Rasl11b Knock Down in Zebrafish Suppresses One-Eyed-Pinhead Mutant Phenotype

The EGF-CFC factor Oep/Cripto1/Frl1 has been implicated in embryogenesis and several human cancers. During vertebrate development, Oep/Cripto1/Frl1 has been shown to act as an essential coreceptor in the TGFβ/Nodal pathway, which is crucial for germ layer formation. Although studies in cell cultures suggest that Oep/Cripto1/Frl1 is also implicated in other pathways, in vivo it is solely regarded as a Nodal coreceptor. We have found that Rasl11b, a small GTPase belonging to a Ras subfamily of putative tumor suppressor genes, modulates Oep function in zebrafish independently of the Nodal pathway. rasl11b down regulation partially rescues endodermal and prechordal plate defects of zygotic oep−/− mutants (Zoep). Rasl11b inhibitory action was only observed in oep-deficient backgrounds, suggesting that normal oep expression prevents Rasl11b function. Surprisingly, rasl11b down regulation does not rescue mesendodermal defects in other Nodal pathway mutants, nor does it influence the phosphorylation state of the downstream effector Smad2. Thus, Rasl11b modifies the effect of Oep on mesendoderm development independently of the main known Oep output: the Nodal signaling pathway. This data suggests a new branch of Oep signaling that has implications for germ layer development, as well as for studies of Oep/Frl1/Cripto1 dysfunction, such as that found in tumors

Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection

The hepatitis C virus (HCV), a linear, single-stranded RNA virus identified in 1989, is a hepatotropic virus that causes liver cirrhosis and hepatocellular cancer and is a global health problem. It is recognized as one of the hepatic viruses most often associated with the development of extrahepatic manifestations (EHMs), which can be classified according to the principal underlying etiopathogenic process (autoimmune, inflammatory, metabolic or neoplastic) [1]. HCV infected patients with extrahepatic involvement require a multidisciplinary approach and a complex therapeutic management. In the 1990s, various authors described the association between HCV infection with organ damage beyond the liver and a heterogeneous group of extrahepatic conditions including pulmonary fibrosis, cutaneous vasculitis, glomerulonephritis, Mooren ulcer, porphyria cutanea tarda and lichen planus, among others [2–4]. However, it is currently accepted that there is a weak association with some of these features [1,5], and that cryoglobulinemic vasculitis (CV) is the key extrahepatic disease related to chronic HCV infection. There is growing interest in the association with both systemic and organ-specific autoimmune diseases and with the development of neoplastic haematologic processes due to the specific lymphotropism of HCV [1,6,7]. Currently, there are no international recommendations on the therapeutic management of HCV infected patients with EHMs. The first therapeutic approaches were based on immunosuppressive therapies mirroring the regimens used in non-HCV vasculitides [8]. The introduction of the first antiviral therapies combination (interferon [IFN] alpha and ribavirin [RBV]) clearly improved survival rates[9]. However, this therapeutic approach had limited virological efficacy (eradication \50% for HCV genotype 1), often required several months of therapy and had high rates of intolerance [10]. Direct-acting antiviral (DAA) therapies have recently emerged as a striking therapeutic approach for HCV infection, with a short treatment duration, minimal side effects and efficacy approaching 100% [11–14]. These new drugs are providing the opportunity to effectively cure chronic HCV infection and reduce the burden caused by both the hepatic and extrahepatic complications of HCV, thereby offering hope for a dramatic change in patient outcomes. The objective of this international multidisciplinary consensus is to provide the first set of recommendations on a homogeneous therapeutic approach to HCV infected patients with extrahepatic involvement in the new DAA era