ORCID Profile
0000-0002-8091-2549
Current Organisation
Baker Heart and Diabetes Institute
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Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: 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 ex le, 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 erse 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 .
Publisher: SAGE Publications
Date: 2017
Abstract: Coronary artery disease (CAD) is a leading cause of disease burden worldwide. Referral to cardiac rehabilitation (CR) is a class I recommendation for all patients with CAD based on findings that participation can reduce cardiovascular and all-cause mortality, as well as improve functional capacity and quality of life. However, programme uptake remains low, systematic progression through the traditional CR phases is often lacking, and communication between health care providers is frequently suboptimal, resulting in fragmented care. Only 30% to 50% of eligible patients are typically referred to outpatient CR and fewer still complete the programme. In contemporary models of CR, patients are no longer treated by a single practitioner, but rather by an array of health professionals, across multiples specialities and health care settings. The risk of fragmented care in CR may be great, and a concerted approach is required to achieve continuity and optimise patient outcomes. ‘Continuity of care’ has been described as the delivery of services in a coherent, logical, and timely fashion and which entails 3 specific domains: informational, management, and relational continuity. This is examined in the context of CR.
Publisher: Cold Spring Harbor Laboratory
Date: 03-01-2021
DOI: 10.1101/2020.12.31.425022
Abstract: Over the last two decades, molecular biology has been changed by the introduction of high-throughput technologies. Data sharing requirements have prompted the establishment of persistent data archives. A standardized approach for recording and managing these data was first proposed in the Minimal Information About a Microarray Experiment (MIAME) guidelines. The Minimal Information about a high throughput nucleotide Sequencing Experiment (MINSEQE) proposal was introduced in 2008 as a logical extension of the guidelines to next-generation sequencing (NGS) technologies used for transcriptome analysis. We present a historical snapshot of the data-sharing situation focusing on transcriptomics data from both microarray and RNA-sequencing experiments published between 2009 and 2013, a period during which RNA-seq studies became increasingly popular for transcriptome analysis. We assess how much data from RNA-seq based experiments is actually available in persistent data archives, compared to data derived from microarray based experiments, and evaluate how these types of data differ. Based on this analysis, we provide recommendations to improve RNA-seq data availability, reusability, and reproducibility.
Publisher: Oxford University Press (OUP)
Date: 04-01-2011
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41587-019-0360-3
Abstract: We present Butler, a computational tool that facilitates large-scale genomic analyses on public and academic clouds. Butler includes innovative anomaly detection and self-healing functions that improve the efficiency of data processing and analysis by 43% compared with current approaches. Butler enabled processing of a 725-terabyte cancer genome dataset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project in a time-efficient and uniform manner.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
DOI: 10.1249/MSS.0000000000001845
Abstract: This study investigated the effect of β-blockade on physiological and perceived exertion (RPE) responses during incremental treadmill exercise. Sixteen healthy participants ( n = 8 men age, 25.3 ± 4.6 yr) performed a maximal treadmill exercise test after ingestion of 100 mg metoprolol or placebo, with a double-blind, randomized, and counterbalanced design. Heart rate (HR), ventilatory, and gas exchange variables were measured continuously, and participants reported RPE at the end of each minute. Physiological and RPE responses during each condition were compared at the ventilatory threshold (VT), respiratory compensation point, and at maximal exercise using repeated-measures ANOVA. Linear regression modeled relationships between perceived exertion and physiological variables. The HR and V˙O 2 at the VT, respiratory compensation point, and maximal exercise were all significantly lower after β-blockade ( P 0.05). However, when standardized to within condition peak values, differences were no longer significant. The RPE associated with VT was higher after β-blockade (12.9 ± 1.0 vs 12.3 ± 1.2, P 0.05) but lower at maximal exercise (19.1 ± 0.6 vs 19.4 ± 0.5, P 0.05). Increases in RPE relative to HR were greater after β-blockade and remained significant when expressed relative to peak HR. There was no difference in the growth of the relationship between RPE and V˙O 2 across conditions, although the origin of the relationship was higher with β-blockade. Although β-blockade resulted in a significant reduction in exercising HR and V˙O 2 , the RPE for a given relative intensity remained unchanged. The relationship between RPE and V˙O 2 was not affected by β-blockade. The results provide evidence that RPE is a useful and reliable measure for exercise testing and prescription in patients prescribed β-blockade therapy.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2014
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1970-0
Abstract: Transcript alterations often result from somatic changes in cancer genomes 1 . Various forms of RNA alterations have been described in cancer, including overexpression 2 , altered splicing 3 and gene fusions 4 however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom s les have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 5 . Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis , of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13885-W
Abstract: The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT , MDM2 , CDK4 , ERBB2 , CD274 , PDCD1LG2 , and IGF2 . TERT -associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non- lified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
Publisher: BMJ
Date: 18-08-2018
DOI: 10.1136/BJSPORTS-2018-099153
Abstract: Assess the role of exercise intensity on changes in cardiorespiratory fitness (CRF) in patients with cardiac conditions attending exercise-based cardiac rehabilitation. Systematic review with meta-analysis. MEDLINE, Embase, CINAHL, SPORTDiscus, PsycINFO and Web of Science. Studies assessing change in CRF (reported as peak oxygen uptake V̇O 2peak ) in patients post myocardial infarction and revascularisation, following exercise-based cardiac rehabilitation. Studies establishing V̇O 2peak via symptom-limited exercise test with ventilatory gas analysis and reported intensity of exercise during rehabilitation were included. Studies with mean ejection fraction % were excluded. 128 studies including 13 220 patients were included. Interventions were classified as moderate, moderate-to-vigorous or vigorous intensity based on published recommendations. Moderate and moderate-to-vigorous-intensity interventions were associated with a moderate increase in relative V̇O 2peak (standardised mean difference±95% CI=0.94±0.30 and 0.93±0.17, respectively), and vigorous-intensity exercise with a large increase (1.10±0.25). Moderate and vigorous-intensity interventions were associated with moderate improvements in absolute V̇O 2peak (0.63±0.34 and 0.93±0.20, respectively), whereas moderate-to-vigorous-intensity interventions elicited a large effect (1.27±0.75). Large heterogeneity among studies was observed for all analyses. Subgroup analyses yielded statistically significant, but inconsistent, improvements in CRF. Engagement in exercise-based cardiac rehabilitation was associated with significant improvements in both absolute and relative V̇O 2peak . Although exercise of vigorous intensity produced the greatest pooled effect for change in relative V̇O 2peak , differences in pooled effects between intensities could not be considered clinically meaningful. Prospero CRD42016035638.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2020
Publisher: Springer Science and Business Media LLC
Date: 30-07-2013
DOI: 10.1038/NMETH.2562
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.JSAMS.2018.05.002
Abstract: Associations between objectively measured sedentary behaviour, physical activity (PA) and metabolic syndrome (MetS)-classified using three different definitions were investigated in an inactive s le of rural Australian adults. Quantitative, cross-sectional. 171 adults (50.7±12.4years) from two rural South Australian regions underwent seven-day accelerometer activity monitoring and MetS classification using the National Cholesterol Education Program, the International Diabetes Federation and the Harmonized definitions. Associations between sedentary and activity variables and MetS (adjusted for age, sex, diet and smoking status) were modelled using logistic regression. In secondary modelling, associations of sedentary and activity outcomes for each MetS definition were assessed, adjusting for other activity and sedentary variables. Prediction differences across the definitions of MetS were directly compared using Akaike's Information Criterion. Sedentary behaviour increased MetS risk, whereas light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) reduced MetS risk, irrespective of definition. In secondary models, LPA predicted MetS independently of MVPA and total sedentary time. Time spent in sedentary bouts (>30min) predicted MetS independently of MVPA and the number of sedentary bouts predicted MetS independently of LPA and MVPA. Prediction differences for MetS definitions failed to reach the critical threshold for difference (>10). This study highlights the importance of sedentary behaviour and LPA on the prevalence of MetS in an inactive s le of rural Australian adults. Studies assessing the efficacy of increasing LPA on MetS in this population are needed. Minimal predictive differences across the three MetS definitions suggest evidence from previous studies can be considered cumulative.
Publisher: Springer Science and Business Media LLC
Date: 06-2014
DOI: 10.1038/NBT.2926
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JSAMS.2018.07.002
Abstract: Rural Australian adults are consistently identified as insufficiently active, likely due to challenges implementing community-based physical activity programs in rural settings. On-line strategies to promote physical activity may be particularly effective in rural settings where isolation and scarcity of qualified support are potential barriers. The Rural Environments and Community Health (REACH) study evaluated the effectiveness of an online-delivered walking intervention among South Australian rural adults. Randomised controlled study design. A twelve-week intervention, with six- and twelve-month follow-up, was conducted. Participants (n=171 50.6±12.5years), recruited through flyers, local newspapers and radio, were randomised to comparison or intervention groups and received a pedometer. The intervention group received access to the REACH website and personalised step goals based on ratings of perceived exertion and daily affect. The comparison group received a paper diary and generic step goals. Outcome measures were accelerometry-assessed sedentary, light (LPA) and moderate-to-vigorous (MVPA) physical activity. Linear mixed models assessed changes over the intervention and follow-ups. Sedentary time decreased, and LPA and MVPA increased in both groups across the intervention (p<0.05). The intervention group demonstrated a larger increase in LPA at six-month follow-up relative to comparison (p<0.05). Both groups decreased sedentary time, overall and in bouts ≥30min, between baseline and twelve-month follow-up (p<0.05). From baseline to twelve-month follow-up, MVPA (total min and bouts ≥10min) declined more in the comparison group than the intervention group (p<0.05). While increased physical activity and decreased sedentary time were observed in both groups during the intervention period, maintenance was only observed for LPA at six-month follow-up in the intervention group. By twelve-month follow-up, post-intervention improvements had largely disappeared, suggesting that additional research is needed to identify ways to improve long-term adherence.
No related grants have been discovered for Braden Mitchell.