the biliary tree. Purpose: To precisely estimate the overall sensitivity and specificity of MRCP in suspected biliary obstruction and to evaluate clinically important subgroups. Data Sources: MEDLINE search (January 1987 to March 2003) for studies in English or French, bibliographies, and subject matter experts. Study Selection: Studies were included if they allowed construction of 2 x 2 contingency tables of MRCP compared with a reasonable gold standard for at least 1 of the following: the presence, level, or cause of biliary obstruction. Data Extraction: Two independent observers graded study quality, which included consecutive enrollment, blinding, use of a single (versus composite) gold standard, and nonselective use of the gold standard. Logistic regression was used to examine the influence of publication year, quality score, proportion of patients having a direct gold standard, and clinical context on diagnostic performance. Data Synthesis: Of 498 studies identified, 67 were included (4711 patients). Mixed-effect models were used to estimate the sensitivity and specificity, and quantitative receiver-operating characteristic analysis was performed. Magnetic resonance cholangiopancreatography had a high overall pooled sensitivity (95% [±1.96 SD: spread of SD, 75% to 99%]) and specificity (97% [spread of SD, 86% to 99%]). The procedure was less sensitive for stones (92%; odds ratio, 0.51 [Cl, 0.35 to 0.75]) and malignant conditions (88%; odds ratio, 0.28 [Cl, 0.18 to 0.44]) than for the presence of obstruction. In addition, diagnostic performance was higher in studies that were larger, did not use consecutive enrollment, and did not use gold standard assessment for some patients. Conclusions: Magentic resonance cholangiopancreatography is a noninvasive imaging test with excellent overall sensitivity and specificity for demonstrating the level and presence of biliary obstruction; however, it seems less sensitive for detecting stones or differentiating malignant from benign obstruction.

Published
2003

209. PGS9: THE COST-EFFECTIVENESS OF HIGH DOSE ORAL VERSUS INTRAVENOUS PROTON PUMP INHIBITION IN HIGH-RISK PATIENTS WITH BLEEDING PEPTIC ULCERS HAVING UNDERGONE THERAPEUTIC ENDOSCOPY

Author

Marc Bardou, Viviane Adam, K Herba, Alan N. Barkun, Carlo A Fallone, and Wendy Kennedy

Subjects
medicine.medical_specialty, High risk patients, Cost effectiveness, business.industry, Health Policy, Peptic, medicine.medical_treatment, Public Health, Environmental and Occupational Health, Gastroenterology, Surgery, Therapeutic endoscopy, Internal medicine, medicine, business
Published
2003

211. Pulmonary symptoms associated with gastro-esophageal reflux disease (GERD) are inhibited by nociceptin an agonist of ORL1 or OP4 receptor: an experimental approach

Author

Céline Rouget, Young Y. Cui, Marc Bardou, Emmanuel Naline, and Charles Advenier

Subjects
Agonist, medicine.medical_specialty, Hepatology, business.industry, medicine.drug_class, Gastroenterology, Gastro-esophageal reflux disease, medicine.disease, Nociceptin receptor, Internal medicine, medicine, GERD, Receptor, business
Published
2003

213. The cost-effectiveness of high dose oral proton pump inhibition in high-risk patients with bleeding peptic ulcers having undergone therapeutic endoscopy

Author

Carl Herba, Carlo A Fallone, Wendy Kennedy, Viviane Adam, Marc Bardou, and Alan N. Barkun

Subjects
medicine.medical_specialty, High risk patients, Hepatology, Cost effectiveness, business.industry, Peptic, medicine.medical_treatment, Gastroenterology, Rapid urease test, digestive system diseases, Duodenal ulcer, Internal medicine, Therapeutic endoscopy, medicine, Peptic ulcer bleeding, business, Acute hemorrhage
Abstract

of IgG class were determined by an immunoblot method H.pylori was determined positive if histology and/or urease test were positive. Results: The use of NSA1D was significantly more common in bleeding patients (60 vs.37, p = 0.001) and they had siguificantly more often tt.pylori intectiou (77 vs.40, p 20 cigarettes) for peptic ulcer bleeding. Conchision: H,D, Iori intectinn, use of N SAID or ASA, hea W smoking and history of duodenal ulcer are independent risk factors for peptic ulcer bleeding. However, C.agA strains are common also in non-uker patients and their role in acute hemorrhage remains obscure

Published
2003

215. Effect of statin therapy on colorectal cancer.

Author

Marc Bardou

Abstract

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also called statins, are commonly prescribed medications that lower serum cholesterol and decrease cardiac morbidity and mortality. They also possess beneficial effects beyond their cholesterol-lowering properties. Preclinical data suggest statins exhibit pleiotropic antineoplastic effects in a variety of tumours, but clinical studies have provided conflicting data as to whether statins influence the risk of cancer. The biological underpinning of potential effects of statins in colorectal cancer and their role in its prevention or as adjuvant therapy are reviewed. Following a meta-analysis of both randomised clinical trials and epidemiological studies, it is concluded that available clinical data only support a modest, although statistically significant, protective effect of statins in colorectal cancer. Statins may impact on outcomes by decreasing the invasiveness or metastatic properties of colorectal cancer. The data supporting these hypotheses, however, are few and further studies are required to better assess these hypotheses. Statins may also exert a beneficial effect on colorectal cancer by sensitising the tumour to chemotherapeutic agents. Further research is needed to better define the role of statins in overcoming chemoresistance. The combination of statins with other drugs, such as low-dose aspirin or safer non-steroidal anti-inflammatory medications, may be useful in both the prevention and treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Published
2010
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216. Increased superoxide anion production is associated with early atherosclerosis and cardiovascular dysfunctions in a rabbit model.

Author

Bertrand Collin, David Busseuil, Marianne Zeller, Caroline Perrin, Olivier Barthez, Laurence Duvillard, Catherine Vergely, Marc Bardou, Monique Dumas, Yves Cottin, and Luc Rochette

Abstract

AbstractObjective??Hypercholesterolemia (HC) has been associated with impairment of vascular and myocardial functions. As HC could generate an alteration in the oxidative status, we studied the effects of a 1-month cholesterol diet on cardiovascular oxidative stress.Methods and Results??New Zealand rabbits received cholesterol (1%) or normal chow for 1?month. At 30?days, superoxide anion levels, assessed by ESR spectroscopy, NAD(P)H oxidase (NOX) activity, and dihydroethidium (DHE) staining of aortas were higher in the cholesterol-fed (CF) group compared with control (respectively, 4.0 ? 0.6?Arbitrary?Units/mg (AU/mg) vs. 2.6 ? 0.3,p< 0.05; 4231 ? 433 vs. 2931 ? 373?AU/mg,p< 0.05; 21.4 ? 1.2 vs. 12.9 ? 1.7% fluorescence/mm2,p< 0.001). NOX gp91phox and p67phox expression in the aortas were higher in the CF group vs. control (1.5 ? 0.2 vs. 0.5 ? 0.2,p< 0.001; 0.9 ? 0.2 vs. 0.3 ? 0.2,p< 0.05). The endothelium-dependent relaxation evaluated on the iliac arteries was higher in control than in the CF group (64.8 ? 10.1 vs. 13.1 ? 3.70%,p< 0.001). The cardiac diastolic pressure estimated on isolated hearts was higher in the CF group than in control (21.1 ? 4.1 vs. 10.3 ? 1.4?mmHg,p< 0.05) after 60?min of ischemia.Conclusions??Hypercholesterolemia induced increased levels of superoxide in the aortas and a higher expression of NOX subunits, associated with altered vasorelaxation. The increased diastolic pressure observed in hearts, consistent with a post-ischemic contractile dysfunction might be mediated by the production of superoxide. [ABSTRACT FROM AUTHOR]

Published
2007
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217. Efficacy of a Novel Prefilled, Single-Use, Needle-Free Device (Zeneo®) in Achieving Intramuscular Agent Delivery: An Observational Study

Author

Maxime Luu, Xavière Castano, Paul Walker, Christophe Auriel, Marc Bardou, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Electronique, Informatique et Image ( Le2i ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Crossject, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, and HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
Male, Epinephrine/adrenaline, medicine.medical_treatment, Thigh, Body Mass Index, 0302 clinical medicine, Subcutaneous Tissue, Auto-injector, Pharmacology (medical), Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Saline, Original Research, Skin, Medicine(all), Intramuscular, General Medicine, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, medicine.anatomical_structure, Needles, Anesthesia, Female, Subcutaneous tissue, Adult, Risk, medicine.medical_specialty, Length, Injections, Intramuscular, Update, 03 medical and health sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Muscle, Skeletal, Anaphylaxis, Needle free, Skin-to-muscle depth, Single use, business.industry, Single injection, Epinephrine Auto-Injectors, Food Allergy, Surgery, Autoinjectors, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, 030228 respiratory system, Needle length, Observational study, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background It is recognized that, as a result of variation in tissue anatomy, current auto-injectors may have insufficient needle length to achieve successful intramuscular agent delivery in a number of patients. The Zeneo® auto-injector is a novel prefilled, single-use, needle-free device currently in development for intradermal, subcutaneous, and intramuscular agent delivery across a variety of clinical indications. We aimed to evaluate delivery depth of the device calibrated at pressure appropriate for intramuscular (IM) administration. Methods This was a prospective single-center study in healthy adult volunteers, in whom each received a single injection of saline into the anterolateral thigh. Using sequential MRI scans, we measured skin-to-muscle distance (STMD) agent delivery depth, and the success of IM agent penetration. Device dynamic pressure measurements were also recorded. Results Results are reported for 37 subjects with evaluable MRI scans; 19 men, 18 women; mean age 38 years (range 20–58); mean BMI 27.0 kg/m2 (range 21.2–30.8 kg/m2). Mean STMD values were 18.6 mm (range 13.4–23.6 mm) in women and 10.0 mm (range 5.0–21.7 mm) in men, with gender differences due primarily to greater subcutaneous thickness in women. A trend for greater STMD in subjects with BMI greater than 25 kg/m2 was seen. Mean injectate penetration depths of 30.1 mm (range 20.2–45.6 mm) were observed with values similar in male and female subjects. Successful IM delivery was reported in 95% of subjects. When failure occurred, this was not due to inadequate injection depth. Device pressure (P max) had the greatest influence on injectate muscle penetration. Conclusion Use of the Zeneo® auto-injector achieves delivery depth that ensures intramuscular delivery in both men and women, regardless of BMI. Consistent with other reported data, STMD is greater in women. Funding Crossject.

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218. Biphasic Erk1/2 activation sequentially involving Gs and Gi signaling is required in beta3-adrenergic receptor-induced primary smooth muscle cell proliferation

Author

Marc Bardou, Marina Barrichon, Maeva Wendremaire, Paul Sagot, Carmen Garrido, Frédéric Lirussi, Tarik Hadi, and Pascal Mourtialon

Subjects
Beta-3 adrenergic receptor, Gs alpha subunit, MAP Kinase Signaling System, Myocytes, Smooth Muscle, Proliferation, G protein coupled receptor, Biology, GTP-Binding Protein alpha Subunits, Gi-Go, Pertussis toxin, chemistry.chemical_compound, Erk1/2, Protein kinases, Cyclins, Receptors, Adrenergic, beta, GTP-Binding Protein alpha Subunits, Gs, Humans, Molecular Biology, PI3K/AKT/mTOR pathway, Cells, Cultured, G protein-coupled receptor, Cell Proliferation, Forskolin, Colforsin, Cell Biology, Cell biology, chemistry, Gene Expression Regulation, Pertussis Toxin, Myometrium, Female, Signal transduction, Proto-oncogene tyrosine-protein kinase Src
Abstract

The beta3 adrenergic receptor (B3-AR) reportedly induces cell proliferation, but the signaling pathways that were proposed, involving either Gs or Gi coupling, remain controversial. To further investigate the role of G protein coupling in B3-AR induced proliferation, we stimulated primary human myometrial smooth muscle cells with SAR150640 (B3-AR agonist) in the absence or presence of variable G-protein inhibitors. Specific B3-AR stimulation led to an Erk1/2 induced proliferation. We observed that the proliferative effects of B3-AR require two Erk1/2 activation peaks (the first after 3 min, the second at 8 h). Erk1/2 activation at 3 min was mimicked by forskolin (adenylyl-cyclase activator), and was resistant to pertussis toxin (Gi inhibitor), suggesting a Gs protein signaling. This first signaling also required the downstream Gs signaling effectors PKA and Src. However, Erk1/2 activation at 8 h turned out to be pertussis toxin-dependent, and PKA-independent, indicating a Gi signaling pathway in which Src and PI3K were required. The pharmacological inhibition of both the Gs and Gi pathway abolished B3-AR-induced proliferation. Altogether, these data indicate that B3-AR-induced proliferation depends on the biphasic activation of Erk1/2 sequentially induced by the Gs/PKA/Src and Gi/Src/PI3K signaling pathways.

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219. Clinical outcomes after treatment with direct antiviral agents: beyond the virological response in patients with previous HCV-related decompensated cirrhosis

Author

Pageaux, G. (Georges-Philippe), Nzinga, C. (Clovis Lusivika), Ganne, N. (Nathalie), Samuel, D. (Didier), Dorival, C. (Céline), Zoulim, F. (Fabien), Cagnot, C. (Carole), Decaens, T. (Thomas), Thabut, D. (Dominique), Asselah, T. (Tarik), Mathurin, P. (Philippe), Habersetzer, F. (Francois), Bronowicki, J. (Jean-Pierre), Guyader, D. (Dominique), Rosa, I. (Isabelle), Leroy, V. (Vincent), Chazouilleres, O. (Olivier), de Ledinghen, V. (Victor), Bourliere, M. (Marc), Causse, X. (Xavier), Cales, P. (Paul), Metivier, S. (Sophie), Loustaud-Ratti, V. (Véronique), Riachi, G. (Ghassan), Alric, L. (Laurent), Gelu-Simeon, M. (Moana), Minello, A. (Anne), Gournay, J. (Jérôme), Geist, C. (Claire), Tran, A. (Albert), Abergel, A. (Armand), Portal, I. (Isabelle), d'Alteroche, L. (Louis), Raffi, F. (François), Fontaine, H. (Hélène), Carrat, F. (Fabrice), Pol, S. (Stanislas), Baumert, Thomas F., Doffoel, M. (Michel), Mutter, C. (Catherine), Simo-Noumbissie, P. (Pauline), Razi, E. (Esma), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathogénèse et Traitement des Maladies du Foie, Hôpital Paul Brousse-Université Paris-Saclay, 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), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHI Créteil, Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Joseph [Marseille], Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), CHU Toulouse [Toulouse], Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Nutrition, Inflammation et axe Microbiote-Intestin-Cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, 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 ), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, 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), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), French ANRS CO22 Hepather Cohort: Delphine Bonnet, Virginie Payssan-Sicart, Chloe Pomes, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard, Eric Billaud, David Boutoille, Morane Cavellec, Caroline Chevalier, Isabelle Hubert, Pierre Goepfert, Adrien Lannes, Françoise Lunel, Jérôme Boursier, Nathalie Boyer, Nathalie Giuily, Corinne Castelnau, Giovanna Scoazec, Aziza Chibah, Sylvie Keser, Karim Bonardi, Anaïs Vallet-Pichard, Philippe Sogni, Juliette Foucher, Jean-Baptiste Hiriart, Amandine Legendre, Faiza Chermak, Marie Irlès-Depé, Si Nafa Si Ahmed, Christelle Ansaldi, Nisserine Ben Amara, Valérie Oules, Jacqueline Dunette, Rodolphe Anty, Eve Gelsi, Régine Truchi, Elena Luckina, Nadia Messaoudi, Joseph Moussali, Barbara De Dieuleveult, Héloïse Goin, Damien Labarrière, Pascal Potier, Si Nafa Si Ahmed, Véronique Grando-Lemaire, Pierre Nahon, Séverine Brulé, Rym Monard, Caroline Jezequel, Audrey Brener, Anne Laligant, Aline Rabot, Isabelle Renard, Thomas F Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie, Esma Razi, Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani, Marie-Albertine Bernard, Georges-Philippe Pageaux, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Marie Pierre Ripault, Christophe Bureau, Sarah Launay, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Jean-Pierre Zarski, Odile Goria, Victorien Grard, Hélène Montialoux, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty, Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti, Abdenour Babouri, Virginie Filipe, Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques, Guillaume Lassailly, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet, Marianne Latournerie, Marc Bardou, Thomas Mouillot, Yannick Bacq, Didier Barbereau, Charlotte Nicolas, Caroline Chevalier, Isabelle Archambeaud, Sarah Habes, Nisserine Ben Amara, Danièle Botta-Fridlund, Eric Saillard, Marie-Josée Lafrance, Carole Cagnot, Alpha Diallo, Lena Wadouachi, Ventzi Petrov-Sanchez, Douae Ammour, Loubna Ayour, Jaouad Benhida, Fabrice Carrat, Frederic Chau, Céline Dorival, Audrey Gilibert, Isabelle Goderel, Warda Hadi, Clovis Luzivika Nzinga, Grégory Pannetier, François Pinot, Odile Stahl, François Téloulé, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), 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 Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Jonchère, Laurent

Subjects
Liver Cirrhosis, medicine.medical_specialty, Carcinoma, Hepatocellular, Survival, Hepatocellular carcinoma, [SDV]Life Sciences [q-bio], Decompensated cirrhosis, Infectious and parasitic diseases, RC109-216, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, complications, drug therapy, Gastroenterology, Antiviral Agents, Virological response, Internal medicine, Medicine, Humans, In patient, business.industry, Hepatitis C virus, Research, Liver Neoplasms, Hepatitis C, [SDV] Life Sciences [q-bio], Sustained virological response, Infectious Diseases, Direst-acting antiviral agents, therapeutic use, business, After treatment
Abstract

Background In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7–51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24–0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08–0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15–0.54, p Conclusion Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. Trial registration: ClinicalTrials.gov registry number: NCT01953458.

Published
2022

220. Liver fibrosis and all‐cause mortality in chronic HCV‐infected diabetic patients: A paradoxical association? (ANRS CO22 HEPATHER)

Author

Tangui, Barré, Clémence, Ramier, Vincent, Di Beo, Fabrice, Carrat, Hélène, Fontaine, Fabienne, Marcellin, Patrizia, Carrieri, Stanislas, Pol, Camelia, Protopopescu, Marie-Josée, Lafrance, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS/AFEF Hepather study group: Delphine Bonnet, Virginie Sicart, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard, Morane Cavellec, Marjorie Cheraud-Carpentier, François Raffi, Florian Vivrel, Jaouad Benhida, Jérôme Boursier, Paul Calès, Françoise Lunel, Frédéric Oberti, Nathalie Boyer, Audrey Gilibert, Nathalie Giuily, Giovanna Scoazec, Sandrine Fernandes, Sylvie Keser, Philippe Sultanik, Anaïs Vallet-Pichard, Juliette Foucher, Jean-Baptiste Hiriart, Aurore Mathias, Julien Vergniol, Chrystelle Ansaldi, Laëtitia Chouquet, Emilie De Luca, Valérie Oules, Rodolphe Anty, Eve Gelsi, Régine Truchi, Elena Luckina, Nadia Messaoudi, Joseph Moussali, Barbara De Dieuleveult, Damien Labarriere, Pascal Poter, Si Nafa Si Ahmed, Nathalie Ganne-Carrié, Véronique Grando-Lemaire, Pierre Nahon, Alan Peltier, Judith Ung, Mariette Gougeon, Anne Guillygomarch, Caroline Jezequel, Romain Moirand, Thomas F Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie, Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani, Marie-Albertine Bernard, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Georges-Philippe Pageaux, Marie P Ripault, Karl Barange, Christophe Bureau, Jean M Peron, Marie A Robic, Léa Tarallo, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Vincent Leroy, Odile Goria, Victorien Grard, Hélène Montialoux, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty, Teresa Antonini, Audrey Coilly, Jean-Charles D Vallée, Mariagrazia Tateo, Armand Abergel, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti, Abdenour Babouri, Virginie Filipe, Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet, Marc Bardou, Donya Da Costa Souhiel, Patrick Hillon, Marianne Latournerie, Yannick Bacq, Didier Barbereau, Charlotte Nicolas, Nisserine B Amara, Danièle Botta-Fridlund, Isabelle Portal, Moana Gelu-Simeon, Marie-Josée Lafrance, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), The cohort received financial support from the INSERM-ANRS (France Recherche Nord and Sud Sida-HIV Hépatites), the French ANR (Agence Nationale de la Recherche), the French DGS (Direction Générale de la Santé), Merck Sharp and Dohme, Janssen-Cilag, Gilead, Abbvie, Bristol-Myers Squibb and Roche. FC reports grants from INSERM-ANRS, during the conduct of the study, and personal fees from Imaxio, outside the submitted work. MB reports grants and personal fees from AbbVie and Gilead, outside the submitted work, and personal fees from MSD, Janssen, Boehringher Ingelheim, Intercept and Bristol-Myers Squibb, outside the submitted work. SP has received consulting and lecturing fees from Bristol-Myers Squibb, Janssen, Gilead, Roche, MSD, MYR-Pharma, Shionogi, Biotest and Abbvie, as well as grants from Bristol-Myers Squibb, Gilead, Roche and MSD. HF reports personal fees and invitations for medical meetings from Gilead, AbbVie, Bristol-Myers Squibb, MSD and Janssen, outside the submitted work. Other authors declare no financial support., and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Liver Cirrhosis, 0303 health sciences, medicine.medical_specialty, Hepatology, business.industry, Liver fibrosis, [SDV]Life Sciences [q-bio], Hepatitis C, Chronic, Antiviral Agents, Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Text mining, Internal medicine, Diabetes Mellitus, medicine, Humans, 030211 gastroenterology & hepatology, business, All cause mortality, ComputingMilieux_MISCELLANEOUS, Follow-Up Studies, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2021

221. Effectiveness of direct‐acting antivirals for chronic hepatitis C treatment in migrant and non‐migrant populations in France

Author

Mélanie Simony, Stanislas Pol, Elisabeth Delarocque-Astagneau, Hélène Fontaine, Fabrice Carrat, Tchadine Djaogol, Maël Baudoin, Fabienne Marcellin, Patrizia Carrieri, Ventzislava Petrov-Sanchez, Marc Bourlière, Camelia Protopopescu, Céline Dorival, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherches fondamentales, cliniques et thérapeutiques sur les hépatites virales [Paris] (ANRS), ANRS France Recherche Nord & sud Sida-hiv hépatites, Hôpital Saint-Joseph [Marseille], Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses (B2PHI), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), The cohort received financial support from INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), the French ANR (Agence Nationale de la Recherche), the French DGS (Direction Générale de la Santé), Merck Sharp and Dohme, Janssen-Cilag, Gilead, Abbvie, Bristol-Myers Squibb and Roche., ANRS CO22 Hepather study group, ANRS-AFEF HEPATHER STUDY GROUP: Delphine Bonnet, Virginie Sicart (CHU Purpan, Toulouse, France), François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard(Hospices Civils de Lyon, Lyon, France), Morane Cavellec, Marjorie Cheraud-Carpentier, François Raffi, Florian Vivrel (Hôpital Hôtel-Dieu, Nantes, France), Jaouad Benhida, Jérôme Boursier, Paul Calès, Françoise Lunel, Frédéric Oberti (CHU Angers, Angers, France), Nathalie Boyer, Audrey Gilibert, Nathalie Giuily (Hôpital Beaujon, Clichy, France), Giovanna Scoazec (Hôpital Beaujon, Clichy, France and Hôpital Henri Mondor, Créteil, France), Sandrine Fernandes, Sylvie Keser, Philippe Sultanik, Anaïs Vallet-Pichard (Hôpital Cochin, Paris, France), Juliette Foucher, Jean-Baptiste Hiriart, Aurore Mathias, Julien Vergniol (Hôpital Haut-Lévêque, Pessac, Bordeaux, France), Chrystelle Ansaldi, Laëtitia Chouquet, Emilie De Luca, Valérie Oules (Hôpital Saint Joseph, Marseille, France), Rodolphe Anty, Eve Gelsi, Régine Truchi (CHU de Nice, Nice, France), Elena Luckina, Nadia Messaoudi, Joseph Moussali, (Groupe Hospitalier Pitié-Salpétrière, Paris, France), Barbara De Dieuleveult, Damien Labarriere, Pascal Poter, Si Nafa Si Ahmed (CHR La Source, Orléans, France), Nathalie Ganne-Carrié, Véronique Grando-Lemaire, Pierre Nahon, Alan Peltier, Judith Ung (Hôpital Jean Verdier, Bondy, France), Mariette Gougeon, Anne Guillygomarch, Caroline Jezequel (CHU Rennes, Rennes, France), Romain Moirand, Thomas F. Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie (Hôpitaux Universitaires de Strasbourg, Strasbourg, France), Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani (CHU de Nancy, Vandoeuvre-lès-Nancy, France), Marie-Albertine Bernard (CHU de Nancy, Vandoeuvre-lès-Nancy, France and Centre Hospitalier Régional, Metz, France), Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Georges-Philippe Pageaux, Marie Pierre Ripault (Hôpital Saint Eloi, Montpellier, France), Karl Barange, Christophe Bureau, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo (CHU Purpan, Toulouse, France), Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Vincent Leroy (CHU de Grenoble, Grenoble, France), Odile Goria, Victorien Grard, Hélène Montialoux (CHU Charles Nicolle, Rouen, France), Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault (Hôpital Henri Mondor, Créteil, France), Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty (Hôpital Saint-Antoine, Paris, France), Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo (Hôpital Paul Brousse, Villejuif, France), Armand Abergel, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti (Hôpital Estaing, Clermont-Ferrand, France), Abdenour Babouri, Virginie Filipe (Centre Hospitalier Régional, Metz, France), Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah (Centre Hospitalier Intercommunal, Créteil, France), Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques (CHU Limoges, Limoges, France), Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet (CHRU Claude Huriez, Lille, France), Marc Bardou, Donya Da Costa Souhiel, Patrick Hillon, Marianne Latournerie (Dijon University Hospital, Dijon, France), Yannick Bacq, Didier Barbereau, Charlotte Nicolas (CHU Trousseau, 37 044 Tours, France), Nisserine Ben Amara, Danièle Botta-Fridlund, Isabelle Portal (CHU Timone, Marseille, France), Moana Gelu-Simeon and Marie-Josée Lafrance (CHU de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe)., Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, [SDV]Life Sciences [q-bio], Hepacivirus, Antiviral Agents, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Central Asia, Chronic hepatitis, Interquartile range, medicine, Humans, Prospective Studies, Poisson regression, Prospective cohort study, Socioeconomic status, direct-acting antivirals, Aged, Transients and Migrants, Hepatology, business.industry, virus diseases, Hepatitis C, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, migrant, Cross-Sectional Studies, vulnerable population, 030220 oncology & carcinogenesis, symbols, Population study, population characteristics, 030211 gastroenterology & hepatology, France, hepatitis C, sustained virological response, business, Social vulnerability, Demography
Abstract

International audience; Despite universal health coverage in France, migrants face specific socioeconomic barriers that increase the likelihood of a suboptimal cascade of care for chronic hepatitis C virus (HCV) infection and impaired treatment effectiveness in this sub-population. We selected data collected from 2012 to 2018 from the ANRS CO22 HEPATHER prospective cohort study for chronic HCV participants with available data on treatment failure (defined as the presence of a detectable HCV-RNA load 12 weeks after their first DAA treatment ended). We performed multivariable Poisson regression models to test whether treatment failure rates differed significantly between HCV-infected migrants and non-migrants receiving DAA in France (cross-sectional analysis), while taking into account the former's world region of birth and other potential social vulnerability factors. Among the study population's 7,879 patients, 5,829 (74%) were non-migrants and 2,050 (26%) migrants. Median [interquartile range] age was 57 [51-65] years, 4433 (56%) were men and 369 (5%) of the entire study population had treatment failure. After multivariable adjustment, only migrants from Central Asia were at higher risk of treatment failure than non-migrants (aIRR = 2.83; 95% CI [1.72, 4.65]). Results from this large-scale study performed in France suggest a higher risk of DAA treatment failure in migrants from Central Asia than in non-migrants and confirm the overall low treatment failure rate in chronic HCV patients treated with DAA (whether migrants or not). Simplified models of care taking into account language and cultural barriers are needed to improve DAA effectiveness in migrants from Central Asia.

Published
2021

222. Intérêt des méthodes alternatives dans l’évaluation du médicament dans les populations particulières

Author

Luu, Vinh-Phuc, Lipides - Nutrition - Cancer [Dijon - U1231] (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, Université Bourgogne Franche-Comté, Marc Bardou, and STAR, ABES

Subjects
Particular populations, Anti-TNFα, Grossesse, Maladies inflammatoires chroniques intestinales, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Populations particulières, Pharmaco-Epidemiology, Pregnancy, Snds, Inflammatory Bowel Diseases, Pharmaco-Épidémiologie, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Well conducted randomized clinical trial is considered gold standard in drug safety and efficacy evaluation. Drug development can be challenging in rare diseases, or in ethically sensitive populations (pregnant women, children, patient with cognitive defect), because of low number of subjects. The low rate of observed events at a sample scale in this population can lead to a biased evaluation of drugs compared to the general population. The aim of this work was to address alternative methods for drug evaluation in particular populations, especially pharmaco-epidemiology on populational database of the SNDS (Système National des Données de Santé). We first evaluate the safety of anti-TNFα in French pregnant women with a diagnosis of Inflammatory Bowel Disease (IBD), and in their children during their first year of life, using the SNDS database. Anti-TNFα use was associated with an increased risk of overall maternal complications during pregnancy, whatever the duration of treatment. There was no increased risk in children up to 1 year of age. In this same cohort, we then studies the security of recommended vaccines during the first year of life in children exposed in utero to antiTNF, and born to mothers with IBD. No adverse event related to tuberculosis or measles was observed. Those results demonstrate the value of alternative methods as useful tools for drug evaluation, and can strengthen the quality of clinical recommendations, in populations where clinical trial cannot be considered., La référence de l’évaluation clinique de l’efficacité et la sécurité du médicament est l’essai thérapeutique randomisé rigoureux sur le plan méthodologique. Le développement du médicament peut être compliqué dans les maladies rares, ou dans les populations éthiquement difficiles à inclure dans les essais cliniques (femme enceinte, enfants, pathologies avec atteinte cognitive), faute d’effectif suffisant. Le manque de puissance ou d’événements observables à l’échelle de l’échantillon entraine un défaut d’évaluation du médicament comparé à la population générale. L’objectif de cette thèse est d’aborder les autres méthodes possibles d’évaluation du médicament dans ces populations particulières, et particulièrement la pharmaco-épidémiologie sur la base populationnelle du Système National des Données de Santé (SNDS). Nous avons d’abord évalué la sécurité des anti-TNFα chez les femmes françaises enceintes atteintes de Maladies Inflammatoires Chroniques Intestinales (MICI), et chez leurs enfants durant la première année de vie à partir des données du SNDS. Les anti-TNFα étaient associés à un risque accru de complications maternelles durant la grossesse, indépendamment de la durée de traitement. Il n’y avait pas de risque infectieux accru chez l’enfant jusqu’à 1 an. Dans cette même cohorte, nous avons ensuite étudié la sécurité des vaccins recommandés durant la première année de vie chez les enfants exposés in utero aux anti-TNFα. Aucun événement indésirable lié au vaccin contre la tuberculose ou la rougeole n’a été détecté chez ces enfants. Ces résultats permettent de démontrer l’intérêt de ces méthodes alternatives comme outil de l’évaluation du médicament, et peuvent participer à l’amélioration des recommandations cliniques de meilleure qualité, dans les populations où l’essai clinique randomisé n’est pas envisageable.

Published
2020

223. Cannabis use is associated with a lower risk of diabetes in chronic hepatitis C-infected patients (ANRS CO22 Hepather cohort)

Author

Barré, Tangui, Nishimwe, Marie Libérée, Protopopescu, Camelia, Marcellin, Fabienne, Carrat, Fabrice, Dorival, Céline, Delarocque-Astagneau, Elisabeth, Larrey, Dominique G., Bourlière, Marc, Petrov-Sanchez, Ventzislava, Simony, Mélanie, Pol, Stanislas, Fontaine, Hélène, Carrieri, Patrizia Maria, Pageaux, Georges Philippe, HAL UVSQ, Équipe, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses (B2PHI), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'hépatologie et de gastroentérologie [Hôpital Saint-Joseph - Marseille], Aix Marseille Université (AMU)-Hôpital Saint-Joseph [Marseille], Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Merck Sharp and Dohme, MSD Agence Nationale de la Recherche, ANR AbbVie Bristol-Myers Squibb, BMS AbbVie Association Française pour l'Etude du Foie, AFEF Roche Gilead Sciences Shionogi Cilag MSD France, FC reports grants from INSERM-ANRS, during the conduct of the study, and personal fees from Imaxio, outside the submitted work. MB reports grants and personal fees from AbbVie and Gilead, outside the submitted work, and personal fees from MSD, Janssen, Boehringher Ingelheim, Intercept, and Bristol-Myers Squibb, outside the submitted work. SP has received consulting and lecturing fees from Bristol-Myers Squibb, Janssen, Gilead, Roche, MSD, MYR-Pharma, Shionogi, Biotest and Abbvie, as well as grants from Bristol-Myers Squibb, Gilead, Roche and MSD. HF reports personal fees and invitations for medical meetings from Gilead, AbbVie, Bristol-Myers Squibb, MSD, and Janssen, outside the submitted work. Other authors declare no financial support. The cohort received financial support from the INSERM-ANRS (France Recherche Nord & Sud Sida-HIV H?patites), the French ANR (Agence Nationale de la Recherche), the French DGS (Direction Générale de la Santé), Merck Sharp and Dohme, Janssen-Cilag, Gilead, Abbvie, Bristol-Myers Squibb, and Roche. Those funding sources had no role in the writing of the manuscript or the decision to submit it for publication. We thank the study participants and the participating clinicians at each site. We also thank the INSERM-ANRS for sponsoring, funding and conducting the ANRS CO22 Hepather cohort in collaboration with the French Association for the Study of the Liver (Association Fran?aise pour l'Etude du Foie: AFEF). Finally, our thanks to Jude Sweeney for the English revision and editing of our manuscript., On behalf of the ANRS/AFEF Hepather study group : Delphine Bonnet, Virginie Sicart (CHU Purpan, Toulouse, France), François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig‐Lavie, Marianne Maynard (Hospices Civils de Lyon, Lyon, France), Morane Cavellec, Marjorie Cheraud‐Carpentier, François Raffi, Florian Vivrel (Hôpital Hôtel‐Dieu, Nantes, France), Jaouad Benhida, Jérôme Boursier, Paul Calès, Françoise Lunel, Frédéric Oberti (CHU Angers, Angers, France), Nathalie Boyer, Audrey Gilibert, Nathalie Giuily (Hôpital Beaujon, Clichy, France), Giovanna Scoazec (Hôpital Beaujon, Clichy, France and Hôpital Henri Mondor, Créteil, France), Sandrine Fernandes, Sylvie Keser, Philippe Sultanik, Anaïs Vallet‐Pichard (Hôpital Cochin, Paris, France), Juliette Foucher, Jean‐Baptiste Hiriart, Aurore Mathias, Julien Vergniol (Hôpital Haut‐Lévêque, Pessac, Bordeaux, France), Chrystelle Ansaldi, Laëtitia Chouquet, Emilie De Luca, Valérie Oules (Hôpital Saint Joseph, Marseille, France), Rodolphe Anty, Eve Gelsi, Régine Truchi (CHU de Nice, Nice, France), Elena Luckina, Nadia Messaoudi, Joseph Moussali, (Groupe Hospitalier Pitié‐Salpétrière, Paris, France), Barbara De Dieuleveult, Damien Labarriere, Pascal Poter, Si Nafa Si Ahmed (CHR La Source, Orléans, France), Nathalie Ganne‐Carrié, Véronique Grando‐Lemaire, Pierre Nahon, Alan Peltier, Judith Ung (Hôpital Jean Verdier, Bondy, France), Mariette Gougeon, Anne Guillygomarch, Caroline Jezequel (CHU Rennes, Rennes, France), Romain Moirand, Thomas F. Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo‐Noumbissie (Hôpitaux Universitaires de Strasbourg, Strasbourg, France), Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani‐Nani (CHU de Nancy, Vandoeuvre‐lès‐Nancy, France), Marie‐Albertine Bernard (CHU de Nancy, Vandoeuvre‐lès‐Nancy, France and Centre Hospitalier Régional, Metz, France), Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Georges‐Philippe Pageaux, Marie Pierre Ripault (Hôpital Saint Eloi, Montpellier, France), Karl Barange, Christophe Bureau, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo (CHU Purpan, Toulouse, France), Marine Faure, Bruno Froissart, Marie‐Noelle Hilleret, Vincent Leroy (CHU de Grenoble, Grenoble, France), Odile Goria, Victorien Grard, Hélène Montialoux (CHU Charles Nicolle, Rouen, France), Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault (Hôpital Henri Mondor, Créteil, France), Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty (Hôpital Saint‐Antoine, Paris, France), Teresa Antonini, Audrey Coilly, Jean‐Charles Duclos Vallée, Mariagrazia Tateo (Hôpital Paul Brousse, Villejuif, France), Armand Abergel, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti (Hôpital Estaing, Clermont‐Ferrand, France), Abdenour Babouri, Virginie Filipe (Centre Hospitalier Régional, Metz, France), Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah (Centre Hospitalier Intercommunal, Créteil, France), Paul Carrier, Maryline Debette‐Gratien, Jérémie Jacques (CHU Limoges, Limoges, France), Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet (CHRU Claude Huriez, Lille, France), Marc Bardou, Donya Da Costa Souhiel, Patrick Hillon, Marianne Latournerie (Dijon University Hospital, Dijon, France), Yannick Bacq, Didier Barbereau, Charlotte Nicolas (CHU Trousseau, 37044 Tours, France), Nisserine Ben Amara, Danièle Botta‐Fridlund, Isabelle Portal (CHU Timone, Marseille, France), Moana Gelu‐Simeon, Marie‐Josée Lafrance (CHU de Pointe‐à‐Pitre, Pointe‐à‐Pitre, Guadeloupe)., Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Eloi, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], 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), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Liver Cirrhosis, cannabis, medicine.medical_specialty, Population, HIV Infections, 030209 endocrinology & metabolism, marijuana smoking, Lower risk, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Diabetes mellitus, Internal medicine, medicine, Humans, Risk factor, education, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, education.field_of_study, Hepatology, biology, business.industry, 1. No poverty, Hepatitis C, Hepatitis C, Chronic, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, biology.organism_classification, 3. Good health, chronic, Cross-Sectional Studies, Infectious Diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort, diabetes mellitus, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030211 gastroenterology & hepatology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cannabis, France, business
Abstract

International audience; Chronic hepatitis C virus (HCV) infection is a risk factor of insulin resistance, and HCV-infected patients are at a high risk of developing diabetes. In the general population, research has shown the potential benefit of cannabis use for the prevention of diabetes and related metabolic disorders. We aimed to test whether cannabis use is associated with a lower risk of diabetes in chronic HCV-infected patients. Chronic HCV-infected patients (n = 10 445) were selected from the French national, multicenter, observational ANRS CO22 Hepather cohort. Cross-sectional data collected at cohort enrollment were used to assess the association between patients’ clinical and behavioural characteristics and the risk of diabetes. Logistic regression model was performed with cannabis use as the main independent variable and a significance level set at 5%. A similar model stratified by the presence of advanced liver fibrosis (FIB-4 > 3.25) was also run. After multivariable adjustment, current (AOR [95%CI]: 0.49 [0.38-0.63]) and former (0.81 [0.67-0.98], P

Published
2020

224. Simulation in patient education : Recommendations of the conditions of use and skills referred to

Author

Penneçot, Christelle, STAR, ABES, Laboratoire Educations et Pratiques de Santé (LEPS), Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté, Marc Bardou, and Claire Marchand

Subjects
Patient education as topic, Simulation en santé, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Patient, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Outil pedagogique en santé, Health teaching tool, Education therapeutique du patient, Health simualtion, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Maladie chronique, Chronic disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Abstract :Introduction: Research in TPE shows that it can still benefit from developing the full range of patient skills through the use of interactive teaching methods. Simulation is rarely used to help individuals with chronic diseases to develop these skills. The objective of the thesis work was to promote the use of simulation in patient therapeutic education by: (i) conducting a consensus conference on the subject and (ii) conducting a pilot study of S-ETP.(S-TPE).Methods: Expert consensus was achieved with the participation of expert patients and caregivers; health professionals specialized in TPE; and simulation experts. Each recommendation was subject to an extensive literature review. The quality of the evidence and the strength of the recommendations were assessed through the evaluation, development and evaluation criteria categories [GRADE criteria].The pilot study is being conducted on a sample of 24 diabetic patients in order to test its feasibility.Results: At the end of the consensus, the experts identified 26 recommendations specific to the use of S-TPE. They proposed examples of skills in different diseases and stressed the importance of adapting the conditions of use (location, equipment, time of the care) to the circumstances of the patient learner and skills to be developed. Experts should exercise great caution as this technique presents ethical requirements.Conclusion: These recommendations underline the fact that simulation could bring added value to TPE. They provide the first framework of the use of simulation in TPE. Research on the feasibility and acceptability of using this method with patients was based on expert consensus. This step was necessary before assessing efficiency and establishing a taxonomy of the S-TPE., Résumé :Introduction: Les recherches sur l’Education Thérapeutique du Patient (ETP) montrent qu’elle peut encore gagner à développer l’ensemble des compétences des patients en utilisant des méthodes pédagogiques interactives. La simulation est rarement utilisée pour aider les personnes atteintes de maladies chroniques à développer ces compétences. L’objectif du travail de thèse était de promouvoir l'utilisation de la simulation dans l'éducation thérapeutique des patients (S-ETP) par : i) la réalisation d’une conférence de consensus sur le sujet et ii) la réalisation d’une étude pilote de la S-ETP.Méthode: Un consensus d'experts a été obtenu avec la participation des patients et des proches aidants experts; des professionnels de la santé spécialisés experts en (ETP) et des experts en simulation. Chaque recommandation a été soumise à un examen exhaustif de la littérature. La qualité des éléments de preuve et la solidité des recommandations ont été évaluées au moyen de critères d'évaluation [GRADE]. L’étude pilote est réalisée sur un échantillon de 24 patients diabètiques dans le but de tester sa faisabilité.Résultats: A la fin du consensus, les experts ont identifié 26 recommandations spécifiques à l'utilisation de la S-ETP. Ils ont proposé des exemples de compétences dans différentes maladies et ont insisté sur l'importance d'adapter les conditions d'utilisation (emplacement, équipement, temps des soins) aux circonstances de l'apprenant et des compétences du patient à développer. Les experts doivent faire preuve d'une grande prudence car cette technique présente des conditions éthiques. L’essai de faisabilité a permis d’étudier la faisabilité de la S-ETP auprés des patients et des soignants.Conclusion: Ces recommandations soulignent le fait que la simulation pourrait apporter une valeur ajoutée en ETP. Elles fournissent le premier cadre pour l'utilisation de la simulation en ETP. La recherche sur la faisabilité et l'acceptabilité de l’utilisation de cette méthode auprès des patients, s’est basé sur le consensus d’expert. Cette étape était nécessaire avant d’évaluer l’efficience et d’établir une taxonomie de la S-ETP.

Published
2019

225. Sensibilisation aux drogues chimiothérapeutiques des tumeurs P53 négatives par activation de la phosphatase Wip1

Author

Clausse, Victor, STAR, ABES, Lipides - Nutrition - Cancer [Dijon - U1231] (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, Université Bourgogne Franche-Comté, Marc Bardou, and Carmen Garrido

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, P53, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, WIP1, Chemotherapy, WEE1, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Chimiothérapie, Cancer
Abstract

P53 is mutated in more than half of human cancers and when inactivated is often associated with a resistance to anti-cancer therapy. Our team has hown that in the case of p53-negative tumors, overexpression of Wip1 phosphatase sensitizes tumor cells to chemotherapy, while protecting normal tissues from the side effects of the treatment. To improve this strategy, two main objectives were studied. Firstly, to find a protein which can interact with Wip1 pathway and potentiate its action in this therapeutic strategy. Secondly, to find a molecule which can activate Wip1. We realized a siRNA screening of the whole human kinome to identify several kinases, whose inhibition could potentiate anti-tumoral action of Wip1. We have shown that Wee1 and Hipk2, which both have available inhibitors, have an action on Wip1 pathway. Inhibiting Wee1 with a low dose of MK-1775, a specific inhibitor of this kinase, allowed us to decrease effective cisplatin concentration, inducing a caspase-3-dependent apoptosis. Moreover, the combination of MK-1775 with Wip1 overexpression does not impair the protective effect that this phosphatase provides towards normal tissues. We then showed that the Vorinostat, an HDAC inhibitor, induces an increase in Wip1 transcription in breast cancer cells with inactive p53. This work uncovered a way to potentiate the Wip1-based therapeutic strategy of p53-negative tumors., P53 est mutée dans plus de la moitié des cancers humains et son inactivation est souvent associée à une résistance à la thérapie anti-cancer. Notre équipe a montré que dans le cas de tumeurs où p53 est inactive, la surexpression de la phosphatase Wip1 permettait la restauration de l’efficacité de la chimiothérapie, et une protection des tissus sains face aux effets secondaires du traitement. Afin d’améliorer cette stratégie, deux objectifs principaux ont été étudiés : trouver une protéine qui peut interagir avec la voie de signalisation de Wip1 et potentialiser son action dans cette stratégie thérapeutique, et trouver des molécules chimiques pouvant activer Wip1. Nous avons réalisé un criblage d’interférence à ARN de l’intégralité du kinome humain afin d’identifier plusieurs kinases, dont l’inhibition potentialise l’action anti-tumorale de Wip1. Cela a ainsi mis en évidence l’action de Wee1 et Hipk2, dont des inhibiteurs existent, sur la voie de signalisation de Wip1. Inhiber Wee1 avec une faible dose de MK-1775, un inhibiteur spécifique de cette kinase, a permis de réduire la concentration efficace de cisplatine, en entraînant une apoptose caspase-3-dépendante. De plus, combiner MK-1775 avec la surexpression de Wip1 n’a pas d’impact sur l’effet protecteur de cette phosphatase envers les tissus sains. Nous avons ensuite montré que le Vorinostat, un inhibiteur des histone-déacétylases, permettait une augmentation de la transcription de Wip1 dans des cellules de cancer du sein mutées pour p53. Ce travail de thèse a permis de mettre en évidence un moyen de potentialiser la stratégie de traitement des tumeurs p53-négatives basée sur la phosphatase Wip1.

Published
2017

226. Obésité et grossesse : étude de l'influence d'un marqueur de l'obésité sur les mécanismes cellulaires et tissulaires de l'accouchement dans un modèle d'explants myométriaux humains

Author

Wendremaire, Maeva, Lipides - Nutrition - Cancer (U866) (LNC), 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, Université de Bourgogne, Marc Bardou, Françoise Goirand, 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 ), STAR, ABES, and 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)

Subjects
Leptin, Myomètre, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Remodelage de la matrice extracellulaire, Apoptose, Apoptosis, Grossesse, Pregnancy, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Extracellular matrix remodelling, Human myometrium, [ SDV.SA ] Life Sciences [q-bio]/Agricultural sciences, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Leptine
Abstract

Maternal obesity is associated with a wide spectrum of delivery disorders, such as delayed or post-term delivery, that might be explained partly by the increase in plasma leptin levels in obese women, as leptin inhibits in vitro myometrial contractility. Delivery involves uterine apoptosis and remodelling of the extracellular matrix, via the activation of matrix metalloproteinases (MMP). This study was aimed to assess the role of leptin on human myometrium, by studying the interaction of leptin with lipopolysaccharide (LPS)-induced apoptosis and degradation of myometrial collagen.Myometrial biopsies were obtained from women undergoing caesarean delivery before labour onset. The effects of leptin on myometrial apoptosis and remodelling were assessed by incubating the strips for 48h with LPS (10 µg/ml) alone or with leptin (from 10-10 to 10-8 M).Leptin prevented LPS-induced apoptosis, in a concentration-dependent manner, by down-regulating cleaved caspase-3, BAX and up-regulating BCL2 expression. This effect was specifically mediated through leptin receptors stimulation followed by ERK1/2 signalling pathway activation. Leptin prevented, in a concentration-dependent manner, an LPS-induced decrease in myometrial collagen content, and this effect was associated with a decrease in MMP2 and MMP9 activity and overexpression. These effects of leptin were abolished by pre-treatment with a selective leptin receptor antagonist. These results suggest new potential pathways involved in delivery disorders of obese women and propose a role for leptin-induced inhibition of myometrial apoptosis and extracellular matrix remodelling in the development of such disorders., L’obésité maternelle, dont la prévalence ne cesse d’augmenter, est associée à de nombreux troubles de l’accouchement, tels que des dépassements de terme à l’origine d’une augmentation du taux de césariennes. Ces troubles pourraient, en partie, s’expliquer par une concentration plasmatique de leptine plus élevée chez les femmes enceintes obèses ainsi que par les effets inhibiteurs, démontrés in vitro, de cette adipokine sur la contractilité myométriale. Au moment de l’accouchement, la transition phénotypique du myomètre d’un état de quiescence utérine à un état contractile est une étape clé indispensable à la mise en route du travail. Elle est associée à une activation de l’apoptose des cellules myométriales ainsi qu’à un remodelage de la matrice extracellulaire utérine. Le but de notre travail était d’étudier la capacité de la leptine à moduler l’apoptose et le remodelage myométriaux induits par le lipopolysaccharide (LPS).Les échantillons de myomètre ont été prélevés lors de césariennes réalisées avant la mise en route du travail, à la maternité du CHU de Dijon. Les effets de la leptine ont été évalués après incubation des explants myométriaux pendant 48 heures avec du LPS (10 µg/ml) avec ou sans leptine (de 10-10 à 10-8 M).Nos résultats ont démontré la capacité de la leptine à inhiber, de façon concentration-dépendante, l’apoptose induite par le LPS en diminuant l’expression des protéines pro-apoptotiques (caspase-3 clivée, BAX) et en augmentant celle du médiateur anti-apoptotique BCL2. Cet effet anti-apoptotique de la leptine dans le myomètre gestant était associé à l’activation de la voie de signalisation ERK1/2. De plus, nos résultats ont montré que la leptine était également capable de s’opposer, de façon concentration-dépendante, à la dégradation du collagène de la matrice extracellulaire myométriale induite par le LPS. Cet effet était associé à l’inhibition de l’activation et de la surexpression des métalloprotéinases MMP2 et MMP9 induites par le LPS.Ce travail a permis d’approfondir les connaissances sur le rôle de la leptine dans la régulation de l'activité du myomètre. Nos résultats suggèrent que les troubles de l’accouchement observés chez les femmes obèses résulteraient de l’inhibition de l’apoptose et du remodelage myométriaux par la leptine, en plus de l’inhibition de la contractilité utérine déjà décrite.

Published
2012

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