IDH1 mutation is associated with improved overall survival in patients with glioblastoma: a meta-analysis.

Previous studies proposed that isocitrate dehydrogenase 1 (IDH1) mutation was associated with improved survival in patients with glioblastoma, but those studies reported varying estimates and yielded inconclusive results. The purpose of the present study was to determine the effect of IDH1 mutation on the prognosis of patients with glioblastoma by performing a meta-analysis. Pubmed and Embase databases were searched for eligible studies. Studies reporting overall survival by IDH1 mutation in patients with glioblastoma were considered potentially eligible for the meta-analysis. For the quantitative aggregation of the survival results, the IDH mutation effect was measured by the pooled hazard ratio (HR) with its 95% confidence interval (95%CI). Nine studies with a total of 1,669 patients with glioblastoma were finally included into this meta-analysis. Overall, the IDH1 mutation was associated with improved survival in patients with glioblastoma (random effects model HR = 0.45, 95%CI 0.29-0.69, P < 0.001). Sensitivity analysis further showed that the pooled estimates were stable in this meta-analysis. Therefore, the findings from this meta-analysis suggest that IDH1 mutation is associated with improved overall survival in patients with glioblastoma.

Integrate Molecular Phenome and Polygenic Interaction to Detect the Genetic Risk of Ischemic Stroke.

Ischemic stroke (IS) is one of the leading causes of death, and the genetic risk of which are continuously calculated and detected by association study of single nucleotide polymorphism (SNP) and the phenotype relations. However, the systematic assessment of IS risk still needs the accumulation of molecular phenotype and function from the level of omics. In this study, we integrated IS phenome, polygenic interaction gene expression and molecular function to screen the risk gene and molecular function. Then, we performed a case-control study including 507 cases and 503 controls to verify the genetic associated relationship among the candidate functional genes and the IS phenotype in a northern Chinese Han population. Mediation analysis revealed that the blood pressure, high density lipoprotein (HDL) and glucose mediated the potential effect of SOCS1, CD137, ALOX5AP, RNLS, and KALRN in IS, both for the functional analysis and genetic association. And the SNP-SNP interactions analysis by multifactor dimensionality reduction (MDR) approach also presented a combination effect of IS risk. The further interaction network and gene ontology (GO) enrichment analysis suggested that CD137 and KALRN functioning in inflammatory could play an expanded role during the pathogenesis and progression of IS. The present study opens a new avenue to evaluate the underlying mechanisms and biomarkers of IS through integrating multiple omics information.

Comprehensive analysis of circRNA expression pattern and circRNA-miRNA-mRNA network in the pathogenesis of atherosclerosis in rabbits.

Atherosclerosis is a chronic and multifactorial inflammatory disease and is closely associated with cardiovascular and cerebrovascular diseases. circRNAs can act as competing endogenous RNAs to mRNAs and function in various diseases. However, there is little known about the function of circRNAs in atherosclerosis. In this study, three rabbits in the case group were fed a high-fat diet to induce atherosclerosis and another three rabbits were fed a normal diet. To explore the biological functions of circRNAs in atherosclerosis, we analyzed the circRNA, miRNA and mRNA expression profiles using RNA-seq. Many miRNAs, mRNAs and circRNAs were identified as significantly changed in atherosclerosis. We next predicted miRNA-target interactions with the miRanda tool and constructed a differentially expressed circRNA-miRNA-mRNA triple network. A gene ontology enrichment analysis showed that genes in the network were involved in cell adhesion, cell activation and the immune response. Furthermore, we generated a dysregulated circRNA-related ceRNAs network and found seven circRNAs (ocu-cirR-novel-18038, -18298, -15993, -17934, -17879, -18036 and -14389) were related to atherosclerosis. We found these circRNAs also functioned in cell adhesion, cell activation and the immune response. These results show that the crosstalk between circRNAs and their competing mRNAs might play crucial roles in the development of atherosclerosis.

Effects of photodynamic therapy on the ultrastructure of glioma cells.

OBJECTIVE: To study the change in ultrastructure of C6 glioma cells after photodynamic therapy (PDT), to compare morphological differences in necrosis and apoptosis before and after PDT treatment, and to evaluate the effect of photodynamic therapy on the blood brain tumor barrier (BTB) of C6 glioma. METHODS: The model was produced by transplanting C6 glioma cells cultured in vitro using Peterson method into the caudate nuclei of Wister rats. The experiment group received PDT for two weeks after the operation. The sub-cellular structure, blood-brain-barrier (BBB) and BTB in both groups were observed under electron microscope. RESULTS: Apoptosis in different phases and necrosis could be observed in some C6 glioma cells. Swelling occurred on the ultrastructure of cellular organs such as mitochondria and endoplasmic reticulum in most of the cells. Damage to the BTB, reduction of the number of cellular organs in endothelial cells of the capillary blood vessels, stretch of the tight junction, and enlargement of the gaps between endothelial cells were also seen in the experiment group. Meanwhile, limited impact on the normal sub-cellular structures and BBB was observed. CONCLUSION: PDT could induce apoptosis and necrosis of C6 glioma cells due to the damage to the ultrastructure of mitochondria and endoplasmic reticulum. The weakened function of C6 glioma BTB initiated by PDT makes it possible to perform a combined therapy of PDT and chemotherapy for glioma.

Novel CD137 Gene Polymorphisms and Susceptibility to Ischemic Stroke in the Northern Chinese Han Population.

Ischemic stroke is a leading cause of mortality and morbidity worldwide, and atherosclerosis is one of the major risk factors for this neurologic deficit. Recent studies have revealed the important role of CD137 in human atherosclerosis. Here, we analyzed the association of CD137 single nucleotide polymorphisms (SNPs) with ischemic stroke. We assessed three SNPs (rs161827, rs161818, and rs161810) of the CD137 gene and their association with ischemic stroke in a northern Chinese Han population. A total of 496 ischemic stroke patients and 486 gender-matched control subjects were genotyped. We classified these patients according to complications with diabetes and hypertension and also by ischemic stroke subtypes. Allele, genotype, and haplotype association studies were tested in all patients and subgroups. We used multivariable logistic regression analysis combined with 10,000 permutations to analyze the association of CD137 polymorphisms with ischemic stroke. After adjusting for relevant factors, rs161827 was significantly different between patients with and without diabetes and the control group (p = 0.0001, p = 0.014, and p = 0.0001, respectively). In addition, rs161818 and rs161810 differed significantly between patients without diabetes and the control subjects (p = 0.0001 and p = 0.004, respectively). rs161827, rs161818, and rs161810 were all statistically significant among the combination stroke subgroup compared with the controls. These results indicate that the CD137 gene is associated with risk of ischemic stroke in the northern Han Chinese. Moreover, CD137 gene polymorphism may be one mediating factor between diabetes and ischemic stroke.

Contrast-Enhanced Ultrasound Imaging Quantification of Adventitial Vasa Vasorum in a Rabbit Model of Varying Degrees of Atherosclerosis.

This study used an atherosclerotic rabbit model to investigate the feasibility of quantifying adventitial vasa vasorum (VV) via contrast-enhanced ultrasound (CEUS) imaging to identify early atherosclerosis. Recent evidence has linked adventitial VV with atherosclerotic plaque progression and vulnerability. A growth in VV density has been detected preceding intimal thickening and even endothelial dysfunction. In our study, carotid atherosclerosis rabbit models were used, and animals underwent CEUS imaging at the end of the atherosclerotic induction period. Normalized maximal video-intensity enhancement (MVE) was calculated to quantify VV density. After CEUS imaging, animals were euthanized, and their carotids were processed for histopathological analysis following staining for CD31 and VEGF. Adventitial normalized MVE increased as atherosclerosis progressed (p < 0.001), and normalized MVE also progressed, demonstrating a linear correlation with histological findings (r = 0.634, p < 0.001 for VEGF-positive; r = 0.538, p < 0.001 for CD31-positive). Thus, we histologically validated that CEUS imaging can be used to quantify the development of adventitial VV associated with atherosclerosis progression. This method can be used for monitoring the VV to detect early atherosclerosis.

A Novel Association of the Suppressor of Cytokine Signaling 1 (SOCS1) Gene Polymorphisms in Ischemic Stroke Patients.

Ischemic stroke is a common neurological disease and a leading cause of permanent disability in many countries. Recent studies provide evidence on the role of the suppressor of the cytokine signaling 1 (SOCS1) gene in the development and progression of atherosclerotic lesions. However, few studies have assessed the association between single nucleotide polymorphisms (SNPs) on SOCS1 gene and ischemic stroke. Therefore, the present study aimed to investigate the role of SOCS1 polymorphism in ischemic stroke risk in a northern Chinese Han population. We examined 475 patients with ischemic stroke and 486 normal controls. Three SNPs (rs243327, rs243330, and rs33932899) of SOCS1 gene were determined for TaqMan genotyping assays. We also classified these case samples in depth by complications with hypertension or diabetes and by ischemic stroke subtypes. When adjusting models by multiple factor analysis by logistic regression, then calculated 10,000 permutations were performed for each model to correct the multiple test. Under additive model, the rs243327 was associated with ischemic stroke with hypertension (p = 0.047). Under heterozygous model, the rs33932899 and rs243330 were significantly associated with ischemic stroke subtypes by atherosclerosis (p = 0.038, p = 0.048, respectively). In summary, our data demonstrated for the first time that the polymorphisms of the SOCS1 gene are associated with the risk of ischemic stroke in a northern Chinese Han population, suggesting that SOCS1 gene polymorphisms may play an important role in the pathogenesis of ischemic stroke.

KALRN Rare and Common Variants and Susceptibility to Ischemic Stroke in Chinese Han Population.

Stroke is the second most common cause of mortality worldwide, and it is a major cause of physical disability. Several genome-wide association studies have yielded numerous common variants which increase the risk of ischemic stroke, including the Kalirin-coding gene, KALRN. KALRN strongly associates with early-onset coronary artery disease and atherosclerosis and plays an important role in stroke in the European population. In this study, we analyzed four KALRN gene SNPs in 503 ischemic stroke patients and 493 control subjects, separating the patients into separate research groups based on comorbidity with hypertension or diabetes and stroke type (atherosis or lacunar and combination type). We found a rare variant of KALRN, rs11712619, that associated with lacunar stroke in the northern Chinese Han population with an average-risk allele frequency 0.009 (OR 2.95, 95 % CI 1.08-8.01, p = 0.028). However, after adjusting for relevant factors, including sex, age, body mass index, dyslipidemia, alcohol consumption, and smoking, this association was not evident. Additionally, the KALRN variant rs6438833 was associated with ischemic stroke, ischemic stroke comorbid with diabetes, and lacunar stroke after adjusting for the relevant factors (p = 0.046, p = 0.019 and p = 0.046, respectively), which remained significant after 10,000 permutation procedure test (p' = 0.047, p' = 0.018 and p' = 0.048, respectively). The association of these rare and common variants of KALRN with ischemic stroke in northern Chinese Han population offers insight for potential therapeutic research.

Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene rs4073259 polymorphism not associated with ischemic stroke in the northeastern Chinese Han population.

OBJECTIVE: Although recent evidence has implicated that 5-lipoxygenase activating protein (ALOX5AP) gene is associated with ischemic stroke (IS) risk, the underlying molecular mechanism remains to be defined. This study aimed to investigate the role of ALOX5AP rs4073259 in ischemic stroke in a Northeastern Chinese Han population. METHODS: A total of 501 IS patients and 497 healthy controls were enrolled for polymerase chain reaction (PCR) and ligase detection reaction (LDR) analysis of ALOX5AP rs4073259 single nucleotide polymorphism (SNP). RESULTS: There were no statistically significant differences in ALOX5AP rs4073259 allele and genotype frequencies between IS or subtypes of IS and controls. There was no significant difference in genotype and allele frequencies of atherosclerosis degree between ischemic subjects with carotid artery plaque or absence. However, total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in women patients were significantly higher than those in men (p=0.015, 0.000, and 0.008, respectively). Total homocysteine (tHcy) was higher in men patients than that in women (p=0.021). CONCLUSION: There was no statistically significant association of ALOX5AP rs4073259 SNP with ischemic stroke in this northeastern Chinese Han population living in Heilongjiang province, China.

Association of imaging classification of intracranial cerebral atherosclerotic vascular stenosis in ischemic stroke and renalase gene polymorphisms.

Cerebral atherosclerosis vascular stenosis is a common etiology for ischemic stroke and a major factor in recurrent stroke and vascular mortality. Recent studies suggest that renalase plays a role in hypertension and ischemic stroke, and may be involved in atherosclerosis. The aim of the present study was to investigate whether there were correlations between single-nucleotide polymorphisms (SNPs) in the renalase gene and severity of intracranial cerebral atherosclerotic vascular stenosis in ischemic stroke patients as determined by imaging. A total of 212 ischemic stroke patients and 244 healthy controls from the north Chinese Han population were enrolled in this study. Polymerase chain reaction and ligase detection reaction were used for SNP analysis. We classified the case samples by severity of the intracranial cerebral atherosclerotic vascular stenosis. Allele, genotype, and haplotype were analyzed in cases and controls, and logistic regression was used to adjust for bias due to conventional stroke risk factors. The allele and the genotype of rs10887800 in the renalase gene were both associated with severe intracranial cerebral atherosclerotic vascular stenosis (p = 0.013 and p = 0.049, respectively). No association was observed with severity for SNP rs2576178 or SNP rs2296545. Our findings show that the SNP rs10887800 in the renalase gene is closely associated with severe intracranial cerebral atherosclerotic vascular stenosis in ischemic stroke patients of north Chinese Han origin.

Xeroderma pigmentosum complementation group f polymorphisms influence risk of glioma.

We conducted an exploratory investigation of whether variation in six common SNPs of xeroderma pigmentosum complementation group F (XPF) is associated with risk of glioma in a Chinese population. Six single nucleotide polymorphisms (SNPs) were genotyped in 207 glioma cases and 236 cancer-free controls by a 384-well plate format on the Sequenom MassARRAY platform (Sequenom, San Diego, USA). The rs1800067 G and rs2276466 G allele frequencies were significantly higher in the glioma group than controls. Individuals with the rs1800067 GG genotype were at greater risk of glioma when compared with the A/A genotype in the codominant model, with an OR (95% CI) of 2.63 (1.04-7.25). The rs2276466 polymorphism was significantly associated with moderate increased risk of glioma in codominant and dominant models, with ORs (95% CI) of 1.90 (1.05-3.44) and 1.55 (1.07-2.47), respectively. The combination genotype of rs1800067 G and rs2276466 G alleles was associated with a reduced risk of glioma (OR=0.44, 95% CI=0.19-0.98). These findings indicate that genetic variants of the XPF gene have critical functions in the development of glioma.

An association study on renalase polymorphisms and ischemic stroke in a Chinese population.

Ischemic stroke is a leading cause of death and adult disability worldwide. Recent research suggests that renalase is strongly associated with heart disease and hypertension and may play a role in ischemic stroke. In this study, we investigate the genetic association between renalase and ischemic stroke in a northern Chinese Han population. We genotyped single-nucleotide polymorphisms of the renalase gene in 507 ischemic stroke patients and 503 gender-matched controls from a northern Chinese Han population, and we classified these case samples in depth by complications with diabetes or hypertension and by ischemic stroke subtypes. We undertook allele, genotype, and haplotype association studies in all the cases and in the subgroups, as well as multiple factor analysis by logistic regression. rs10887800 and rs2576178 were significantly associated with ischemic stroke with hypertension by logistic regression (p = 0.041 and p = 0.038, respectively). The recessive model showed a strong association of rs2296545 with ischemic stroke patients in hypertension subgroups (OR = 1.927, 95 % CI = 1.012-3.669, p = 0.046). The renalase gene is closely related to ischemic stroke in this northern Chinese Han population, suggesting that renalase may be mechanistically involved in stroke pathology.

MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status.

MicroRNAs are single-stranded small non-coding RNA molecules which regulate mammalian cell growth, differentiation, and apoptosis by altering the expression of other genes and play a role in tumor genesis and progression. MiR-106a is upregulated in several types of malignancies and provides a pro-tumorigenic effect. However, its role in glioma is largely unknown. Our findings demonstrate that the low expression of miR-106a in human glioma specimens is significantly correlated with high levels of E2F1 protein and high-grade glioma. Here, we present the first evidence that miR-106a provides a tumor-suppressive effect via suppressing proliferation of and inducing apoptosis in human glioma cells. We further show that E2F1 is a direct functional target of miR-106a, suggesting that the effect of miR-106a on the glioma suppressive effect may result from inhibition of E2F1 via post-transcriptional regulation. In addition, our results reveal that miR-106a can increase p53 expression via E2F1 inhibition, whereas the effect of miR-106a on the proliferation of glioma cells is independent of p53 status. Further investigations will focus on the therapeutic use of miR-106a-mediated antitumor effects in glioma.