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08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
08 rencontres biomédicale LIR Richard Moreau
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08 rencontres biomédicale LIR Richard Moreau

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2ND INTERNATIONAL RESEARCH MEETING …

2ND INTERNATIONAL RESEARCH MEETING
4 JUNE 2010- HÔTEL DE MARIGNY PARIS

Published in: Health & Medicine, Business
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  • Slide 76 NAFLD: Spectrum of Hepatic Pathology The next several slides illustrate the histopathology of NAFLD. As mentioned earlier, nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology that ranges from fatty liver (steatosis) on the most clinically-benign end of the spectrum to cirrhosis on the opposite extreme where most liver-related morbidity and mortality occur. Nonalcoholic steatohepatitis (NASH) is an intermediate form of liver damage that sometimes progresses to cirrhosis. Some individuals who become cirrhotic from NAFLD develop hepatocellular carcinoma. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:3-20.
  • Slide 76 NAFLD: Spectrum of Hepatic Pathology The next several slides illustrate the histopathology of NAFLD. As mentioned earlier, nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology that ranges from fatty liver (steatosis) on the most clinically-benign end of the spectrum to cirrhosis on the opposite extreme where most liver-related morbidity and mortality occur. Nonalcoholic steatohepatitis (NASH) is an intermediate form of liver damage that sometimes progresses to cirrhosis. Some individuals who become cirrhotic from NAFLD develop hepatocellular carcinoma. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:3-20.
  • On the right Residues 186–192 (shown in pink stick presentation) of the D2 domain of gp130 that are deleted in IHCAs are intimately involved in interactions with IL-6, as shown in the crystal structure of the IL-6R–IL-6–gp130 complex (PDB: 1P9M)7. IHCA deletions 173–177 and 215 (labelled in red) are also predicted to disrupt the IL-6–gp130 interface. The numbering of residues corresponds to the IL6ST complementary DNA, which has 22 additional amino-terminal residues compared with the polypeptide chain due to the peptide signal.
  • On the right Residues 186–192 (shown in pink stick presentation) of the D2 domain of gp130 that are deleted in IHCAs are intimately involved in interactions with IL-6, as shown in the crystal structure of the IL-6R–IL-6–gp130 complex (PDB: 1P9M)7. IHCA deletions 173–177 and 215 (labelled in red) are also predicted to disrupt the IL-6–gp130 interface. The numbering of residues corresponds to the IL6ST complementary DNA, which has 22 additional amino-terminal residues compared with the polypeptide chain due to the peptide signal.
  • Transcript

    • 1. <ul><li>Obesity, Inflammation and Liver Cancer Richard Moreau, M.D., 1 INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, 2 Université Denis Diderot Paris 7, 3 Service d’Hépatologie, Hôpital Beaujon, Clichy/Paris, France [email_address] </li></ul>
    • 2. Steatosis Steato-hepatitis (NASH) Cirrhosis HUMANS Obesity Causes Non-Alcoholic Fatty Liver Disease (NAFLD) Spectrum of Hepatic Pathology Hepatocellular carcinoma
    • 3. Cirrhosis MICE Obesity Promotes Liver Inflammation and Cancer by Enhancing Pro-Inflammatory Cytokines Inflammation
    • 4. Human NAFLD: Where Are We? <ul><li>Genes associated with progression to cancer: </li></ul><ul><li>Unknown </li></ul><ul><li>Role of meta-genome: Unknown </li></ul><ul><li>Biomarkers for different stages of NAFLD, </li></ul><ul><li>including cancer: Unknown </li></ul><ul><li>Intra-hepatic cytokine signaling associated </li></ul><ul><li>with cancer: Unknown </li></ul><ul><li>Current therapies: ineffective or poorly </li></ul><ul><li>effective </li></ul>
    • 5. Where Should We Go? <ul><li>Perform GWAS of cancer in NAFLD </li></ul><ul><li>Investigate meta-genome </li></ul><ul><li>Identify biomarkers for disease progression </li></ul><ul><li>Investigate intra-hepatic cytokine signaling </li></ul><ul><li>to identify targets for new molecules </li></ul><ul><li>Evaluate new molecules in clinical trials </li></ul>
    • 6. Where Should We Go? <ul><li>Perform GWAS of cancer in NAFLD </li></ul><ul><li>Investigate meta-genome </li></ul><ul><li>Identify biomarkers for disease progression </li></ul><ul><li>Investigate intra-hepatic cytokine signaling </li></ul><ul><li>to identify targets for new molecules </li></ul><ul><li>Evaluate new molecules in clinical trials </li></ul>
    • 7. Cohorts For GWAS, Metagenomics & Biomarkers <ul><li>Cohort of patients with NAFLD: </li></ul><ul><li>- FLIP (Fatty Liver: Inhibition of Progression) </li></ul><ul><li>- French PI; Sponsor: EU/FP7-HEALTH, </li></ul><ul><li>- Recruiting (01-2010) ; size: 1,200 patients. </li></ul><ul><li>The ‘culture of cohort’ in France: </li></ul><ul><li>- 4 Cohorts; cirrhotics (alcohol, HBV, HCV) </li></ul><ul><li>- Sponsor: French Ministry of Health </li></ul><ul><li>- 2,800 patients already enrolled. </li></ul>
    • 8. Where Should We Go? <ul><li>Perform GWAS of cancer in NAFLD </li></ul><ul><li>Investigate meta-genome </li></ul><ul><li>Identify biomarkers for disease progression </li></ul><ul><li>Investigate intra-hepatic cytokine signaling </li></ul><ul><li>to identify targets for new molecules </li></ul><ul><li>Evaluate new molecules in clinical trials </li></ul>
    • 9. Cannabinoids Affect Liver Inflammation and Fibrosis Sophie Lotersztajn and colleagues, Nat Med 2006 38 French Academic Labs Dedicated to Liver Diseases: Aviesan Identify Targets of New Molecules For NAFLD
    • 10. gp130 Mutations in Inflammatory Hepatocellular Tumors Jessica Zucman-Rossi and colleagues, Nature 2009 38 French Academic Labs Dedicated to Liver Diseases: Aviesan Identify Targets of New Molecules For NAFLD gp130 IL-6 IL-6R
    • 11. Tumor Samples Are Already Available: French Collection of Liver Tumors BIOBANKS INSTITUTIONS USE <ul><li>8 liver biobanks in </li></ul><ul><li>France </li></ul><ul><li>1,200 samples: </li></ul><ul><li>- partial or total </li></ul><ul><li>hepatectomy </li></ul><ul><li>- standardized </li></ul><ul><li>clinical, biological </li></ul><ul><li>and histological </li></ul><ul><li>annotations. </li></ul><ul><li>Inserm </li></ul><ul><li>Institut National du </li></ul><ul><li>Cancer </li></ul><ul><li>University Hospitals : </li></ul><ul><li>- AP-HP Paris: </li></ul><ul><li>Beaujon, H. Mondor, </li></ul><ul><li>A. Béclère, and </li></ul><ul><li>P. Brousse hospitals </li></ul><ul><li>- Bordeaux, Rennes, </li></ul><ul><li>Toulouse, Grenoble </li></ul><ul><li>International </li></ul><ul><li>Cancer </li></ul><ul><li>Genome </li></ul><ul><li>Consortium: </li></ul><ul><li>500 paired </li></ul><ul><li>non-tumor </li></ul><ul><li>and tumor </li></ul><ul><li>tissues </li></ul>
    • 12. Where Should We Go? <ul><li>Perform GWAS of cancer in NAFLD </li></ul><ul><li>Investigate metagenome </li></ul><ul><li>Identify biomarkers for disease progression </li></ul><ul><li>Investigate intra-hepatic cytokine signaling </li></ul><ul><li>to identify target for new molecules </li></ul><ul><li>Evaluate new molecules in clinical trials </li></ul>
    • 13. Liver Units in French Academic Health Centers (AHCs) For Randomized Clinical Trials (RCTs) <ul><li>27 Liver Units in AHCs, 22 with liver transplantation </li></ul><ul><li>Expertise for management of liver diseases </li></ul><ul><li>Routine liver biopsy </li></ul><ul><li>Pathologists and radiologists dedicated to </li></ul><ul><li>liver diseases </li></ul><ul><li>Involvement in international consortia: </li></ul><ul><li>- EUROIRON 1 (EU/FP6) </li></ul><ul><li>- Chronic liver failure (CLIF) Consortium </li></ul><ul><li>(European Association for the Study of the Liver) </li></ul><ul><li>- European Network for Vascular Disorders of the Liver </li></ul>
    • 14. The ‘Anti-inflammatory’ Pentoxifylline For Patients With Advanced Cirrhosis Marcellin et al. N Engl J Med 2008 Tenofovir vs. Adefovir For Chronic Hepatitis B Telaprevir and Peginterferon With or Without Ribavirin For Chronic Hepatitis C Hézode et al. N Engl J Med 2009 Lebrec et al. Gastroenterology 2010 Survival Without Complications Pentoxifylline (n=164) Placebo (n=171) P =0.03
    • 15. Conclusions <ul><li>In the next years, in the field of NAFLD, </li></ul><ul><li>French research will contribute to: </li></ul><ul><li>- Identify genetic and/or ‘meta-genonomic’ factors </li></ul><ul><li>associated with disease progression, </li></ul><ul><li>- Identify biomarkers for different disease stages, </li></ul><ul><li>- Identify targets for new molecules. </li></ul><ul><li>French Liver Units are good candidates </li></ul><ul><li>for performing RCTs of new molecules for </li></ul><ul><li>NAFLD. </li></ul>

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