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- Thompson, B.A., et al.
(författare)
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Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:2, s. 107-115
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Tidskriftsartikel (refereegranskat)abstract
- The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.
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- Carmona-Gutierrez, D., et al.
(författare)
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Guidelines and recommendations on yeast cell death nomenclature
- 2018
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Ingår i: Microbial Cell. - : Shared Science Publishers OG. - 2311-2638. ; 5:1, s. 4-31
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Forskningsöversikt (refereegranskat)abstract
- Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research.
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- Ancelle-Park, R., et al.
(författare)
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Summary of the evidence of breast cancer service screening outcomes in Europe and first estimate of the benefit and harm balance sheet
- 2012
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Ingår i: Journal of Medical Screening. - : SAGE Publications. - 0969-1413 .- 1475-5793. ; 19, s. 5-13
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To construct a European 'balance sheet' of key outcomes of population-based mammographic breast cancer screening, to inform policy-makers, stakeholders and invited women. Methods From the studies reviewed, the primary benefit of screening, breast cancer mortality reduction, was compared with the main harms, over-diagnosis and false-positive screening results (FPRs). Results Pooled estimates of breast cancer mortality reduction among invited women were 25% in incidence-based mortality studies and 31% in case-control studies (38% and 48% among women actually screened). Estimates of over-diagnosis ranged from 1% to 10% of the expected incidence in the absence of screening. The combined estimate of over-diagnosis for screened women, from European studies correctly adjusted for lead time and underlying trend, was 6.5%. For women undergoing 10 biennial screening tests, the estimated cumulative risk of a FPR followed by non-invasive assessment was 17%, and 3% having an invasive assessment. For every 1000 women screened biennially from age 50-51 until age 68-69 and followed up to age 79, an estimated seven to nine lives are saved, four cases are over-diagnosed, 170 women have at least one recall followed by non-invasive assessment with a negative result and 30 women have at least one recall followed by invasive procedures yielding a negative result. Conclusions The chance of saving a woman's life by population-based mammographic screening of appropriate quality is greater than that of over-diagnosis. Service screening in Europe achieves a mortality benefit at least as great as the randomized controlled trials. These outcomes should be communicated to women offered service screening in Europe.
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- Guimond, S. E., et al.
(författare)
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Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
- 2022
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Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 8:5, s. 527-545
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
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- Fryk, Emanuel, et al.
(författare)
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Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients
- 2016
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:7, s. 998-1006
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. Methods. Proteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16 weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4 weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. Results. Galectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p < 0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p < 0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p < 0.05) and increased by overfeeding (p < 0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p < 0.05) but this was independent of the insulin signal. Conclusion. Proteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes. (C) 2016 Elsevier Inc. All rights reserved.
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- Holmgren, Christina M, et al.
(författare)
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Out-of-hospital cardiac arrest : Causes according to autopsy and electrocardiography - Analysis of 781 patients with neither hospital care nor prescribed medication during the preceding two years.
- 2020
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 150, s. 65-71
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is a knowledge gap regarding aetiology of and potential for predicting out-of-hospital cardiac arrest (OHCA) among individuals who are healthy before the event.AIM: To describe causes of OHCA and the potential for predicting OHCA in apparently healthy patients.METHODS: Patients were recruited from the Swedish Register of Cardiopulmonary Resuscitation from November 2007 to January 2011. Inclusion criteria were: OHCA with attempted CPR but neither dispensed prescription medication nor hospital care two years before the event The register includes the majority of patients suffering OHCA in Sweden where cardiopulmonary resuscitation (CPR) was attempted. Medication status was defined by linkage to the Swedish Prescribed Drug Register. Cause of death was assessed based on autopsy and the Swedish Cause of Death Register. Prediction of OHCA was attempted based on available electrocardiograms (ECG) before the OHCA event.RESULTS: Altogether 781 individuals (16% women) fulfilled the inclusion criteria. Survival to 30 days was 16%. Autopsy rate was 72%. Based on autopsy, 70% had a cardiovascular aetiology and 59% a cardiac aetiology. An ECG recording before the event was found in 23% of cases. The ECG was abnormal in 22% of them.CONCLUSION: Among OHCA victims who appeared to be healthy prior to the event, the cause was cardiovascular in the great majority according to autopsy findings. A minority had a preceding abnormal ECG that could have been helpful in avoiding the event.
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