We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

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The role of the anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in the mouse model of liver injury induced by carbon tetrachloride (CCl 4 ). To address the role of endogenous IL-10 production, acute hepatitis was induced by CCl 4 in C57Bl/6 IL-10 gene knock out (KO) and wild-type (WT) mice. After CCl 4 challenge, serum and liver levels of tumor necrosis factor-alpha (TNF-␣) and serum levels of transforming growth factor-beta 1 (TGF-␤1) increased and were significantly higher in IL-10 KO mice, whereas IL-6 serum levels were only slightly increased compared with WT mice. At histological examination, the livers disclosed a significantly more prominent neutrophilic infiltration in IL-10 KO mice 12 and 24 hours after CCl 4 injection. In contrast, hepatocyte necrosis, evaluated by histological examination and serum alanine aminotransferase levels, was only marginally affected. The proliferative response of hepatocytes, assessed by the proliferating cell nuclear-antigen labeling index, was significantly increased in IL-10 KO mice, compared with WT mice 48 hours after CCl 4 injection. Finally, repeated CCl 4 injections led to more liver fibrosis in IL-10 KO mice after 7 weeks. In conclusion, endogenous IL-10 marginally affects the hepatocyte necrosis although it controls the acute inflammatory burst induced by CCl 4 . During liver repair, it limits the proliferative response of hepatocytes and the development of fibrosis. (HEPATOLOGY 1998;28:1607-1615.)

Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n 5 229]; Hannover, Germany [n 5 171]; Lyon, France [n 5 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C>G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C>T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08-6.03, P 5 0.034), fibrosis (OR 3.13, 95% CI 1.50-6.51, P 5 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22-5.67, P 5 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46-2.49, P 5 0.875) and did not influence clinical or biological variables. Conclusion: The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage. (HEPATOLOGY 2011;54:60-69)