Tumor suppressor and hepatocellular carcinoma.

A few signaling pathways are driving the growth of hepatocellular carcinoma. Each of these pathways possesses negative regulators. These enzymes, which normally suppress unchecked cell proliferation, are circumvented in the oncogenic process, either the over-activity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective.

Targeting vessels to treat hepatocellular carcinoma.

The process of blood vessel proliferation, known as angiogenesis, is essential during embryonic development and organogenesis. In adult life, it participates in normal tissue repair, wound healing, and cyclical growth of the corpus luteum and the endometrium. Crucial as it is, angiogenesis can become pathological, and abnormal angiogenesis contributes to the pathogenesis of inflammatory and neoplasic diseases.

Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C.

Background/aim: Both steatosis and insulin resistance have been linked to accelerated fibrosis in chronic hepatitis C. Connective tissue growth factor (CTGF) plays a major role in extracellular matrix production in fibrotic disorders including cirrhosis, and its expression is stimulated in vitro by insulin and glucose. We hypothesized that CTGF may link steatosis, insulin resistance and fibrosis.

Effects on hepatocellular carcinoma of doxorubicin-loaded immunoliposomes designed to target the VEGFR-2.

To maintain a tumour vasculature in proportion of the tumour growth, the endothelial cells proliferate and up-regulate the expression of the VEGF receptor 2 (VEGFR-2), whose expression is restricted to this cell type. This specificity implies that one therapeutically target the tumour endothelium. We investigated the use of immunoliposomes (IL), containing conjugated Fab' fragments of the monoclonal rat anti-VEGFR-2 antibody DC101 (DC101-IL) to cargo doxorubicin to the tumour endothelium.

Tumour suppressors in liver carcinogenesis.

The circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of cell proliferation. Each signalling pathway that has been implicated in carcinogenesis is influenced by both oncogenic factors that promote tumour growth when activated as well as tumour suppressor proteins that have to be impaired to favour tumour growth.

Expression and activity of the cytochrome P450 2E1 in patients with nonalcoholic steatosis and steatohepatitis.

Background/aims: Nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver (NAFL) have a different prognosis and should be dealt with differently. The pathogenesis of NASH implicates the overexpression of cytochrome P450 2E1 (CYP2E1). We investigated whether the noninvasive determination of CYP2E1 activity could replace a liver biopsy in order to differentiate NASH from NAFL.

Activation of non-ischemic, hypoxia-inducible signalling pathways up-regulate cytoprotective genes in the murine liver.

Background/aims: We investigated the molecular response of a non-ischemic hypoxic stress in the liver, in particular, to distinguish its hepatoprotective potential.

Methods: The livers of mice were subjected to non-ischemic hypoxia by clamping the hepatic-artery (HA) for 2h while maintaining portal circulation. Hypoxia was defined by a decrease in oxygen saturation, the activation of hypoxia-inducible factor (HIF)-1 and the mRNA up-regulation of responsive genes.

Bridging hyperacute liver failure by ABO-incompatible auxiliary partial orthotopic liver transplantation.

Uncontrollable intracranial pressure elevation in hyperacute liver failure often proves fatal if no suitable liver for transplantation is found in due time. Both ABO-compatible and auxiliary partial orthotopic liver transplantation have been described to control such scenario. However, each method is associated with downsides in terms of immunobiology, organ availability and effects on the overall waiting list.

Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma.

Background/aims: Hepatocellular carcinoma (HCC) is amenable to only few treatments. Inhibitors of the kinase mTOR are a new class of immunosuppressors already in use after liver transplantation. Their antiproliferative and antiangiogenic properties suggest that these drugs could be considered to treat HCC.

Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a frequent liver disease that can progress to cirrhosis and for which there is no recognized therapy. UDCA and vitamin E have been considered separately as therapeutic options and have not been shown to be effective. This study tested their combination.

Efficiency and safety of bosentan in child C cirrhosis with portopulmonary hypertension and renal insufficiency.

Bosentan has lately been described as a successful therapeutic agent for portopulmonary hypertension consecutive to child A cirrhosis. This is the first report of the effect of this substance with advanced liver cirrhosis (child C) and renal insufficiency. Low doses of bosentan (initially twice 31.

Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma.

Background & Aims: Hints, histidine triad nucleotide-binding proteins, are adenosine monophosphate-lysine hydrolases of uncertain biological function. Here we report the characterization of human Hint2.

Methods: Tissue distribution was determined by real-time quantitative polymerase chain reaction and immunoblotting, cellular localization by immunocytochemistry, and transfection with green fluorescent protein constructs.

Activation of CREB by tauroursodeoxycholic acid protects cholangiocytes from apoptosis induced by mTOR inhibition.

Tauroursodeoxycholic acid (TUDCA) is a cytoprotective bile acid frequently prescribed to patients with cholestatic diseases. Several mechanisms of action have been investigated, but the possibility that cyclic adenosine monophosphate responsive element binding protein (CREB), a transcription factor promoting cell survival, mediates TUDCA's protective effects has not been considered. We examined whether TUDCA activates CREB and whether this activation can protect biliary epithelial cells.

Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients.

Background/aims: Liver steatosis is a frequent finding in chronic hepatitis C. An association has been suggested between steatosis and fibrosis progression rate, but the pathogenetic mechanisms linking fatty infiltration and collagen deposition are unknown.

Methods: We measured the levels of insulin resistance (as HOMA score) and leptin in 221 non-diabetic chronic hepatitis C patients, to assess their impact on liver steatosis and fibrosis, relative to other factors, using a multivariable logistic regression.

The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer.

Bile acids have been implicated in the development of colorectal cancers. We investigated the expression of the transcription factor regulated by bile acids, farnesoid X receptor (FXR), as well as other components of this pathway in human colorectal tumors and cell lines. The most significant changes were a decrease in FXR mRNA levels in adenomas (5-fold average) and carcinomas (10 fold average) and an increase in peroxisome proliferator activated receptor-gamma (2-fold average).

Nontumoral dermatologic problems after liver transplantation.

The skin, easily accessible for medical examination, is affected in many ways by liver transplantation. Mucocutaneous manifestations of advanced liver disease and dermatologic conditions associated with specific hepatic diagnoses generally improve after liver transplantation. Vasculitic lesions due to cryoglobulinemia associated with hepatitis C, and photosensitivity due to porphyria are occasional exceptions.

Cholestasis shuts down calcium signaling in cholangiocytes.

Background & Aims: Cholestasis is one of the principal manifestations of liver disease and often results from disorders involving bile duct epithelia rather than hepatocytes. A range of disorders affects biliary epithelia, and no unifying pathophysiologic event in these cells has been identified as the cause of cholestasis. Here we examined the role of the inositol 1,4,5-trisphosphate receptor (InsP3R)/Ca(2+) release channel in Ca(2+) signaling and ductular secretion in animal models of cholestasis and in patients with cholestatic disorders.

Effect of vascular endothelial growth factor on functional recovery after hepatectomy in lean and obese mice.

Background/aims: Liver regeneration is dependent upon coordinated proliferation of hepatocytes and endothelial cells. Vascular endothelial growth factor (VEGF) promotes angiogenesis. Hepatic steatosis delays regeneration and increases liver resection morbidity.

Hyperdynamic circulation in liver cirrhosis: desensitization of vasoconstrictive receptors by G protein-coupled receptor kinases.

Liver cirrhosis is complicated by a hyperdynamic circulation characterized by a generalized arterial vasodilatation. This vasodilatation occurs despite high plasma concentration of several potent vasoconstrictive substances like angiotensin, vasopressin, endothelin and norepinephrine. The experimental evidence available shows that compensatory adrenergic and vasoconstrictive signals are not normally transmitted intracellularly.

Twenty-four vs. forty-eight weeks of re-therapy with interferon alpha 2b and ribavirin in interferon alpha monotherapy relapsers with chronic hepatitis C.

Background/aim: Roughly 50% of patients with chronic hepatitis C, who relapsed after a previous monotherapy with interferon alpha, will respond in a sustained fashion to 24 weeks of re-therapy with the combination of interferon alpha plus ribavirin. Whether prolonging treatment duration to 48 weeks will further increase sustained response rates remains ill defined. In this randomised controlled pilot trial we compared the efficacy and tolerability of a 24 week with that of a 48 week course of combination therapy with interferon alpha and ribavirin in interferon monotherapy relapsers with chronic hepatitis C.