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- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)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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- Robinson, N. A., et al.
(författare)
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Applying genetic technologies to combat infectious diseases in aquaculture
- 2022
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Ingår i: Reviews in Aquaculture. - : Wiley. - 1753-5123 .- 1753-5131. ; 15:2, s. 491-535
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Tidskriftsartikel (refereegranskat)abstract
- Disease and parasitism cause major welfare, environmental and economic concerns for global aquaculture. In this review, we examine the status and potential of technologies that exploit genetic variation in host resistance to tackle this problem. We argue that there is an urgent need to improve understanding of the genetic mechanisms involved, leading to the development of tools that can be applied to boost host resistance and reduce the disease burden. We draw on two pressing global disease problems as case studies—sea lice infestations in salmonids and white spot syndrome in shrimp. We review how the latest genetic technologies can be capitalised upon to determine the mechanisms underlying inter- and intra-species variation in pathogen/parasite resistance, and how the derived knowledge could be applied to boost disease resistance using selective breeding, gene editing and/or with targeted feed treatments and vaccines. Gene editing brings novel opportunities, but also implementation and dissemination challenges, and necessitates new protocols to integrate the technology into aquaculture breeding programmes. There is also an ongoing need to minimise risks of disease agents evolving to overcome genetic improvements to host resistance, and insights from epidemiological and evolutionary models of pathogen infestation in wild and cultured host populations are explored. Ethical issues around the different approaches for achieving genetic resistance are discussed. Application of genetic technologies and approaches has potential to improve fundamental knowledge of mechanisms affecting genetic resistance and provide effective pathways for implementation that could lead to more resistant aquaculture stocks, transforming global aquaculture. © 2022 The Authors. Reviews in Aquaculture published by John Wiley & Sons Australia, Ltd.
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| 8. |
- Ahola, T, et al.
(författare)
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N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: A randomized controlled trial
- 2003
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Ingår i: Journal of Pediatrics. - 1097-6833 .- 0022-3476. ; 143:6, s. 713-719
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate whether N-acetyleysteine (NAC) infusion during the first week of life reduces the risk of death or bronchopulmonary dysplasia (BPD in infants with extremely low birth weight. Study design In a Nordic multicenter, double-blind trial, infants (n = 391) weighing 500 to 999 g and on ventilator or nasal continuous positive airway pressure were randomized before the age of 36 hours to receive NAC 16 to 32 mg/kg/d (n = 194) or placebo (n = 197) intravenously for 6 days. Primary end points were death or BPD, defined as supplementary oxygen requirement at 36 weeks' gestational age. Results There was no difference in the combined incidence of the primary end points death or BPD, 51% vs. 49%, between the NAC group and control group. Also similar was the incidence of BPD in survivors at 36 weeks' gestational age, 40% vs. 40%, and the mean oxygen requirement at the age of 28 days, 31.2% vs. 30.7%, respectively. The severity of BPD was similar in both groups. Conclusions A 6-day course of intravenous N-acetylcysteine at the dosage used does not prevent BPD or death in infants with extremely low birth weight.
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| 9. |
- Avall, Karin, et al.
(författare)
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Apolipoprotein CIII links islet insulin resistance to beta-cell failure in diabetes
- 2015
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:20, s. E2611-E2619
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance and beta-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and beta-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of beta-cell cytoplasmic free Ca2+ concentration ([Ca2+](i)) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+](i) response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of beta-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.
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