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| 7. |
- Thomas, HS, et al.
(author)
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- 2019
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swepub:Mat__t
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| 8. |
- Bravo, L, et al.
(author)
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- 2021
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| 9. |
- Tabiri, S, et al.
(author)
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- 2021
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| 11. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)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 scale1–3. 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 promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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- Glasbey, JC, et al.
(author)
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- 2021
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| 15. |
- Bulluck, H, et al.
(author)
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Independent Predictors of Cardiac Mortality and Hospitalization for Heart Failure in a Multi-Ethnic Asian ST-segment Elevation Myocardial Infarction Population Treated by Primary Percutaneous Coronary Intervention
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10072-
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Journal article (peer-reviewed)abstract
- We aimed to identify independent predictors of cardiac mortality and hospitalization for heart failure (HHF) from a real-world, multi-ethnic Asian registry [the Singapore Myocardial Infarction Registry] of ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention. 11,546 eligible STEMI patients between 2008 and 2015 were identified. In-hospital, 30-day and 1-year cardiac mortality and 1-year HHF rates were 6.4%, 6.8%, 8.3% and 5.2%, respectively. From the derivation cohort (70% of patients), age, Killip class and cardiac arrest, creatinine, hemoglobin and troponin on admission and left ventricular ejection fraction (LVEF) during hospitalization were predictors of in-hospital, 30-day and 1-year cardiac mortality. Previous ischemic heart disease (IHD) was a predictor of in-hospital and 30-day cardiac mortality only, whereas diabetes was a predictor of 1-year cardiac mortality only. Age, previous IHD and diabetes, Killip class, creatinine, hemoglobin and troponin on admission, symptom-to-balloon-time and LVEF were predictors of 1-year HHF. The c-statistics were 0.921, 0.901, 0.881, 0.869, respectively. Applying these models to the validation cohort (30% of patients) showed good fit and discrimination (c-statistic 0.922, 0.913, 0.903 and 0.855 respectively; misclassification rate 14.0%, 14.7%, 16.2% and 24.0% respectively). These predictors could be incorporated into specific risk scores to stratify reperfused STEMI patients by their risk level for targeted intervention.
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- Wong, Charlene Hl, et al.
(author)
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Barriers and Facilitators to Receiving the COVID-19 Vaccination and Development of Theoretically-Informed Implementation Strategies for the Public: Qualitative Study in Hong Kong
- 2022
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In: Vaccines. - : MDPI. - 2076-393X. ; 10:5
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Journal article (peer-reviewed)abstract
- Objectives: enhancing uptake of COVID-19 vaccines is an important tool for managing the pandemic. However, in Hong Kong, the COVID-19 vaccination rate in the general population was unsatisfactory during the early phase of the vaccination program. This two-part study aimed to (i) identify barriers and facilitators to receiving vaccinations, and (ii) develop theoretically-informed implementation strategies for promoting uptake. Methods: in part 1, 45 Hong Kong residents who differed in their willingness to vaccinate (willing (n = 15), were unwilling (n = 15), and were hesitant (n = 15)), were interviewed individually in February 2021. They were invited to express their perceptions of receiving the COVID-19 vaccination. The theoretical domains framework (TDF) was applied to guide the interviews and analyses. Behavioral diagnoses from these findings were then used to develop theoretically-informed implementation strategies in part 2, composed of behavior change techniques (BCTs) informed by the established BCT taxonomy. Results: in part 1, the five main barriers were (i) concerns on severe and long-term side effects; (ii) low confidence in the safety and effectiveness due to concerns of their accelerated development; (iii) unclear information on logistical arrangements of the vaccination program; (iv) insufficient data on safety and effectiveness; and (v) perceived low protection ability conferred by the vaccines. The five main facilitators included (i) healthcare professionals recommendations; (ii) news from TV, radio, and newspapers as main sources of trustworthy information; (iii) vaccine-related health education delivered by healthcare professionals; (iv) expectations of resuming to a normal social life; and (v) perceived benefits outweighing risks of mild and short-term side effects. Conclusions: seven implementation strategies were developed in part 2 based on the results above, namely (i) providing trustworthy vaccine-related information and scaling up the promotion; (ii) encouraging healthcare professionals to recommend vaccinations; (iii) giving incentives; (iv) using social influence approaches; (v) allowing a selection of COVID-19 vaccine brands; (vi) increasing accessibility for vaccinations; and (vii) emphasizing social responsibility.
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- Bauermeister, S, et al.
(author)
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The Dementias Platform UK (DPUK) Data Portal
- 2020
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In: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 35:6, s. 601-611
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Journal article (peer-reviewed)abstract
- The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure ‘lab’ using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
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| 25. |
- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 28. |
- Keung, W, et al.
(author)
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Non-cell autonomous cues for enhanced functionality of human embryonic stem cell-derived cardiomyocytes via maturation of sarcolemmal and mitochondrial KATP channels
- 2016
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 34154-
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Journal article (peer-reviewed)abstract
- Human embryonic stem cells (hESCs) is a potential unlimited ex vivo source of ventricular (V) cardiomyocytes (CMs), but hESC-VCMs and their engineered tissues display immature traits. In adult VCMs, sarcolemmal (sarc) and mitochondrial (mito) ATP-sensitive potassium (KATP) channels play crucial roles in excitability and cardioprotection. In this study, we aim to investigate the biological roles and use of sarcKATP and mitoKATP in hESC-VCM. We showed that SarcIK, ATP in single hESC-VCMs was dormant under baseline conditions, but became markedly activated by cyanide (CN) or the known opener P1075 with a current density that was ~8-fold smaller than adult; These effects were reversible upon washout or the addition of GLI or HMR1098. Interestingly, sarcIK, ATP displayed a ~3-fold increase after treatment with hypoxia (5% O2). MitoIK, ATP was absent in hESC-VCMs. However, the thyroid hormone T3 up-regulated mitoIK, ATP, conferring diazoxide protective effect on T3-treated hESC-VCMs. When assessed using a multi-cellular engineered 3D ventricular cardiac micro-tissue (hvCMT) system, T3 substantially enhanced the developed tension by 3-folds. Diazoxide also attenuated the decrease in contractility induced by simulated ischemia (1% O2). We conclude that hypoxia and T3 enhance the functionality of hESC-VCMs and their engineered tissues by selectively acting on sarc and mitoIK, ATP.
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| 34. |
- Pulit, SL, et al.
(author)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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In: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Journal article (peer-reviewed)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 41. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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