Search

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.

Glioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)‐4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secretory Par‐4 induces apoptosis in cancer cells, its potential in drug‐resistant tumors remains to be fully explored. Multicellular spheroids (MCS) of cancer cells often acquire multi‐drug resistance and serve as ideal experimental models. We investigated the role of Par‐4 in Tamoxifen (TAM)‐induced cell death in MCS of human cell lines and primary cultures of GBM tumors. TCGA and REMBRANT data analysis revealed that low levels of Par‐4 correlated with low survival period (21.85 ± 19.30 days) in GBM but not in astrocytomas (59.13 ± 47.26 days) and oligodendrogliomas (58.04 ± 59.80 days) suggesting low PAWR expression as a predictive risk factor in GBM. Consistently, MCS of human cell lines and primary cultures displayed low Par‐4 expression, high level of chemo‐resistance genes and were resistant to TAM‐induced cytotoxicity. In monolayer cells, TAM‐induced cytotoxicity was associated with enhanced expression of Par‐4 and was alleviated by silencing of Par‐4 using specific siRNA. TAM effectively induced secretory Par‐4 in conditioned medium (CM) of cells cultured as monolayer but not in MCS. Moreover, MCS were rendered sensitive to TAM‐induced cell death by exposure to conditioned medium (CM)‐containing Par‐4 (derived from TAM‐treated monolayer cells). Also TAM reduced the expression of Akt and PKCζ in GBM cells cultured as monolayer but not in MCS. Importantly, combination of TAM with inhibitors to PI3K inhibitor (LY294002) or PKCζ resulted in secretion of Par‐4 and cell death in MCS. Since membrane GRP78 is overexpressed in most cancer cells but not normal cells, and secretory Par‐4 induces apoptosis by binding to membrane GRP78, secretory Par‐4 is an attractive candidate for potentially overcoming therapy‐resistance not only in malignant glioma but in broad spectrum of cancers.

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors—rapamycin, temsirolimus, torin 1, and PP242—suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M-induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol-myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as “stemness-inhibiting drugs” and a promising therapeutic approach to target glioma stem cells.

Background and Objectives: Evaluating the sagittal apical base relationship during orthodontic diagnosis and treatment planning is an important step. This study was aimed at comparison of Beta angle, ANB angle and Wit’s appraisal for assessment of sagittal skeletal discrepancy. Materials and Methods: Eighty six young adults (43 female and 43 male) were selected from the patient’s reporting to Department of Orthodontics, College of Dental Sciences, Davangere, India. Family lineage was studied to know the nativity of Davangere. The standardized pre-treatment lateral cephalogram of the chosen sample was traced. The sample was divided into three skeletal pattern groups: Class I, Class II and Class III, based on the ANB angle and profile, Beta angle was assessed in each group. Statistical Analysis: The data was subjected to statistical analysis student’s t-test, ANOVA test and correlation and regression analysis, using the software namely SPSS Software version 13. Microsoft word and Excel were used to generate graphs and tables. Results: In the local Davangere population, Class I skeletal pattern group exhibited Beta angle between 26º–34º, Beta angle less than 27º was found in Class II skeletal pattern, and Beta angle greater than 32º was seen Class III skeletal pattern. The coefficient of variation of Beta angle in all the three groups was significantly homogenous compared to ANB angle and Wits appraisal. The correlation and regression analysis of the total sample indicated a highly significant correlation between Beta angle and ANB angle (p

Gliomas are the most common and aggressive of brain tumors in adults. Cancer stem cells (CSC) contribute to chemoresistance in many solid tumors including gliomas. The function of prostate apoptosis response-4 (Par-4) as a pro-apoptotic protein is well documented in many cancers; however, its role in CSC remains obscure. In this study, we aimed to explore the role of Par-4 in drug-induced cytotoxicity using human glioma stem cell line--HNGC-2 and primary culture (G1) derived from high grade glioma. We show that among the panel of drugs- lomustine, carmustine, UCN-01, oxaliplatin, temozolomide and tamoxifen (TAM) screened, only TAM induced cell death and up-regulated Par-4 levels significantly. TAM-induced apoptosis was confirmed by PARP cleavage, Annexin V and propidium iodide staining and caspase-3 activity. Knock down of Par-4 by siRNA inhibited cell death by TAM, suggesting the role of Par-4 in induction of apoptosis. We also demonstrate that the mechanism involves break down of mitochondrial membrane potential, down regulation of Bcl-2 and reduced activation of Akt and ERK 42/44. Secretory Par-4 and GRP-78 were significantly expressed in HNGC-2 cells on exposure to TAM and specific antibodies to these molecules inhibited cell death suggesting that extrinsic Par-4 is important in TAM-induced apoptosis. Interestingly, TAM decreased the expression of neural stem cell markers--Nestin, Bmi1, Vimentin, Sox2, and Musashi in HNGC-2 cell line and G1 cells implicating its potential as a stemness inhibiting drug. Based on these data and our findings that enhanced levels of Par-4 sensitize the resistant glioma stem cells to drug-induced apoptosis, we propose that Par-4 may be explored for evaluating anti-tumor agents in CSC.

Groundwater is the only source of fresh water in the Thar Desert which is located in an arid region of Pakistan with dense population and spreads over 19,638km2. Low rainfall, low groundwater recharge, high evaporation and absence of perennial streams are the general reasons for water scarcity. Being the single water source for drinking, domestic and industrial uses, and livestock activities, this source is highly overexploited. Realizing the gravity of the situation, this paper presents a groundwater quality evaluation of Islamkot, Tharparkar, using Water Quality Index (WQI) and Geospatial tools. 40 samples were collected from dug wells. The TDS of 28 samples was found higher than 3000mg/L and 12 samples ranged from 1500 to 3000mg/L. Many (28) samples were not further analyzed due to their very high TDS which made the water unfit for drinking. Twelve samples with TDS ranging from 1500 to 3000 mg/L were further analyzed. The analyzed results revealed the average values of pH, EC, TDS, salinity, chloride, total alkalinity, fluoride, and arsenic. The results did not meet NEQS and WHO guidelines. Pearson correlation analysis was conducted among parameters. Further, groundwater quality was assessed by WQI and indicated that water quality varied from very poor to unsuitable for drinking. The consumption of polluted groundwater has been the main cause of prevalent waterborne diseases and poses a very high risk for public health. [ABSTRACT FROM AUTHOR]

We have previously demonstrated immunostimulatory activity of a fungal lectin, Rhizoctonia bataticola lectin (RBL), towards normal human peripheral blood mononuclear cells. The present study aimed to explore the anticancer activities of RBL using human leukemic T-cell lines, Molt-4, Jurkat and HuT-78. RBL exhibited significant binding (>90%) to the cell membrane that was effectively inhibited by complex glycoproteins such as mucin (97% inhibition) and asialofetuin (94% inhibition) but not simple sugars such as N-acetyl-D-galactosamine, glucose and sucrose. RBL induced a dose and time dependent inhibition of proliferation and induced cytotoxicity in the cell lines. The percentage of apoptotic cells, as determined by hypodiploidy, was 33% and 42% in Molt-4 and Jurkat cells, respectively, compared to 3.11% and 2.92% in controls. This effect was associated with a concomitant decrease in the G0/G1 population. Though initiator caspase-8 and -9 were activated upon exposure to RBL, inhibition of caspase-8 but not caspase-9 rescued cells from RBL-induced apoptosis. Mechanistic studies revealed that RBL induced cleavage of Bid, loss of mitochondrial membrane potential and activation of caspase-3. The expression of the anti-apoptotic proteins Bcl-2 and Bcl-X was down regulated without altering the expression of pro-apoptotic proteins- Bad and Bax. In contrast to leukemic cells, RBL did not induce apoptosis in normal PBMC, isolated CD3+ve cells and undifferentiated CD34+ve hematopoietic stem and progenitor cells (HSPCs). The findings highlight the differential effects of RBL on transformed and normal hematopoietic cells and suggest that RBL may be explored for therapeutic applications in leukemia. [ABSTRACT FROM AUTHOR]