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The allele frequency of CYP3A4*4 was 3.32% among the hyperlipidemic patients from the Chinese mainland. CYP3A4*4 was an allelic variant related to a functional decrease of CYP3A4 activity, and *4 expression seemed to increase the lipid-lowering effects of simvastatin.

To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.Trial RegistrationClinicalTrials.gov NCT02065388

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Background: The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel that has been shown to promote tumor metastasis and progression. In this study, we determined the expression of TRPM7 in ovarian carcinomas and investigated its possible prognostic value. Materials and Methods: Samples were collected from 138 patients with ovarian cancer. Expression of TRPM7 was assessed by real-time PCR and immunohistochemistry, expressed with reference to an established scoring system and related to clinical pathological factors. Kaplan-Meier survival analysis was applied to estimate disease-free survival (DFS) and overall survival (OS). Univariate and multivariate cox regression analyses were performed to correlate TRPM7 expression levels with DFS and OS. Results: TRPM7 was highly expressed in ovarian carcinoma and significantly associated with decreased disease-free survival (DFS: median 20 months vs. 42 months, P=0.0002) and overall survival (OS: median 27 months vs. 46 months, P<0.001). Conclusion: Overexpression of TRPM7 expression is significantly associated with poor prognosis in patients with ovarian cancer.

Background/Aims: Rap1 interacting factor 1 (RIF1) was deemed to be involved in replication timing regulation and DNA damage response. However, little is known about the role of RIF1 in malignancies. Thus, this study aimed to investigate whether the expression of RIF1 is relevant to the response of epithelial ovarian cancer (EOC) patients to cisplatin chemotherapy and its underlying mechanism. Methods: Immunohistochemistry was used for detecting the expression of RIF1 in 72 human ovarian cancer tissues followed by association analysis of RIF1 expression with patients’ responses to platinum-based chemotherapy. The survival analysis of ovarian patients based on platinum chemotherapy was analyzed using online databases. RNA interference of RIF1 was carried out in OVCAR3 and A2780 cell lines, to determine the effect of lacking RIF1 expression on cellular responses to cisplatin by using MTS assay. The nucleotide excision repair (NER) capacity of these cells was assessed by using host-cell reactivation and UV sensitivity assay. Western Blot analysis was carried out to determine the effect of RIF1 on the proteins of NER and apoptosis signaling pathway by using RIF1 knockdown cells. BALB/c nude mice model was used for detection of response to cisplatin in vivo. Results: RIF1 expression was significantly associated with the response of ovarian patients to platinum-based chemotherapy (P< 0.01). In cohorts from online databases, high expression of RIF1 was associated with higher mortality of EOC patients based on platinum chemotherapy (P < 0.01). RIF1 knockdown increased sensitivity to cisplatin in EOC in vitro and in vivo. Deletion of RIF1 impaired the NER activity by inhibiting the NER proteins in ovarian cancer cells. Besides, knockdown of RIF1 enhanced cisplatin-induced apoptosis. Conclusions: RIF1 plays an important role in regulating the expression of NER proteins, which in turn contributes to cellular response to cisplatin and EOC patients’ response to platinum-based chemotherapy. RIF1 knockdown also promotes cisplatin-induced apoptosis. RIF1 may serve as a novel biomarker for predicting platinum-based chemosensitivity and the prognosis of EOC patients.

A high expression of CD44v6 has been reported in numerous malignant cancers, including stomach, prostate, lung and colon. However, the pathological role and the regulatory mechanisms of CD44v6 have yet to be elucidated. In the present study, the expression levels of CD44v6 were shown to be significantly higher in ovarian cancer tissues, as compared with adjacent normal tissues. Furthermore, the upregulated expression levels of CD44v6 were correlated with disease recurrence and poor survival in patients. The expression of CD44v6 was knocked down in the CAOV3 ovarian cell line, by transfection of a specific small hairpin RNA. The present study showed a correlation between the aggression, viability, invasion and migration of the ovarian cancer cells, with the expression of CD44v6. In addition, the expression of CD44v6 was positively correlated with the expression levels of β‑catenin and tumor growth factor‑β, which indicates that the effects of CD44v6 on ovarian cancer cell aggression may be mediated by these two signaling pathways. In conclusion, the present study provides a novel insight into the association between CD44v6 expression and ovarian cancer. CD44v6 may provide a novel target for the prognosis and treatment of ovarian cancer.

A sensitive, reliable and specific LC-MS-MS method was developed and validated for the identification and quantitation of all-trans retinoic acid (ATRA) in human plasma. Acitretin was used as the internal standard (IS). After liquid-liquid extraction of 500 μL plasma with methyl tert-butyl ether (MTBE), ATRA and the IS were chromatographed on a HyPURITY C18 column (150 mm × 2.1 mm, 5 μm) with the column temperature set at 40 °C. The mobile phase was consisted of 40% phase A (MTBE-methanol-acetic acid, 50:50:0.5, v/v) and 60% phase B (water-methanol-acetic acid, 50:50:0.5, v/v) with a flow rate of 0.3 mL/min. The API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM) mode via the positive electrospray ionization interface using the transition m/z 301.4 → 123.1 for ATRA and m/z 326.9 → 177.1 for IS, respectively. The calibration curve was linear over the range of 0.45-217.00 ng/mL (r ≥ 0.999) with a lower limit of quantitation (LLOQ) of 0.45 ng/mL. The intra-and inter-day precisions values were below 8% relative standard deviation and the accuracy was from