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

Screening of selected ethnomedicinal plants from South Africa for larvicidal activity against the mosquito <it>Anopheles arabiensis</it>

<p>Abstract</p> <p>Background</p> <p>This study was initiated to establish whether any South African ethnomedicinal plants (indigenous or exotic), that have been reported to be used traditionally to repel or kill mosquitoes, exhibit effective mosquito larvicidal properties.</p> <p>Methods</p> <p>Extracts of a selection of plant taxa sourced in South Africa were tested for larvicidal properties in an applicable assay. Thirty 3^rd instar <it>Anopheles arabiensis</it> larvae were exposed to various extract types (dichloromethane, dichloromethane/methanol) (1:1), methanol and purified water) of each species investigated. Mortality was evaluated relative to the positive control Temephos (Mostop; Agrivo), an effective emulsifiable concentrate larvicide.</p> <p>Results</p> <p>Preliminary screening of crude extracts revealed substantial variation in toxicity with 24 of the 381 samples displaying 100% larval mortality within the seven day exposure period. Four of the high activity plants were selected and subjected to bioassay guided fractionation. The results of the testing of the fractions generated identified one fraction of the plant, <it>Toddalia asiatica</it> as being very potent against the <it>An. arabiensis</it> larvae.</p> <p>Conclusion</p> <p>The present study has successfully identified a plant with superior larvicidal activity at both the crude and semi pure fractions generated through bio-assay guided fractionation. These results have initiated further research into isolating the active compound and developing a malaria vector control tool.</p

A Design and Evaluation of Layered Matrix Tablet Formulations of Metoprolol Tartrate

The aim of this paper was to evaluate the performance of different swellable polymers in the form of layered matrix tablets to provide controlled therapeutic effect of metoprolol tartrate for twice daily administration. Seven different swellable polymers (carrageenan, hydroxypropylmethyl cellulose, pectin, guar gum, xanthan gum, chitosan, and ethyl cellulose) were evaluated alone or in combination as release-retardant layer. Tablets were tested for weight variation, hardness, diameter/thickness ratio, friability, and drug content uniformity and subjected to in vitro drug-release studies. In addition, the target-release profile of metoprolol tartrate was plotted using its clinical pharmacokinetic data, and the release profiles of the tablets were evaluated in relation to the plotted target release profile. Carrageenan was determined as the best polymer in two-layered matrix tablet formulations due to its better accordance to the target release profile and was selected for preparing three-layered matrix tablets. Carrageenan formulations exhibited super case II release mechanism. Accelerated stability testing was performed on two- and three-layered matrix tablet formulations of carrageenan. The tablets were stored at 25°C/60% relative humidity and 40°C/75% relative humidity for 6 months and examined for physical appearance, drug content, and release characteristics. At the end of the storage time, formulations showed no change either in physical appearance, drug content, or drug-release profile. These results demonstrated the suitability of three-layered tablet formulation of carrageenan to provide controlled release and improved linearity for metoprolol tartrate in comparison to two-layered tablet formulation