Pharmacogenomics Journal最新文献

Cisplatin is widely used as a conventional chemotherapy drug for lung adenocarcinoma (LUAD) patients. However, the chemical resistance greatly limits its therapeutic potential. The study aimed to uncover the specific role and new mechanisms of CPT1B in the cisplatin resistance of LUAD. Bioinformatics analysis was utilized to analyze the expression level and enriched pathway of CPT1B in LUAD. The expression of CPT1B in LUAD cells was determined by utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB). The cisplatin resistance in LUAD was measured with IC₅₀ values obtained from the CCK-8 assay. We used the corresponding reagent kit and WB analysis to determine the levels of triglycerides, cholesterol, phospholipids, fatty acid β-oxidation (FAO) rate, and expression of lipid metabolism-related proteins. Finally, the regulation relationship between CPT1B and ZNF263 was confirmed through bioinformatics analysis, dual-luciferase, and chromatin immunoprecipitation assays. The present investigation revealed that CPT1B was upregulated in LUAD, participating in fatty acid metabolism pathways. In vitro studies have shown that upregulation of CPT1B promoted cisplatin resistance in LUAD cells. This promotion effect induced by the high expression of CPT1B on cisplatin resistance in LUAD was weakened after the addition of the FAO inhibitor Etomoxir. Mechanistically, ZNF263 was capable of binding to the promoter of CPT1B to activate its transcription, thereby enhancing FAO and promoting cisplatin resistance in LUAD cells. In summary, ZNF263 enhances cisplatin resistance in LUAD cells by upregulating CPT1B expression. This study enriches the molecular mechanisms of LUAD chemotherapy resistance and provides new directions for exploring therapeutic targets for LUAD.

CYP2C19 loss of function (LOF) carriers undergoing percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. PCI patients in TAILOR-PCI were randomized to clopidogrel or genotype-guided (GG) therapy in which LOF carriers received ticagrelor and non-carriers clopidogrel. Direct medical costs associated with a GG approach have not been described before. TAILOR-PCI participants for whom direct medical costs were available for the duration from the date of PCI to one-year post PCI were included. Primary cost estimates were obtained from the Mayo Clinic Cost Data Warehouse. There were no differences in direct medical costs between the GG and clopidogrel groups (mean $20,682 versus $19,747, p = 0.11) however total costs were greater in the GG group (mean $21,245 versus $19,891, p = 0.02) which was primarily driven by ticagrelor costs. In conclusion the increased expense of a GG strategy post PCI as compared to clopidogrel for all is primarily driven by the cost of ticagrelor.

Our study investigated the impact of genetic variations on metformin glycemic response in a cohort from the Rotterdam Study, comprising 14,926 individuals followed for up to 27 years. Among 1285 metformin users of European ancestry, using linear mixed models, we analyzed the association of single nucleotide polymorphisms (SNPs) and a Polygenic Risk Score (PRS) with glycemic response, measured by changes in metformin dosage or HbA1c levels. While individual genetic variants showed no significant association, rs622342 on SLC2A1 correlated with increased glycemic response only in metformin monotherapy patients (β = -2.09, P-value < 0.001). The collective effect of variants, as represented by PRS, weakly correlated with changes in metformin dosage (β = 0.023, P-value = 0.027). Synergistic interaction was observed between rs7124355 and rs8192675. Our findings suggest that while higher PRS correlates with increased metformin dosage, its modest effect size limits clinical utility, emphasizing the need for future research in diverse populations to refine genetic risk models.