Beschreibung: Objective To determine, in one low income country (Nepal), which characteristics of medical students are associated with graduate doctors staying to practise in the country or in its rural...

Beschreibung: Prioritizing molecular alterations that act as drivers of cancer remains a crucial bottleneck in therapeutic development. Here we introduce HIT'nDRIVE, a computational method that integrates genomic and transcriptomic data to identify a set of patient-specific, sequence-altered genes, with sufficient collective influence over dysregulated transcripts. HIT'nDRIVE aims to solve the "random walk facility location" (RWFL) problem in a gene (or protein) interaction network, which differs from the standard facility location problem by its use of an alternative distance measure: "multihitting time," the expected length of the shortest random walk from any one of the set of sequence-altered genes to an expression-altered target gene. When applied to 2200 tumors from four major cancer types, HIT'nDRIVE revealed many potentially clinically actionable driver genes. We also demonstrated that it is possible to perform accurate phenotype prediction for tumor samples by only using HIT'nDRIVE-seeded driver gene modules from gene interaction networks. In addition, we identified a number of breast cancer subtype-specific driver modules that are associated with patients’ survival outcome. Furthermore, HIT'nDRIVE, when applied to a large panel of pan-cancer cell lines, accurately predicted drug efficacy using the driver genes and their seeded gene modules. Overall, HIT'nDRIVE may help clinicians contextualize massive multiomics data in therapeutic decision making, enabling widespread implementation of precision oncology.

Beschreibung: Introduction Malignant pleural effusion can complicate most cancers. It causes breathlessness and requires hospitalisation for invasive pleural drainages. Malignant effusions often herald advanced cancers and limited prognosis. Minimising time spent in hospital is of high priority to patients and their families. Various treatment strategies exist for the management of malignant effusions, though there is no consensus governing the best choice. Talc pleurodesis is the conventional management but requires hospitalisation (and substantial healthcare resources), can cause significant side effects, and has a suboptimal success rate. Indwelling pleural catheters (IPCs) allow ambulatory fluid drainage without hospitalisation, and are increasingly employed for management of malignant effusions. Previous studies have only investigated the length of hospital care immediately related to IPC insertion. Whether IPC management reduces time spent in hospital in the patients’ remaining lifespan is unknown. A strategy of malignant effusion management that reduces hospital admission days will allow patients to spend more time outside hospital, reduce costs and save healthcare resources. Methods and analysis The Australasian Malignant Pleural Effusion (AMPLE) trial is a multicentred, randomised trial designed to compare IPC with talc pleurodesis for the management of malignant pleural effusion. This study will randomise 146 adults with malignant pleural effusions (1:1) to IPC management or talc slurry pleurodesis. The primary end point is the total number of days spent in hospital (for any admissions) from treatment procedure to death or end of study follow-up. Secondary end points include hospital days specific to pleural effusion management, adverse events, self-reported symptom and quality-of-life scores. Ethics and dissemination The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study as have the ethics boards of all the participating hospitals. The trial results will be published in peer-reviewed journals and presented at scientific conferences. Trial registration numbers Australia New Zealand Clinical Trials Registry—ACTRN12611000567921; National Institutes of Health—NCT02045121.

Beschreibung: The human Ig repertoire is vast, producing billions of unique Abs from a limited number of germline Ig genes. The IgH V region (IGHV) is central to Ag binding and consists of 48 functional genes. In this study, we analyzed whether HIV-1–infected individuals who develop broadly neutralizing Abs show a distinctive germline IGHV profile. Using both 454 and Illumina technologies, we sequenced the IGHV repertoire of 28 HIV-infected South African women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing Abs. Of the 259 IGHV alleles identified in this study, approximately half were not found in the International Immunogenetics Database (IMGT). This included 85 entirely novel alleles and 38 alleles that matched rearranged sequences in non-IMGT databases. Analysis of the rearranged H chain V region genes of mAbs isolated from seven of these women, as well as previously isolated broadly neutralizing Abs from other donors, provided evidence that at least eight novel or non-IMGT alleles contributed to functional Abs. Importantly, we found that, despite a wide range in the number of IGHV alleles in each individual, including alleles used by known broadly neutralizing Abs, there were no significant differences in germline IGHV repertoires between individuals who do and do not develop broadly neutralizing Abs. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive Ig database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing Ab development in HIV-1 infection, with positive implications for HIV vaccine design.

Beschreibung: Dye-decolorizing peroxidases (DyPs) comprise a new family of heme peroxidases, which has received much attention due to their potential applications in lignin degradation. A new DyP from Thermomonospora curvata (TcDyP) was identified and characterized. Unlike other A-type enzymes, TcDyP is highly active toward a wide range of substrates including model lignin compounds, in which the catalytic efficiency with ABTS (kcatapp/Kmapp = (1.7 × 107) m−1 s−1) is close to that of fungal DyPs. Stopped-flow spectroscopy was employed to elucidate the transient intermediates as well as the catalytic cycle involving wild-type (wt) and mutant TcDyPs. Although residues Asp220 and Arg327 are found necessary for compound I formation, His312 is proposed to play roles in compound II reduction. Transient kinetics of hydroquinone (HQ) oxidation by wt-TcDyP showed that conversion of the compound II to resting state is a rate-limiting step, which will explain the contradictory observation made with the aspartate mutants of A-type DyPs. Moreover, replacement of His312 and Arg327 has significant effects on the oligomerization and redox potential (E°′) of the enzyme. Both mutants were found to promote the formation of dimeric state and to shift E°′ to a more negative potential. Not only do these results reveal the unique catalytic property of the A-type DyPs, but they will also facilitate the development of these enzymes as lignin degraders.

Beschreibung: Background: There has been little research on the economic status of those with multiple health conditions, particularly on the relationship between multiple health conditions and wealth. This paper will assess the difference in the value and type of wealth assets held by Australians who have multiple chronic health conditions. Methods: Using Health&WealthMOD, a microsimulation model of the 45–64-year-old Australian population in 2009, a counterfactual analysis was undertaken. The actual proportion of people with different numbers of chronic health conditions with any wealth, and the value of this wealth was estimated. This was compared with the counterfactual values had the individuals had no chronic health conditions. Results: There was no change in the proportion of people with one health condition who actually had any wealth, compared to the counterfactual proportion had they had no chronic health conditions. Ninety-four percent of those with four or more health conditions had some accumulated wealth; however, under the counterfactual, 100% would have had some accumulated wealth. There was little change in the value of non-income-producing assets under the counterfactual, regardless of number of health conditions. Those with four or more chronic health conditions had a mean value of $17 000 in income-producing assets; under the counterfactual, the average would have been $78 000. Conclusion: This study has highlighted the variation in the value of wealth according to number of chronic health conditions, and hence the importance of considering multiple morbidities when discussing the relationship between health and wealth.

Beschreibung: Objectives To project the number of older workers with lost productive life years (PLYs) due to chronic disease and resultant lost income; and lost taxes and increased welfare payments from 2015 to 2030. Design, setting and participants Using a microsimulation model, Health&WealthMOD2030, the costs of chronic disease in Australians aged 45–64 were projected to 2030. The model integrates household survey data from the Australian Bureau of Statistics Surveys of Disability, Ageing and Carers (SDACs) 2003 and 2009, output from long-standing microsimulation models (STINMOD (Static Incomes Model) and APPSIM (Australian Population and Policy Simulation Model)) used by various government departments, population and labour force growth data from Treasury, and disease trends data from the Australian Burden of Disease and Injury Study (2003). Respondents aged 45–64 years in the SDACs 2003 and 2009 formed the base population. Main outcome measures Lost PLYs due to chronic disease; resultant lost income, lost taxes and increased welfare payments in 2015, 2020, 2025 and 2030. Results We projected 380 000 (6.4%) people aged 45–64 years with lost PLYs in 2015, increasing to 462 000 (6.5%) in 2030—a 22% increase in absolute numbers. Those with lost PLYs experience the largest reduction in income than any other group in each year compared to those employed full time without a chronic disease, and this income gap widens over time. The total economic loss due to lost PLYs consisted of lost income modelled at $A12.6 billion in 2015, increasing to $A20.5 billion in 2030—a 62.7% increase. Additional costs to the government consisted of increased welfare payments at $A6.2 billion in 2015, increasing to $A7.3 billion in 2030—a 17.7% increase; and a loss of $A3.1 billion in taxes in 2015, increasing to $A4.7 billion in 2030—a growth of 51.6%. Conclusions There is a need for greater investment in effective preventive health interventions which improve workers’ health and work capacity.

Beschreibung: Fusarium ear rot (FER) incited by Fusarium verticillioides is a major disease of maize that reduces grain quality globally. Host resistance is the most suitable strategy for managing the disease. We report the results of genome-wide association study (GWAS) to detect alleles associated with increased resistance to FER in a set of 818 tropical maize inbred lines evaluated in three environments. Association tests performed using 43,424 single-nucleotide polymorphic (SNPs) markers identified 45 SNPs and 15 haplotypes that were significantly associated with FER resistance. Each associated SNP locus had relatively small additive effects on disease resistance and accounted for 1–4% of trait variation. These SNPs and haplotypes were located within or adjacent to 38 candidate genes, 21 of which were candidate genes associated with plant tolerance to stresses, including disease resistance. Linkage mapping in four biparental populations to validate GWAS results identified 15 quantitative trait loci (QTL) associated with F. verticillioides resistance. Integration of GWAS and QTL to the maize physical map showed eight colocated loci on chromosomes 2, 3, 4, 5, 9, and 10. QTL on chromosomes 2 and 9 are new. These results reveal that FER resistance is a complex trait that is conditioned by multiple genes with minor effects. The value of selection on identified markers for improving FER resistance is limited; rather, selection to combine small effect resistance alleles combined with genomic selection for polygenic background for both the target and general adaptation traits might be fruitful for increasing FER resistance in maize.

Beschreibung: Purpose: Enzalutamide resistance has emerged as a major problem in the management of castration-resistant prostate cancer (CRPC). Research on therapy resistance of CRPCs has primarily focused on the androgen receptor pathway. In contrast, there is limited information on antiapoptotic mechanisms that may facilitate the treatment resistance. The inhibitor of apoptosis proteins (IAP) family is well recognized for its role in promoting treatment resistance of cancers by inhibiting drug-induced apoptosis. Here, we examined whether BIRC6, an IAP family member, has a role in enzalutamide resistance of CRPCs and could provide a therapeutic target for enzalutamide-resistant CRPC. Experimental Design: Use of enzalutamide-resistant CRPC models: (i) the transplantable, first high-fidelity LTL-313BR patient-derived enzalutamide-resistant CRPC tissue xenograft line showing primary enzalutamide resistance, (ii) MR42D and MR49F CRPC cells/xenografts showing acquired enzalutamide resistance. Specific BIRC6 downregulation in these models was produced using a BIRC6 -targeting antisense oligonucleotide (ASO-6w2). Gene expression was determined by qRT-PCR and gene expression profiling. Molecular pathways associated with growth inhibition were assessed via gene enrichment analysis. Results: Of eight IAPs examined, BIRC6 was the only one showing elevated expression in both enzalutamide-resistant CRPC models. Treatment with ASO-6w2 markedly suppressed growth of LTL-313BR xenografts and increased tumor apoptosis without inducing major host toxicity. Pathway enrichment analysis indicated that GPCR and matrisome signaling were the most significantly altered pathways. Furthermore, ASO-6w2 inhibited expression of prosurvival genes that were upregulated in the LTL-313BR line. Conclusions: BIRC6 targeting inhibited the growth of enzalutamide-resistant CRPC models and may represent a new option for clinical treatment of advanced, enzalutamide-resistant prostate cancer. Clin Cancer Res; 23(6); 1542–51. ©2016 AACR .

Beschreibung: The molecular pathogenesis of the NUP98-HOXA9 fusion protein in acute myeloid leukemia Leukemia 31, 2000 (September 2017). doi:10.1038/leu.2017.194 Authors: A Rio-Machin, G Gómez-López, J Muñoz, F Garcia-Martinez, A Maiques-Diaz, S Alvarez, R N Salgado, M Shrestha, R Torres-Ruiz, C Haferlach, M J Larráyoz, M J Calasanz, J Fitzgibbon & J C Cigudosa