Riluzole is a radio‐sensitizing agent in an in vivo model of brain metastasis derived from GRM1 expressing human melanoma cells

Approximately 50% of patients having metastatic melanoma develop brain metastases during the course of their illness. Evidence exists that melanoma cells have increased aptitude for the repair of sublethal DNA damage caused by ionizing radiation therapy. To address the radio‐resistance of melanoma, many groups adopted radiotherapy schedules that deliver larger daily fractions of radiation, but due to the risk of neurotoxicity, these large fractions cannot be delivered to the whole brain for patients with brain metastases. Here, we used orthotopic implanted GRM1 expressing human melanoma cell xenografts in mice, to demonstrate that animals receiving concurrent glutamate signaling blockade (riluzole) and radiation led to a decrease in intracranial tumor growth compared to either modality alone. These preclinical results suggest riluzole may cause radio‐sensitization that offers enhanced efficacy for a subset of human melanoma patients undergoing radiotherapy for brain metastasis.     

The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor. Despite optimal treatment and evolving standard of care, the median survival of patients diagnosed with GBM is only 12–15 months. In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects. Two WHO grade IV human GBM cells lines (U87MG and U118MG) and primary human dermal fibroblasts (HDFs) were repeatedly exposed to PROG and TMZ either alone or in combination for 3 and 6 days. Cell death was measured by MTT reduction assay. PROG and TMZ individually induced tumor cell death in a dose-dependent manner. PROG at high doses produced more cell death than TMZ alone. When combined, PROG enhanced the cell death-inducing effect of TMZ. In HDFs, PROG did not reduce viability even at the same high cytotoxic doses, but TMZ did so in a dose-dependent manner. In combination, PROG reduced TMZ toxicity in HDFs. PROG alone and in combination with TMZ suppressed the EGFR/PI3K/Akt/mTOR signaling pathway and MGMT expression in U87MG cells, thus suppressing cell proliferation. PROG and TMZ individually reduced cell migration in U87MG cells but did so more effectively in combination. PROG enhances the cytotoxic effects of TMZ in GBM cells and reduces its toxic side effects in healthy primary cells.     

ADSBET2: Automated Determination of Salt-Bridge Energy-Terms version 2

AvailabilityADSBET2 is freely available at http://sourceforge.net/projects/ADSBET2/ for all users.     

Wnt and SHH in prostate cancer: trouble mongers occupy the TRAIL towards apoptosis

Prostate cancer is a serious molecular disorder that arises because of reduction in tumour suppressors and overexpression of oncogenes. The malignant cells survive within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These signals are, nonetheless, deregulated through perturbations to mechanotransduction, from the nanoscale level to the tissue level. Increasingly sophisticated interpretations have uncovered significant contributions of signal transduction cascades in governing prostate cancer progression. To dismantle the major determinants that lie beneath disruption of spatiotemporal patterns of activity, crosstalk between various signalling cascades and their opposing and promoting effects on TRAIL-mediated activities cannot be ruled out. It is important to focus on that molecular multiplicity of cancer cells, various phenotypes reflecting expression of a variety of target oncogenes, reversible to irreversible, exclusive, overlapping or linked, coexist and compete with each other. Comprehensive investigations into TRAIL-mediated mitochondrial dynamics will remain a worthwhile area for underlining causes of tumourigenesis and for unravelling interference options.     

Protein intake and stress levels in nurses and housewives of Pakistan

Stress has many biological effects on human daily life. In the present study, dietary protein intake was correlated with the investigated stress levels of nurses and housewives of the targeted urban population. Age group ranged from 30 to 45 years and both the groups belonged to middle socioeconomic status. After calculations of environmental, psychological and physiological stresses, it was observed that the levels of stress in housewives were significantly higher than those of nurses. Recommended dietary allowances, RDA and actual protein intakes, API were also compared in both the groups. The found protein intake was less in housewives as compared to that of nurses.     

The effects of dsRNA mycoviruses on growth and murine virulence of Aspergillus fumigatus

Some isolates of the opportunistic human pathogenic fungus Aspergillus fumigatus are known to be infected with mycoviruses. The dsRNA genomes of two of these mycoviruses, which include a chrysovirus and a partitivirus, have been completely sequenced and an RT-PCR assay for the viruses has been developed. Through curing virus-infected A. fumigatus isolates by cycloheximide treatment and transfecting virus-free isolates with purified virus, as checked by RT-PCR, isogenic virus-free and virus-infected lines of the fungus were generated whose phenotypes and growth have been directly compared. Mycovirus infection of A. fumigatus with either the chrysovirus or the partitivirus resulted in significant aberrant phenotypic alterations and attenuation of growth of the fungus but had no effect on susceptibility to common antifungals. Chrysovirus infection of A. fumigatus caused no significant alterations to murine pathogenicity.     

Microbial transformation of (-)-isolongifolol and butyrylcholinesterase inhibitory activity of transformed products

The microbial transformation of (-)-isolongifolol (1) by using the standard two-stage fermentation technique with Fusarium lini afforded polar oxygenated metabolites: 10-oxoisolongifolol (2), 10alpha-hydroxyisolongifolol (3), and 9alpha-hydroxyisolongifolol (4). Metabolites 3 and 4 were also formed with the incubation of 1 with Aspergillus niger. All three metabolites were found to be new. Compounds 3 and 4 inhibited butyrylcholinesterase enzyme in a concentration-dependent manner with IC50 values 13.6 and 299.5 microM, respectively. Compound 3 showed un-competitive mode of inhibition against butyrylcholinesterase with Ki value 15.0 microM. The structures of metabolites 2-4 were deduced on the basis of spectroscopic techniques and single-crystal X-ray diffraction techniques.