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Sökning: WFRF:(Allen David) > (2020)

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  • Thaventhiran, James E D, et al. (författare)
  • Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
  • 2020
  • Ingår i: Nature. - 1476-4687. ; 583:7814, s. 90-95
  • Tidskriftsartikel (refereegranskat)abstract
    • Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
  • Gonzalez-Ericsson, Paula, et al. (författare)
  • The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers into breast cancer clinical trials and daily practice
  • 2020
  • Ingår i: Journal of Pathology. - John Wiley and Sons Inc.. - 1096-9896. ; 250:5, s. 667-684
  • Forskningsöversikt (refereegranskat)abstract
    • Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
  • Turro, Ernest, et al. (författare)
  • Whole-genome sequencing of patients with rare diseases in a national health system.
  • 2020
  • Ingår i: Nature. - 1476-4687. ; 583:7814, s. 96-102
  • Tidskriftsartikel (refereegranskat)abstract
    • Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
  • Abercrombie, Daniel, et al. (författare)
  • Dark Matter benchmark models for early LHC Run-2 Searches : Report of the ATLAS/CMS Dark Matter Forum
  • 2020
  • Ingår i: Physics of the Dark Universe. - 0953-8585 .- 2212-6864. ; 27
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>This document is the final report of the ATLAS-CMS Dark Matter Forum, a forum organized by the ATLAS and CMS collaborations with the participation of experts on theories of Dark Matter, to select a minimal basis set of dark matter simplified models that should support the design of the early LHC Run-2 searches. A prioritized, compact set of benchmark models is proposed, accompanied by studies of the parameter space of these models and a repository of generator implementations. This report also addresses how to apply the Effective Field Theory formalism for collider searches and present the results of such interpretations.</p>
  • Hinman, R. S., et al. (författare)
  • Development of a core capability framework for qualified health professionals to optimise care for people with osteoarthritis : an OARSI initiative
  • 2020
  • Ingår i: Osteoarthritis and Cartilage. - Elsevier. - 1063-4584. ; 28:2, s. 154-166
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Develop a generic trans-disciplinary, skills-based capability framework for health professionals providing care for people with OA. Design: e-Delphi survey. An international inter-professional Delphi Panel (researchers; clinicians; consumer representatives) considered a draft framework (adapted from elsewhere) of 131 specific capabilities mapped to 14 broader capability areas across four domains (A: person-centred approaches; B: assessment, investigation and diagnosis; C: management, interventions and prevention; D: service and professional development). Over three rounds, the Panel rated their agreement (Likert or numerical rating scales) on whether each specific capability in Domains B and C was essential (core) for all health professionals when providing care for all people with OA. Those achieving consensus (≥80% of Panel) rating of ≥ seven out of ten (Round 3) were retained. Generic domains (A and D) were included in the final framework and amended based on Panel comments. Results: 173 people from 31 countries, spanning 18 disciplines and including 26 consumer representatives, participated. The final framework comprised 70 specific capabilities across 13 broad areas i) communication; ii) person-centred care; iii) history-taking; iv) physical assessment; v) investigations and diagnosis; vi) interventions and care planning; vii) prevention and lifestyle interventions; viii) self-management and behaviour change; ix) rehabilitative interventions; x) pharmacotherapy; xi) surgical interventions; xii) referrals and collaborative working; and xiii) evidence-based practice and service development). Conclusion: Experts agree that health professionals require an array of skills in person-centred approaches; assessment, investigation and diagnosis; management, interventions and prevention; and service and professional development to provide optimal care for people with OA.
  • Hsieh, Samantha, et al. (författare)
  • Polysaccharide Capsules Equip the Human Symbiont Bacteroides thetaiotaomicron to Modulate Immune Responses to a Dominant Antigen in the Intestine
  • 2020
  • Ingår i: Journal of Immunology. - 1550-6606 .- 0022-1767. ; 204:4, s. 1035-1046
  • Tidskriftsartikel (refereegranskat)abstract
    • Bacteria express multiple diverse capsular polysaccharides (CPSs) for protection against environmental and host factors, including the host immune system. Using a mouse TCR transgenic CD4+ T cell, BθOM, that is specific for B. thetaiotaomicron and a complete set of single CPS-expressing B. thetaiotaomicron strains, we ask whether CPSs can modify the immune responses to specific bacterial Ags. Acapsular B. thetaiotaomicron, which lacks all B. thetaiotaomicron CPSs, stimulated BθOM T cells more strongly than wild-type B. thetaiotaomicron Despite similar levels of BθOM Ag expression, many single CPS-expressing B. thetaiotaomicron strains were antistimulatory and weakly activated BθOM T cells, but a few strains were prostimulatory and strongly activated BθOM T cells just as well or better than an acapsular strain. B. thetaiotaomicron strains that expressed an antistimulatory CPS blocked Ag delivery to the immune system, which could be rescued by Fc receptor-dependent Ab opsonization. All single CPS-expressing B. thetaiotaomicron strains stimulated the innate immune system to skew toward M1 macrophages and release inflammatory cytokines in an MyD88-dependent manner, with antistimulatory CPS activating the innate immune system in a weaker manner than prostimulatory CPS. The expression of antistimulatory versus prostimulatory CPSs on outer membrane vesicles also regulated immune responses. Moreover, antistimulatory and prostimulatory single CPS-expressing B. thetaiotaomicron strains regulated the activation of Ag-specific and polyclonal T cells as well as clearance of dominant Ag in vivo. These studies establish that the immune responses to specific bacterial Ags can be modulated by a diverse set of CPSs.
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