Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling has been found in several types of human cancer, including hepatocellular carcinoma (HCC). NVP-BEZ235 is a novel, orally bioavailable dual PI3K/mTOR inhibitor that has exhibited promising activity against HCC in preclinical models. Autophagy is a cellular lysosomal degradation pathway essential for the regulation of cell survival and death to maintain homeostasis. This process is negatively regulated by mTOR signaling and often counteracts the efficacy of certain cancer therapeutic agents. In this study, we explored the role of autophagy in apoptosis induced by NVP-BEZ235 in two HCC cell lines, Hep3B and PLC/PRF/5, and identified the mechanism of combinatorial treatment. NVP-BEZ235 was effective in inhibiting the growth of the two HCC cell lines possibly though induction of apoptosis. NVP-BEZ235 also potently increased the expression of LC3-II and decreased the expression of p62, indicating induction of autophagy. When NVP-BEZ235 was used in combination with Atg5 siRNA or the autophagy inhibitor 3-methyladenine (3-MA), enhancement of the inhibitory effects on the growth of HCC cells was detected. In addition, enhanced induction of apoptosis was observed in cells exposed to the combination of NVP-BEZ235 and Atg5 siRNA or 3-MA. Thus, induction of autophagy by NVP-BEZ235 may be a survival mechanism that counteracts its anticancer effects. Based on these data, we suggest a strategy to enhance the anticancer efficacy of BEZ235 by blockade of autophagy. Thus, our study provides a rationale for the clinical development of combinations of NVP-BEZ235 and autophagy inhibitors for the treatment of HCC and other malignancies.

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A growing body of evidence suggests that microRNA-124 (miR-124) functions as tumor-suppressor, and involves in tumor initiation, development and metastasis in major classes of human cancers; however, the biological role and underlying molecular mechanism of miR-124 in retinoblastoma (RB) remain unknown. Therefore, we investigated the biological activity and underlying molecular mechanism of miR-124 in human retinoblastoma. In the present study, our results demonstrated the downregulation of miR-124 in RB tissues and RB cell lines compared with normal retinal tissues. The ectopic expression of miR-124 in the RB cell lines (Y79 and SO-RB50) suppresses cell proliferation, migration and invasion, induced cell apoptosis in vitro. Furthermore, signal transducer and activator of transcription 3 (STAT3) was identified as a new target of miR-124, and overexpression of miR-124 decreased STAT3 expression on mRNA level and protein level in human RB cells. We also found that STAT3 mRNA expression was upregulated and inversely correlated with miR-124 expression in the RB tissues (r=-0.683; P<0.001). Restoration of the expression of STAT3 rescues the effects induced by miR-124 in RB cells. The findings of the present study suggested that miR-124 functioned as tumor suppressor in RB, at least in part, by targeting STAT3, and that it could serve as a potential candidate for RB therapeutics.

Objective: To evaluate the effects of different intervention measures to prevent falls in elderly osteoporotic patients.Methods: A randomized controlled trial was conducted in our outpatient ward from August 2014 to September 2015.A total of 420 patients over 60 years of age were assigned to four groups. NA VitD group took 800 mg calcium and 800 IU non-active vitamin D. P-NA VitD group took 800 mg calcium, 800 IU non-active vitamin D, and received physical exercise. A VitD group took 800 mg calcium and 0.5 μg active vitamin D. P-A VitD took 800 mg calcium, 0.5 μg active vitamin D, and received physical exercise. Physical exercise includes guidance in improving muscle strength and balance ability. Short physical performance battery (SPPB), grip strength, modified falls efficacy scale (MFES), blood calcium, and 25-hydroxyl vitamin D were measured before interventions and at 3, 6, and 12 months after interventions. Bone mineral density (BMD) was detected before interventions and at 12 months after interventions. The incidence of falls and fractures, adverse events, and drug reactions were recorded for 12 months.Results: A total of 420 patients were allocated in the four groups: 98 cases into the NA VitD group (11 males, 87 females), 97 cases into the P-NA VitD group (13 males, 84 females), 99 cases in the A VitD group (15 males, 84 females), and 98 cases into the P-A VitD group (11 males, 87 females). At 6 months after interventions, the SPPB of A VitD group significantly increased from 6.9 AE 1.9 to 8.0 AE 2.4 (P < 0.05), and the SPPB of A VitD group significantly increased from 7.2 AE 2.1 to 8.6 AE 1.7 (P < 0.05). At 6 months after interventions, MFES of P-NA VitD group 7.0 AE 1.6 to 7.6 AE 1.6 (P < 0.05), and MFES of P-A VitD group significantly increased from 6.7 AE 1.6 to 7.5 AE 1.6 (P < 0.05). At 12 months after interventions, SPPB of all groups, grip strength, and MFES of P-NA VitD group, A VitD group, P-A VitD group were significantly improved (P < 0.05). The BMD of lumbar vertebrae of A VitD group significantly increased from 0.742 AE 0.042 to 0.776 AE 0.039, and P-A VitD group significantly increased from 0.743 AE 0.048 to 0.783 AE 0.042 (P < 0.05). No serious adverse events occurred during the 12 months of follow-up. Conclusion:Active vitamin D is better than non-active vitamin D to improve physical ability and the BMD of lumbar vertebrae and reduce the risk of falls.