Integrating Multi-Omics Analysis for Enhanced Diagnosis and Treatment of Glioblastoma: A Comprehensive Data-Driven Approach.

The most aggressive primary malignant brain tumor in adults is glioblastoma (GBM), which has poor overall survival (OS). There is a high relapse rate among patients with GBM despite maximally safe surgery, radiation therapy, temozolomide (TMZ), and aggressive treatment. Hence, there is an urgent and unmet clinical need for new approaches to managing GBM. The current study identified modules (MYC, EGFR, PIK3CA, SUZ12, and SPRK2) involved in GBM disease through the NeDRex plugin. Furthermore, hub genes were identified in a comprehensive interaction network containing 7560 proteins related to GBM disease and 3860 proteins associated with signaling pathways involved in GBM. By integrating the results of the analyses mentioned above and again performing centrality analysis, eleven key genes involved in GBM disease were identified. ProteomicsDB and Gliovis databases were used for determining the gene expression in normal and tumor brain tissue. The NetworkAnalyst and the mGWAS-Explorer tools identified miRNAs, SNPs, and metabolites associated with these 11 genes. Moreover, a literature review of recent studies revealed other lists of metabolites related to GBM disease. The enrichment analysis of identified genes, miRNAs, and metabolites associated with GBM disease was performed using ExpressAnalyst, miEAA, and MetaboAnalyst tools. Further investigation of metabolite roles in GBM was performed using pathway, joint pathway, and network analyses. The results of this study allowed us to identify 11 genes (UBC, HDAC1, CTNNB1, TRIM28, CSNK2A1, RBBP4, TP53, APP, DAB1, PINK1, and RELN), five miRNAs (hsa-mir-221-3p, hsa-mir-30a-5p, hsa-mir-15a-5p, hsa-mir-130a-3p, and hsa-let-7b-5p), six metabolites (HDL, N6-acetyl-L-lysine, cholesterol, formate, N, N-dimethylglycine/xylose, and X2. piperidinone) and 15 distinct signaling pathways that play an indispensable role in GBM disease development. The identified top genes, miRNAs, and metabolite signatures can be targeted to establish early diagnostic methods and plan personalized GBM treatment strategies.

Molecular mechanisms of microRNAs in glioblastoma pathogenesis.

Glioblastoma (GBM) is human's most prevalent and severe brain cancer. Epigenetic regulators, micro(mi)RNAs, significantly impact cellular health and disease because of their wide range of targets and functions. The "epigenetic symphony" in which miRNAs perform is responsible for orchestrating the transcription of genetic information. The discovery of regulatory miRNA activities in GBM biology has shown that various miRNAs play a vital role in disease onset and development. Here, we summarize our current understanding of the current state-of-the-art and latest findings regarding the interactions between miRNAs and molecular mechanisms commonly associated with GBM pathogenesis. Moreover, by literature review and reconstruction of the GBM gene regulatory network, we uncovered the connection between miRNAs and critical signaling pathways such as cell proliferation, invasion, and cell death, which provides promising hints for identifying potential therapeutic targets for the treatment of GBM. In addition, the role of miRNAs in GBM patient survival was investigated. The present review, which contains new analyses of the previous literature, may lead to new avenues to explore in the future for the development of multitargeted miRNA-based therapies for GBM.

Osteoprotegerin Assessment Improves Prediction of Mortality in Stroke Patients.

BACKGROUND: Elevated circulating osteoprotegerin (OPG) level is associated with an increased risk of hospitalization for ischemic stroke and coronary artery disease. The aim of the present study was to analyze whether OPG assessment may improve the prediction of mortality in patients with stroke. PATIENTS AND METHODS: Serum OPG, fetuin A, 25-OH-D3, intact parathyroid hormone levels were assessed in serum samples which were left over after routine tests in a hospital laboratory. This assessment was conducted in 240 consecutive patients with acute ischemic stroke, admitted within 24hours after the onset of symptoms to the Stroke Unit. Mortality data were obtained from the local registry office. RESULTS: The mean OPG serum level was 14.6 ± 6.0pmol/L (range: 3.7-43.4). There were no significant differences in the OPG values between men and women (13.9 ± 5.0 versus 15.1 ± 6.7 pmol/L; P = .12). Therefore, tertiles were calculated for the whole group. During the follow-up, 85 (35.4%) patients died and 92 (38.3%) died or had recurrent stroke. OPG level appeared a significant predictors of death and composite end-point (death/recurrent stroke), in addition to the well-established once (age, atrial fibrillation, diabetes RANKIN at admission and discharge, severity of stroke). In multivariable stepwise backward analyses, the OPG level persisted as a significant and independent predictor of death (hazard ratio [HR] = 1.084 (95% confidence intervals: 1.036-1.134)] and composite and point (HR = 1.082 [1.037-1.129]). CONCLUSIONS: OPG level may be considered as a predictor of mortality in stroke patients.

Altered Fibrin Clot Properties in Patients With Cerebral Venous Sinus Thrombosis: Association With the Risk of Recurrence.

BACKGROUND AND PURPOSE: Venous thromboembolism and ischemic stroke are associated with unfavorable fibrin clot structure and function. We hypothesized that denser fibrin networks displaying impaired lysability characterize patients with cerebral venous sinus thrombosis (CVST). METHODS: We assessed plasma fibrin clot properties in 50 patients (aged 38.9±9.8 years, 36 women) after the first CVST unrelated to trauma or malignancy after anticoagulation withdrawal and 50 well-matched controls. Recurrences were recorded during follow-up (18-46; median, 36 months). RESULTS: Clot permeability was lower in patients with CVST than in controls (Ks, 6.43±0.97 versus 7.3±1.2 10(-9) cm(2); P<0.001) and was associated with prolonged clot lysis time (103.0±16.8 versus 92.4±16.2 minutes; P<0.001), lower maximum rate of D-dimer release from clots (0.068 [0.064-0.071] versus 0.072 [0.067-0.078] mg/L per minute; P<0.001) and higher maximum D-dimer levels in the lysis assay (4.39±0.56 versus 4.19±0.46 mg/L, respectively; P=0.03). Patients with CVST had a slightly shorter lag phase (P=0.02) and higher maximum absorbance of fibrin gels on turbidimetry (P<0.001) compared with controls. Deficiencies in natural anticoagulants or antiphospholipid syndrome, and factor V Leiden occurred more often in the patients (P<0.05). CVST recurred in 6 patients (12%) and was associated with 21% higher baseline fibrinogen (P=0.007), 20% lower Ks (P=0.04) and 17% greater D-Dmax (P=0.01). Multiple logistic regression showed that only elevated D-Dmax (>4.83 mg/L) predicted CVST recurrence (odds ratio, 5.1; 95% confidence interval, 1.63-16.19) after adjustment for fibrinogen. CONCLUSIONS: CVST is associated with the formation of more compact plasma fibrin clots and resistance to fibrinolysis, which may predispose to the recurrence.

Decompressive hemicraniectomy in ischaemic stroke.

BACKGROUND AND PURPOSE: Hemispheric ischaemic stroke complicated by oedema is associated with high mortality. The results of randomized studies showed that decompressive hemicraniectomy performed in this group of patients could be beneficial. First experiences with implementation of hemi-craniectomy in patients with brain infarct in our stroke centre are presented. MATERIAL AND METHODS: Between August 2007 and July 2008, four patients with hemispheric brain infarcts complicated by malignant oedema underwent decompressive hemicraniectomy within 72 hours from symptoms onset. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Clinical outcome was assessed 3, 6 and 12 months after the event using the modified Rankin scale (mRS). RESULTS: In the first patient, the neurosurgical procedure included only decompressive hemicraniectomy, whereas in the other three duraplasty was performed additionally. The first patient died 23 days after the stroke onset due to acute respiratory failure. Another died at four months after the event, due to infectious complications. The remaining two patients presented severe functional disability 12 months after the procedure (mRS score 4). CONCLUSIONS: Decompressive surgery with duraplasty can be a life-saving procedure for patients with brain oedema. To our knowledge, the presented cases are among the first reported cases of hemispheric ischaemic stroke treated with decompressive hemicraniectomy in Poland. Extended follow-up with a larger group of patients is necessary to assess long-term outcome.