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Aims: To investigate the effect of zebularine, a stable inhibitor of DNA methylation, on hepatic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) under liver-specific factors induction in vitro., Main Methods: BM-MSCs were isolated from the mononuclear cell fraction of rabbit bone marrow samples. The identification of these cells was carried out by immunophenotype analysis. The three hepatic differentiation protocols of BM-MSCs were as follows: liver-specific factors (hepatocyte growth factor and epidermal growth factor) without zebularine, liver-specific factors combined with a 24 h zebularine pre-treatment, and liver-specific factors combined with continuous zebularine treatment. BM-MSCs cultured in basic medium without the differentiation stimuli were set as the control. Morphological features, liver-specific gene and protein expression, and functional analyses were assessed to evaluate hepatic differentiation of BM-MSCs. Global DNA methylation status was tested for investigating the underlying mechanism., Key Findings: Flow cytometry immunophenotyping proved the isolated cells with plastic adherence and a spindle shape were CD29, CD90 positive and CD34, CD45 negative. Albumin (ALB) and alpha-fetoprotein (AFP) messenger RNA and protein expression, glycogen storage and urea production were significantly higher in the continuous zebularine-treated group than the other groups while the differences between the zebularine-untreated group and 24 h zebularine pre-treated group were not significant. Meanwhile, significant decrease of global DNA methylation was observed in the continuous zebularine-treated group., Significance: We conclude that continuous zebularine treatment can improve hepatic differentiation of BM-MSCs under liver-specific factors induction in vitro, and the decrease of global DNA methylation maybe involved in this process., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background & Aims: Placement of an irradiation stent has been demonstrated to offer longer patency and survival than an uncovered self-expandable metallic stent (SEMS) in patients with unresectable malignant biliary obstruction (MBO). We aim to further assess the efficacy of an irradiation stent compared to an uncovered SEMS in those patients., Methods: We performed a randomized, open-label trial of participants with unresectable MBO at 20 centers in China. A total of 328 participants were allocated in parallel to the irradiation stent group (ISG) or the uncovered SEMS group (USG). Endpoints included stent patency (primary), technical success, relief of jaundice, overall survival, and complications., Results: The first quartile stent patency time (when 25% of the patients experienced stent restenosis) was 212 days for the ISG and 104 days for the USG. Irradiation stents were significantly associated with a decrease in the rate of stent restenosis (9% vs. 15% at 90 days; 16% vs. 27% at 180 days; 21% vs. 33% at 360 days; p = 0.010). Patients in the ISG obtained longer survival time (median 202 days vs. 140 days; p = 0.020). No significant results were observed in technical success rate (93% vs. 95%; p = 0.499), relief of jaundice (85% vs. 80%; p = 0.308), and the incidence of grade 3 and 4 complications (8.5% vs. 7.9%; p = 0.841)., Conclusions: Insertion of irradiation stents instead of uncovered SEMS could improve patency and overall survival in patients with unresectable MBO., Lay Summary: For patients with unresectable malignant biliary obstruction (MBO), placement of a self-expandable metallic stent (SEMS) is a recommended palliative modality to relieve pruritus, cholangitis, pain, and jaundice. However, restenosis is a main pitfall after stent placement. Data from this first multicenter randomized controlled trial showed that insertion of an irradiation stent provided longer patency and better survival than a conventional metal stent. ClinicalTrials.gov ID: NCT02001779., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Hypoxia up-regulates vascular endothelial growth factor (VEGF) and stimulates the growth of hepatocellular carcinoma (HCC) cells. This study was designed to investigate the association between changes in plasma VEGF levels after transcatheter arterial chemoembolization (TACE) and HCC progression, especially in relation to metastasis., Methods: Plasma VEGF levels were measured by quantitative sandwich enzyme-linked immunosorbent assay (ELISA R&D system). Plasma VEGF levels were measured before, 3 days and 4 weeks after TACE in 30 patients with HCC. The development of metastasis was evaluated at the end of the third month after TACE., Results: The plasma VEGF levels of the 30 patients with HCC were 154.47+/-90.17 pg/ml. The total plasma VEGF levels after TACE increased compared with their basal levels (P<0.05), and the plasma VEGF levels had a tendency to increase in patients with heterogeneous uptake of iodizdoil and portal vein thrombosis. Follow-up for six months showed metastatic foci in 20 patients (74%) with increased plasma VEGF, but none of the patients with decreased plasma VEGF developed metastasis., Conclusion: Increased plasma VEGF expression is associated with the development of metastasis in HCC after TACE.

Objective: To study relationship between apoptosis and invasive and metastatic potential of hepatocellular carcinoma(HCC)., Methods: Apoptotic rate (AR), proliferative index (PI) and S-phase fraction (SPF) were measured by flow cytometry, and p170, p21 and nucleoside diphosphate kinase (ndpk) by strept avidin-biotin complex immunohistochemical technique in 57 patients with HCC., Results: In this group, AR was 1.77%+/-0.19%, SPF 12.55%+/-0.68%, and PI 20.91%+/-1.12% (r=-0.173). p170, p21 and ndpk positive rates were 61.36%, 68.18%, 52.27% respectively in patients with a mean AR of 1.77% (all P<0.05). In patients with positive tumor invasiveness and metastasis, ndpk (+) was 43.75%, p21 (+) 75.00%, p170 (+) 65.63%, AR 1.12%+/-0.16%, PI 23.78%+/-1.48%, and SPF 13.90%+/-0.99%. In patients with negative invasiveness and metastasis, however, ndpk (+) was 80.00%, p21 (+) 44.00%, p170 (+) 36.00%, AR 2.32%+/-0.52%, PI 18.53%+/-0.82% and SPF 11.43%+/-0.70%., Conclusion: Apoptosis of HCC is negatively correlated with its invasive and metastatic potential or other factors as proliferative activity, p21, p170 and ndpk.