Inhibition of the Wnt/ß-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma.

Sorafenib, a multikinase inhibitor, is currently the only approved drug for advanced hepatocellular carcinoma (HCC). The current study tested the hypothesis whether inhibition of the Wnt/ß-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC. ICG-001, a small molecule which blocks the interaction of ß-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth-suppressive and apoptosis-induction effects of sorafenib in multiple HCC cell lines. Downregulation of ß-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of ß-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated ß-catenin downregulation in Huh7 cells was attenuated by ß-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA-mediated ß-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. Our data indicate that inhibition of the Wnt/ß-catenin signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo.

ß-catenin (CTNNB1) mutations are not associated with prognosis in advanced hepatocellular carcinoma.

OBJECTIVES: Mutation of the exon 3 of CTNNB1, the coding gene of ß-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/ß-catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of CTNNB1 mutations in advanced HCC remain unclear. METHODS: Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of CTNNB1 was performed to detect somatic mutations. The associations between CTNNB1 mutations and clinicopathologic features were analyzed. RESULTS: A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have CTNNB1 mutations, all of which were missense mutations. The CTNNB1 mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have CTNNB1 mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features. CONCLUSION: In patients with advanced HCC, CTNNB1 mutations were not prognostically significant. No apparent increase of CTNNB1 mutations occurred during the progression of HCC.

Pulmonary function in children with development coordination disorder.

The purpose of this study was to compare pulmonary function in children with developmental coordination disorder (DCD) with children who are typically developing (TD), and also analyze possible gender differences in pulmonary function between these groups. The Movement ABC test was used to identify the movement coordination ability of children. Two hundred and fifty participants (90 children with DCD and 160 TD children) aged 9-10 years old completed this study. Using the KoKo spirometry, forced vital capacity (FVC) and forced expiratory volume in 1s (FEV(1.0)) were used to measure pulmonary function. The 800-m run was also conducted to assess cardiopulmonary fitness of children in the field. There was a significant difference in pulmonary function between TD children and those with DCD. The values of FVC and FEV(1.0) in TD children were significantly higher than in children with DCD. A significant, but low correlation (r = -0.220, p < .001) was found between total score on the MABC and FVC; similarly, a positive but low correlation (r = 0.252, p < .001) was found between total score on the MABC and the completion time of 800-m run. However, no significant correlation between FVC and the time of 800-m run was found (p > .05). Significant correlations between total score on the MABC and the completion time of the 800-m run (r = 0.352, p < .05) and between FVC and the time of 800-m run (r = -0.285, p < .05) were observed in girls with DCD but not boys with this condition. Based on the results of this study, pulmonary function in children with DCD was significantly lower than that of TD children. The field test, 800-m run, may not be a good indicator to distinguish aerobic ability between children with DCD and those who are TD. It is possible that poor pulmonary function in children with DCD is due to reduced physical activity in this population.

Cardiopulmonary fitness and endurance in children with developmental coordination disorder.

The purpose of this study was to compare cardiopulmonary fitness and endurance in 9-11-year-old children with DCD against a group of typically developing children in Taiwan. The Movement ABC test was used to evaluate the motor abilities of children. Forty-one participants (20 children with DCD and 21 children without DCD) were recruited for this study. The cardiopulmonary tests included the 800-m run test and the peak oxygen consumption (peak VO(2)) test using the Bruce treadmill protocol. No significant differences in age, body height, body weight, body mass index, and percentage of body fat between children with DCD and without DCD were found. However, there were significant differences in the cardiopulmonary endurance tests between children with DCD and without DCD. Children with DCD had significantly lower peak VO(2) results than children without DCD. In addition, children with DCD ran 800 m in a slower time than children without DCD. A significant negative correlation (r=-0.437) was found between the peak VO(2) results and time to completion for the 800-m run test. Based on the results, cardiopulmonary endurance in children with DCD was worse than that of children without DCD. Due to the small sample size in this study, the results may not be a direct reflection of the entire population.