EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma.

Background: Enhancer of zeste homolog 2 (EZH2), well known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied noncanonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical su(var)3-9, enhancer-of-zeste and trithorax domain show limited efficacy and lack durable response, suggesting that underlying differences in the noncanonical pathway may yield new knowledge.

Recording of single-unit activities with flexible micro-electrocorticographic array in rats for decoding of whole-body navigation.

Micro-electrocorticographic (ECoG) arrays are able to record neural activities from the cortical surface, without the need to penetrate the brain parenchyma. Owing in part to small electrode sizes, previous studies have demonstrated that single-unit spikes could be detected from the cortical surface, and likely from Layer I neurons of the neocortex. Here we tested the ability to useECoG arrays to decode, in rats, body position during open field navigation, through isolated single-unit activities.

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.

Background: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype.

Methods: We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells and public clinical datasets to identify key protein kinases implicated in temozolomide resistance.

Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma Using an Advanced Human In Vitro Model of the Blood-Brain Barrier and Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment, particularly the blood-brain barrier (BBB), is unknown.

Multiplexed RNA profiling by regenerative catalysis enables blood-based subtyping of brain tumors.

Current technologies to subtype glioblastoma (GBM), the most lethal brain tumor, require highly invasive brain biopsies. Here, we develop a dedicated analytical platform to achieve direct and multiplexed profiling of circulating RNAs in extracellular vesicles for blood-based GBM characterization. The technology, termed 'enzyme ZIF-8 complexes for regenerative and catalytic digital detection of RNA' (EZ-READ), leverages an RNA-responsive transducer to regeneratively convert and catalytically enhance signals from rare RNA targets.

Integrative multi-omics approach to targeted therapy for glioblastoma.

This review describes recent technological advances applied to glioblastoma (GBM), a brain tumor with dismal prognosis. International consortial efforts suggest the presence of molecular subtypes within histologically identical GBM tumors. This emphasizes that future treatment decisions should no longer be made based solely on morphological analyses, but must now take into consideration such molecular and cellular heterogeneity.

Adaptive mechanoproperties mediated by the formin FMN1 characterize glioblastoma fitness for invasion.

Glioblastoma are heterogeneous tumors composed of highly invasive and highly proliferative clones. Heterogeneity in invasiveness could emerge from discrete biophysical properties linked to specific molecular expression. We identified clones of patient-derived glioma propagating cells that were either highly proliferative or highly invasive and compared their cellular architecture, migratory, and biophysical properties.

Pharmacokinetics of levetiracetam in neurosurgical ICU patients.

Background/objectives: The pharmacokinetics (PK) of drugs is dramatically altered in critical illness. Augmented renal clearance (ARC), a phenomenon characterized by creatinine clearance (CrCl) greater than 130 ml/min/1.73m, is commonly described in critically ill patients.

Topography of transcriptionally active chromatin in glioblastoma.

Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts.

Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation.

Hypoxic microenvironment is a hallmark of solid tumors, especially glioblastoma. The strong reliance of glioma-propagating cells (GPCs) on hypoxia-induced survival advantages is potentially exploitable for drug development. To identify key signaling pathways for hypoxia adaptation by patient-derived GPCs, we performed a kinase inhibitor profiling by screening 188 small molecule inhibitors against 130 different kinases in normoxia and hypoxia.

Incidence of biomarkers in high-grade gliomas and their impact on survival in a diverse SouthEast Asian cohort - a population-based study.

Background: Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population.

Methods: Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained.

The National Neuroscience Institute External Ventricular Drain Study: A Pragmatic Multisite Risk-Stratification Pathway to Reduce Ventriculostomy-Related Infection.

Objective: Ventriculostomy-related infection (VRI) is associated with potential serious morbidity, extended hospitalization duration, increased health care costs, and mortality. We assessed the effectiveness of a pragmatic risk-stratification pathway for external ventricular drain (EVD) management, allowing for surgical decision making, in reducing the rate of VRIs.

Methods: Two studies were performed concurrently.

A STAT3-based gene signature stratifies glioma patients for targeted therapy.

Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition.

Regression based overall survival prediction of glioblastoma multiforme patients using a single discovery cohort of multi-institutional multi-channel MR images.

Glioblastoma multiforme (GBM) are malignant brain tumors, associated with poor overall survival (OS). This study aims to predict OS of GBM patients (in days) using a regression framework and assess the impact of tumor shape features on OS prediction. Multi-channel MR image derived texture features, tumor shape, and volumetric features, and patient age were obtained for 163 GBM patients.

Pathogenic mutations in neurofibromin identifies a leucine-rich domain regulating glioma cell invasiveness.

Glioblastoma (GBM) is the most aggressive tumor of the brain. NF1, a tumor suppressor gene and RAS-GTPase, is one of the highly mutated genes in GBM. Dysregulated NF1 expression promotes cell invasion, proliferation, and tumorigenesis.

Overall survival prediction in glioblastoma multiforme patients from volumetric, shape and texture features using machine learning.

Glioblastoma multiforme (GBM) are aggressive brain tumors, which lead to poor overall survival (OS) of patients. OS prediction of GBM patients provides useful information for surgical and treatment planning. Radiomics research attempts at predicting disease prognosis, thus providing beneficial information for personalized treatment from a variety of imaging features extracted from multiple MR images.

Effects of surgery on neurocognitive function in patients with glioma: a meta-analysis of immediate post-operative and long-term follow-up neurocognitive outcomes.

Purpose: This study aims to identify the neuropsychological tests commonly used for assessment in each neurocognitive domain, and quantify the post-operative changes in neurocognitive function in the immediate post-operation and follow-up.

Methods: With the use of the PubMed, a comprehensive search of the English literature was performed following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. There were 1021 publications identified for screening.

Awake Craniotomy for Resection of Brain Metastases: A Systematic Review.

Background: Surgery for brain metastases aims to reduce mass effect and achieve local control through maximizing resection. There is increasing recognition that awake craniotomy (AC) is especially relevant for resection of brain metastases in eloquent areas. This study seeks to examine the neurologic outcomes of using AC for brain metastases resection.

Microglial SMAD4 regulated by microRNA-146a promotes migration of microglia which support tumor progression in a glioma environment.

Glioma tumors constitute a significant portion of microglial cells, which are known to support tumor progression. The present study demonstrates that transforming growth factor-β (TGFβ) signaling pathway in microglia in a glioma environment is involved in tumor progression and pathogenesis. It has been shown that the TGFβ level is elevated in higher grades of gliomas and its signaling pathway regulates tumor progression through phosphorylation of SMAD2 and SMAD3, which form a complex with SMAD4 to regulate target gene transcription.

Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma.

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells.

Biobanking: An Important Resource for Precision Medicine in Glioblastoma.

The Cancer Genome Atlas effort has generated significant interest in a new paradigm shift in tumor tissue analysis, patient diagnosis and subsequent treatment decision. Findings have highlighted the limitation of sole reliance on histology, which can be confounded by inter-observer variability. Such studies demonstrate that histologically similar grade IV brain tumors can be divided into four molecular subtypes based on gene expression, with each subtype demonstrating unique genomic aberrations and clinical outcome.