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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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- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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- Khatri, C, et al.
(författare)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Tidskriftsartikel (refereegranskat)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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- Yao, JT, et al.
(författare)
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Early modulation of macrophage ROS-PPARγ-NF-κB signalling by sonodynamic therapy attenuates neointimal hyperplasia in rabbits
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 11638-
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Tidskriftsartikel (refereegranskat)abstract
- Disruption of re-endothelialization and haemodynamic balance remains a critical side effect of drug-eluting stents (DES) for preventing intimal hyperplasia. Previously, we found that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) suppressed macrophage-mediated inflammation in atherosclerotic plaques. However, the effects on intimal hyperplasia and re-endothelialization remain unknown. In this study, 56 rabbits were randomly assigned to control, ultrasound, ALA and ALA-SDT groups, and each group was divided into two subgroups (n = 7) on day 3 after right femoral artery balloon denudation combined with a hypercholesterolemic diet. Histopathological analysis revealed that ALA-SDT enhanced macrophage apoptosis and ameliorated inflammation from day 1. ALA-SDT inhibited neointima formation without affecting re-endothelialization, increased blood perfusion, decreased the content of macrophages, proliferating smooth muscle cells (SMCs) and collagen but increased elastin by day 28. In vitro, ALA-SDT induced macrophage apoptosis and reduced TNF-α, IL-6 and IL-1β via the ROS-PPARγ-NF-κB signalling pathway, which indirectly inhibited human umbilical artery smooth muscle cell (HUASMC) proliferation, migration and IL-6 production. ALA-SDT effectively inhibits intimal hyperplasia without affecting re-endothelialization. Hence, its clinical application combined with bare-metal stent (BMS) implantation presents a potential strategy to decrease bleeding risk caused by prolonged dual-antiplatelet regimen after DES deployment.
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- Fang, MY, et al.
(författare)
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T Cell Repertoire Abnormality in Immunodeficiency Patients with DNA Repair and Methylation Defects
- 2022
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Ingår i: Journal of clinical immunology. - : Springer Science and Business Media LLC. - 1573-2592 .- 0271-9142. ; 42:2, s. 375-393
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Tidskriftsartikel (refereegranskat)abstract
- Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B,ZBTB24,RAG1,DCLRE1C, andJAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients withDNMT3BandZBTB24mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.
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