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Anti-hepatitis C virus potency of a new autophagy inhibitor using human liver slices model

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World Journal of Hepatology 2016年第21期8卷 902-914页

作者： Sylvie Lagaye Sonia Brun Jesintha Gaston Hong Shen Ruzena Stranska Claire Camus Clarisse Dubray Géraldine Rousseau Pierre-Philippe Massault Jerome Courcambeck Firas Bassisi Philippe Halfon Stanislas Pol institut Pasteur INSERM institut cochin INSERM U1016CNRS UMR8104Universite Paris Descartes(UMR S1016) Genoscience Pharma KU Leuven Rega Institute Laboratoire Alphabio APHP Groupe Hospitalier La Pitie Salpe-triereService de Chirurgie digestive et Hepato bilio pancreatique APHP Groupe Hospitalier CochinService de Chirurgie digestiveHepato-biliaire et Endocrinienne Universite Paris Descartes APHP Groupe Hospitalier CochinUnite d’Hepatologie institut Pasteur Departement de Recherche TranslationnelleINSERM

AIM: To evaluate the antiviral potency of a new antihepatitis C virus(HCV) antiviral agent targeting the cellular autophagy machinery. METHODS: Non-infected liver slices, obtained from human liver resection and cut in 350 μm-thick slices(2.7 × 106 cells per slice) were infected with cell culture-grown HCV Con1b/C3 supernatant(multiplicity of infection = 0.1) cultivated for up to ten days. HCV infected slices were treated at day 4 post-infection with GNS-396 for 6 d at different concentrations. HCV replication was evaluated by strand-specific real-time quantitative reverse transcription- polymerase chain reaction. The infectivity titers of supernatants were evaluated by foci formation upon inoculation into naive Huh-7.5.1 cells. The cytotoxic effect of the drugs was evaluated by lactate dehydrogenase leakage assays. RESULTS: The antiviral efficacy of a new antiviral drug, GNS-396, an autophagy inhibitor, on HCV infection of adult human liver slices was evidenced in a dosedependent manner. At day 6 post-treatment, GNS-396 EC50 was 158 nmol/L without cytotoxic effect(compared to hydroxychloroquine EC50 = 1.17 μmol/L).CONCLUSION: Our results demonstrated that our ex vivo model is efficient for evaluation the potency of autophagy inhibitors, in particular a new quinoline derivative GNS-396 as antiviral could inhibit HCV infection in a dosedependent manner without cytotoxic effect.

关键词： Host antiviral therapy Hepatitis C virus Tissue culture Autophagy Quinoline derivative

MicroRNA-feedback loop as a key modulator of liver tumorigenesis and inflammation

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World Journal of Gastroenterology 2013年第4期19卷 440-444页

作者： Angélique Gougelet Sabine Colnot institut cochin INSERM U1016 75014 Paris France Centre National de la Recherche Scientifique UMR8104 75014 Paris France Université Paris Des- cartes Sorbonne Paris Cité 75013 Paris France

A recent work of Iliopoulos et al published in Cell highlighted a circuit orchestrated by microRNAs (miRNAs) that results in liver tumorigenesis and inflammation. This feedback loop, governed by miR-24 and miR-629, promotes a hepatocyte nuclear factor-4α transient inhibition resulting in miR-124 induction and signal transducer and activator of transcription 3 activation. These promising data support the use of miRNA mimics or inhibitors as potent therapeutic approaches in liver cancer.

关键词： Hepatocyte nuclear factor-4α MicroRNA Interleukin-6 Signal transducer and activator of transcription 3 Hepatocellular oncogenesis

Helical tomotherapy and systemic targeted therapies in solitary plasmacytoma: Pilot study

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World Journal of Radiology 2013年第6期5卷 248-252页

作者： Nadia Wiazzane Cyrus Chargari Corine Plancher Jerome Tamburini Bernard Asselain Alain Fourquet Didier Bouscary Youlia M Kirova Department of Radiation Oncology Institut Curie75005 Paris France Department of Biostatistics Institut Curie75005 Paris France Department of Haematology Cochin Hospital75014 Paris France

AIM: To assess the feasibility of the combination of helical tomotherapy(HT) and a concurrent systemic targeted therapy in patients with solitary plasmacytoma (SP) with the aim to decrease toxicity while improving therapeutic efficacy. METHODS: Six patients with biologically, histologically, and radiologically confirmed SP were treated using HT and a systemic targeted treatment concomitantly. Total dose was 40 Gy/20 fractions. Four patients received 4 cycles of concurrent lenalidomide-dexamethasone combination and two patients were treated with concomitant bortezomib-dexamethasone. All toxicities were described using the Common Terminology Criteria for Adverse Effects ***: Five patients had a bone tumor and one patient had an isolated pancreatic mass. Five patients presented with pain, one had neurologic symptoms related to medullary compression, which was treated by an emergency surgery. Median age was 59.5 years (range, 50-74 years). All patients had initial positron emission tomography-computed tomographys, three patients had total body bone magnetic resonance imaging examination, and three patients had computed tomodensitometry scans. The toxicity profile was excellent with no higher than grade 1 toxicity. Four of the six patients experienced a partial radiological response, four had complete response on positions emission tomography and 5/6 patients experienced a complete relief of their symptoms 4 mo after treatment. At a median follow-up of 18 mo, 5/6 patients were controlled clinically, radiologically, and biologically. CONCLUSION: Using HT, we could deliver a highly conformal irradiation concurrently with a molecularly targeted therapy. This association yielded in a high response rate and a low toxicity. A prospective study with longer follow-up will help determining the true benefit of such strategy.

关键词： Plasmacytoma Radiation therapy Targeted treatment Tolerance Lenalidomide Bortezomib

Comprehensive review of telbivudine in pregnant women with chronic hepatitis B

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World Journal of Hepatology 2016年第9期8卷 452-460页

作者： Teerha Piratvisuth Guo Rong Han Stanislas Pol Yuhong Dong Aldo Trylesinski Department of Medicine NKC Institute of Gastroenterology and Hepatology Prince of Songkla University Department of Gynecology and Obstetrics the Second Affiliated Hospital of the Southeast University Département d’Hépatologie Inserm USM20 Institut Pasteur AP-HP hopital Cochin Université Paris Descartes Novartis Pharma AG

AIM:To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during ***:A pooled analysis of data from a literature search reported 1739 pregnancy outcomes(1673 live births)from 1725 non-overlapping pregnant women treated with *** prevalence of live birth defects(3.6/1000)was similar to that of the nonantiviral controls(3.0/1000)and not increased as compared with overall prevalence(14.5 to 60/1000).No target organ toxicity was *** prevalence of spontaneous abortion in pregnant women treated with telbivudine(4.2/1000)was not increased compared with the overall prevalence(16/1000).The mother-to-child transmission rate was significantly reduced in pregnant women treated with telbivudine(0.70%)compared to those treated with the non-antiviral controls(11.9%;P<0.0001)or compared to the historical rates of hepatitis B virus(HBV)-infected population without antiviral treatment(10%-15%).RESULTS:Cumulatively 489 pregnancy cases have been reported in the telbivudine pharmacovigilance database(with a cut-off date 31 August 2014),of those,308 had known pregnancy outcomes with 249 cases of live births(239 cases of live birth without congenital anomaly and 10 cases of live birth with congenital anomaly).In the latest antiretroviral pregnancy registry report(1 January 1989 through 31 January 2015)of27 patients exposed to telbivudine during pregnancy(18,6 and 3 during first,second and third trimester,respectively)19 live births were reported and there were no cases of birth defects ***:Telbivudine treatment during pregnancy presents a favorable safety profile without increased rates of live birth defects,spontaneous abortion or elective termination,or fetal/neonatal *** to telbivudine in the first,second and third trimester of pregnancy has been shown to significantly reduce the risk of HBV transmission from mother to child on the basis of standard immune prophylaxis procedure.

关键词： Telbivudine Hepatitis B virus Pregnancy Mother-to-child transmission Vertical transmission

Multiparametric characterization of red blood cell physiology after hypotonic dialysis based drug encapsulation process

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Acta Pharmaceutica Sinica B 2022年第4期12卷 2089-2102页

作者： Mélanie Robert Bastien Laperrousaz Diana Piedrahita Emilie-Fleur Gautier Travis Nemkov Florian Dupuy Elie Nader Virginie Salnot Patrick Mayeux Angelo D’Alessandro Catherine Lavazec Philippe Joly Alexander Scheer Philippe Connes Agnès Cibiel Erytech Pharma Lyon 69008France Laboratoire interuniversitaire de Biologie de la Motricité(LIBM)EA7424 Team«Vascular Biology and Red Blood Cell»Universite´Claude Bernard Lyon 1Universite´de LyonLyon 69008France Labex GR-Ex Paris 75015France 3P5 proteom’IC facility Universitéde ParisInstitut CochinINSERMCNRSParis 75014France University of Colorado Anschutz Medical CampusAuroraCO 80045USA Omix Technologies Inc.AuroraCO 80045USA Inserm U1016 CNRS 8104Universitéde ParisInstitut CochinParis 75014France Laboratoire de Biochimie et de Biologie Moléculaire UF de biochimie des pathologies e´rythrocytairesCentre de Biologie et de Pathologie EstHospices Civils de LyonBron 69500France

Red blood cells(RBCs)can act as carriers for therapeutic agents and can substantially improve the safety,pharmacokinetics,and pharmacodynamics of many *** RBCs integrity and lifespan is important for the efficacy of RBCs as drug *** investigated the impact of drug encapsulation by hypotonic dialysis on RBCs physiology and *** parameters were compared between processed RBCs loaded with l-asparaginase(“eryaspase”),processed RBCs without drug and non-processed *** RBCs were less hydrated and displayed a reduction of intracellular *** observed a change in the metabolomic but not in the proteomic profile of processed *** process caused moderate morphological changes and was accompanied by an increase of RBCs-derived Extracellular Vesicles *** a decrease in deformability,processed RBCs were not mechanically retained in a spleen-mimicking device and had increased surface-to-volume ratio and osmotic *** RBCs half-life was not significantly affected in a mouse model and our previous phase 1 clinical study showed that encapsulation of asparaginase in RBCs prolonged its in vivo half-life compared to free *** study demonstrated that encapsulation by hypotonic dialysis may affect certain characteristics of RBCs but does not significantly affect the in vivo longevity of RBCs or their drug carrier function.

关键词： Red blood cells Drug carrier Hypotonic dialysis L-Asparaginase Omics Rheology Morphology Senescence markers

Mitochondrial dysfunction activates the AMPK signaling and autophagy to promote cell survival

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Genes & Diseases 2016年第1期3卷 82-87页

作者： Baozhong Zhao Lei Qiang Joy Joseph Balaraman Kalyanaraman Benoit Viollet Yu-Ying He Department of Medicine Section of DermatologyUniversity of ChicagoChicagoILUSA Free Radical Research Center Medical College of WisconsinMilwaukeeWIUSA INSERM U567 CNRS UMR8104Department of EndocrinologyMetabolism and CancerInstitut CochinUniversite´Paris 575014 ParisFrance

Autophagy is a cellular self-eating process essential for stress response and maintainingtissue homeostasis by lysosomal degradation of unwanted or damaged proteins and ***, we show that cells with defective mitochondria induce autophagy to promotecell survival through activating the AMPK pathway. Loss of mitochondrial complex III proteincytochrome b activates the AMPK signaling and induced autophagy. Inhibiting mitochondria energeticsby mitochondria-targeted agents activates the AMPK signaling and induced *** inhibition of AMPK inhibits autophagy induction in cells with defective mitochondria,while genetic inhibition of autophagy has no effect on AMPK activation. Mitochondria dysfunctionhas no effect of DNA repair of UV-induced DNA damage. However, mitochondria dysfunctionsensitizes cells to apoptosis induced by UV radiation. Genetic inhibition of autophagy orAMPK sensitized cells to apoptosis in cells with defective mitochondria. Our results demonstratethat AMPK and autophagy senses mitochondria dysfunction and serves as a mechanismfor survival. Our findings may provide new insights into the interplay between mitochondriafunction and autophagy process in maintaining tissue homeostasis, and suggest that this interactionmay play important roles in diseases such as cancer and neurodegeneration.

关键词： AMPK Apoptosis Autophagy DNA repair Mitochondria Ultraviolet radiation UV

Genome-wide differences in hepatitis C-vs alcoholism-associated hepatocellular carcinoma

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World Journal of Gastroenterology 2008年第11期14卷 1749-1758页

作者： Céline Derambure Cédric Coulouarn Frédérique Caillot Romain Daveau Martine Hiron Michel Scotte Arnaud Franois Celia Duclos Odile Goria Marie Gueudin Catherine Cavard Benoit Terris Maryvonne Daveau Jean-Philippe Salier Inserm Unité519 and institut Fédératif de Recherches Multidisciplinaires sur les Peptides Facultéde Médecine-PharmacieRouenFrance Inserm Unité519 and institut Fédératif de Recherches Multidisciplinaires sur les Peptides Facultéde Médecine-PharmacieRouenFrance Service de Chirurgie Générale et DigestiveCentre Hospitalier UniversitaireRouenFrance Département de Pathologie Centre Hospitalier UniversitaireRouenFrance Inserm Unité519 and institut Fédératif de Recherches Multidisciplinaires sur les Peptides Facultéde Médecine-PharmacieRouenFrance Service d'Hépato-gastro-enterologieCentre Hospitalier UniversitaireRouenFrance Laboratoire de Virologie and UPRES EA 2646 Centre Hospitalier UniversitaireRouenFrance Inserm Unité567 CNRS UMR 8104 UniversitéParis 5Département GDPMInstitut CochinParis France

AIM:To look at a comprehensive picture of etiology- dependent gene abnormalities in hepatocellular carcinoma in Western Europe. METHODS:With a liver-oriented microarray,transcript levels were compared in nodules and cirrhosis from a training set of patients with hepatocellular carcinoma (alcoholism,12;hepatitis C,10)and 5 *** or tight selection of informative transcripts with an abnormal abundance was statistically valid and the tightly selected transcripts were next quantified by qRTPCR in the nodules from our training set(12+10) and a test set(6+7). RESULTS:A selection of 475 transcripts pointed to significant gene over-representation on chromosome 8 (alcoholism)or-2(hepatitis C)and ontology indicated a predominant inflammatory response(alcoholism)or changes in cell cycle regulation,transcription factors and interferon responsiveness(hepatitis C).A stringent selection of 23 transcripts whose differences betweenetiologies were significant in nodules but not in cirrhotic tissue indicated that the above dysregulations take place in tumor but not in the surrounding *** 23 transcripts separated our test set according to etiologies. The inflammation-associated transcripts pointed to limited alterations of free iron metabolism in alcoholic vs hepatitis C tumors. CONCLUSION:Etiology-specific abnormalities(chromo- some preference;differences in transcriptomes and related functions)have been identified in hepatocellular carcinoma driven by alcoholism or hepatitis *** may open novel avenues for differential therapies in this disease.

关键词： Alcoholism Chromosome Cirrhosis Hepatitis C Transcriptomes Protein function

Liver insulin-like growth factor 2 methylation in hepatitis C virus cirrhosis and further occurrence of hepatocellular carcinoma

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World Journal of Gastroenterology 2008年第35期14卷 5419-5427页

作者： Philippe Couvert Alain Carrié Jacques Pariès Jenny Vaysse Audrey Miroglio Antoine Kerjean Pierre Nahon Jamel Chelly Jean-Claude Trinchet Michel Beaugrand Nathalie Ganne-Carrié INSERM U551 Dyslipopro-teinemia and Atherosclerosis Research UnitParis F-75013France Université Paris6 UMR S551Paris F-75013France AP-HP Groupe hospitalier Pitié SalpétrièreService de Biochimie endocrinienne et OncologiqueParis F-75013France Department of Public health Jean Verdier HospitalAP-HPBondy 93140France Department of Biochemistry Jean Verdier HospitalAP-HPBondy 93140France cochin institut-INSERM-CNRS-University Paris 5-CHU cochin Paris 75014France Department of Hepato-Gastroenterology Jean Verdier HospitalAP-HPBondy 93140France UPRES EA3409 University Paris 13Paris F-75651France

AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied. After DNA extraction from liver samples and bisulfite treatment, unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus. The predictive value of the Igf2 methylation profile for HCC wasassessed by Kaplan-Meier and Cox methods. RESULTS: Among 94 included patients, 20 developed an HCC during follow-up (6.9 ± 3.2 years). The methylation profile was hypomethylated, intermediate and hypermethylated in 13, 64 and 17 cases, respectively. In univariate analysis, two baseline parameters were associated with the occurrence of HCC: age (P = 0.01) and prothrombin (P = 0.04). The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank, P = 0.043; Breslow, P = 0.037; Tarone-Ware, P = 0.039). CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.

关键词： Liver cancer Cirrhosis Insulin-growth factor 2, DNA methylation

Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

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World Journal of Gastroenterology 2022年第13期28卷 1288-1303页

作者： Thomas Lambin Cyril Lafon Robert Andrew Drainville Mathieu Pioche Frédéric Prat LabTAU INSERMCentre Léon BérardUniversitéLyon 1Univ LyonLyon 69003France Department of Gastroenterology Hospices Civils de LyonEdouard Herriot HospitalLyon 69008France Service d’Endoscopie Digestive Hôpital BeaujonAssistance Publique-Hôpitaux de ParisClichy 92110France INSERM U1016 Institut CochinUniversitéde ParisParis 75014France

Pancreatic ductal adenocarcinoma(PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment(TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients’ quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy-most commonly using a local high single dose-are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.

关键词： Pancreatic ductal adenocarcinoma Tumoral microenvironment Stroma Hyperthermia Radiation therapy High-intensity focused ultrasound