223 research outputs found
StratosPHere 2: study protocol for a response-adaptive randomised placebo-controlled phase II trial to evaluate hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2
No full textBackground. Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate.
Methods. This three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease.
Discussion. The results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease
Author Correction: Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood (Nature Communications, (2021), 12, 1, (7104), 10.1038/s41467-021-27326-0)
No full text\ua9 2022, The Author(s).The original version of this Article omitted Richard C Trembath from the UK National PAH Cohort Study consortium from Health and Life Sciences, King’s College London. This has been corrected in both the PDF and HTML versions of the Article
Whole-lake Herbicide Treatments for Eurasian Watermilfoil in Four Wisconsin Lakes: Effects on Vegetation and Water Clarity
No full textThe impact of hypoxia on B cells in COVID-19
No full textBackground: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. Methods: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. Findings: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. Interpretation: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. Funding: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trus
A thermostable, closed SARS-CoV-2 spike protein trimer
No full textThe spike (S) protein of SARS-CoV-2 mediates receptor binding and cell entry and is the dominant target of the immune system. It exhibits substantial conformational flexibility. It transitions from closed to open conformations to expose its receptor-binding site and, subsequently, from prefusion to postfusion conformations to mediate fusion of viral and cellular membranes. S-protein derivatives are components of vaccine candidates and diagnostic assays, as well as tools for research into the biology and immunology of SARS-CoV-2. Here we have designed mutations in S that allow the production of thermostable, disulfide-bonded S-protein trimers that are trapped in the closed, prefusion state. Structures of the disulfide-stabilized and non-disulfide-stabilized proteins reveal distinct closed and locked conformations of the S trimer. We demonstrate that the designed, thermostable, closed S trimer can be used in serological assays. This protein has potential applications as a reagent for serology, virology and as an immunogen
Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy
No full text\ua9 The Author(s) 2021. Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon’s two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes \ub7 s \ub7 cm−5, success is defined by an absolute reduction in PVR of ≥300 dynes \ub7 s \ub7 cm−5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes \ub7 s \ub7 cm−5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study
Erratum to: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data (Scientific Reports, (2018), 8, 1, (1300), 10.1038/s41598-017-14403-y)
No full text\ua9 2018, The Author(s). A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper
How can we ensure accessible and high-quality specialist care for patients with pulmonary hypertension?
No full textThe CRASH report: Emergency management dilemmas facing acute physicians in patients with pulmonary arterial hypertension
No full text\ua9 2017 Article author(s) (or their employer(s) unless otherwise stated in the text of the article). All rights reserved. No commercial use is permitted unless otherwise expressly granted. Treatment of acute emergencies in patients with pulmonary arterial hypertension (PAH) can be challenging. In the UK and Ireland, management of adult patients with PAH is centred in eight nationally designated pulmonary hypertension (PH) centres. However, many patients live far from these centres and physicians in local hospitals are often required to manage PAH emergencies. A committee of physicians from nationally designated PH centres identified the \ue2 most common\u27 emergency clinical scenarios encountered in patients with PAH. Thereafter, a review of the literature was performed centred on these specified topics and a management approach was developed based on best available evidence and expert consensus. Management protocols were developed on the following PAH emergencies: Chest pain (including myocardial ischaemia), right ventricular failure, arrhythmias, sepsis, haemoptysis (\ue2 CRASH\u27), as well as considerations relevant to surgery, anaesthesia and pregnancy. Emergencies are not uncommon in PAH. While expertise in PAH management is essential, all physicians involved in acute care should be aware of the principles of acute management of PAH emergencies. A multidisciplinary approach is necessary, with physicians from tertiary PH centres supporting care locally and planning safe transfer of patients to PH centres when appropriate
Myeloid angiogenic cells exhibit impaired migration, reduced expression of endothelial markers and increased apoptosis in idiopathic pulmonary arterial hypertension
No full textIdiopathic pulmonary arterial hypertension (IPAH) is a rare and devastating condition. There is no known cure for IPAH, and current treatment options are not always effective. Autologous myeloid angiogenic cells (MACs) have been explored as a novel therapy for IPAH but preliminary data from clinical trials show limited beneficial effects. A complete understanding of IPAH MAC function remains elusive. This study was designed to comprehensively compare cell function between IPAH MACs and healthy control MACs. MACs were procured through the culture of peripheral blood mononuclear cells in endothelial selective medium for 7 days. Compared with healthy MACs, IPAH MACs exhibited 1) significantly lower levels of endothelial markers as shown by fluorescence microscopy; 2) a markedly higher rate of apoptosis under both normal culture condition and serum starvation as shown by the TUNEL assay; 3) significantly decreased migration towards VEGF as shown by a modified Boyden chamber migration assay; and 4) similar VEGF and eNOS mRNA levels as shown by RT-qPCR. In conclusion, various aspects of IPAH MAC function are impaired. In order to achieve greater therapeutic benefits, pharmacologic and/or genetic manipulations to improve IPAH MAC function, particularly to promote cell survival and migration, are warranted.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
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