Publications
395 results found
Herbert S, Harries C, Barbosa J, et al., 2018, EXERCISE CAPACITY IMPROVEMENT IN ADULT CONGENITAL HEART DISEASE PATIENTS SWITCHING FROM BOSENTAN TO MACITENTAN THERAPY, Annual Meeting of the British-Congenital-Cardiac-Association, Publisher: BMJ PUBLISHING GROUP, Pages: A8-A9, ISSN: 1355-6037
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- Citations: 1
Farmery JHR, Smith ML, Lynch AG, et al., 2018, Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data, Scientific Reports, Vol: 8, ISSN: 2045-2322
Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.
George PM, Price L, Wort SJ, 2018, Pulmonary hypertension and other disorders of the pulmonary vasculature, Essentials of Clinical Pulmonology, Pages: 590-608, ISBN: 9781498715799
Pulmonary hypertension (PH) is a pathophysiological disorder that can complicate many clinical conditions. PH has a hemodynamic definition of a mean pulmonary artery (PA) pressure of greater than or equal to 25mmHg at rest, assessed by right heart catheterization (RHC). PH is further divided from a hemodynamic perspective into precapillary PH and postcapillary PH, depending on whether the PA wedge pressure (PAWP) at RHC is less than or more than 15 mm Hg, respectively (Table 47.1). Clinically, PH is classified into five groups that share similar pathophysiological characteristics and expected response to treatment (Figure 47.1).
Toshner M, Church A, Harlow L, et al., 2018, Transform-UK: A Phase 2 Trial of Tocilizumab in Pulmonary Arterial Hypertension, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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- Citations: 3
Connolly M, Garfield B, Crosby A, et al., 2017, miR-322-5p targets IGF-1 and is suppressed in the heart of rats with pulmonary hypertension, FEBS Open Bio, Vol: 8, Pages: 339-348, ISSN: 2211-5463
Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here we show that miR-322-5p (the rodent orthologue of miR-424-5p) expression is decreased in the right ventricle of monocrotaline-treated rats, a model of PAH, whereas a putative target insulin-like growth factor 1 (IGF-1) is increased. IGF-1 mRNA was enriched 16-fold in RNA immunoprecipitated with Ago2, indicating binding to miR-322-5p. In cell transfection experiments, miR-322-5p suppressed the activity of a luciferase reporter containing a section of the IGF-1 3′ untranslated region (UTR) as well as IGF-1 mRNA and protein levels. Taken together, these data suggest that miR-322 targets IGF-1, a process downregulated in PAH-related RV hypertrophy.
Kemp P, Connolly, Paul R, et al., 2017, miR-424-5p reduces ribosomal RNA and protein synthesis in muscle wasting, Journal of Cachexia, Sarcopenia and Muscle, Vol: 9, Pages: 400-416, ISSN: 2190-6009
Background: A loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis so changes in the control of ribosome synthesis is a potential contributor to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR-424-5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD).Methods: Targets of miR-424-5p were identified by Ago2 pull-down and the effects of the miRNA on RNA and protein expression were determined by qPCR and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over-expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by qPCR in patients with COPD, intensive care unit acquired weakness (ICUAW), and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study.Results: Pull-down assays showed that miR-424-5p bound to mRNAs encoding proteins associated with muscle protein synthesis. The most highly enriched mRNAs encoded proteins required for the Pol I RNA pre-initiation complex (PIC) required for rRNA transcription, (PolR1A and Upstream binding transcription factor, UBTF). In vitro, miR-424-5p reduced expression of these RNAs, reduced rRNA levels and inhibited protein synthesis. In mice, over-expression of miR-322 (rodent miR-424 orthologue) caused fibre atrophy and reduced UBTF expression and rRNA levels. In humans elevated miR-424-5p as
Bax SRB, Breedy C, Dimopoulos K, et al., 2017, PULMONARY VASCULAR DISEASE MARKERS PREDICT DEATH IN INTERSTITIAL LUNG DISEASE PATIENTS PROVEN NOT TO HAVE PULMONARY HYPERTENSION AT RIGHT HEART CATHETER, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A168-A169, ISSN: 0040-6376
Bax SRB, Breedy C, Dimopoulos K, et al., 2017, DERIVATION AND VALIDATION OF A SIMPLE LONGITUDINAL SCORE WHICH STRONGLY PREDICTS MORTALITY IN INTERSTITIAL LUNG DISEASE (ILD) ASSOCIATED PULMONARY HYPERTENSION (ILD-PH), Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A35-A36, ISSN: 0040-6376
Newnham M, Toshner M, Bleda M, et al., 2017, GENOME-WIDE ASSOCIATION STUDY IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION REVEALS NEW INSIGHTS INTO AETIOLOGY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A66-A66, ISSN: 0040-6376
Hadinnapola C, Bleda M, Haimel M, et al., 2017, Phenotypic characterisation of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension, Circulation, Vol: 136, Pages: 2022-2033, ISSN: 0009-7322
Background -Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis (PVOD/PCH). Here, we determined the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods -Whole genome sequencing was performed on DNA from patients with idiopathic and heritable PAH, as well as PVOD/PCH recruited to the NIHR BioResource - Rare Diseases Study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of < 1:10,000 in control data sets and predicted to be deleterious (by CADD, PolyPhen-2 and SIFT predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results -Eight hundred and sixty-four patients with idiopathic or heritable PAH and 16 with PVOD/PCH were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of PVOD/PCH. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (KCO: 33 [IQR: 30 - 35] % predicted) and younger age at diagnosis (29 [23 - 38] years) as well as more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest, compared to PAH patients without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. PAH patients with biallelic EIF2AK4 mutations had a shorter survival. Conclusions -Biallelic EIF2A
Shovlin CL, Condliffe R, Donaldson JW, et al., 2017, Pulmonary arteriovenous malformations emerge from the shadows, Thorax, Vol: 72, Pages: 1071-1073, ISSN: 1468-3296
Shovlin CL, Condliffe R, Donaldson JW, et al., 2017, British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations., Thorax, Vol: 72, Pages: 1154-1163, ISSN: 1468-3296
Pulmonary arteriovenous malformations (PAVMs) are structurally abnormal vascular communications that provide a continuous right-to-left shunt between pulmonary arteries and veins. Their importance stems from the risks they pose (>1 in 4 patients will have a paradoxical embolic stroke, abscess or myocardial infarction while life-threatening haemorrhage affects 1 in 100 women in pregnancy), opportunities for risk prevention, surprisingly high prevalence and under-appreciation, thus representing a challenging condition for practising healthcare professionals. The driver for the current Clinical Statement was the plethora of new data since previous hereditary haemorrhagic telangiectasia (HHT) guidelines generated in 2006 and a systematic Cochrane Review for PAVM embolisation in 2011. The British Thoracic Society (BTS) identified key areas in which there is now evidence to drive a change in practice. Due to the paucity of data in children, this Statement focused on adults over 16 years. The Statement spans the management of PAVMs already known to be present (interventional and medical), screening and diagnosis (for PAVMs and HHT) and follow-up of patients following a first diagnosis, intervention or negative screen for PAVMs. The Good Practice Points (in bold) were generated for a target audience of general respiratory, medical and specialist clinicians and were approved by the BTS Standards of Care Committee, before formal peer review and public consultation. The Statement spans embolisation treatment, accessory medical management and issues related to the likelihood of underlying HHT.
Shackshaft T, Wort S, Quinlan G, et al., 2017, Conditioned media from human pulmonary arterial endothelial cells treated with hepcidin or haemoglobin cause proliferation and migration of human pulmonary artery smooth muscle cells, British Thoracic Society Annual Meeting, Publisher: BMJ Publishing Group, Pages: A68-A69, ISSN: 1468-3296
Bohnen MS, Ma L, Zhu N, et al., 2017, Loss of Function ABCC8 Mutations Are Associated With Pulmonary Arterial Hypertension, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Price LC, Dimopoulos K, Marino P, et al., 2017, The CRASH report: emergency management dilemmas facing acute physicians in patients with pulmonary arterial hypertension, THORAX, Vol: 72, Pages: 1035-1045, ISSN: 0040-6376
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- Citations: 23
Michelakis ED, Gurtu V, Webster L, et al., 2017, Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients, Science Translational Medicine, Vol: 9, Pages: 1-13, ISSN: 1946-6234
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
Nashat H, Brida M, Price LS, et al., 2017, Pulmonary Arterial Hypertension Complicating Congenital Heart Disease: Advances in Therapy, SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 38, Pages: 636-650, ISSN: 1069-3424
Kempny A, Hjortshoj CS, Li W, et al., 2017, Response by Kempny et al to Letter Regarding Article, "Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study", CIRCULATION, Vol: 136, Pages: 1078-1079, ISSN: 0009-7322
Bax S, Bredy C, Dimopoulos K, et al., 2017, The composite physiological index strongly predicts mortality in interstitial lung disease (ILD) associated pulmonary hypertension (PH-ILD), European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bax S, Bredy C, Dimopoulos K, et al., 2017, Right ventricular dimensions on CTPA predict pulmonary hypertension and prognosis in interstitial lung disease (ILD), European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wort S, Kempny A, Dimopoulos K, et al., 2017, Pulmonary embolism in England 1998-2015: increasing incidence and declining mortality, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bax S, Bredy C, Dimopoulos K, et al., 2017, Rate of change in main pulmonary artery diameter predicts mortality in interstitial lung disease, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bax S, Wells A, Price L, et al., 2017, Pulmonary hypertension in idiopathic interstitial pneumonias, Pulmonary Hypertension and Interstitial Lung Disease, Pages: 103-128, ISBN: 9783319499161
Constantine AH, Kempny A, Swan L, et al., 2017, Pregnancy in adults with congenital heart disease in England: birth rate and delivery practices between 1997 and 2014, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 212-212, ISSN: 0195-668X
Dimopoulos K, Alonso-Gonzalez R, Wort SJ, et al., 2017, The incidence of aortic dissection in tetralogy of Fallot, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 56-56, ISSN: 0195-668X
Kempny A, Dimopoulos K, Price LC, et al., 2017, Incidence of pulmonary embolism, associated mortality and bleeding risk in england between 1998-2015, Publisher: OXFORD UNIV PRESS, Pages: 865-866, ISSN: 0195-668X
Drakopoulou M, Nashat H, Kempny A, et al., 2017, Incidence of arrhythmia and relation to mortality in a contemporary cohort of adults with pulmonary arterial hypertension associated with congenital heart disease, Publisher: OXFORD UNIV PRESS, Pages: 954-954, ISSN: 0195-668X
Martin Garcia AC, Arachchillage DRJ, Kempny A, et al., 2017, Low platelet count and its relation to death in adults with eisenmenger syndrome, Publisher: OXFORD UNIV PRESS, Pages: 953-954, ISSN: 0195-668X
Martin Garcia AC, Arachchillage DRJ, Kempny A, et al., 2017, Abnormalities in platelet volume and count as predictors of thrombosis and bleeding in patients with Eisenmenger syndrome, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 146-146, ISSN: 0195-668X
Martin-Garcia AC, Arachchillage DR, Kempny A, et al., 2017, Platelet count and mean platelet volume predict outcome in adults with Eisenmenger syndrome, Heart, Vol: 104, Pages: 45-50, ISSN: 1355-6037
OBJECTIVES: Although a significant proportion of patients with cyanotic congenital heart disease are thrombocytopaenic, its prevalence and clinical significance in adults with Eisenmenger syndrome (ES) is not well studied. Accordingly, we examined the relationship of thrombocytopaenia and mean platelet volume (MPV) to bleeding or thrombotic complications and survival in a contemporary cohort of patients with ES, including patients with Down syndrome. METHODS: Demographics, laboratory and clinical data were analysed from 226 patients with ES under active follow-up over 11 years. RESULTS: Age at baseline was 34.6±11.4 years and 34.1% were men. Mean platelet count and MPV were 152.6±73.3×10⁹/L and 9.6±1.2 fL, respectively. A strong inverse correlation was found between platelet count and haemoglobin concentration and MPV. During the study, there were 39 deaths, and 21 thrombotic and 43 bleeding events. On univariate Cox regression analysis, patients with a platelet count <100×10⁹/L had a twofold increased mortality (HR 2.10, 95% CI 1.10 to 4.01, p=0.024). Platelet count was not associated with an increased risk of thrombosis. However, there was a threefold increased thrombotic risk with MPV >9.5 fL (HR 3.50, 95% CI 1.28 to 9.54, p=0.015). Patients with either severe secondary erythrocytosis (>220g/L) or anaemia (<130g/L) were at higher risk of thrombotic events (HR 3.93, 95% CI 1.60 to 9.67, p=0.003; and HR 4.75, 95% CI 1.03 to 21.84, p=0.045, respectively). CONCLUSIONS: Thrombocytopaenia significantly increased the risk of mortality in ES. Furthermore, raised MPV, severe secondary erythrocytosis and anaemia, but not platelet count, were associated with an increased risk of thrombotic events in our adult cohort.
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