Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

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

Transcriptomic analysis of insecticide resistance in the lymphatic filariasis vector Culex quinquefasciatus

Culex quinquefasciatus plays an important role in transmission of vector-borne diseases of public health importance, including lymphatic filariasis (LF), as well as many arboviral diseases. Currently, efforts to tackle C. quinquefasciatus vectored diseases are based on either mass drug administration (MDA) for LF, or insecticide-based interventions. Widespread and intensive insecticide usage has resulted in increased resistance in mosquito vectors, including C. quinquefasciatus. Herein, the transcriptome profile of Ugandan bendiocarb-resistant C. quinquefasciatus was explored to identify candidate genes associated with insecticide resistance. High levels of insecticide resistance were observed for five out of six insecticides tested, with the lowest mortality (0.97%) reported to permethrin, while for DDT, lambdacyhalothrin, bendiocarb and deltamethrin the mortality rate ranged from 1.63–3.29%. Resistance to bendiocarb in exposed mosquitoes was marked, with 2.04% mortality following 1 h exposure and 58.02% after 4 h. Genotyping of the G119S Ace-1 target site mutation detected a highly significant association (p 8-fold increase vs unexposed controls). These results provide evidence that bendiocarb resistance in Ugandan C. quinquefasciatus is mediated by both target-site mechanisms and over-expression of detoxification enzymes

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Not AvailableTHE BULLETIN CONTAINS VERY USEFUL DATA WITH RESPECT TO RUNOFF , SOIL AND NUTRIENT LOSSES BASED ON STUDIES CONDUCTED AT THE CSWCRTI , RESEARCH CENTRE KOTA DURING PAST FOUR DECADES . THE RESULTS OF STUDIES ON RUNOFF AND SOIL LOSS AS WELL AS NUTRIENT LOSSES UNDER FOUR SLOPE LENGTHS VIZ. 22,44, 66 AND 88 m WITH UNIFORM WIDTH UNIFORM WIDTH OF 1.83 m AT 1% SLOPE INDICATED MAXIMUM RUNOFF ( 432.3%OF RAINFALL) AND SOIL LOSS (7.12 t/ha/yr SOIL LOSS) UNDER 88 m PLOT IN CULTIVATED FALLOW SITUATIONS . SIMILARLY , RUNOFF AND SOIL LOSS WITH SOYABEAN CROPPING WAS 15.9% AND 525 kg/ha/yr UNDER 22m PLOT LENGTH WHICH PROGRESSIVELY DECREASED TO 2% AND 90 kg/ha/yr RESPECTIVELY UNDER 88m PLOT LENGTH. THE NUTRIENT LOSSES FOLLOWED THE TREND OF SOIL LOSS.Not Availabl

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Not AvailableCHHAJAWA WATERSHED ( 453.75HA) LOCATED IN DRY SUB- HUMID TRACT OF SOUTH- EASTERN RAJASTHAN IS ONE OF THE 47 WATERSHEDS SELECTED BY THE INDIAN COUNCIL OF AGRICULTURAL RESEARCH DURING 1983 TO SERVE AS A MODEL WATERSHED. THE WATERSHED WAS DEVELOPED BY ADOPTING THE PLAN AND TECHNICAL GUIDANCE OF CSWCRTI , RESEARCH CENTRE , KOTA BY RAJASTHAN STATE SOIL CONSERVATION DEPARTMENT DURING FEBRUARY 1986 MARCH 1989. THE WATERSHED WAS CONTINUOUSLY MONITORED FOR THE CHANGES BROUGHT ABOUT IN PRODUCTION AND PRODUCTIVITY, GROUND WATER RECHARGE, VEGETATION, EMPLOYMENT GENERATION, INCOME AND ITS DISTRIBUTION, HYDROLOGICAL BEHAVIOUR ETC. AS A RESULT OF VARIOUS DEVELOPMENTAL WORKS CARRIED OUT IN THE WATERSHED. THIS BULLETIN CONTAINS VALUABLE LONG- TERM DATA GENERATED DURING THE EXECUTION OF THE PROJECT AND AFTERWARDS IN THE AREAS.Not Availabl