Effect of polymorphisms in drug metabolism and transportation on plasma concentration of atorvastatin and its metabolites in patients with chronic kidney disease.

Dyslipidemia due to renal insufficiency is a common complication in patients with chronic kidney diseases (CKD), and a major risk factor for the development of cardiovascular events. Atorvastatin (AT) is mainly used in the treatment of dyslipidemia in patients with CKD. However, response to the atorvastatin varies inter-individually in clinical applications. We examined the association between polymorphisms in genes involved in drug metabolism and transport, and plasma concentrations of atorvastatin and its metabolites (2-hydroxy atorvastatin (2-AT), 2-hydroxy atorvastatin lactone (2-ATL), 4-hydroxy atorvastatin (4-AT), 4-hydroxy atorvastatin lactone (4-ATL), atorvastatin lactone (ATL)) in kidney diseases patients. Genotypes were determined using TaqMan real time PCR in 212 CKD patients, treated with 20 mg of atorvastatin daily for 6 weeks. The steady state plasma concentrations of atorvastatin and its metabolites were quantified using ultraperformance liquid chromatography in combination with triple quadrupole mass spectrometry (UPLC-MS/MS). Univariate and multivariate analyses showed the variant in ABCC4 (rs3742106) was associated with decreased concentrations of AT and its metabolites (2-AT+2-ATL: ß = -0.162, p = 0.028 in the dominant model; AT+2-AT+4-AT: ß = -0.212, p = 0.028 in the genotype model), while patients carrying the variant allele ABCC4-rs868853 (ß = 0.177, p = 0.011) or NR1I2-rs6785049 (ß = 0.123, p = 0.044) had higher concentrations of 2-AT+2-ATL in plasma compared with homozygous wildtype carriers. Luciferase activity was enhanced in HepG2 cells harboring a construct expressing the rs3742106-T allele or the rs868853-G allele (p < 0.05 for each) compared with a construct expressing the rs3742106G or the rs868853-A allele. These findings suggest that two functional polymorphisms in the ABCC4 gene may affect transcriptional activity, thereby directly or indirectly affecting release of AT and its metabolites from hepatocytes into the circulation.

High expression of forkhead box M1 (FOXM1) is a poor prognostic biomarker in lung adenocarcinoma.

BACKGROUND: Forkhead box M1 (FOXM1) is closely related to the formation and development of cancer. Because of differences in cellular origin, lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) usually exhibit different signatures. Therefore, it is essential to investigate the abnormalities of FOXM1 in the two subtypes separately. METHODS: Through the Oncomine and TCGA databases, we investigated the expression of FOXM1 mRNA, its prognostic value and possible mechanisms leading to its dysregulation. Furthermore, networks involving FOXM1 and its significantly altered neighboring genes were identified using the cBioPortal database. GO and KEGG enrichment analyses were performed using DAVID. RESULTS: Expression of FOXM1 mRNA was higher in lung tumor tissues than in normal tissues, and higher in SCC tissues than in ADC tissues. FOXM1 mRNA expression was correlated with N stage, TNM stage, age, sex and smoking history in ADC, but only correlated with N stage, age and sex in SCC. Survival analysis indicated that high expression of FOXM1 mRNA resulted to poor overall survival (OS) for ADC patients, but not for SCC patients. Cox regression analysis confirmed that FOXM1 mRNA expression was an independent prognostic indicator for ADC patients, and regression analysis identified a moderately positive correlation between FOXM1 mRNA levels and copy number alterations (CNAs), but a weakly negative association with DNA methylation. FOXM1 was mainly involved in cell cycle regulation, G2/M transition, G1/S transition and p53, PI3K-Akt and TGF-beta signaling pathway. CONCLUSIONS: High expression of FOXM1 mRNA might be an independent biomarker of poor OS in ADC patients.

[Application of perfusion of low molecular dextran via splenic artery in portal azygous devascularization for portal hypertension].

OBJECTIVE: To evaluate the effects of the perfusion of low molecular dextran via the splenic artery in portal azygous devascularization for portal hypertension in the prevention from portal vein thrombosis. METHODS: A total of 92 patients with portal hypertension were randomly divided into a control group (46 cases) that received the extensive devascularization around the cardia, and a trial group (46 cases) that received the above-mentioned operation and the perfusion of low molecular dextran via the splenic artery. The incidence of portal vein thrombus after the operation and the preoperative and postoperative blood transfusion were observed and the results were analyzed and compared between the two groups. RESULTS: The incidence of thrombosis and blood transfusion were 26.1% (12/46) and CRBC 4~6 U respectively in the control group, while those were 4.3% (2/46) and CRBC 2~3 U respectively in the trial group. The differences were statistically significant (P < 0.05). CONCLUSION: The perfusion of low molecular dextran via the splenic artery in portal azygous devascularization for portal hypertension is effective and safe in the prevention from portal vein thrombosis.

[Thrombogenesis and its treatment in portal system after devascularization].

OBJECTIVE: To discuss the occurrence of thrombosis in portal system of patients with cirrhotic portal hypertension after devascularization and the methods for treatment and prevention. METHODS: The clinical data of 113 patients with cirrhotic portal hypertension after the devascularization were collected and analyzed retrospectively, and the occurrence time, parts as well as the treatment and prevention methods were discussed. RESULTS: Among the 113 patients, 33 of them were found with thrombosis in their portal system, and the occurrence rate was 29.2%. The occurrence time of thrombosis was 2-15 days post-devascularization, and the median time was 6 days post-operation. Among the 33 cases with thrombosis, there were 19 cases of splenic vein thrombosis, 10 cases of portal thrombosis, and 4 cases of both of them. After the thrombolytic therapy, the thrombosises in 30 cases disappeared. CONCLUSIONS: Most of the thrombosises in portal system happen in splenic vein post-devascularization. Avoiding clamping the trunk of splenic vein in the operation and taking thrombolytic therapy at the early stage after the operation can effectively prevent the occurrence of thrombosis.