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- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 4. |
- Kousathanas, A, et al.
(author)
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Whole-genome sequencing reveals host factors underlying critical COVID-19
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 607:7917, s. 97-
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Journal article (peer-reviewed)abstract
- Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
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| 6. |
- Ammirati, Enrico, et al.
(author)
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Acute Myocarditis Associated With Desmosomal Gene Variants
- 2022
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In: JACC. Heart failure. - : ELSEVIER SCI LTD. - 2213-1779 .- 2213-1787. ; 10:10, s. 714-727
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Journal article (peer-reviewed)abstract
- BACKGROUND The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown.OBJECTIVES The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV.METHODS In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up.RESULTS In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM. CONCLUSIONS Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk. (J Am Coll Cardiol HF 2022;10:714-727) (c) 2022 by the American College of Cardiology Foundation.
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| 8. |
- Clifton, O. E., et al.
(author)
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Influence of Dynamic Ozone Dry Deposition on Ozone Pollution
- 2020
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In: Journal of Geophysical Research-Atmospheres. - : American Geophysical Union (AGU). - 2169-897X .- 2169-8996. ; 125:8
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Journal article (peer-reviewed)abstract
- Identifying the contributions of chemistry and transport to observed ozone pollution using regional-to-global models relies on accurate representation of ozone dry deposition. We use a recently developed configuration of the NOAA GFDL chemistry-climate model - in which the atmosphere and land are coupled through dry deposition-to investigate the influence of ozone dry deposition on ozone pollution over northern midlatitudes. In our model, deposition pathways are tied to dynamic terrestrial processes, such as photosynthesis and water cycling through the canopy and soil. Small increases in winter deposition due to more process-based representation of snow and deposition to surfaces reduce hemispheric-scale ozone throughout the lower troposphere by 5-12 ppb, improving agreement with observations relative to a simulation with the standard configuration for ozone dry deposition. Declining snow cover by the end of the 21st-century tempers the previously identified influence of rising methane on winter ozone. Dynamic dry deposition changes summer surface ozone by -4 to +7 ppb. While previous studies emphasize the importance of uptake by plant stomata, new diagnostic tracking of depositional pathways reveals a widespread impact of nonstomatal deposition on ozone pollution. Daily variability in both stomatal and nonstomatal deposition contribute to daily variability in ozone pollution. Twenty-first century changes in summer deposition result from a balance among changes in individual pathways, reflecting differing responses to both high carbon dioxide (through plant physiology versus biomass accumulation) and water availability. Our findings highlight a need for constraints on the processes driving ozone dry deposition to test representation in regional-to-global models.
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| 10. |
- Bernson, Elin, 1987, et al.
(author)
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Identification of Tissue-Resident Natural Killer and T Lymphocytes with Anti-Tumor Properties in Ascites of Ovarian Cancer Patients
- 2023
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In: Cancers. - 2072-6694. ; 15:13
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Journal article (peer-reviewed)abstract
- Simple Summary Ovarian cancer is the deadliest among gynecological cancers, and there is a huge demand for new treatments for these patients. Immunotherapy holds great potential in cancer treatment, but has not yet proven successful for the majority of ovarian cancer patients. To better understand the immunological landscape of the disease, we have characterized lymphocytes in patients with high-grade serous ovarian cancer. Natural killer cells and T cells are present in both primary tumors and in the metastasizing environment of ascites, a fluid in the abdominal cavity that is developed in many patients with ovarian cancer. Our data reveal that a large fraction of these natural killer cells and T cells express tissue-resident markers and the inhibitory receptor, NKG2A, and are able to kill ovarian cancer cells. In summary, we report a functional subset of lymphocytes that may be targeted in future immunotherapeutic approaches. Women with ovarian cancer have limited therapy options, with immunotherapy being unsatisfactory for a large group of patients. Tumor cells spread from the ovary or the fallopian tube into the abdominal cavity, which is commonly accompanied with massive ascites production. The ascites represents a unique peritoneal liquid tumor microenvironment with the presence of both tumor and immune cells, including cytotoxic lymphocytes. We characterized lymphocytes in ascites from patients with high-grade serous ovarian cancer. Our data reveal the presence of NK and CD8(+) T lymphocytes expressing CD103 and CD49a, which are markers of tissue residency. Moreover, these cells express high levels of the inhibitory NKG2A receptor, with the highest expression level detected on tissue-resident NK cells. Lymphocytes with these features were also present at the primary tumor site. Functional assays showed that tissue-resident NK cells in ascites are highly responsive towards ovarian tumor cells. Similar results were observed in an in vivo mouse model, in which tissue-resident NK and CD8(+) T cells were detected in the peritoneal fluid upon tumor growth. Together, our data reveal the presence of highly functional lymphocyte populations that may be targeted to improve immunotherapy for patients with ovarian cancer.
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