The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Preliminary Phytochemical Studies, Evolution of antimicrobial and in vitro cytotoxic studies of selected polyherbal mixture of dietary importance

Background: In the present study we were evaluated pharmacognostical; antimicrobial and cytotoxic studies of the aqueous and Ethanolic extracts of the dietary polyherbal powders because they are great importance in the treatment of various metabolic disorder. Materials and methods: the following powder mixtures of Malus pumiplus (fruit), Momordica chirata (fruit) powder, Citrus limon (fruit), Pleurotus ostreatus (Mushroom), and Triticum aestivum (wheat grass) were extracted with distilled water and with ethanol. Results and conclusion: The result indicates that the above solvents having better extractive values with good bioactive components like Polyphenols, Glycosides, and Saponins. These are responsible bioactive phytochemical used in the herbal therapy. The aqueous and the Ethanolic were evaluated for The anti-microbial activity by cup plate method and the diameter of zone of inhibition is nearly equal to the standard drug and both the extracts showed potential cytotoxic activity through the in-vitro cytotoxic studies by MTT assay

Examining the Structure-Activity Relationship of Benzopyran Based Inhibitors of the Hypoxia Inducible Factor-1 Pathway

Many forms of solid tumor have a characteristic feature known as hypoxia, which describes a low or non-existent presence of oxygen in the cellular microenvironment. This decrease in oxygen causes activation of the hypoxia inducible factor (HIF) pathway, which activates the transcription of many genes that cause cell proliferation, metastasis, increased glycolysis and angiogenesis. Increased HIF expression has been linked with poor patient prognosis, increased malignancy, and therapeutic resistance. Previous work in our lab has identified 1 and 2 as inhibitors of the HIF pathway, specifically as disrupters of the p300-HIF-1α complex formation. A library of sulfonamide analogs has been designed and synthesized with the intent of examining the SAR of this series of compounds and improving potency and physicochemical properties as compared with lead compounds 1 and 2. At the end, we have achieved a thorough understanding of the structural features critical for future optimization work

Design and in Vitro Activities of <i>N</i>-Alkyl-<i>N</i>-[(8-<i>R</i>-2,2-dimethyl-2<i>H</i>-chromen-6-yl)methyl]heteroarylsulfonamides, Novel, Small-Molecule Hypoxia Inducible Factor-1 Pathway Inhibitors and Anticancer Agents

The hypoxia inducible factor (HIF) pathway is an attractive target for cancer, as it controls tumor adaptation to growth under hypoxia and mediates chemotherapy and radiation resistance. We previously discovered 3,4-dimethoxy-<i>N</i>-[(2,2-dimethyl-2<i>H</i>-chromen-6-yl)­methyl]-<i>N</i>-phenylbenzenesulfonamide as a novel, small-molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; log <i>P</i>_7.4 = 3.7). Here we describe the synthesis of 12 <i>N</i>-alkyl-<i>N</i>-[(8-<i>R</i>-2,2-dimethyl-2<i>H</i>-chromen-6-yl)­methyl]­heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log <i>P</i>_7.4 values of 8 of the 12 new analogs ranged from 1.2–3.1. Aqueous solubilities of three analogs were measured, among which the most soluble <i>N</i>-[(8-methoxy-2,2-dimethyl-2<i>H</i>-chromen-6-yl)­methyl]-<i>N</i>-(propan-2-yl)­pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g., a solubility improvement of ∼9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC₅₀ values at or below 5 μM in our HIF-dependent reporter assay