Identification of potential serum biomarkers of glioblastoma: serum osteopontin levels correlate with poor prognosis

Background: The aim of this study is to identify serum biomarkers with classification and prognosis utility for astrocytoma, in particular glioblastoma (GBM). Methods: Our previous glioma microarray database was mined to identify genes that encode secreted or membrane-localized proteins. Subsequent analysis was done using significant analysis of microarrays, followed by reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemical validation in tumor tissues, ELISA and Western blot validation in sera, and correlation with survival of GBM patients. Results: Significant analysis of microarrays identified 31 upregulated and 3 downregulated genes specifically in GBMs. RT-qPCR validation on an independent set of samples confirmed the GBM-specific differential expression of several genes, including three upregulated (CALU, CXCL9, and TIMP1) and two downregulated (GPX3 and TIMP3) novel genes. With respect to osteopontin (OPN), we show the GBM-specific upregulation by RT-qPCR and immunohistochemical staining of tumor tissues. Elevated serum OPN levels in GBM patients were also shown by ELISA and Western blot. GBM patients with high serum OPN levels had poorer survival than those with low serum OPN levels (median survival 9 versus 22 months respectively; P = 0.0001). Further, we also show high serum TIMP1 levels in GBM patients compared with grade II/III patients by ELISA and downregulation of serum GPX3 and TIMP3 proteins in GBMs compared with normal control by Western blot analysis. Conclusions: Several novel potential serum biomarkers of GBM are identified and validated. High serum OPN level is found as a poor prognostic indicator in GBMs. Impact: Identified serum biomarkers may have potential utility in astrocytoma classification and GBM prognosis

Cerebellar Liponeurocytoma: A Rare Fatty Tumor and its Literature Review

Cerebellar liponeurocytoma is a rare oncological entity, and the knowledge about the treatment and outcome of these rare tumors is still evolving. Very few cases have been described in literature. We report a middle-aged male who presented with raised intracranial pressure features and gait ataxia. His imaging features revealed classical features of liponeurocytoma in cerebellar vermis, with abundant fat component evident in both computed tomography and magnetic resonance imaging. He underwent resection of the lesion and has been asymptomatic for 4 years. This report describes the classical radiological and immunohistochemical features of this rare entity with favorable outcome and reviews the existing literature

Assessment of Radiation Resistance and Therapeutic Targeting of Cancer Stem Cells: A Raman Spectroscopic Study of Glioblastoma

Radiation is the standard therapy used for treating Glioblastoma (GBM), a grade IV brain cancer. Glioma Stem like Cells (GSCs), an integral part of GBM, enforces resistance to radiation therapy of GBM. Studying the differential biomolecular composition of GSCs with varying levels of radiation sensitivity can aid in identifying the molecules and their associated pathways which impose resistance to cells thereby unraveling new targets which would serve as potential adjuvant therapy. Raman spectroscopy being a noninvasive, label free technique can determine the biomolecular constituent of cells under live conditions. In this study, we have deduced Raman spectral signatures to predict the radiosensitivity of any GSC accurately using the inherent and radiation induced biomolecular composition. Our study identified the differential regulation of several biomolecules which can be potential targets for adjuvant therapy. We radiosensitized the resistant GSCs using small molecule inhibitors specific to the metabolic pathways of these biomolecules. Efficient antitumor therapy can be attained with lower dosage of radiation along with these inhibitors and thus improving the survival rate of GBM patients with reduced side effects from radiation

Surgery for drug-resistant focal epilepsy

During the colloquium on drug-resistant epilepsy (DRE) at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore on August 16-18, 2013, a number of presentations were made on the surgically remediable lesional epilepsy syndromes, presurgical evaluation, surgical techniques, neuropathology of drug resistance focal epilepsy and surgical outcome. This pictorial essay with the illustrative case examples provides an overview of the various surgical techniques for the management of drug-resistant focal epilepsy

Spectrum of primary intracranial tumors at a tertiary care neurological institute: A hospital?based brain tumor registry

ABSTRACTBackground: Hospital?based cancer registries (HBCRs) provide information on the magnitude and distribution of cancersin a given hospital. Hospital?based brain tumor registry (HBBTR) data on primary intracranial tumors from a tertiary careneurological center is presented. This is compared with related national and international data.Materials and Methods: Data of patients operated for brain tumors at the National Institute of Mental Health andNeurosciences, Bangalore, India, between January 2010 and December 2014 was collected. Patients' clinical details andhistopathological diagnosis were recorded. Data was analyzed and compared with that of Tata Memorial Hospital (TMH),Mumbai, and the Central Brain Tumor Registry of the United States (CBTRUS).Results: A total of 4295 primary intracranial tumors in 1847 (43%) females and 2448 (57%) male patients were recorded.Pediatric and adult patients accounted for 16.2% and 83.8% of the cases, respectively. The maximum proportion of tumorswas noted in the fourth decade. Among children, astrocytomas (25.1%), embryonal (20.6%), and ependymal tumors (14.8%)were the most frequently reported histology. In adults, meningiomas (23.2%), glioblastomas (15.5%), and nerve sheathtumors (12.7%) were common. Glioblastomas and all other tumors showed a male predilection whereas meningiomaspresented more commonly in females. While our HBBTR followed similar trends as TMH data, marked difference was seenin the median age of some tumor subtypes when compared to CBTRUS.Conclusion: This HBBTR data gives a glimpse of the prevalence of varied primary intracranial tumors. Such data can belinked to other HBCRs and population?based cancer registries in India for improved research and policy?making decisions

Cbx7 is epigenetically silenced in glioblastoma and inhibits cell migration by targeting YAP/TAZ-dependent transcription

Glioblastomas (GBM) are the most malignant form of astrocytomas which are difficult to treat and portend a grave clinical course and poor prognosis. In this study, we identified Chromobox homolog 7 (Cbx7), a member of Polycomb Repressive Complex 1 (PRC1), as a downregulated gene in GBM owing to its promoter hypermethylation. Bisulphite sequencing and methylation inhibitor treatment established the hypermethylation of Cbx7 in GBM. Exogenous overexpression of Cbx7 induced cell death, inhibited cell proliferation, colony formation and migration/invasion of the glioma cells. GSEA of Cbx7 regulated genes identified Cbx7 as a repressor of transcription co- activators YAP/TAZ, the inhibitory targets of the Hippo signalling pathway. In good correlation, the exogenous expression of Cbx7 repressed the YAP/TAZ- dependent transcription and downregulated CTGF, a bonafide YAP/TAZ target. We also observed reduced levels of phospho-JNK in Cbx7 expressing cells. Additionally, CTGF silencing and pharmacological inhibition of JNK also inhibited glioma cell migration. Further, Cbx7 failed to inhibit cell migration significantly in the presence of exogenously overexpressed CTGF or constitutively active JNK. Thus, our study identifies Cbx7 as an inhibitor of glioma cell migration through its inhibitory effect on YAP/TAZ-CTGF-JNK signalling axis and underscores the importance of epigenetic inactivation of Cbx7 in gliomagenesis

Data from: An eighteen serum cytokine signature for discriminating glioma from normal healthy individuals

Glioblastomas (GBM) are largely incurable as they diffusely infiltrate adjacent brain tissues and are difficult to diagnose at early stages. Biomarkers derived from serum, which can be obtained by minimally invasive procedures, may help in early diagnosis, prognosis and treatment monitoring. To develop a serum cytokine signature, we profiled 48 cytokines in sera derived from normal healthy individuals (n = 26) and different grades of glioma patients (n = 194). We divided the normal and grade IV glioma/GBM serum samples randomly into equal sized training and test sets. In the training set, the Prediction Analysis for Microarrays (PAM) identified a panel of 18 cytokines that could discriminate GBM sera from normal sera with maximum accuracy (95.40%) and minimum error (4.60%). The 18-cytokine signature obtained in the training set discriminated GBM sera from normal sera in the test set as well (accuracy 96.55%; error 3.45%). Interestingly, the 18-cytokine signature also differentiated grade II/Diffuse Astrocytoma (DA) and grade III/Anaplastic Astrocytoma (AA) sera from normal sera very efficiently (DA vs. normal–accuracy 96.00%, error 4.00%; AA vs. normal–accuracy 95.83%, error 4.17%). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using 18 cytokines resulted in the enrichment of two pathways, cytokine-cytokine receptor interaction and JAK-STAT pathways with high significance. Thus our study identified an 18-cytokine signature for distinguishing glioma sera from normal healthy individual sera and also demonstrated the importance of their differential abundance in glioma biology