NPS-2143 inhibit glioma progression by suppressing autophagy through mediating AKT-mTOR pathway.

Gliomas are the most common tumours in the central nervous system. In the present study, we aimed to find a promising anti-glioma compound and investigate the underlying molecular mechanism. Glioma cells were subjected to the 50 candidate compounds at a final concentration of 10 µM for 72 h, and CCK-8 was used to evaluate their cytotoxicity. NPS-2143, an antagonist of calcium-sensing receptor (CASR), was selected for further study due to its potent cytotoxicity to glioma cells. Our results showed that NPS-2143 could inhibit the proliferation of glioma cells and induce G1 phase cell cycle arrest. Meanwhile, NPS-2143 could induce glioma cell apoptosis by increasing the caspase-3/6/9 activity. NPS-2143 impaired the immigration and invasion ability of glioma cells by regulating the epithelial-mesenchymal transition process. Mechanically, NPS-2143 could inhibit autophagy by mediating the AKT-mTOR pathway. Bioinformatic analysis showed that the prognosis of glioma patients with low expression of CASR mRNA was better than those with high expression of CASR mRNA. Gene set enrichment analysis showed that CASR was associated with cell adhesion molecules and lysosomes in glioma. The nude mice xenograft model showed NPS-2143 could suppress glioma growth in vivo. In conclusion, NPS-2143 can suppress the glioma progression by inhibiting autophagy.

UPLC-MS/MS method for the determination of voriconazole plasma concentration from pediatric patients with hematologic tumors: An application toward personalized therapy.

Untreated invasive fungal infection is one of the important risk factors affecting the prognosis of pediatric patients with hematologic tumors. Voriconazole (VOR) is the first-line antifungal drug for the treatment of Aspergillus infections. In order to reduce the risk of adverse drug reactions while producing an ideal antifungal effect, therapeutic drug monitoring was performed to maintain the VOR plasma concentration in a range of 1,000-5,500 ng/ml. In the present study, a reliable, accurate, sensitive and quick ultra-high performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of the VOR level. Protein precipitation was performed using acetonitrile, and then the chromatographic separation was carried out by UPLC using a C18 column with the gradient mobile phases comprising 0.1% methanoic acid in acetonitrile (A) and 0.1% methanoic acid in water (B). In the selective reaction monitor mode, the mass spectrometric detection was carried out using an TSQ Endura triple quadruple mass spectrometer. The performance of this UPLC-MS/MS method was validated as per the National Medical Products Administration for Bioanalytical Method Validation. Additionally, the plasma concentrations of VOR in pediatric patients with hematologic tumors were detected using this method, and the analyzed results were used for personalized therapy.

Aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the progression of gliomas.

Gliomas are the most common form of malignant tumour in the central nervous system. However, the molecular mechanism of the tumorigenesis and progression of gliomas remains unclear. In this study, we used the GEO database to identify genes differentially expressed in gliomas and predict the prognosis of glioma. We observed that ASPM mRNA was increased obviously in glioma tissue, and higher ASPM mRNA expression predicted worse disease prognosis. ASPM was highly expressed in glioma cell lines U87-MG and U251, and knockdown of ASPM expression in these cells significantly repressed the proliferation, migration and invasion ability and induced G0/G1 phase arrest. In addition, down-regulation of ASPM suppressed the growth of glioma in nude mice. Five potential binding sites for transcription factor FoxM1 were predicted in the ASPM promoter. FoxM1 overexpression significantly increased the expression of ASPM and promoted the proliferation and migration of glioma cells, which was abolished by ASPM ablation. ChIP and dual-luciferase reporter analysis confirmed that FoxM1 bound to the ASPM promoter at -236 to -230 bp and -1354 to -1348 bp and activated the transcription of ASPM directly. Collectively, our results demonstrated for the first time that aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the malignant properties of glioma cells.

Usefulness of preoperative coronary computed tomography angiography in high risk non-cardiovascular surgery old patients with unknown or suspected coronary artery disease.

BACKGROUND: Cumulative evidence has shown that the non-invasive modality of coronary computed tomography angiography (CCTA) has evolved as an alternative to invasive coronary angiography, which can be used to quantify plaque burden and stenosis and identify vulnerable plaque, assisting in diagnosis, prognosis and treatment. With the increasing elderly population, many patients scheduled for non-cardiovascular surgery may have concomitant coronary artery disease (CAD). The aim of this study was to investigate the usefulness of preoperative CCTA to rule out or detect significant CAD in this cohort of patients and the impact of CCTA results to clinical decision-making. METHODS: 841 older patients (age 69.5 ± 5.8 years, 74.6% males) with high risk non-cardiovascular surgery including 771 patients with unknown CAD and 70 patients with suspected CAD who underwent preoperative CCTA were retrospectively enrolled. Multivariate logistic regression analysis was performed to determine predictors of significant CAD and the event of cancelling scheduled surgery in patients with significant CAD. RESULTS: 677 (80.5%) patients had non-significant CAD and 164 (19.5%) patients had significant CAD. Single-, 2-, and 3- vessel disease was found in 103 (12.2%), 45 (5.4%) and 16 (1.9%) patients, respectively. Multivariate analysis demonstrated that positive ECG analysis and Agatston score were independently associated with significant CAD, and the optimal cutoff of Agatston score was 195.9. The event of cancelling scheduled surgery was increased consistently according to the severity of stenosis and number of obstructive major coronary artery. Multivariate analysis showed that the degree of stenosis was the only independent predictor for cancelling scheduled surgery. In addition, medication using at perioperative period increased consistently according to the severity of stenosis. CONCLUSIONS: In older patients referred for high risk non-cardiovascular surgery, preoperative CCTA was useful to rule out or detect significant CAD and subsequently influence patient disposal. However, it might be unnecessary for patients with negative ECG and low Agatston score. Trial registration Retrospectively registered.

Factors influencing cognitive reactivity among young adults at high risk for depression in China: a cross-sectional study.

BACKGROUND: Understanding the factors influencing cognitive reactivity (CR) may help identify individuals at risk for first episode depression and relapse and facilitate routine access to preventative treatments. However, few studies have examined the relationship between CR and depression in Asian countries. This study was performed to assess the current status of CR among Chinese young adults and explore influencing factors. METHODS: A national cross-sectional online study using convenience sampling was conducted among 1597 healthy young adults in China (response rate: 93.94%) with a mean age of 24.34 (SD = 5.76) years. RESULTS: The mean CR score was 51.36 ± 18.97 (range 0-130). Binary logistic regression showed that a low level of CR was associated with the following factors: high self-compassion, high social support, high resilience, high monthly household income, and living in a rural area, with odds ratios (ORs) ranging from 0.14 to 0.70. Young adults in full-time employment, experiencing poor sleep, with high neuroticism, who reported frequent sad mood, and who had a high intensity of negative life events had increased CR to depression, with ORs ranging from 1.18 to 6.66. The prediction probability of these factors was 75.40%. Causal relationships among the influencing factors and CR could not be explored. CONCLUSIONS: The self-reported CR levels among Chinese young adults were moderate. Enhancing self-compassion, resilience, and social support for young adults and reducing negative life events, neuroticism, and poor sleep may help decrease CR. These findings may help healthcare providers or researchers determine how to cultivate and improve the CR of young adults by establishing documented policies and/or improving intervention efficacies.

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas.

BACKGROUND/AIMS: In the current study, we performed an integrated analysis of genome-wide methylation and gene expression data to find novel prognostic genes for lower-grade gliomas (LGGs). METHODS: First, TCGA methylation data were used to identify prognostic genes associated with promoter methylation. Second, candidate genes that were stably regulated by promoter methylation were explored. Third, Cox proportional hazards regression analysis was used to generate a prognostic signature, and the signature genes were used to construct a survival risk score system. RESULTS: Three genes (EMP3, GSX2 and EMILIN3) were selected as signature genes. These three signature genes were used to construct a survival risk score system. The high-risk group exhibited significantly worse overall survival (OS) and relapse-free survival (RFS) as compared to the low-risk group in the TCGA dataset. The association of the three-gene prognostic signature with patient' survival was then validated using the CGGA dataset. Moreover, Kaplan-Meier plots showed that the three-gene prognostic signature risk remarkably stratified grade II and grade III patients in terms of both OS and RFS in the TCGA cohort. There was also a significant difference between the low- and high-risk groups in IDH wild-type glioma patients, indicating that the three-gene signature may be able to help in predicting prognosis for patients with IDH wild-type gliomas. CONCLUSION: We identified and validated a three-gene (EMP3, GSX2 and EMILIN3) prognostic signature in LGGs by integrating multidimensional genomic data from the TCGA and CGGA datasets, which may help in fine-tuning the current histology-based tumors classification system and providing better stratification for future clinical trials.

Daurisoline suppress glioma progression by inhibiting autophagy through PI3K/AKT/mTOR pathway and increases TMZ sensitivity.

Glioma is one of the most common primary malignant tumors of the central nervous system. Temozolomide (TMZ) is the only effective chemotherapeutic agent, but it easily develops resistance and has unsatisfactory efficacy. Consequently, there is an urgent need to develop safe and effective compounds for glioma treatment. The cytotoxicity of 30 candidate compounds to glioma cells was detected by the CCK-8 assay. Daurisoline (DAS) was selected for further investigation due to its potent anti-glioma effects. Our study revealed that DAS induced glioma cell apoptosis through increasing caspase-3/6/9 activity. DAS significantly inhibited the proliferation of glioma cells by inducing G1-phase cell cycle arrest. Meanwhile, DAS remarkably suppressed the migration and invasion of glioma cells by regulating epithelial-mesenchymal transition. Mechanistically, our results revealed that DAS impaired the autophagic flux of glioma cells at a late stage by mediating the PI3K/AKT/mTOR pathway. DAS could inhibit TMZ-induced autophagy and then significantly promote TMZ chemosensitivity. Nude mice xenograft model revealed that DAS could restrain glioma proliferation and promote TMZ chemosensitivity. Thus, DAS is a potential anti-glioma drug that can improve glioma sensitivity to TMZ and provide a new therapeutic strategy for glioma in chemoresistance.

[Effects of magnetic c-erbB-2 antisense probe of different concentrations on morphology and expression of SK-Br-3 cancer cell lines in vitro].

OBJECTIVE: To explore the effects of the magnetic c-erbB-2 antisense probe of different concentrations on the morphology and expression of SK-Br-3 cancer cells in vitro. METHODS: Breast cancer SK-Br-3 cells were transfected for 24 h by antisense probe at an iron concentration of 5, 10, 25, 50, and 100 mg/L, respectively. The distribution and content of iron particles in SK-Br-3 cells was determined by Prussian blue staining, electron microscopy, and atomic absorption spectrometry. Cell viability was observed by trypan-blue exclusion and CCK-8 test. The protein expression of c-erbB-2 was assessed by the Western blot analysis. The changes of the signal strength were considered by magnetic resonance imaging (MRI). RESULTS: c-erbB-2 antisense probe was uptake by SK-Br-3 cells in a concentration-dependence manner within a certain range (5, 10, and the Medicine Scientific Research Project of Chongqing Health Bureau (062025)25 mg/L). When the probe concentration was 25 mg/L, iron content in cells was (18.38±0.28) pg, the cell vitality, survival, and c-erbB-2 protein expression were reduced significantly (all P<0.05), and the T2 value was lower significantly (P<0.05). However, the results of 50 mg/L or 100 mg/L group showed no significant difference with the 25 mg/L group (P>0.05). CONCLUSION: The magnetic c-erbB-2 antisense probe can effectively transfect and specifically inhibit the expression of SK-Br-3 cell lines at the iron concentration of 25 mg/L.

[Optimal time for MRI scanning of tumors in BALB/c mice using c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles].

OBJECTIVE: To determine the optimal time for MRI scanning of tumors in BALB/c mice using c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles. METHODS: SK-Br-3 tumor-bearing BALB/c mice (n= 30) were injected with antisense probe (12.0 mg Fe/kg). MRI scanning was performed on 5 mice before the injection and 60 min, 180 min, 360 min, 720 min and 1 440 min after the injection, respectively. Tumor tissues were taken immediately after the scanning and fixed with 10% formalin and paraffin-embedded sections. The MRI signal strength of the tumors and adjacent muscles were compared with changes detected under a microscope using HE and Prussian blue staining. RESULTS: SK-Br-3 tumors were introduced to the BALB/c mice successfully. The strongest signal intensity was detected by the MRI 360 min after injection with the antisense probe. The pathological examination revealed structural disorders of the tumor issues, with a large number of special-shaped cells arranged in a cancer nest shape. Punctuate blue iron particles were observed in all of the tumor issues, with the greatest density occurring at 360 min after the injection with the antisense probe. CONCLUSION: The MR4 optimal time for MRI scanning of tumors in BALB/c mice using c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles should be set at 360 min after injection.

HMGB1 Upregulates RAGE to Trigger the Expression of Inflammatory Factors in the Lung Tissue in a Hypoxic Pulmonary Hypertension Rat Model.

Hypoxic pulmonary hypertension (HPH), a form of pulmonary hypertension (PH) caused by hypoxia, could cause serious complications and has a high mortality rate, and no clinically effective treatments are currently available. In this study, we established an HPH preclinical model in rats by simulating clinicopathological indicators of the disease. Our results showed that high mobility group box-1 protein (HMGB1) aggravated the clinical symptoms of HPH. We aimed at establishing protocols and ideas for the clinical treatment of HPH by identifying downstream HMGB1 binding receptors. Our investigation showed that continuous hypoxia could cause significant lung injury in rats. ELISA and western blotting experiments revealed that HPH induces inflammation in the lung tissue and increases the expression of a hypoxia-inducible factor. Testing of lung tissue proteins in vivo and in human pulmonary artery endothelial cells in vitro revealed that the HMGB1-mediated increase in the receptor for advanced glycation end products (RAGE) expression promoted inflammation. In summary, we successfully established an HPH rat model providing a new model for preclinical HPH research and elucidated the role of HMGB1 in HPH. Furthermore, we describe that HMGB1 induced inflammation in the HPH model via RAGE, causing severe lung dysfunction. This study could potentially provide novel ideas and methods for the clinical treatment of HPH.

A Pan-Cancer Analysis Reveals CLEC5A as a Biomarker for Cancer Immunity and Prognosis.

Background: CLEC5A is a member of the C-type lectin superfamily. It can activate macrophages and lead to a series of immune-inflammation reactions. Previous studies reveal the role of CLEC5A in infection and inflammation diseases. Method: We acquire and analyze data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database, and other comprehensive databases via GSCALite, cBioPortal, and TIMER 2.0 platforms or software. Single-cell sequencing analysis was performed for quantifying the tumor microenvironment of several types of cancers. Results: CLEC5A is differentially expressed in a few cancer types, of which overexpression accompanies low overall survival of patients. DNA methylation mainly negatively correlates with CLEC5A expression. Moreover, CLEC5A is positively related to immune infiltration, including macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs). Immune checkpoint genes are significantly associated with CLEC5A expression in diverse cancers. In addition, CLEC5A expression correlates with mismatch repair (MMR) in several cancers. Tumor mutation burden (TMB), microsatellite instability (MSI), and neoantigens show a positive association with CLEC5A expression in several cancers. Furthermore, CLEC5A in cancer correlates with signal transduction, the immune system, EMT, and apoptosis process. The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B. Conclusion: CLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy.

The features of reserpine-induced gastric mucosal lesions.

AIM: To reinvestigate the characteristics of reserpine-induced gastric mucosal lesions (GMLs). METHODS: The GML-inducing effect of reserpine and the time-course of recovery from reserpine-induced GMLs were examined in Sprague-Dawley (SD) rats. The GML-inducing and blood pressure-decreasing effects of Compound Hypotensive Tablets (CHTs) were investigated in spontaneously hypertensive rats (SHRs). Intracerebroventricular (icv) injection and vagotomy were performed to verify the central vagal mechanism in reserpine-induced GMLs. RESULTS: Single intraperitoneal (ip) injections of reserpine (0.25, 0.5, 1, 2, 4, and 6 mg/kg) dose-dependently induced GMLs in SD rats. Both single and repeated (2 weeks) oral administrations of reserpine led to slight GMLs at doses of 24 mg/kg and 10 mg/kg, respectively. Blood pressure was significantly decreased in SHRs after 2 months of CHT administration (0.01 and 0.03 mg/kg; doses were expressed as the amount of reserpine in the CHT). CHT doses of 0.3 mg/kg induced GMLs, but 0.1 mg/kg did not. Examining the time course of recovery from GMLs, severe GMLs occurred 18 h after ip reserpine (4 mg/kg), obviously lessened at 1 week and healed spontaneously at 3 weeks. Intracerebroventricular injections of reserpine caused GMLs at much lower doses (0.08 and 0.4 mg/kg), and reserpine-induced GMLs were greatly inhibited by vagotomy, suggesting the involvement of a central vagal mechanism. CONCLUSION: Reserpine-induced GMLs were dose-dependent, and the lesions healed spontaneously within 3 weeks. Long-term treatment with CHT at doses adequate to decrease blood pressure will not induce GMLs. A central vagal mechanism was involved in reserpine-induced GMLs.

Identification of gene expression and DNA methylation of SERPINA5 and TIMP1 as novel prognostic markers in lower-grade gliomas.

BACKGROUND: Lower-grade gliomas (LGGs) is characteristic with great difference in prognosis. Due to limited prognostic biomarkers, it is urgent to identify more molecular markers to provide a more objective and accurate tumor classification system for LGGs. METHODS: In the current study, we performed an integrated analysis of gene expression data and genome-wide methylation data to determine novel prognostic genes and methylation sites in LGGs. RESULTS: To determine genes that differentially expressed between 44 short-term survivors (<2 years) and 48 long-term survivors (≥2 years), we searched LGGs TCGA RNA-seq dataset and identified 106 differentially expressed genes. SERPINA5 and TIMP1 were selected for further study. Kaplan-Meier plots showed that SERPINA5 and TIMP1 expression were significantly correlated with overall survival (OS) and relapse-free survival (RFS) in TCGA LGGs patients. We next validated the correlation between the candidate genes expression and clinical outcome in CGGA LGGs patients. Multivariate analysis showed that TIMP1 mRNA expression had a significant prognostic value independent of other variables (HR = 4.825, 95% CI = 1.370-17.000, P = 0.014). Then, differential methylation sites were identified from differentially candidate gene expression groups, and all four methylation sites were significantly negatively correlated with gene expression (spearman r <  - 0.5, P < 0.0001). Moreover, hyper-methylation of four methylation sites indicated better OS (P < 0.05), and three of them also shown statistical significantly association with better RFS, except for SERPINA5 cg15509705 (P = 0.0762). CONCLUSION: Taken together, these findings indicated that the gene expression and methylation of SERPINA5 and TIMP1 may serve as prognostic predictors in LGGs and may help to precise the current histology-based tumors classification system and to provide better stratification for future clinical trials.

Differentiation between Luminal A and B Molecular Subtypes of Breast Cancer Using Pharmacokinetic Quantitative Parameters with Histogram and Texture Features on Preoperative Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

OBJECTIVE: The aim of the present study was to use pharmacokinetic quantitative parameters with histogram and texture features on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to differentiate between the luminal A and luminal B molecular subtypes of breast cancer. METHODS: We retrospectively reviewed the data of 94 patients with histopathologically proven breast cancer. The pharmacokinetic quantitative parameters (Ktrans, Kep, and Ve) with their corresponding histogram and texture features based on preoperative DCE-MRI were obtained. The parameters were compared using the Mann-Whitney U-test between the luminal A and luminal B groups, the human epidermal growth factor receptor-2 (HER2)-positive luminal B and HER2-negative luminal B groups, and the lymph node metastasis (LNM)-positive and LNM-negative groups. Receiver operating characteristic curves were generated for parameters that presented significant between-group differences. RESULTS: The maximum values of Ktrans, Kep, and Ve, and the mean and 90th percentile values of Ve were significantly higher in the luminal B group than in the luminal A group. Among the texture features, only skewness of Ktrans significantly differed between the luminal A and B groups. All histogram features of Ktrans were higher in the HER2-positive luminal B group than in the HER2-negative luminal B group. However, no parameter differed between the LNM-positive and LNM-negative groups. CONCLUSION: Pharmacokinetic quantitative parameters with histogram and texture features obtained from DCE-MRI are associated with the molecular subtypes of breast cancer, and may serve as potential imaging biomarkers to differentiate between the luminal A and luminal B molecular subtypes.

Protective effects of betaglucin on myocardial tissue during myocardial infarction in rats and dogs.

AIM: To test the protective effects of betaglucin, a novel beta-glucan, on models of myocardial infarction (MI) in rats and dogs. METHODS: The left anterior descending (LAD) coronary artery occlusion model was used to induce an MI in rats and dogs. Three doses of betaglucin (10, 30 and 100 mg/kg), propranolol (positive control, 1 mg/kg) and vehicle alone (5% glucose solution) were administered before LAD occlusion, and characteristics of the resulting MI were subsequently assessed. In anesthetized dogs, blood pressure, heart rate, ventricular function, coronary artery blood flow and myocardial oxygen consumption were determined before and after the drug administration. RESULTS: The MI mass in both rats and dogs was significantly reduced by betaglucin (30 and 100 mg/kg, P<0.01) and propranolol (P<0.01). In anesthetized dogs, coronary artery blood flow was increased significantly by betaglucin (30 and 100 mg/kg, P<0.01), but blood pressure, heart rate and ventricular function were not changed (P>0.05). High-dose betaglucin (100 mg/kg) increased myocardial oxygen consumption, but not to a statistically significant level (P>0.05). The hemodynamic indexes were significantly changed by propranolol. CONCLUSION: Betaglucin has protective effects on myocardial tissue during MI in rats and dogs and has no influence on hemodynamic parameters at a therapeutic dose. The increase in coronary artery blood flow induced by betaglucin might be beneficial in the treatment of patients with MI.

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux.

BACKGROUND: Gliomas are the most common primary tumors in central nervous system. Despite advances in diagnosis and therapy, the prognosis of glioma remains gloomy. Autophagy is a cellular catabolic process that degrades proteins and damaged organelles, which is implicated in tumorigenesis and tumor progression. Autophagy related 4C cysteine peptidase (ATG4C) is an autophagy regulator responsible for cleaving of pro-LC3 and delipidation of LC3 II. This study was designed to investigate the role of ATG4C in glioma progression and temozolomide (TMZ) chemosensitivity. METHODS: The association between ATG4C mRNA expression and prognosis of gliomas patients was analyzed using the TCGA datasets. The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo. Ectopic xenograft nude mice model was established to investigate the effects of ATG4C on glioma growth in vivo. RESULTS: The median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 × 10- 7). ATG4C mRNA expression was evidently increased with the rising of glioma grade (p = 2.97 × 10- 8). Knockdown ATG4C suppressed glioma cells proliferation by inducing cell cycle arrest at G1 phase. ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation. Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ. Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice. CONCLUSION: ATG4C is a potential prognostic predictor for glioma patient. Targeting ATG4C may provide promising therapy strategies for gliomas treatment.

Under explored epigenetic modulators: role in glioma chemotherapy.

Patients with somatic mutations of epigenetic regulators are characterized by aberrant chromatin modification patterns. Recent mechanistic studies pairing chemical tool compounds and deep-sequencing technology have greatly broadened our understanding of epigenetic regulation in glioma progression and underpinned alternative treatment of epigenetic inhibitors. However, the effect of most inhibitors is condition-dependent, and the overall results of clinical trials still have not been applied to patients. There is an intense need to develop more potent and specific compounds as well as identify the population who may achieve clinical benefits. Besides, combination therapy with conventional therapeutics is another alternative strategy. In this review, we summarize well-characterized chemical probes in glioma research and clinical translation. We also discuss the target population and combination of therapy regimens of various agents. In a holistic sense, we try to provide guidance for selecting targeted chemical probes and pave the way for personalized rational therapy.

Influence of G-protein ß-Polypeptide 3 C825T Polymorphism on Antihypertensive Response to Telmisartan and Amlodipine in Chinese Patients.

BACKGROUND: G-protein ß-polypeptide 3 (GNB3) is a ß subunit isoform of G-protein that plays important role in signal transduction of membrane G-protein coupled receptors (GPCRs). The GNB3 splice variant C825T (rs5443) is associated with risk for essential hypertension (EH) and efficacy of therapeutic drugs targeting GPCRs. It is unknown whether the polymorphism is associated with blood pressure (BP) response to telmisartan or amlodipine, two widely prescribed antihypertensive drugs. METHODS: A total of 93 subjects initially diagnosed as EH were recruited and underwent a 4-week treatment with telmisartan (42 patients) or amlodipine (51 patients) monotherapy. Both baseline and after-treatment BP were measured. GNB3 C825T polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Baseline systolic BP (SBP) and diastolic BP (DBP) were comparable among C825T genotypes in both telmisartan and amlodipine treatment groups. Patients with the CT or TT genotypes showed significantly lower body mass index (BMI) as compared with CC homozygotes in both groups (P < 0.05, respectively). GNB3 825TT homozygotes showed significantly higher after-treatment DBP and mean arterial pressure (MAP) than those carrying at least one 825C allele (P < 0.01) in the telmisartan treatment group. No difference in after-treatment SBP, DBP, and MAP levels among C825T genotypes was observed in the amlodipine treatment group. No significant difference in absolute changes in BP levels was observed among the genotypes in either treatment group. CONCLUSION: The GNB3 C825T splice variant is associated with the DBP-lowering effect of telmisartan but not amlodipine in Chinese EH patients.

Influence of acylpeptide hydrolase polymorphisms on valproic acid level in Chinese epilepsy patients.

BACKGROUND: Concomitant use of meropenem (MEPM) can dramatically decrease valproic acid (VPA) plasma level. It is accepted that inhibition in acylpeptide hydrolase (APEH) activity by MEPM coadministration was the trigger of this drug-drug interaction. AIM: To investigate the influence of APEH genetic polymorphisms on VPA plasma concentration in Chinese epilepsy patients. PATIENTS & METHODS: Urinary VPA-d6 ß-D-glucuronide concentration was determined in 19 patients with VPA treatment alone (n = 10) or concomitant use with MEPM (n = 9). A retrospective study was performed on 149 epilepsy patients to investigate the influence of APEH polymorphisms rs3816877 and rs1131095 on adjusted plasma VPA concentration (CVPA) at steady-state. RESULTS: Urinary VPA-d6 ß-D-glucuronide (VPA-G) concentration was increased significantly in patients with MEPM coadministration. The CVPA of patients carrying the APEH rs3816877 C/C genotype was significantly higher than that of C/T carriers, and the difference was still obvious when stratified by UGT2B7 rs7668258 polymorphism. CONCLUSION: APEH polymorphism has significant influence on VPA pharmacokinetics in Chinese population.

Influence of P2Y12 polymorphisms on platelet activity but not ex-vivo antiplatelet effect of ticagrelor in healthy Chinese male subjects.

Activation of platelet implicated a series of signal conduction including outside-in and inside-out related receptor-mediated signaling pathways. Ticagrelor is the first reversible P2Y12 receptor antagonist that exhibits rapid antiplatelet effect. Given that platelet aggregation varies among individuals, genetic polymorphisms in P2Y12 and subsequent signal molecular such as the G-protein beta 3 subunit (GNB3) are supposed to influence the antiplatelet effect of ticagrelor. The aim of this study was to determine whether genetic polymorphisms in P2Y12 and GNB3 genes influence ex-vivo antiplatelet activity of ticagrelor in healthy Chinese subjects. A total of 196 healthy Chinese male individuals were recruited. ADP-induced platelet aggregation was determined by using light transmittance aggregometry at baseline and after incubation of the platelet-rich plasma with 15 and 50 µmol/l ticagrelor, respectively. Nine single-nucleotide polymorphisms (SNPs) in P2Y12 and the GNB3 rs5443 polymorphism were genotyped by PCR-direct sequencing. P2Y12 haplotypes were inferred. Baseline platelet aggregation was increased in carriers of the common alleles of P2Y12 SNPs (rs1907637, rs2046934, and rs6809699) and rs6787801 TC heterozygotes (P < 0.05 for all). Results of the haplotype analyses were consistent with those of the single SNPs. Ticagrelor at both concentrations of 15 and 50 µmol/l decreased ADP-induced platelet aggregation significantly (P < 0.05, respectively). Neither single SNPs nor haplotypes of P2Y12 affected ticagrelor-induced ex-vivo inhibition of platelet aggregation. P2Y12 and GNB3 polymorphisms have no effect on the ex-vivo antiplatelet activity of ticagrelor in healthy Chinese male subjects.