| 1. |
- Butler-Laporte, G, et al.
(författare)
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
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Tidskriftsartikel (refereegranskat)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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| 2. |
- Regev, A, et al.
(författare)
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The Human Cell Atlas
- 2017
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Ingår i: eLife. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 6
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Goubet, AG, et al.
(författare)
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Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis
- 2021
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 28:12, s. 3297-3315
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Tidskriftsartikel (refereegranskat)abstract
- Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus–host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B+FasL+, EomeshighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.
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| 4. |
- Casanova-Acebes, M, et al.
(författare)
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Neutrophils instruct homeostatic and pathological states in naive tissues
- 2018
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 215:11, s. 2778-2795
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Tidskriftsartikel (refereegranskat)abstract
- Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone marrow niches. In contrast, diurnal accumulation of neutrophils within the pulmonary vasculature influenced circadian transcription in the lungs. Neutrophil-influenced transcripts in this organ were associated with carcinogenesis and migration. Consistently, we found that neutrophils dictated the diurnal patterns of lung invasion by melanoma cells. Homeostatic infiltration of tissues unveils a facet of neutrophil biology that supports organ function, but can also instigate pathological states.
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| 9. |
- Hammerich, Linda, et al.
(författare)
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Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination
- 2019
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Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 25:5, s. 814-824
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Tidskriftsartikel (refereegranskat)abstract
- Indolent non-Hodgkin’s lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8+ T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial (NCT01976585). Non-responding patients developed a population of PD1+CD8+ T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.
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| 10. |
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IMPROVER D2.2 Report of criteria for evaluating resilience
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- In the recent years, the focus has moved from critical infrastructure protection to that of resilience. But how do we know whether a critical infrastructure is resilient or not, how can it be evaluated, measured and enhanced? Drawing on, combining and developing the ideas of the existing literature and practices, the current report develops a holistic, easy-to-use and computable methodology to evaluate critical infrastructure resilience, called Critical Infrastructure Resilience Index (CIRI). The methodology is applicable to all types of critical infrastructure, including a possibility to tailor it to the specific needs of different sectors, facilities and hazard scenarios. The proposed methodology is especially suitable for organizational and technological resilience evaluation, but permits including also elements of societal resilience indicators to the evaluations. The methodology is based on four levels of hierarchically organized indicators. Level 1 consists of the phases well known from the so-called crisis management cycle. Under these phases, we find sets of Level 2 rather generic indicators. Thus under level 1 ‘Prevention’, for instance, we may find a Level 2 indicator such as ‘Resilient design’, further divided into Level 3 more detailed indicators such as ‘Physical robustness’, ‘Cyber robustness’, ‘Redundancy’, ‘Modularity’, and ‘Independency’. The task is to study these indicators on Level 4 in the context of concrete critical infrastructure facilities and hazard scenarios, that is, applying Level 3 indicators into concrete circumstances. The methodology then permits to transfer quantitative, semi-quantitative and qualitative evaluations of individual sector-specific resilience indicators into uniform metrics, based on process maturity levels. This in turn makes it possible to give a specific critical infrastructure, or its part, a resilience value on the scale 0-5. While the real resilience value becomes clear only when one engages in the analysis of several indicators, the methodology can be used also as a step-by-step measurement and development tool for resilience, without necessary immediately engaging in time-consuming total resilience analysis. The user of this methodology is supposed to be the operator of critical infrastructure, or part of it, in the spirit of self-auditing. In case it would be implemented in a wider scale, in cooperation between the operators and authorities, it would give the authorities a holistic picture about the respective society’s critical infrastructure resilience. In this report, we draw a concise picture of the methodology and illustrate how this methodology could be applied to a specific infrastructure and hazard scenario.
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