Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.
Glioblastoma (GBM), the most malignant of the brain tumors is classified on the basis of molecular signature genes using TCGA data into four subtypes- classical, mesenchymal, proneural and neural. The mesenchymal phenotype is associated with greater aggressiveness and low survival in contrast to GBMs enriched with proneural genes. The proinflammatory cytokines secreted in the microenvironment of gliomas play a key role in tumor progression. The study focused on the role of Oncostatin-M (OSM), an IL-6 family cytokine in inducing mesenchymal properties in GBM. Analysis of TCGA and REMBRANDT data revealed that expression of OSMR but not IL-6R or LIFR is upregulated in GBM and has negative correlation with survival. Amongst the GBM subtypes, OSMR level was in the order of mesenchymal > classical > neural > proneural. TCGA data and RT-PCR analysis in primary cultures of low and high grade gliomas showed a positive correlation between OSMR and mesenchymal signature genes-YKL40/CHI3L1, fibronectin and vimentin and a negative correlation with proneural signature genes-DLL3, Olig2 and BCAN. OSM enhanced transcript and protein level of fibronectin and YKL-40 and reduced the expression of Olig2 and DLL3 in GBM cells. OSM-regulated mesenchymal phenotype was associated with enhanced MMP-9 activity, increased cell migration and invasion. Importantly, OSM induced mesenchymal markers and reduced proneural genes even in primary cultures of grade-III glioma cells. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. The data suggest that OSMR can be explored as potential target for therapeutic intervention.
This novel technique of the combined trans-sphenoidal and simultaneous trans-ventricular-endoscopic approach is a viable option for patients with giant fibrous pituitary adenoma when the tumour is not yielding to the trans-sphenoidal route alone.
Objectives:To study 1)the efficacy of transforaminal percutaneous endoscopic lumbar discectomy in lumbar disc herniations.2) limitations and advantages of the surgical procedure. 3)morbidity and complications associated with the procedure.Materials and Methods:This study was carried out on 120 patients who had single level herniated disc Pre-operative assessment of VAS and MSS scoring systems were documented one day prior to surgery. Post operative results were determined by MacNab criteria and by modified Suezawa and Schreiber clinical scoring system (MSS score).Results:Maximum patients were in the age group of 31 to 40 years and 83.43% of the patients were males. 80% patients had lumbar disc herniation at L4-L5 level, The mean operative time of endoscopic discectomy was 52.28 minutes and the mean hospital stay was 2.1days.8 cases of L5-S I were abandoned due to high iliac bone and hence their disc could not be accessed. Out of 112 patients who underwent operation, 2 patients developed discitis and 1 was found to have dysesthesia. Also recurrent prolapsed intervertebral disc was seen in 6 cases The mean preoperative and 6 months follow-up VAS score was 8.4 and 1.89 respectively. Mean preoperative and 6 months follow-up Modified Suezawa And Schreiber Clinical Scoring System(MSS Score) was 3.47 and 7.92 respectively. MSS score showed excellent and good outcome in 82.12% patients and Modified Macnab Criteria showed excellent and good outcome in 89.3% patients at 6months follow-up.Conclusion:TPELD can be a reasonable alternative to conventional microscopic discectomy for the treatment of patients with LDH. We also conclude that TPELD is not an effective procedure for L5-S 1 disc and an open procedure should be opted for better outcomes.
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