Human Umbilical Cord MSC Delivered-Soluble TRAIL Inhibits the Proliferation and Promotes Apoptosis of B-ALL Cell In Vitro and In Vivo.

The TNF-related apoptosis-inducing ligand (TRAIL) could induce apoptosis of leukemic cells, while showed no cytotoxic effect on normal cells. One of the limitations for application of recombinant TRAIL (rhTRAIL) in leukemia treatment is that the serum half-life of this protein is short. Gene delivery is a good strategy to prolong the half-life of TRAIL. In this study, we genetically engineered umbilical cord-MSCs to continuously express and secrete soluble TRAIL (MSC-sTRAIL), to investigate the effects of MSC-sTRAIL on B-cell acute lymphocytic leukemia (B-ALL) cells. In vitro, MSC-sTRAIL significantly inhibited the proliferation of B-ALL cells by suppressing PI3K/AKT and MEK/ERK signaling pathways, and induced apoptosis of B-ALL cells via the caspase cascade-mediated pathway and mitochondrial-mediated pathway. In vivo, MSC-sTRAIL dramatically inhibited B-ALL cell growth. Meanwhile, B-ALL-induced splenic and renal injuries were significantly alleviated after MSC-sTRAIL treatment. Moreover, the serum levels of MSC-secreted sTRAIL were still high in MSC-sTRAIL treated mice, indicating an extended half-life of sTRAIL. Our study suggests that MSC delivered-TRAIL secretion is a potential therapeutic strategy for B-ALL treatment.

Impact of Vascular Endothelial Growth Factor Gene Polymorphisms and Their Interactions with Environmental Factors on Susceptibility to Renal Cell Carcinoma.

AIMS: This study aimed to investigate the association of single nucleotide polymorphisms (SNPs) within vascular endothelial growth factor (VEGF) gene and additional gene-environment interaction with renal cell carcinoma (RCC) risk. METHODS: PCR-restriction fragment length polymorphism was performed to detect SNPs. Hardy-Weinberg equilibrium and allele frequencies in cases and controls were calculated using SNPStats (http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among 4 SNPs, smoking, and alcohol drinking. Logistic regression was performed to investigate the association between 4 SNPs within VEGF gene, additional gene-smoking interaction, and RCC risk. RESULTS: RCC risk was significantly higher in carriers with the T allele of rs833061 within VEGF gene than those with CC genotype (CT+TT vs. CC) {adjusted odds ratio (OR) (95% confidence interval [CI]) = 1.71 (1.17-2.32), p = 0.002} and higher in carriers with the A allele of rs699947 within VEGF gene than those with GG genotype (GA+AA vs. GG) (adjusted OR [95% CI] = 1.64 [1.27-2.10], p < 0.001). GMDR analysis indicated a significant 2-locus model (p = 0.0010) involving rs833061 and smoking. The cross-validation consistency of the 2-locus model was 10/10, and the testing accuracy was 60.72%. Current smokers with rs833061-CT+TT genotype had the highest RCC risk, compared to never smokers with rs833061-CC genotype within VEGF gene (OR [95% CI] = 3.02 [1.84-4.23], p < 0.001). CONCLUSIONS: We found that the T allele of rs833061 and the A allele of rs699947 within VEGF gene, and the interaction between rs833061 and smoking were all associated with increased RCC risk.

Associations between Folate Metabolism Enzyme Polymorphisms and Lung Cancer: A Meta-Analysis.

Some previous studies already investigated potential associations between folate metabolism enzyme polymorphisms and lung cancer (LC). However, the results of these studies were inconsistent. Thus, we performed this meta-analysis to explore associations between folate metabolism enzyme polymorphisms and LC in a larger pooled population. Systematic literature research of PubMed, WOS, Embase and CNKI was performed to identify eligible studies. Review Manager Version 5.3.3 was used to conduct statistical analyses. Totally 37 genetic association studies were included for analyses. The pooled analyses showed that MTRR rs1801394 (dominant model: p = 0.01; recessive model: p = 0.04; allele model: p = 0.005) and MTHFR rs1801133 (dominant model: p = 0.008; recessive model: p = 0.0003; allele model: p = 0.0002) polymorphisms were both significantly associated with susceptibility to LC in overall population. Subgroup analyses revealed similar significant findings for MTHFR rs1801133 polymorphism in East Asians. Significant associations with LC were also observed for MTRR rs1801394 and MTHFR rs1801133 polymorphisms in smokers. In conclusion, this meta-analysis indicated that MTRR rs1801394 was significantly associated with LC in smokers, and MTHFR rs1801133 polymorphisms was also significantly associated with LC in smokers and East Asians. These results suggested that these two polymorphisms could be used to identify individuals at high risk of developing LC in certain populations.

Clinical significance and role of up-regulation of SERPINA3 expression in endometrial cancer.

BACKGROUND: Serpin peptidase inhibitor, clade A member 3 (SERPINA3) belongs to the serpin family with an inhibitory activity against proteases. Its aberrant expression has been observed in a wide range of tumor cells. However, its clinical significance and biological function in endometrial cancer have been rarely studied. We designed a study to determine the levels of SERPINA3 and its significance in patients with endometrial cancer. AIM: To investigate the clinical significance and role of SERPINA3 expression in endometrial cancer cells. METHODS: Eighty endometrial tissue samples collected from patients with endometrial cancer were included in an observation group and 80 paraffin-embedded tissues samples collected from patients with normal endometrial tissues undergoing myomectomy were employed as a control group between January 2014 and December 2018. The expression of SERPINA3 mRNA was detected by quantitative polymerase chain reaction (PCR) for all endometrial tissues included in the study. RESULTS: The positive expression rate of SERPINA3 protein in endometrial cancer cells was 71.25% in the observation group, which was significantly higher than that in the control group (31.25%; P < 0.05). There was no correlation between SERPINA3 protein in endometrial cancer cells and the age range at which women experienced menopause (P > 0.05). However, it was associated with pathological grade, clinical stage, vascular invasion, and lymph node metastasis (P < 0.05). Pathological grade, clinical stage, vascular invasion, and lymph node metastasis were independent prognostic factors for endometrial cancer. CONCLUSION: The follow-up study of SERPINA3 can be used as a prognostic biomarker for endometrial cancer and as one of the targets for bio-targeted therapy for endometrial cancer.