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Glioblastoma multiforme (GBM) is the most commonly occurring brain cancer, and is characterized by its poor patient outcomes. The present study examined the mRNA expression levels of the transient receptor potential melastatin (TRPM) family in various types of cancer using the ONCOMINE database, along with their corresponding expression profiles in an array of cancer cell lines based on the Cancer Cell Line Encyclopedia (CCLE) datasets. Kaplan-Meier plotter survival analysis via the Chinese Glioma Genome Atlas (CGGA) database was also used to evaluate the prognostic value of transient receptor potential melastatin 8 (TRPM8). For the activity test on the TRPM8 channel, patch-clamp recordings and Ca 2+ measurements by fluorescence imaging of Fluo-4am were performed. Short hairpin RNA (shRNA) targeting TRPM8 was designed, synthesized and then transfected into the U251 cells via Lipofectamine 2000. The expression of extracellular singnal-regulated kinase (ERK), cyclin D1 and Bcl-2 were detected by performing western blotting and immunofluorescence. The apoptosis, proliferation and invasion of glioma cells were detected by using flow cytometry, and CCK-8 and Transwell invasion assays. In the present study, TRPM8 was distinctively upregulated in GBM cell lines. TRPM8 is functional and has the characteristic of outward rectification, which was verified via electrophysiology and Ca 2+ fluorescence imaging in U251 cells. The western blot and immunofluorescence results revealed that the expression of ERK, cyclin D1 and Bcl-2 were decreased in the shRNA interference group. The CCK-8 assay demonstrated that the proliferation ability of U251 cells in the U251/TRPM8 group was higher than that in the U251 group and U251/Con group (P<0.05). The result of the Transwell invasion assay indicated that the invasion of human glioblastoma U251 cells was positively correlated with the expression level of TRPM8. Collectively, the results of the present study indicated that Ca 2+-permeable TRPM8 nonselective cation channels contribute to survival, proliferation, apoptosis, and local tumor invasion of glioblastoma. Therefore, TRPM8 is a promising biomarker for aggressiveness of GBM, and a potential target in future anti-glioblastoma therapies.

Cerebral ischemia/reperfusion (IR) after ischemic stroke causes deleterious microglial activation. Protein tyrosine phosphatase 1B (PTP1B) exacerbates neuroinflammation, yet the effect of the inhibition on microglial activation and cerebral IR injury is unknown. A cerebral IR rat model was induced by middle cerebral artery occlusion (MCAO) and reperfusion. The PTP1B inhibitor, sc-222227, was administered intracerebroventricularly. Neurologic deficits, infarct volume, and brain water content were examined. An in vitro oxygen glucose deprivation/reoxygenation (OGD/R) model was established in primary microglia and BV-2 cells. Microglial activation/polarization, endoplasmic reticulum (ER) stress, autophagy, and apoptosis were detected using western blot, immunohistology, ELISA, and real-time PCR. Protein interaction was assessed by a proximity ligation assay. The results showed a significant increase in microglial PTP1B expression after IR injury. Sc-222227 attenuated IR-induced microglial activation, ER stress, and autophagy and promoted M2 polarization. Upon OGD/R, sc-222227 mitigated microglial activation by inhibiting ER stress-dependent autophagy, the effect of which was abolished by PERK activation, and PERK inhibition attenuated microglial activation. The PTP1B-phosphorylated PERK protein interaction was significantly increased after OGD/R, but decreased upon sc-222227 treatment. Finally, sc-222227 mitigated neuronal damage and neurologic deficits after IR injury. Treatment targeting microglial PTP1B might be a potential therapeutic strategy for ischemic stroke treatment.

The Transient Receptor Potential Melastatin (TRPM) protein family members have been demonstrated to be involved in a variety of different types of human cancer. However, to the best of our knowledge, there has not yet been a systematic study regarding the mRNA expression of the TRPM protein family or its prognostic value in human cancer. The present study investigated TRPM expression and its prognostic value in various human cancer types via the Oncomine database, Kaplan-Meier plotter, and the PrognoScan and Gene Expression Profiling Interactive Analysis databases. It was revealed that the transcriptional levels of TRPM1, TRPM3 and TRPM6 were decreased in the majority of cancer tissues, while TRPM2 was increased in most cancer types. In addition, the high or low transcriptional levels of the TRPM protein family members were associated with survival outcomes of different types of solid tumors. The present study suggested that certain TRPM protein family members may serve as useful biomarkers for cancer prognosis and anticancer targets for cancer treatment.

Background - Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. Methods - We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were 18 years or older, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range (%TTR) of the international normalized ratio (INR) during the first 12 weeks after starting warfarin therapy. Results - A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher %TTR than the control group (58.8% vs. 53.2%, 95% confidence interval of group difference (95%CI): 1.1-10.2; P=0.01). The genotype-guided dosing group also achieved the target INR sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher %TTR during the first 12 weeks compared to the control group (60.8% vs. 48.9%; 95% CI: 1.1-24.4). The incidence of adverse events was low in both groups. Conclusions - The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China.

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These results confirm selectively induction of apoptosis and growth suppression by the mda-7/IL-24 gene with replication-incompetent adenovirus vector in human hepatocellular carcinoma cell line HepG2.