miR-125b reverses cisplatin resistance by regulating autophagy via targeting RORA/BNIP3L axis in lung adenocarcinoma

The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the clinic.It has been shown that microRNAs(miRNAs)play a significant role in tumor chemoresistance.In this study,miR-125b was identified as a specific cisplatin(DDP)-resistant gene in LUAD,as indicated by the bioinformatics analysis and the real-time quantitative PCR assay.The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time.MiR-125b decreased the A549/DDP proliferation,and the multiple drug resistance-and autophagy-related protein expression levels,which were all reversed by the inhibition of miR-125b.In addition,xenografts of human tumors in nude mice were suppressed by miR-125b,demonstrating that through autophagy regulation,miR-125b could reverse the DDP resistance in LUAD cells,both in vitro and in vivo.Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L,which in turn inhibited autophagy and reversed chemoresistance.Based on these findings,miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.

Positive Correlation between PMS2 Deficiency and PD-L1 Expression in Pancreatic Cancer

Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze the differential expression of MMR and PD-L1 genes in 33 common cancer types including pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded from the GEPIA and GEO databases to analyze the correlation between MMR genes and PD-L1, and the clinicopathological and survival information were downloaded from the TCGA databases to analyze the relationship between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis. Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected, and the protein expression levels of MMR and PD-L1 were detected by immunohistochemical assay. Furthermore, we analyzed the correlation between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and PMS2 were highly expressed in most cancer types including pancreatic cancer (P P = 0.012), clinical stage (I vs II: P = 0.016), MSH2 expression was related to clinical stage (P < 0.05), T stage (T3 vs T4: P = 0.039), and MSH3 expression was related to T stage (P < 0.05). Besides, both MSH2 expression (P P = 0.044) were significantly associated with prognosis. GEPIA data also showed that MSH2 expression was related to prognosis (P = 0.008). The correlation analysis revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1 both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1 was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2 was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697), MSH2 (P = 0.956), PMS2 (P = 0.341), and PD-L1 (P = 0.734) appeared to have no impact on overall survival among patients with pancreatic cancer. Conclusion: Both bioinformatics and real-world data showed that there were correlation between PMS2 deletion and PD-L1 expression, and correlation between MLH1, MSH2 and clinical stage.

Hopf bifurcation of nonlinear system with multisource stochastic factors

The article mainly explores the Hopf bifurcation of a kind of nonlinear system with Gaussian white noise excitation and bounded random parameter.Firstly,the nonlinear system with multisource stochastic fac-tors is reduced to an equivalent deterministic nonlinear system by the sequential orthogonal decomposi-tion method and the Karhunen-Loeve(K-L)decomposition theory.Secondly,the critical conditions about the Hopf bifurcation of the equivalent deterministic system are obtained.At the same time the influence of multisource stochastic factors on the Hopf bifurcation for the proposed system is explored.Finally,the theorical results are verified by the numerical simulations.