Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of ​interferon-λ4 (​IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.

Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms

Successive Oligopolies, Vertical Downstream Integration and Foreclosure

Vertically integrated firms have repeatedly been accused of abusing a dominant position by refusing to sell the intermediate product to non-integrated downstream producers and thus to practice foreclosure. To evaluate the merit of such an accusation requires an adequate theory of vertical integration which allows to decide whether a refusal to sell follows straightforwardly from profit maximization or is driven by an intent to monopolize. We investigate whether in the case of successive oligopolies vertical integration is profitable for the participating firms and to what extent cross deliveries between integrated and non-integrated firms can be expected to arise. By contrast to the previous literature where at the downstream level Cournot competition has been assumed to prevail between integrated firms and non-integrated downstream producers, we propose a model where integrated firms and non-integrated upstream suppliers meet in Cournot competition and take as given the inverse demand function for both the final and the intermediate product. Game theory is invoked to examine whether an integrated firm will participate in the intermediate market. If marginal costs at the downstream level are constant and identical as between integrated and non-integrated firms, integrated firms will never wish to sell to non-integrated downstream producers they can, however, be expected to buy from non-integrated upstream suppliers. Utilizing theoretical implications regarding pass through of changes in marginal costs we find empirical evidence supporting the applicability of our model to the gasoline industry in Germany. We finally examine to what extent issues of competition policy and public regulation arise. Copyright Springer Science + Business Media, Inc. 2005Oligopoly, vertical integration, foreclosure,

A biologic without guidelines: the YODA project and the future of bone morphogenetic protein-2 research

Scientific Assessment and Innovation in Neurosurgical Treatment Strategie