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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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- Brevini, T, et al.
(författare)
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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7950, s. 134-
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Tidskriftsartikel (refereegranskat)abstract
- Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
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- Glasner, J, et al.
(författare)
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A small molecule alpha(4)beta(1) antagonist prevents development of murine Lyme arthritis without affecting protective immunity
- 2005
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Ingår i: Journal of Immunology. - 1550-6606. ; 175:7, s. 4724-4734
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Tidskriftsartikel (refereegranskat)abstract
- After infection with Borrelia burgdorferi, humans and mice under certain conditions develop arthritis. Initiation of inflammation is dependent on the migration of innate immune cells to the site of infection, controlled by interactions of a variety of adhesion molecules. In this study, we used the newly synthesized compound S18407, which is a prodrug of the active drug S16197, to analyze the functional importance of alpha(4)beta(1)-dependent cell adhesion for the development of arthritis and for the antibacterial immune response. S16197 is shown to interfere specifically with the binding of alpha(4)beta(1) integrin to its ligands VCAM-1 and fibronectin in vitro. Treatment of B. burgdorferi-infected C3H/Hej mice with the alpha(4)beta(1), antagonist significantly ameliorated the outcome of clinical arthritis and the influx of neutrophilic granulocytes into ankle joints. Furthermore, local mRNA up-regulation of the proinflammatory mediators IL-1, IL-6, and cyclooxygenase-2 was largely abolished. Neither the synthesis of spirochete-specific Igs nor the development of a Th1-dominated immune response was altered by the treatment. Importantly, the drug also did not interfere with Ab-mediated control of spirochete load in the tissues. These findings demonstrate that the pathogenesis, but not the protective immune response, in Lyme arthritis is dependent on the alpha(4)beta(1)-mediated influx of inflammatory cells. The onset of inflammation can be successfully targeted by treatment with S18407.
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- Curley, J P, et al.
(författare)
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Increased body fat in mice with a targeted mutation of the paternally expressed imprinted gene Peg3.
- 2005
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Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 19:10, s. 1302-4
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Tidskriftsartikel (refereegranskat)abstract
- Peg3 encodes a C2H2 type zinc finger protein that is implicated in a novel physiological pathway regulating core body temperature, feeding behavior, and obesity in mice. Peg3+/- mutant mice develop an excess of abdominal, subcutaneous, and intra-scapular fat, despite a lifetime of lower food intake than wild-type animals. However, they start life with reduced fat reserves and are slower to enter puberty. These mice maintain a lower core body temperature, fail to respond to a cold challenge, and have lower metabolic activity as measured by oxygen consumption. Plasma leptin levels are significantly higher than in wild types, and Peg3+/- mice appear to have developed leptin resistance. Administration of exogenous leptin resulted in a significant reduction in food intake in wild-type mice that was not observed in Peg3+/- mutants. This mutation, which is strongly expressed in hypothalamic tissue during development, has the capacity to regulate multiple events relating to energy homeostasis.
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- Engler, Ian D, et al.
(författare)
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Revision Rates After Primary Allograft ACL Reconstruction by Allograft Tissue Type in Older Patients.
- 2023
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Ingår i: Orthopaedic journal of sports medicine. - 2325-9671. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- While there is extensive literature on the use of allograft versus autograft in anterior cruciate ligament (ACL) reconstruction, there is limited clinical evidence to guide the surgeon in choice of allograft tissue type.To assess the revision rate after primary ACL reconstruction with allograft and to compare revision rates based on allograft tissue type and characteristics.Cohort study; Level of evidence, 3.Patients who underwent primary allograft ACL reconstructions at a single academic institution between 2015 and 2019 and who had minimum 2-year follow-up were included. Exclusion criteria were missing surgical or allograft tissue type data. Demographics, operative details, and subsequent surgical procedures were collected. Allograft details included graft tissue type (Achilles, bone-patellar tendon-bone [BTB], tibialis anterior or posterior, semitendinosus, unspecified soft tissue), allograft category (all-soft tissue vs bone block), donor age, irradiation duration and intensity, and chemical cleansing process. Revision rates were calculated and compared by allograft characteristics.Included were 418 patients (age, 39 ± 12years; body mass index, 30 ± 9kg/m2). The revision rate was 3% (11/418) at a mean follow-up of 4.9 ± 1.4years. There were no differences in revision rate according to allograft tissue type across Achilles tendon (3%; 3/95), BTB (5%; 3/58), tibialis anterior or posterior (3%; 5/162), semitendinosus (0%; 0/46), or unspecified soft tissue (0%; 0/57) (P = .35). There was no difference in revision rate between all-soft tissue versus bone block allograft (6/283 [2%] vs 5/135 [4%], respectively; P = .34). Of the 51% of grafts with irradiation data, all grafts were irradiated, with levels varying from 1.5 to 2.7 Mrad and 82% of grafts having levels of <2.0 Mrad. There was no difference in revision rate between the low-dose and medium-to high-dose irradiation cohorts (4% vs 6%, respectively; P = .64).Similarly low (0%-6%) revision rates after primary ACL reconstruction were seen regardless of allograft tissue type, bone block versus all-soft tissue allograft, and sterilization technique in 418 patients with mean age of 39 years. Surgeons may consider appropriately processed allograft tissue with or without bone block when indicating ACL reconstruction in older patients.
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- Masterson, C. H., et al.
(författare)
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Mesenchymal stem/stromal cell-based therapies for severe viral pneumonia: therapeutic potential and challenges
- 2021
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 9:61, s. 1-21
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Forskningsöversikt (refereegranskat)abstract
- Severe viral pneumonia is a significant cause of morbidity and mortality globally, whether due to outbreaks of endemic viruses, periodic viral epidemics, or the rarer but devastating global viral pandemics. While limited anti-viral therapies exist, there is a paucity of direct therapies to directly attenuate viral pneumonia-induced lung injury, and management therefore remains largely supportive. Mesenchymal stromal/stem cells (MSCs) are receiving considerable attention as a cytotherapeutic for viral pneumonia. Several properties of MSCs position them as a promising therapeutic strategy for viral pneumonia-induced lung injury as demonstrated in pre-clinical studies in relevant models. More recently, early phase clinical studies have demonstrated a reassuring safety profile of these cells. These investigations have taken on an added importance and urgency during the COVID-19 pandemic, with multiple trials in progress across the globe. In parallel with clinical translation, strategies are being investigated to enhance the therapeutic potential of these cells in vivo, with different MSC tissue sources, specific cellular products including cell-free options, and strategies to ‘licence’ or ‘pre-activate’ these cells, all being explored. This review will assess the therapeutic potential of MSC-based therapies for severe viral pneumonia. It will describe the aetiology and epidemiology of severe viral pneumonia, describe current therapeutic approaches, and examine the data suggesting therapeutic potential of MSCs for severe viral pneumonia in pre-clinical and clinical studies. The challenges and opportunities for MSC-based therapies will then be considered.
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- O'Sullivan, D., et al.
(författare)
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Inclusion4EU : Co-Designing a Framework for Inclusive Software Design and Development
- 2023
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Ingår i: Studies in Health Technology and Informatics. - : NLM (Medline). - 0926-9630 .- 1879-8365. ; 306, s. 497-502
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Tidskriftsartikel (refereegranskat)abstract
- Digital technology is now pervasive, however, not all groups have uniformly benefitted from technological changes and some groups have been left behind or digitally excluded. Comprehensive data from the 2017 Current Population Survey shows that older people and persons with disabilities still lag behind in computer and internet access. Furthermore unique ethical, privacy and safety implications exist for the use of technology for older persons and people with disabilities and careful reflection is required to incorporate these aspects, which are not always part of a traditional software lifecycle. In this paper we present the Inclusion4EU project that aims to co-design a new framework, guidelines and checklists for inclusive software design and development with end-users from excluded categories, academics with expertise in human-computer interaction and industry practitioners from software engineering.
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