Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17−IL-17R interaction in gliomas. Immunohistochemistry and flow cytometry analysis of 12 tumor samples obtained from patients with high grade gliomas revealed that a considerable population (2–19%) of cells in all malignant gliomas expressed IL-17RA, with remarkable co-expression of the glioma stem cell (GSC) markers CD133, Nestin, and Sox2. IL-17 enhanced the self-renewal of GSCs as determined by proliferation and Matrigel® colony assays. IL-17 also induced cytokine/chemokine (IL-6, IL-8, interferon-γ-inducible protein [IP-10], and monocyte chemoattractant protein-1 [MCP-1]) secretion in GSCs, which were differentially blocked by antibodies against IL-17R and IL-6R. Western blot analysis showed that IL-17 modulated the activity of signal transducer and activator of transcription 3 (STAT3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), glycogen synthase kinase-3β (GSK-3β) and β-catenin in GSCs. While IL-17R-mediated secretion of IL-6 and IL-8 were significantly blocked by inhibitors of NF-κB and STAT3; NF-κB inhibitor was more potent than STAT3 inhibitor in blocking IL-17-induced MCP-1 secretion. Overall, our results suggest that IL-17–IL-17R interaction in GSCs induces an autocrine/paracrine cytokine feedback loop, which may provide an important signaling component for maintenance/self-renewal of GSCs via constitutive activation of both NF-κB and STAT3. The results also strongly implicate IL-17R as an important functional biomarker for therapeutic targeting of GSCs.
Background:Several studies have confirmed the role of prophylactic low-molecular-weight heparin (LMWH) for venous thromboembolism (VTE) in neurosurgery; however, a paucity of literature has assessed its safety and efficacy versus prophylactic unfractionated heparin (UFH). The objective is to present a meta-analysis directly comparing prophylactic LMWH to UFH for the prevention of VTE in neurosurgery.Materials and Methods:Relevant studies that directly compared LMWH to UFH for prophylaxis of VTE in neurosurgery and/or spine surgery were identified by MEDLINE and EMBASE searches plus a scrutiny of references from the original articles and reviews. Three randomized trials were included in the meta-analysis. Efficacy and safety were ascertained per three primary outcome measures: VTE, minor complications (decline in hemoglobin/hematocrit), and major complications. Forest plot analysis provided odds ratio (OR), 95% confidence intervals (CIs), and P-values.Results:Of the 429 patients in the pooled analysis, the postoperative VTE rate of 5.6% (12/213) after LMWH chemoprophylaxis was equivalent to 3.7% (8/216) after UFH chemoprophylaxis (OR = 1.42, 95% CI 0.62–3.75, P = 0.308). Minor complications of 4.7% versus 4.6%, respectively, were nearly equal (OR = 1.01, 95% CI 0.41– 2.50, P = 0.929). All four major complications included intracranial hemorrhages: three after LMWH (1.4%) and one after UFH (0.5%) (OR = 2.32, 95% CI 0.34–16.01, P = 0.831). Tests for heterogeneity were nonsignificant in all three outcome measures.Conclusion:Rates of VTE, minor complications, and major complications were equivalent between prophylactic LMWH and UFH in neurosurgery. Further, randomized clinical trials comparing the two heparin products are required to elucidate superior safety and efficacy in neurosurgical patients.
fMRI is the preeminent method for collecting signals from the human brain in vivo, for using these signals in the service of functional discovery, and relating these discoveries to anatomical structure. Numerous computational and mathematical techniques have been deployed to extract information from the fMRI signal. Yet, the application of Topological Data Analyses (TDA) remain limited to certain sub-areas such as connectomics (that is, with summarized versions of fMRI data). While connectomics is a natural and important area of application of TDA, applications of TDA in the service of extracting structure from the (non-summarized) fMRI data itself are heretofore nonexistent. “Structure” within fMRI data is determined by dynamic fluctuations in spatially distributed signals over time, and TDA is well positioned to help researchers better characterize mass dynamics of the signal by rigorously capturing shape within it. To accurately motivate this idea, we a) survey an established method in TDA (“persistent homology”) to reveal and describe how complex structures can be extracted from data sets generally, and b) describe how persistent homology can be applied specifically to fMRI data. We provide explanations for some of the mathematical underpinnings of TDA (with expository figures), building ideas in the following sequence: a) fMRI researchers can and should use TDA to extract structure from their data; b) this extraction serves an important role in the endeavor of functional discovery, and c) TDA approaches can complement other established approaches toward fMRI analyses (for which we provide examples). We also provide detailed applications of TDA to fMRI data collected using established paradigms, and offer our software pipeline for readers interested in emulating our methods. This working overview is both an inter-disciplinary synthesis of ideas (to draw researchers in TDA and fMRI toward each other) and a detailed description of methods that can motivate collaborative research.
BACKGROUND Despite a proven superior efficacy of prophylactic low-molecular-weight heparin (LMWH) over unfractionated heparin (UFH) in the majority of surgical specialties, chemoprophylactic techniques after spine surgery have not been established because of the fear of epidural hematomas with LMWH. OBJECTIVE To determine the efficacy of LMWH vs UFH in the prevention of venous thromboembolism (VTE) events, balanced against the risk of epidural hematoma. METHODS This is the first matched cohort design that directly compares prophylactic LMWH to UFH after spine surgery for degenerative/deformity pathologies at a tertiary academic center. Prospectively collected patients receiving prophylactic LMWH and a historical cohort of patients receiving prophylactic UFH (prior to 2017) were matched in 1:1 ratio based on age ±5 yr, American Society of Anesthesiologists classification, location in the spinal column, and type of surgery. RESULTS Of 562 patients, VTE events equaled 1.4% (n = 8): 1.4% (n = 4) with LMWH was exactly equal to 1.4% (n = 4) with UFH. Epidural hematomas reached 0.8% (n = 5): 1.4% (n = 4) with UFH vs 0.3% (n = 1) with the LMWH (P = .178). Utilizing adjusted odds ratio (ORadj), the type of chemoprophylaxis after spine surgery failed to predict VTE events. Similarly, the chemoprophylactic technique failed to predict epidural hematoma in the multivariable regression analysis, although UFH trended toward a higher complication rate (ORadj = 3.15 [0.48-20.35], P = .227). CONCLUSION Chemoprophylactic patterns failed to predict VTE. Although no differences in epidural hematoma rates were detected, our analysis does highlight a trend toward a safer profile with LMWH vs UFH. LMWH may be a safe alternative to UFH in spine surgery.
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