Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production

BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-alpha production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Variation in the composition of carbohydrates in the Dona Paula Bay (west of India) during May/June 1998

Suspended particulate material was analysed for particulate carbohydrate concentration and composition and for the bulk parameters: suspended particulate matter, chlorophyll a, particulate organic carbon, particulate organic nitrogen and particulate proteins. Chlorophyll a concentrations increased from May 7 to 15 due to the development of a small scale bloom of diatom Navicula sp. and decreased for the remaining period after the premonsoon rain on 16 and 17 May. Concentrations of particulate organic carbon, organic nitrogen, carbohydrates and proteins increased with the increase in chlorophyll a concentration. Together particulate protein-carbon and carbohydrate-carbon accounted for 10 to 30% of the organic carbon. Glucose contributed 26 to 81% to the total particulate carbohydrates. The decrease in glucose concentration was accompanied by the increase in mannose, galactose, xylose, arabinose, rhamnose and fucose. Chlorophyll a showed significant positive relationship with glucose and negative relationships with arabinose and xylose. Conversely, suspended particulate matter showed significant positive relationships with xylose and arabinose and negative relationships with chlorophyll a and glucose. The hexoses to pentoses ratio increased during 7 to 15 May and decreased thereafter. Relatively higher chlorophyll a, particulate protein-carbon plus carbohydrate-carbon, glucose, hexoses:pentoses ratio and lower rhamnose plus fucose suggested the presence of more fresh marine organic matter during May 8 to 15. Subsequently, chlorophyll a, contribution of particulate protein-carbon plus carbohydrates-carbon to organic carbon, hexoses to pentoses ratio, and weight percentage of glucose decreased whereas, weight percentage of rhamnose plus fucose, arabinose and xylose increased, reflecting highly degraded diagenetically altered particulate organic matter from May 16 to June 2. The carbohydrate content and composition as well as protein data suggest that the nature and source of organic matter Varied within a few days at this tropical coastal site. Such variability in the nutritional quality of organic matter may have a strong influence on the metabolic activity of filter feeding organisms.La concentration en chlorophylle a a augmenté du 7 au 15 mai (floraison de la diatomée Navicula sp.), avant de décroître après l’épisode pluvieux des 16 et 17 mai. Les concentrations de carbone et d’azote organique particulaires, ainsi que les hydrates de carbone et les protéines varient parallèlement à la chlorophylle a. Le carbone particulaire (protéines et hydrates de carbone) représente de 10 à 30% du carbone organique. Le glucose représente de 26 à 81% du total des hydrates de carbone dans le matériel particulaire. Sa décroissance est accompagnée de l’accroissement du mannose, du galactose, du xylose, de l’arabinose, du rhamnose et du fucose. La chlorophylle a présente une corrélation positive avec le glucose et négative avec l’arabinose et le xylose. La matière particulaire en suspension est positivement corrélée au xylose et à l’arabinose et négativement à la chlorophylle a et au glucose. Le rapport hexoses/pentoses s’élève du 7 au 15 mai et décroît après. Les concentrations relativement élevées en chlorophylle a, en carbone sous forme de protéines et d’hydrates de carbone, en glucose et le taux hexoses/pentoses élevé ainsi que les valeurs basses du rhamnose plus fucose suggèrent la présence de matière organique marine néoformée dans la période du 8 au 15 mai. Les tendances inverses s’observent du 16 mai au 2 juin. La teneur et la composition en hydrates de carbone, ainsi que les données de protéines suggèrent une variation de l’origine de la matière organique en peu de jours à ce site côtier tropical. Une telle variabilité de la qualité nutritive de la matière organique doit avoir une forte influence sur l’actvité métabolique des filtreurs

Fluxes of inorganic and organic particulate matter in the Arabian Sea off Bombay

21-23Sedimentation of organic and inorganic matter was determined at 2, 22, 42 and 62 m depths during 19 August to 30 September 1985 at a station in the Arabian Sea off Bombay. All the parameters measured of sedimented material increased with depth, probably due to resuspension. Decreasing ratios of particulate organic carbon (POC)/particulate organic nitrogen (PON); POC/particulate total phosphate (PTP); and PON/PTP suggest the mineralization and microbial growth on the sinking particles whereas, high ratios of POC/chlorophyll a equivalent indicate that less phytoplankton pigments are associated with the sinking particles. Settling particles had less organic carbon than suspended matter