Hepatitis B virus (HBV), a major causative agent of hepatocellular carcinoma (HCC), encodes an oncogenic X protein (HBx) that transcriptionally activates multiple viral and cellular promoters. The present study aimed to identify the specific gene mutation related to the clinical outcome of HCC. Seventy-two HBV-infected patients (38 with chronic HBV infection and 34 with HCC) with well-characterized clinical profiles were enrolled. The HBx region was amplified from patient serum samples and analyzed by sequencing. Genotypes were determined using the National Center for Biotechnology Information genotype tool. All isolates were genotype B or C. Enhancer II nucleotide substitutions in the HCC group were significantly different from those in the chronic hepatitis B (CHB) group (Ρ < 0.05). HCC patients with genotype C had a higher risk of harboring the 1762/1764 double mutation than those with genotype B. The incidence of the 1762/1764 double mutation was higher in the high viral load group (>10(6) copies/ml) than in the low viral load group (≤10(6) copies/ml) (P = 0.03). The 1762/1764 double mutations may be related to the genotype and viral load. We found significantly more direct repeat sequence 1 (DR1) nucleotide substitutions in the HCC group (32.4%, 11/34) than in the CHB group (10.5%, 4/38) (Ρ < 0.05). Patients with higher viral load and genotype C had a higher incidence of 1762/1764 double mutations, which may not be related with development of HCC. Enhancer II and DR1 may play an important role in HCC development via nucleotide substitution.

The polymorphism of IL12B (1188A/C) appears to have some influence on the outcome of HCV infection.

Our findings showed that the functional domains of NS5A were generally conserved over an interval of 10 years. Quasispecies distribution was variable and distinctly clustered over time during the natural course of HCV infection. These results may contribute to better understanding of HCV natural infection.

Biliary fibrosis is a major complication after donation after cardiac death (DCD) liver transplantation. In this process, the roles of serotonin [5-hydroxytryptamine (5-HT)] and the 5-HT2A receptor subtype are still unknown. In this study, we analyzed markers of portal fibroblast (PF)/myofibroblast (MF) transdifferentiation such as transforming growth factor b1 (TGF-b1), phosphorylated smad2/3, a-smooth muscle actin (a-SMA), collagen I, and collagen III in a primary culture system of PFs after the administration of 5-HT or 5-HT plus ketanserin (a selective 5-HT2A receptor antagonist). A rat DCD transplant model was established with 30 minutes of warm ischemia and 4 hours of cold ischemia during organ procurement. Recipients were intraperitoneally injected with ketanserin (1 mgÁkg 21 Áday 21 ) or normal saline. Grafts without in situ warm ischemia instead of minimal cold storage (30 minutes) served as controls. The serum biochemistry, the liver contents of 5-HT and hydroxyproline (HYP), and the expression of fibrosis-related genes (including TGF-b1, matrix metalloproteinase 2, procollagen a1, and a-SMA messenger RNA) were determined. The extent of biliary fibrosis was also assessed histopathologically. The results indicated that ketanserin inhibited 5-HT-activated TGF-b1-smad2/3 signaling in vitro and thereby depressed the MF conversion of PFs. Rats receiving DCD livers showed increased liver contents of 5-HT and HYP, impaired biliary function, up-regulation of fibrosis-related genes, and aggravated biliary fibrosis. However, these phenomena were alleviated by treatment with ketanserin. We concluded that the profibrotic activity of 5-HT occurred through the activation of TGF-b1 signaling and the 5-HT2A receptor. Thus, these data suggest that the 5-HT2A receptor may be a potential therapeutic target for ischemia-related biliary fibrosis after DCD liver transplantation. Liver Transpl 20:1317-1326, 2014. V C 2014 AASLD.Received March 30, 2014; accepted July 2, 2014.The worldwide organ shortage has led to the increased use of donation after cardiac death (DCD) livers. Because of the additional warm ischemia before preservation, DCD liver grafts are at higher risk for failure and bile duct injury. Currently, DCD liver grafts are the most common cause of nonanastomotic biliary strictures, which are characterized as biliary strictures and dilatation at any location in the biliary system of the transplanted liver.1,2 They are associated with an increased incidence of biliary sludge, recurrent Abbreviations: 5-HT, 5-hydroxytryptamine; 5-HT1K, 5-hydroxytryptamine and ketanserin; a-SMA, a-smooth muscle actin; ALP, alkaline phosphatase; BECs, biliary epithelial cells; DCD, donation after cardiac death; GGT, gamma-glutamyl transpeptidase; HSC, hepatic stellate cell; HYP, hydroxyproline; MF, myofibroblast; MMP2, matrix metalloproteinase 2; mRNA, messenger RNA; PF, portal fibroblast; PI, proliferation index; p-smad, phosphorylated drosophila mothers against decapentaplegic protein; RTqPCR, quantitative real-time reverse-transcr...

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