Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.
O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation has been identified as a potential prognostic marker for glioblastoma patients. The relationship between the exact site of promoter methylation and its effect on gene silencing, and the patient's subsequent response to therapy, is still being defined. The aim of this study was to comprehensively characterize cytosine-guanine (CpG) dinucleotide methylation across the entire MGMT promoter and to correlate individual CpG site methylation patterns to mRNA expression, protein expression, and progression-free survival. To best identify the specific MGMT promoter region most predictive of gene silencing and response to therapy, we determined the methylation status of all 97 CpG sites in the MGMT promoter in tumor samples from 70 GBM patients using quantitative bisulfite sequencing. We next identified the CpG site specific and regional methylation patterns most predictive of gene silencing and improved progression-free survival. Using this data, we propose a new classification scheme utilizing methylation data from across the entire promoter and show that an analysis based on this approach, which we call 3R classification, is predictive of progression-free survival (HR = 5.23, 95% CI [2.089–13.097], p<0.0001). To adapt this approach to the clinical setting, we used a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test based on the 3R classification and show that this test is both feasible in the clinical setting and predictive of progression free survival (HR = 3.076, 95% CI [1.301–7.27], p = 0.007). We discuss the potential advantages of a test based on this promoter-wide analysis and compare it to the commonly used methylation-specific PCR test. Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting.
Glioblastoma multiforme (GBM) is the most common and lethal adult brain tumor. Resistance to standard radiation and chemotherapy is thought to involve survival of GBM cancer stem cells (CSCs). To date, no single marker for identifying GBM CSCs has been able to capture the diversity of CSC populations, justifying the needs for additional CSC markers for better characterization. Employing targeted mass spectrometry, here we present five cell-surface markers HMOX1, SLC16A1, CADM1, SCAMP3 and CLCC1 which were found to be elevated in CSCs relative to healthy neural stem cells (NSCs). Transcriptomic analyses of REMBRANDT and TCGA compendiums also indicated elevated expression of these markers in GBM relative to controls and non-GBM diseases. Two markers SLC16A1 and HMOX1 were found to be expressed among pseudopalisading cells that reside in the hypoxic region of GBM, substantiating the histopathological hallmarks of GBM. In a prospective study (N=8) we confirmed the surface expression of HMOX1 on freshly isolated primary GBM cells (P0). Employing functional assays that are known to evaluate stemness, we demonstrate that elevated HMOX1 expression is associated with stemness in GBM and can be modulated through TGFβ. siRNA-mediated silencing of HMOX1 impaired GBM invasion- a phenomenon related to poor prognosis. In addition, surgical resection of GBM tumors caused declines (18%±5.1SEM) in the level of plasma HMOX1 as measured by ELISA, in 8/10 GBM patients. These findings indicate that HMOX1 is a robust predictor of GBM CSC stemness and pathogenesis. Further understanding of the role of HMOX1 in GBM may uncover novel therapeutic approaches.
Summary:Purpose: To determine whether the specific location of electrographic seizure onset in the temporal lobe is related to hippocampal pathology in temporal lobe epilepsy (TLE).Methods: Consecutive presurgical patients with scalp EEGvideo evidence of TLE and no or mild hippocampal atrophy (HA) on magnetic resonance imaging (MRI) were prospectively studied by using depth and subdural strip electrode recordings to identify the site of the initial ictal discharge (IID). Thirty-four patients had either no or mild HA (HA-group). Four additional patients with moderate or marked HA (HA+ group) who required depth and strip electrodes served as a comparison group. Hippocampal pathology was assessed by MRI volumetrics and histopathologic grade of sclerosis (HS).Results: Thirty-eight patients were investigated. In the HAgroup, 10 patients had lobar ictal EEG onsets in the hippocampus (HF), medial paleocortex (MPC), and lateral neocortex (LNC); eight cases had regional IIDs in both HF and MPC; 12 persons had IIDs completely outside the HF; three cases lacked depth electrodes, and only one case (3%) had an IID confined to the HF. By contrast, three (75%) of four HA+ cases had IIDs confined to the HF (p = 0.002). Similarly, in 12 patients with low-grade HS, IIDs confined to the HF area were seen significantly less often than in six cases with high-grade HS (p = 0.025).Conclusions: In this study of a large number of patients with no to mild and a smaller group with moderate to marked HA and HS, the location of seizure onset in the temporal lobe was related to the degree of hippocampal pathology. Absence of HA and low-grade HS was each associated with IIDs in both the hippocampus and medial (with or without lateral) temporal cortex, or only the MPC or LNC. Marked HA and high-grade HS both were associated with IIDs restricted to the HF. Key Words: EEG-Intracranial electrodes-Depth electrodes-Temporal lobe epilepsy-Pathology-Medial temporal sclerosis.Subtypes of temporal lobe epilepsy (TLE) have been proposed based on semiology, pathology, and neuroimaging findings (1-3). When hippocampal sclerosis (HS) is found in specimens from anteromesial temporal resections (AMTR), mesial TLE (MTLE) is often diagnosed (4). Occasionally, the hippocampus exhibits no or low-grade HS in AMTRs. In such instances, lateral or neocortical TLE (NTLE) may be suspected, particularly when seizures persist after resection of only MTL structures. Recent studies have begun to examine whether clinical neurophysiologic recordings can assist in differentiating MTLE from NTLE (5-10).Scalp EEG ictal discharges during temporal lobe complex partial seizures (CPSs) may consist of sequential spikes or sharp waves (11,12), but most commonly appear as rhythmic waves (13-17 (6) depth and subdural electrode recordings, Ebersole and Pacia found that scalp EEG temporal 5-to 9-Hz CPS discharges usually had ictal onset in the hippocampus, and that 2-to 5-Hz (lateralized or diffuse) extracranial ictal patterns often correlated with simultaneous ictal onset in hippocampu...
Lipoprotein lipase (LPL) is involved in regulation of fatty acid metabolism, and facilitates cellular uptake of lipoproteins, lipids and lipid-soluble vitamins. We evaluated LPL distribution in healthy and Alzheimer’s disease (AD) brain tissue and its relative levels in cerebrospinal fluid. LPL immunostaining is widely present in different neuronal subgroups, microglia, astrocytes and oligodendroglia throughout cerebrum, cerebellum and spinal cord. LPL immunoreactivity is also present in leptomeninges, small blood vessels, choroid plexus and ependymal cells, Schwann cells associated with cranial nerves, and in anterior and posterior pituitary. In vitro studies have shown presence of secreted LPL in conditioned media of human cortical neuronal cell line (HCN2) and neuroblastoma cells (SK-N-SH), but not in media of cultured primary human astrocytes. LPL was present in cytoplasmic and nuclear fractions of neuronal cells and astrocytes in vitro. LPL immunoreactivity strongly associates with AD-related pathology, staining diffuse plaques, dystrophic and swollen neurites, possible Hirano bodies and activated glial cells. We observed no staining associated with neurofibrillary tangles or granulovacuolar degeneration. Granule cells of the dentate gyrus and the associated synaptic network showed significantly reduced staining in AD compared to control tissue. LPL was also reduced in AD CSF samples relative to those in controls.
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