J.Y. Cheong

Protective Mechanism of Epigallocatechin-3-Gallate against Helicobacter pylori-Induced Gastric Epithelial Cytotoxicity via the Blockage of TLR-4 Signaling

Background.u2002 Helicobacter pylori infection leads to gastric mucosal damage by several mechanisms including the direct effect of virulence factors produced by H. pylori, propagation of inflammation, oxidative stress, DNA damage, and induction of apoptosis. (‐)‐Epigallocatechin‐3‐gallate (EGCG), one of the green tea catechins, is known to suppress H. pylori‐induced gastritis through its antioxidative and antibacterial actions. In this study, we evaluated the protective mechanism of EGCG against H. pylori‐induced cytotoxicity in gastric epithelial cells.

Low efficacy of entecavir therapy in adefovir-refractory hepatitis B patients with prior lamivudine resistance

Summary.u2002 We determined the virologic response, incidence of entecavir resistance, and evolution of lamivudine and adefovir‐resistant mutants during entecavir (ETV) therapy in adefovir‐refractory patients with prior lamivudine resistance. Forty adefovir‐refractory chronic hepatitis B patients with prior lamivudine resistance who had received entecavir for ≥6u2003months were included and monitored for virologic response and entecavir resistance. Ten per cent of patients achieved HBV DNAu2003<u200350u2003copies/mL by PCR after 24u2003weeks of ETV therapy, and an initial virologic response was observed in 12 of 40 patients (30%). Higher pretreatment ALT (Pu2003=u20030.039) and the presence of the rtL180M mutation (Pu2003=u20030.038) were associated with an initial virologic response. During a mean follow‐up of 11.4u2003months, four patients (10%) experienced virologic breakthrough, while ETV‐resistant mutants were detected in six patients (15%). YMDD and adefovir‐resistant mutants were detected in 57 and 35% of patients at baseline, respectively. At 48u2003weeks of therapy, 96 and 4% of patients had YMDD and adefovir‐resistant mutants, respectively. These data suggest an early development of ETV resistance and low antiviral response during ETV therapy in adefovir‐refractory patients with prior lamivudine resistance.

Association of a microRNA-323b polymorphism with the persistence of hepatitis B virus infection by the enhancement of viral replication

Recent studies have shown that some mammalian microRNAs (miRNAs) play a role in antiviral defence. However, little is known about the role of miRNA‐323b in hepatitis B virus (HBV)‐host interaction. We explored whether single nucleotide polymorphism (SNP) of miRNA‐323b affects HBV replication in a Korean HBV cohort. Genotyping was performed in a total of 1439 subjects composed of 404 spontaneously recovered (SR) subjects as normal controls and 1035 chronic carriers (CC) of HBV who were further classified into 313 patients with chronic hepatitis, 305 patients with liver cirrhosis and 417 patients with hepatocellular carcinoma. To confirm the effect of SNP of miRNA‐323b on HBV replication in vitro, HepAD38 cells were transfected with miRNA‐323b wild type or miRNA‐323b SNP plasmid vectors, and HBV replication was induced for 5 days. HBV DNA was isolated and quantified using real‐time PCR. The polymorphism rs56103835C>T in the pre‐miRNA region of miRNA‐323b revealed significant minor allele frequency (0.273). rs56103835C>T SNP showed significantly affect persistence of HBV in CC group compared with SR group (OR = 1.29, P = 0.009 in a codominant model; OR = 1.29, P = 0.03 in a dominant model; and OR = 1.78, P = 0.03 in a recessive model). In vitro, the total intracellular HBV DNA content was significantly reduced by miRNA‐323b wild‐type plasmid vector transfection (P = 0.014). The polymorphism of miRNA‐323b was significantly associated with persistence of HBV by the enhancement of HBV replication (P = 0.021). Our findings provide a novel perspective on the role SNP of miRNAs in host–virus interactions in HBV infection.

Genetic association between functional haplotype of collagen type III alpha 1 and chronic hepatitis B and cirrhosis in Koreans

Collagen type III alpha 1 (COL3A1) is one of the extracelluar matrix (ECM) proteins. The expression of COL3A1 is closely related to chronic liver diseases. In this study, we investigated whether single nucleotide polymorphisms (SNPs) of COL3A1 confer genetic susceptibility to patients with hepatitis B virus-infected liver diseases including chronic hepatitis B (CH), liver cirrhosis (CIR), and hepatocellular carcinoma (HCC). A total of 399 Korean (KOR) people, 111 patients with CH, 95 patients with CIR, 86 patients with HCC, and 107 spontaneously recovery, were genotyped for 16 SNPs of the COL3A1 gene. The A allele of rs3106796 was highly associated with the CH [odds ratio (OR) = 1.62, P = 0.01], CIR (OR = 1.67, P = 0.01), and HCC (OR = 1.59, P = 0.03). There were six polymorphic SNPs that could be divided into two linkage disequilibrium (LD) blocks. The haplotype pattern of the KOR control seems to be similar to the patterns displayed in the Japanese, Chinese, and Caucasian populations sampled in the International HapMap project. Haplotype 3 (A-G-A) of the LD block 2 was significantly associated with CH (OR = 2.23, P = 0.02), CIR (OR = 2.24, P = 0.03), and HCC (OR = 2.27, P = 0.03). Moreover, diplotype analysis showed that they had increased relative risk for CH and CIR in the two diplotypes, dt3 (A-G-A/G-G-A; OR = 4.05, P = 0.01) and dt6 (A-A-A/A-G-A; OR = 7.42, P = 0.01 and OR = 5.84, P = 0.05) against dt1 (G-G-A/G-G-A), the most common diplotype in both KOR groups. In vitro reporter gene assays showed that the constructs containing the G allele of rs3106796 appear to exert lower transcriptional activity of COL3A1 than the A allele, depending on the promoter types.

P65 MUTATION SPECTRUM ASSOCIATED WITH THE PROGRESSION OF HBV-RELATED HEPATOCELLULAR CARCINOMA

P64 THE ULTRACONSERVED NON CODING RNA UC.158 IS DOWNSTREAM OF THE WNT/b-CATENIN PATHWAY IN LIVER CANCERS V. Paulus-Hock, A. Lampis, G. Ferrari, L. Boulton, R. Guest, D. Athineos, T. Jamieson, A. Veronese, R. Visone, R. Evans, G.J. Feng, T. Dale, M. Negrini, S. Forbes, T. Patel, O. Sansom, N. Valeri, C. Braconi. Institute of Cancer Sciences, University of Glasgow, Glasgow, Division of Molecular Pathology, Institute of Cancer Research, London, Scottish Centre for Regenerative Medicine, MRC Centre for Regenerative Medicine, Edinburgh, Beatson Institute for Cancer Research, Glasgow, United Kingdom; Aging Research Center, University of Chieti, Chieti, Italy; School of Biosciences, University of Cardiff, Cardiff, United Kingdom; University of Ferrara, Ferrara, Italy; Mayo Clinc, Jacksonville, FL, United States; Division of Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom E-mail: chiarabraconi@gmail.com

698 ASSOCIATION OF POLYMORPHISM IN MICRORNA 604 WITH SUSCEPTIBILITY TO PERSISTENT HEPATITIS B VIRUS INFECTION AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B

CD than in the control population (p < 0.001). The two group were indeed similar for age and presence of steatosis (37% of celiac patients and 32.3% in the control subjects, p =n.s.). HH in celiac patients had a median diameter of 1.3 cm (range 0.6–6.8 cm) and presented as a single lesion in 12/14 patients (86%) and as multiple lesions in the other two (14%), with a hyperechoic aspect in 13 patients (93%) without significant differences with control subjects. Conclusions: The prevalence of HH in the setting of CD seems to be higher compared to general population. Although mechanisms underlying this association are still far to be clearly understood, genetic, autoimmune, hormonal or metabolic processes could play an important role.

201 COPY NUMBER ALTERATIONS IN HEPATOCELLULAR CARCINOMA AND IDENTIFICATION OF NUCKS1 AS A PUTATIVE ONCOGENE ON CHROMOSOME 1Q32.1

200 CODING MICROSATELLITE INSTABILITY AFFECTING THE GENES HT001, PTHL3, SEC63, TAF1B AND TGFBR2 IN A LYNCH-SYNDROME ASSOCIATED HEPATOCELLULAR CARCINOMA M. Casper, M. Kloor, M. von Knebel-Doeberitz, R.M. Bohle, J. Raedle, F. Lammert, V. Zimmer. Department of Medicine II, Saarland University Hospital, Homburg, Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Institute of Pathology, Saarland University Hospital, Homburg, Department of Medicine III, Westpfalz Hospital, Kaiserslautern, Germany E-mail: markus.casper@uks.eu

246 Effect of low dose 5-fluorouracil and cisplatin intra-arterial infusion chemotherapy in advanced hepatocellular carcinoma with decompensated cirrhosis

BACKGROUND/AIMSnAdvanced hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) has a poor prognosis. The aim of this study was to evaluate the efficacy and safety of repeated arterial infusions of low dose cisplatin and 5-fluorouracil (FU) in patients with advanced HCC with decompensated cirrhosis.nnnMETHODSnBetween January 1995 and December 2003, a total of 79 decompensated cirrhotic patients having HCC and PVT were enrolled and divided into 2 groups. Group 1 (n=40) received intra-arterial infusion chemotherapy with cisplatin (10 mg for 5 days) and 5-FU (250 mg for 5 days) via an implanted chemoport every 4 weeks and group 2 (n=39) was managed with only conservative treatment.nnnRESULTSnThe two groups were well matched with respect to the features relating to the prognosis, including age, gender and the Child- Pugh class. Although diffuse tumor involvement, main portal vein tumor thrombosis and bi-lobar involvement were more frequent in group 1, the median survival period of group 1 was significantly longer than group 2 (5 months vs. 3 months, respectively, P=0.016). Also, the 1-year survival rate of group 1 (7.5%) was higher than that of group 2 (5.1%) (P=0.016). When we analyzed the patients with the Child class B, the survival benefits of intra-arterial chemotherapy were more significant (P=0.008).nnnCONCLUSIONSnIntra-arterial chemotherapy consisting of low dose 5-FU and cisplatin achieved favorable results for advanced HCC patients who had decompensated cirrhosis, and it showed better survival in selected patients. This therapy may be useful as a palliative treatment for HCC patients with decompensated cirrhosis.