Impact of ABCB1 Polymorphisms on Lacosamide Serum Concentrations in Uygur Pediatric Patients With Epilepsy in China.

BACKGROUND: P-glycoprotein, encoded by ABCB1 (or MDR1), may contribute to drug resistance in epilepsy by limiting gastrointestinal absorption and brain access to antiseizure medications. The study aimed to evaluate the impact of ABCB1 polymorphisms on lacosamide (LCM) serum concentrations in Uygur pediatric patients with epilepsy. METHODS: The serum concentrations of LCM were determined by ultrahigh performance liquid chromatography, and the ABCB1 polymorphism was analyzed through polymerase chain reaction-fluorescence staining in situ hybridization. The χ2 test and the Fisher exact test were used to analyze the allelic and genotypic distributions of ABCB1 polymorphisms between the drug-resistant and drug-responsive patient groups. Differences in steady-state and dose-corrected LCM serum concentrations between different genotypes were analyzed using the one-way analysis of variance and the Mann-Whitney test. RESULTS: A total of 131 Uygur children with epilepsy were analyzed, and of them, 41 demonstrated drug resistance. The frequency of the GT genotype of ABCB1 G2677T/A was significantly higher in the drug-resistant group than that in the drug-responsive group (P < 0.05, OR = 1.966, 95% CI, 1.060-3.647). Patients with the G2677T/A-AT genotype had a statistically significantly lower concentration-to-dose (CD) value than patients with the G2677T/A-GG genotype (mean: 0.6 ± 0.2 versus 0.8 ± 0.5 mcg/mL per mg/kg, P < 0.001). Significantly lower LCM serum concentrations were observed in ABCB1 C3435T CT and TT genotype carriers than those in the CC carriers (P = 0.008 and P = 0.002), and a significantly lower LCM CD value was observed in ABCB1 C3435T CT genotype carriers than that in the CC carriers (P = 0.042). CONCLUSIONS: ABCB1 G2677T/A and C3435T polymorphisms may affect LCM serum concentrations and treatment efficacy in Uygur pediatric patients with epilepsy, leading to drug resistance in pediatric patients.

Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal.

The negative role of the activated stimulator of IFN genes (STING) has been uncovered in autoinflammatory disease and cancer. However, the role of STING in virus-related carcinogenesis is not well known. Herein, HPV(+) tongue squamous cell carcinoma (TSCC) (n=25) and HPV(-) TSCC samples (n=25) were randomly collected and were verified by in situ hybridization (ISH) and p16 immunohistochemistry (IHC) to assess the expression and activated status of STING through IHC. The results showed that the expression of STING was up-regulated during the development of TSCC. Interestingly, although the expression of STING showed no difference between HPV(+/-) TSCC samples, the activated status of STING with dark staining around the nucleus was observed in HPV(+) TSCC samples. The role of activated STING was analyzed in three cell lines by siRNA and indicated that activated STING had no impact on cell viability or apoptosis but promoted the induction of several immunosuppressive cytokines, e.g., IL-10, IDO and CCL22, which facilitated the infiltration of regulatory T cells (Tregs). Moreover, increased infiltration of Foxp3(+) Tregs along with increased expression of CCL22 was confirmed in HPV(+) TSCC samples. An inhibitor of the MAPK/AP-1 pathway (U0126) and the silencing of c-jun significantly suppressed CCL22 induction and the recruitment of Tregs by activated STING. Furthermore, down-regulated miR-27 was verified in independent fresh TSCC samples (n=50) and eight cell lines, which enhanced STING activation and led to increased CCL22 expression for Tregs recruitment in the TSCC microenvironment. Therefore, our findings provided distinct insight into the side effects of activated STING in HPV-related carcinogenesis.

Optimal design of blade in pump as turbine based on multidisciplinary feasible method.

In order to make the pump as turbine (PAT) run efficiently and safely, a multidisciplinary optimization design method for PAT blade, which gives consideration to both the hydraulic and intensity performances, is proposed based on multidisciplinary feasibility (MDF) optimization strategy. This method includes blade parametric design, Latin Hypercube Sampling (LHS) experimental design, CFD technology, FEA technology, GA-BP neural network and NSGA-II algorithm. Specifically, a parameterized PAT blade with cubic non-uniform B-spline curve is adopted, and the control point of blade geometry is taken as the design variable. The LHS experimental design method obtains the sample points of training GA-BP neural network in the design space of variables. The hydraulic performance of each sample point (including the hydraulic pressure load on the blade surface) and the strength performance analysis of blades are completed by CFD and FEA technology respectively. In order to save calculation time of the whole optimization design, the multi-disciplinary performance analysis of each sample in the optimization process is completed by single-coupling method. Then, GA-BP neural network is trained. Finally, the multi-disciplinary optimization design problem of PAT blade is solved by the optimization technology combining GA-BP neural network and NSGA-II algorithm. Based on this optimization method, the PAT blade is optimized and improved. The efficiency of the optimized PAT is improved by 1.71% and the maximum static stress on the blade is reduced by 7.98%, which shows that this method is feasible.