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.

No abstract

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.

Using 11 years of county-level panel data, fixed effect models are estimated to evaluate the impact of the Safe Motherhood (SM) Program in China. Propensity score matching is used to select comparable factual and counterfactual counties. Out of 2013 counties in China, 283 are selected for the treatment group and 1051 for the control group. The results support the causal relationship between the program and its targeted outcomes and the partial effects increases as years of exposure in the program: 7 years' treatment of the program increases hospital delivery rate by 3.992 per 100 live births and decreases Maternal mortality ratio (MMR) due to hemorrhage by 10.229 per 100,000 live births. Further modeling supports the conclusion that the program reduces MMR by enhancing MCH care. With an average annual incremental unit cost for the program of about 318.0 thousand RMB (39.8 thousand USD) per county, we conclude that the SM Program is effective in reducing MMR through the enhancement of hospital delivery.

Testicular dysfunction is one of the serious secondary complications in diabetes. Lycium barbarum polysaccharide (LBP) has long been considered to possess a wide range of beneficial properties including antiaging, anticancer and reproductive-enhancing. Abnormal autophagy was reported to play a significant role in accelerating diabetic reproductive injury. However, the autophagy regulation mechanism of LBP on diabetic testicular dysfunction is incompletely understood. We investigate the protective effects of LBP on diabetic testicular dysfunction and its underlying mechanism with different approaches. Protective effects of LBP (40 mg/kg) on testicular functions were assessed through the use of sperm parameters, testosterone levels and hematoxylin and eosin staining. Antioxidant capacity and serum malondialdehyde levels were determined using assay kits. Immune intensity of Beclin-1 and LC3I in testes was detected by immunofluorescence staining. Western blot analysis was used to detect expressions of p-PI3K, Akt, p-Akt, Beclin-1, LC3I and LC3II proteins. Q-PCR was used to evaluate Beclin-1 and LC3I mRNA expressions in testis. Administration of LBP (40 mg/kg) considerably recovered testicular function, obviously improved testicular histopathologic structure and significantly increased antioxidant enzyme activities. Immunofluorescence staining showed that immune intensity of Beclin-1 and LC3I significantly decreased in the LBP 40 mg/kg group. The results of Q-PCR and western blot analysis showed that LBP 40 mg/kg significantly downregulated Beclin-1 and LC3I protein expressions upregulated p-PI3K and p-Akt protein expressions and decreased Beclin-1 and LC3I mRNA expressions compared with diabetic mice. In conclusion, inhibition of PI3K/Akt pathway-mediated testicular excessive autophagy may be a target for protective effects of LBP on diabetic testicular dysfunction.

No abstract

The aim of the study is to investigate the association of vitamin D receptor (VDR) gene polymorphism, additional gene-gene interaction, and haplotype combination with systemic lupus erythematosus (SLE) risk. Pairwise linkage disequilibrium (LD) analysis was conducted using SNPstats. The association between four SNPs within VDR gene and SLE risk was investigated by logistic regression. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the interaction among four SNPs. Four SNPs within VDR gene were selected for genotyping in this study, including rs2228570, rs1544410, rs7975232, and rs731236. The T allele of rs2228570 and the G allele of the rs1544410 were associated with increased MM risk, adjusted ORs (95%CI) were 1.61(1.25-2.11) and 1.78 (1.34-2.23), respectively. GMDR analysis suggested a significant two-locus model (P = 0.0010) involving rs1544410 and rs2228570, and in this model, the cross-validation consistency was 10/10, and the testing accuracy was 62.70%. The haplotype analysis indicated that the most common haplotype was rs1544410-A and rs7975232-G haplotype, the frequencies of which were 0.4701 and 0.5467 in case and control group. Haplotype containing the rs1544410-G and rs7975232-T alleles were associated with increased SLE risk, OR (95%CI) = 2.08 (1.47-2.72), P < 0.001. We found that rs2228570 and rs1544410 within VDR gene, their interaction and haplotype containing the rs1544410-G and rs7975232-T alleles were all associated with increased SLE risk.