6 research outputs found
Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial
SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication
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Estrogen-mediated SOX17 Regulation in the Development of Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a sexually dimorphic disease with female predominance. This gender bias is attributed, in part, to estrogen signaling and the estrogen metabolite, 16α-hydroxyestrone (16αOHE) is considered a major contributor to the pathogenesis of PAH. Recent studies have also highlighted both, common and rare genetic variants, in the SOX17 gene, an endothelial cell (EC)-specific transcription factor, in patients with PAH, suggesting that SOX17 deficiency contributes to PAH development. To date, however, functional studies of SOX17 in PAH are absent and the relationship between SOX17 and sexual dimorphism in PAH remains unknown. We hypothesized that 16αOHE-mediated estrogen signaling downregulates SOX17 during the development of PAH.
Sox17 mRNA and protein expression were reduced in the lungs of monocrotaline (MCT) and sugen hypoxia (SuHx) rodent models of PH as well as in human pulmonary artery endothelial cells (HPAECs) isolated from patients with PAH compared to controls. Staining of human lung samples from patients with PAH reveals decreased expression of SOX17 in the endothelium. Inducible conditional EC-specific Sox17 knockout (Sox17EC-/-) mice exhibited increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), and PA wall thickness (PAWT) after exposure to chronic hypoxia (4 weeks) compared to controls. While not evident across Sox17EC-/- murine sex, lungs from male rats at baseline, however displayed increased Sox17 expression compared to those from age-matched female rats. To further study these latter expression differences, in silico analysis revealed the presence of five estrogen response element (ERE) sequences on the SOX17 promoter, suggesting estrogen-mediated transcriptional regulation of the SOX17 gene. Treatment of HPAECs with 16αOHE reduced mRNA and protein levels of SOX17 in a dose-dependent manner. HPAECs transfected with the SOX17 promoter and treated with 16αOHE showed reduced activity of SOX17 promoter when measured by dual-luciferase reporter assay. Leveraging ERE mutated constructs for promoter luciferase studies, 16αOHE transcriptionally repressed SOX17 promoter activity at predicted ERE sites and via ERα in HPAECs. Supporting these in vitro observations, ERα loss-of-function (ERα-/-) mutant rats generated via CRISPR-Cas9 editing revealed reduced Sox17 protein expression in vehicle and MCT-exposed lungs compared to cage controls. To validate these data in vivo, we tested whether Sox17 rescues 16αOHE-mediated hypoxic PH in mice. Consistent with prior reports, 16αOHE induced increases in RVSP, RVH, and PAWT in control mice under normoxic and hypoxic conditions. Inducible conditional EC-specific Sox17 transgenic over-expressing (Sox17Tg) mice attenuated chronic hypoxia-induced PH with reduced RVSP, RVH, and PAWT. Hypoxic mice with Sox17Tg exhibited reduced RVSP, RVH, and PAWT after 16αOHE exposure. Inflammatory markers such as NLR family pyrin domain containing 3 (NLRP3), Caspase-1, Interleukin (IL)-1, and IL-18 were reduced in lungs of Sox17Tg mice compared to WT controls despite exposure to chronic hypoxia and 16αOHE. These results suggest that Sox17 mediates PH protection, in part, via regulation of lung inflammation.
To translate these experimental data to patients, we identified a functional common variant residing in the DNA binding domain of the ESR1 gene (encoding ERα), rs746432, which was previously shown to reduce transcriptional activation of ERα protein on target ERE reporter genes. This polymorphism was associated with reduced pulmonary vascular resistance (PVR) in patients with PAH (n=702) in fully adjusted analyses. In summary, validating recent genetic studies, deficiency of Sox17 augments preclinical PAH. Moreover, 16αOHE mediates the development of PAH, in part, via downregulation of SOX17, linking sexual dimorphism in PAH with SOX17-based genetic underpinnings.Release after 08/23/202
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Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes.
Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development
Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes
Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics
RATIONALE/OBJECTIVES: Genetic studies suggest SOX17 deficiency increases pulmonary arterial hypertension (PAH) risk. Based on pathological roles of estrogen and hypoxia inducible factor 2α (HIF-2α) signaling in PA endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF-2α inhibition.
METHODS: We used metabolic (seahorse) and promoter lucifer assays in PAECs along with the chronic hypoxia murine model to test the hypothesis.
MEASUREMENTS AND MAIN RESULTS: Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic PH was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 over-expression (Sox17Tg). Based on untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found HIF-2α levels were increased in the lungs of Sox17EC-/- and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF-2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16alpha-hydroxyestrone (16αOHE, a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic PH. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, with reduced plasma citrate levels (n=1326).
CONCLUSIONS: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF-2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Book of Abstracts of the 2nd International Conference on Applied Mathematics and Computational Sciences (ICAMCS-2022)
It is a great privilege for us to present the abstract book of ICAMCS-2022 to the authors and the delegates of the event. We hope that you will find it useful, valuable, aspiring, and inspiring. This book is a record of abstracts of the keynote talks, invited talks, and papers presented by the participants, which indicates the progress and state of development in research at the time of writing the research article. It is an invaluable asset to all researchers. The book provides a permanent record of this asset.
Conference Title: 2nd International Conference on Applied Mathematics and Computational SciencesConference Acronym: ICAMCS-2022Conference Date: 12-14 October 2022Conference Organizers:Â DIT University, Dehradun, IndiaConference Mode: Online (Virtual