Gfi-1 modulates HMGB1-Mediated autophagy to overcome oxaliplatin resistance in colorectal cancer.

Background: Resistance to oxaliplatin (L-OHP) is a major barrier in the treatment of colorectal cancer (CRC). Autophagy is the main cause of L-OHP tolerance in CRC cells. Method: The human colon cancer cell lines HCT116 and SW480 were treated with L-OHP to obtain the drug-resistant cell lines HCT116/L-OHP and SW480/L-OHP, respectively. To probe the relationship between autophagy and L-OHP tolerance of growth factor independent 1 (Gfi-1) and high-mobility group protein 1 (HMGB1) in CRC cells, gene knockout or overexpression was performed, and Western blotting was used to determine the levels of drug tolerance interrelated proteins. Transwell and CCK-8 assays were employed to analyze the proliferation of cancer cells. Immunofluorescence detection of LC3 reflected autophagy levels. Finally, the relationship between Gfi-1 and HMGB1 was detected by chromatin immunoprecipitation (ChIP). Result: Compared to normal CRC cells, L-OHP-tolerant CRC cells exhibited greater autophagy (8.2 times greater in HCT116/L-OHP cells and 7.4 times greater in SW480/L-OHP cells). In addition, we detected low levels of Gfi-1 (0.6-fold for HCT116/L-OHP cells and 0.4-fold for SW480/L-OHP cells), and OE-Gfi-1 decreased HMGB1 levels (0.6-fold for HCT116/L-OHP + OE-Gfi-1 cells and 0.5-fold for SW480/L-OHP + OE-Gfi-1 cells). The inhibition of Gfi-1 further enhanced cell viability (1.7 times in HCT116+sh-Gfi-1 cells and 1.2 times in SW480+sh-Gfi-1 cells) and invasion (1.8 times in HCT116+sh-Gfi-1 cells and 2.1 times in SW480+sh-Gfi-1 cells) in CRC cells, thus promoting oxaliplatin resistance in these cells. The autophagy inhibitor 3-MA reversed the above effects. Furthermore, we noted that Gfi-1 can restrain HMGB1 expression by binding to its promoter (0.5 times in HCT116+OE-Gfi-1 cells and 0.5 times in SW480+OE-Gfi-1 cells). The inhibitory influence of 3-MA on HMGB1 reversed the influence of Gfi-1 on autophagy and malignant progression in CRC cells. Conclusion: Our study suggested that Gfi-1 inhibited HMGB1 to reduce CRC autophagy levels, increasing CRC sensitivity to L-OHP.

Hypothetical Interventions for Falls Among Older Adults: An Application of the Parametric G-Formula.

Introduction: Falls, which have a higher incidence and mortality due to accidental injuries, are a major global health challenge. The effects of lifestyle factor, health indicator, psychological condition, and functional status interventions on the risk of falls are unknown and the conventional regression model would not adjust for the confounders. This study aimed to evaluate the 4-year risk of falls on the basis of these hypothetical interventions among Chinese older adults. Methods: Data were obtained from 9,692 aged 65 years and over older adults in the China Health and Retirement Longitudinal Study wave, from 2011 to 2015. We used the parametric g-formula to evaluate the risk of falls on the basis of independent hypothetical interventions of sleep duration, social activities, smoking status, drinking status, body mass index (BMI), systolic blood pressure (SBP), vision, depression, activities of daily living (ADL), and their different joint intervention combinations. Results: During the follow-up of 4 years, we documented 1,569 falls. The observed risk of falls was 23.58%. The risk ratios (95% confidence intervals [CIs]) of falls under the intensive hypothetical interventions on increasing sleep duration, participating in more social activities, quit smoking and drinking, reducing BMI and SBP, better vision, alleviating depressive symptoms, and improving ADL capability were 0.93 (0.87-0.96), 0.88 (0.79-0.92), 0.98 (0.95-1.03), 0.97 (0.95-1.02), 0.92 (0.86-1.03), 0.93 (0.87-1.04), 0.86 (0.74-0.91), 0.91 (0.85-0.96), and 0.79 (0.74-0.85), respectively. The feasible and intensive joint hypothetical intervention reduced the 4-year fall risk by 22% (95% CI: 0.52-0.91) and 33% (95% CI: 0.56-0.72), respectively. Conclusions: Hypothetical interventions for increasing sleep duration, participating in more social activities, better vision, alleviating depressive symptoms, and improving ADL capability help protect older adults from falls. Our findings suggest that a combination of lifestyle factors, health indicators, psychological conditions, and functional status may prove to be an effective strategy for preventing falls among older adults.

[Blocking intrauterine infection by telbivudine in pregnant chronic hepatitis B patients].

OBJECTIVE: To investigate the efficacy of telbivudine on intrauterine hepatitis B virus (HBV) infection during the last stage of pregnancy. METHODS: 61 pregnant chronic hepatitis B (CHB) patients were enrolled and 31 patients were treated by telbivudine 600 mg once daily, 30 patients in the control group were not received antiviral treatment. Maternal HBV DNA level and the HBsAg positive rate in newborns were investigated. RESULTS: The levels of serum HBV DNA in patients treated with Telbivudine were significantly reduced (t = 19.09, P less than 0.01). Compared with the control group, serum HBV DNA levels were significantly lower in telbivudine treated patients than those in the control group before parturition (t = 23.64, P less than 0.01). The infection rate of 7-month newborns were 0 and 13.33% (4/30), in telbivudine group and control group, respectively (x2 = 4.29, probability value less than 0.05). CONCLUSIONS: Telbivudine treatment can block intrauterine infection in pregnant chronic hepatitis B patients.

Association of polymorphisms in the MyD88, IRAK4 and TRAF6 genes and susceptibility to type 2 diabetes mellitus and diabetic nephropathy in a southern Han Chinese population.

Type 2 diabetes mellitus (T2DM) has been linked to a state of low-grade inflammation resulting from abnormalities in the innate immune pathway. MyD88 is an essential adaptor protein for TLR signaling, which is involved in activating NF-κB through IRAK4 and TRAF6. To investigate the effects of the MyD88, IRAK4 and TRAF6 polymorphisms in the susceptibility of T2DM and diabetic vascular complications, eight SNPs were analyzed in 553 T2DM patients and 553 matched healthy controls. Gene-gene interactions and haplotype associations were also evaluated. We found a significant increased risk of T2DM for the AG genotype of rs6853 in MyD88 gene and the CT genotype of rs4251532 in IRAK4 gene. Significant association was also found between rs16928973 in TRAF6 gene and diabetic nephropathy (DN) under the allelic model. Moreover, the TA haplotype in TRAF6 was negatively associated with DN. No significant gene-gene interactions were found. In conclusion, our results indicate that the polymorphisms in TLR-MyD88-NF-κB signaling pathway confer genetic susceptibility to T2DM and DN.

The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis.

Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29-1.79) and 1.39 (95 % CI 1.11-1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.