ORCID Profile
0000-0003-4106-8469
Current Organisations
University of Wollongong
,
University of Nottingham
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: European Respiratory Society (ERS)
Date: 21-12-2018
DOI: 10.1183/13993003.00938-2018
Abstract: Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild–moderate asthma into a T2-high phenotype. We examined whether currently available clinical biomarkers can predict AEC-defined T2-high phenotype within the U-BIOPRED cohort. The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from interleukin (IL)-13-exposed AECs. 37% of asthmatics (45% nonsmoking severe asthma, n=49 33% of smoking or ex-smoking severe asthma, n=18 and 28% mild–moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher exhaled nitric oxide fraction ( F eNO ) and blood and sputum eosinophils, but not serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. F eNO (≥30 ppb) and blood eosinophils (≥300 cells·µL −1 ) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression. T2-high severe asthma can be predicted to some extent from raised levels of F eNO , blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.
Publisher: European Respiratory Society (ERS)
Date: 02-10-2020
Publisher: Elsevier BV
Date: 07-2021
Publisher: Elsevier BV
Date: 07-2021
Publisher: Wiley
Date: 02-05-2016
DOI: 10.1111/RESP.12803
Publisher: Elsevier BV
Date: 2021
Publisher: BMJ
Date: 17-07-2015
Publisher: European Respiratory Society (ERS)
Date: 25-11-2021
DOI: 10.1183/13993003.01733-2021
Abstract: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication. Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort 12–18-month longitudinal s les were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. A total of 90 metabolites were identified, with 40 significantly altered (p .05, false discovery rate .05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10 −20 ), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10 −4 ), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
Publisher: Elsevier BV
Date: 09-2008
Publisher: Informa UK Limited
Date: 22-08-2023
Publisher: American Chemical Society (ACS)
Date: 08-05-2018
DOI: 10.1021/ACS.JPROTEOME.8B00018
Abstract: Analysis of induced sputum supernatant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMS
Publisher: European Respiratory Society (ERS)
Date: 17-08-2023
DOI: 10.1183/23120541.00269-2023
Abstract: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. To measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure. Urine collected at baseline in the U-BIOPRED study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study. The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulphate (DHEA-S) concentrations were % of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high dose ICS only, were more suppressed in females than males (p-value .05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p-value .05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12–18 months. The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JAIP.2014.06.001
Abstract: Predictors of asthma exacerbations, poor asthma control, or extreme β-agonist overuse may be of clinical utility in the management of asthma. To investigate characteristics that predict subsequent adverse outcomes in asthma. An independent 24-week, randomized controlled trial of 303 adult patients with asthma who are at risk, which compared the efficacy of SMART (single budesonide-formoterol inhaler as maintenance and reliever therapy) with a fixed-dose regimen with salbutamol as reliever ("Standard"). Inhaled medication use was measured by electronic monitoring. Baseline characteristics that were predictors of subsequent severe asthma exacerbations, poor asthma control (Asthma Control Questionnaire -5 score ≥1.5), and "extreme" β-agonist overuse (>16 budesonide-formoterol actuations/d in SMART and >32 salbutamol actuations/d in Standard) were assessed by multivariate analyses. FEV₁ % predicted (rate ratio [RR] 1.14 [95% CI, 1.03-1.27] per 10% lower), more previous exacerbations (RR 1.15 [95% CI, 1.01-1.31]), Standard therapy (RR 1.62 [95% CI, 1.07-2.47]), and female sex (RR 2.18 [95% CI, 1.29-3.67]) were associated with future severe exacerbations. Asthma Control Questionnaire--5 (regression coefficient 0.20 [95% CI, 0.13-0.27] per 0.5 points higher) and age (regression coefficient 0.09 [95% CI, 0.01-0.17] per decade older) were associated with future poorly controlled asthma. Higher reliever use (RR 1.63 [95% CI, 1.36-1.95] per categorical score in Asthma Control Questionnaire question no. 6), Māori ethnicity (RR 2.20 [95% CI, 1.43-3.38]) and FEV₁ % predicted (RR 1.16 [95% CI, 1.03-1.31] per 10% lower) were associated with future extreme β-agonist overuse. Future severe asthma exacerbations, poor asthma control, and extreme β-agonist overuse are predicted by different baseline clinical and demographic characteristics and management approaches in at-risk asthma.
Publisher: American Thoracic Society
Date: 12-2022
Publisher: Wiley
Date: 02-09-2020
DOI: 10.1002/IJFE.2168
Abstract: Foreign portfolio investment (FPI) has been modelled with the aim of observing patterns, discovering potential inefficiencies and providing evidence for theories. Over the course of many studies, bilateral FPI appears to increase with an increase in the correlation between the gross domestic product growth rates of the sender and the receiver. The Capital Asset Pricing Model in financial theory predicts the opposite—and this is known as the correlation puzzle. One possible explanation is that the correlation is a proxy for both ersification benefits and informational asymmetry. Using seven cross‐sections of bilateral FPI holdings data from the CEPII Coordinated Portfolio Investment Survey for the years 2000–2006, we attempt to explain the correlation puzzle by augmenting the gravity model with random effects to account for heterogeneity in propensity to send and receive investments and with latent space position models to account for effects of unobserved country attributes, as well as transitivity, clustering, and balance in order to capture the information asymmetry and leave the correlation coefficient as a measure of the ersification benefit. We use maximum likelihood Heckman s le selection estimators to account for potential bias in estimators that can be caused by frequent zeros in our data, describing a model for the presence or absence of FPI between the two countries and a model for the level of FPI between two countries conditional on its presence. We find that if there is a presence of FPI between country s and country r , then as the correlation between the economic growth of these countries increases, the level of investment will decrease. However, this correlation has no significant impact on the decision of country s to invest in country r .
Publisher: Oxford University Press (OUP)
Date: 08-2015
DOI: 10.1136/POSTGRADMEDJ-2014-205826REP
Abstract: Over the last decade, technological advances have revolutionised efforts to understand the role played by microbes in airways disease. With the application of ever more sophisticated techniques, the literature has become increasingly inaccessible to the non-specialist reader, potentially h ering the translation of these gains into improvements in patient care. In this article, we set out the key principles underpinning microbiota research in respiratory contexts and provide practical guidance on how best such studies can be designed, executed and interpreted. We examine how an understanding of the respiratory microbiota both challenges fundamental assumptions and provides novel clinical insights into lung disease, and we set out a number of important targets for ongoing research.
Publisher: European Respiratory Society (ERS)
Date: 06-10-2016
DOI: 10.1183/13993003.01129-2016
Abstract: The U-BIOPRED study is a multicentre European study aimed at a better understanding of severe asthma. It included three steroid-treated adult asthma groups (severe nonsmokers (SAn group), severe current/ex-smokers (SAs/ex group) and those with mild–moderate disease (MMA group)) and healthy controls (HC group). The aim of this cross-sectional, bronchoscopy substudy was to compare bronchial immunopathology between these groups. In 158 participants, bronchial biopsies and bronchial epithelial brushings were collected for immunopathologic and transcriptomic analysis. Immunohistochemical analysis of glycol methacrylate resin-embedded biopsies showed there were more mast cells in submucosa of the HC group (33.6 mm −2 ) compared with both severe asthma groups (SAn: 17.4 mm −2 , p .001 SAs/ex: 22.2 mm −2 , p=0.01) and with the MMA group (21.2 mm −2 , p=0.01). The number of CD4 + lymphocytes was decreased in the SAs/ex group (4.7 mm −2 ) compared with the SAn (11.6 mm −2 , p=0.002), MMA (10.1 mm −2 , p=0.008) and HC (10.6 mm −2 , p .001) groups. No other differences were observed. Affymetrix microarray analysis identified seven probe sets in the bronchial brushing s les that had a positive relationship with submucosal eosinophils. These mapped to COX-2 (cyclo-oxygenase-2), ADAM-7 (disintegrin and metalloproteinase domain-containing protein 7), SLCO1A2 (solute carrier organic anion transporter family member 1A2), TMEFF2 (transmembrane protein with epidermal growth factor like and two follistatin like domains 2) and TRPM-1 (transient receptor potential cation channel subfamily M member 1) the remaining two are unnamed. We conclude that in nonsmoking and smoking patients on currently recommended therapy, severe asthma exists despite suppressed tissue inflammation within the proximal airway wall.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.RMED.2019.02.008
Abstract: Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MS
Publisher: Public Library of Science (PLoS)
Date: 21-09-2018
Publisher: American Thoracic Society
Date: 15-02-2017
Publisher: European Respiratory Society (ERS)
Date: 04-11-2021
DOI: 10.1183/13993003.00142-2021
Abstract: Asthma phenotyping requires novel biomarker discovery. To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to s les from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.
Publisher: Springer Science and Business Media LLC
Date: 04-01-2018
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.JACI.2016.08.048
Abstract: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.
Publisher: Wiley
Date: 11-02-2019
DOI: 10.1111/ALL.13727
Abstract: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.JACI.2017.06.037
Abstract: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous s les. We sought to identify gene profiles associated with adult-onset severe asthma. This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (<18 years) were selected from the U-BIOPRED cohort. Gene expression was assessed on the total RNA of induced sputum (n = 83), nasal brushings (n = 41), and endobronchial brushings (n = 65) and biopsies (n = 47) (Affymetrix HT HG-U133+ PM). Gene set variation analysis was used to identify differentially enriched predefined gene signatures of leukocyte lineage, inflammatory and induced lung injury pathways. Significant differentially enriched gene signatures in patients with adult-onset as compared with childhood-onset severe asthma were identified in nasal brushings (5 signatures), sputum (3 signatures), and endobronchial brushings (6 signatures). Signatures associated with eosinophilic airway inflammation, mast cells, and group 3 innate lymphoid cells were more enriched in adult-onset severe asthma, whereas signatures associated with induced lung injury were less enriched in adult-onset severe asthma. Adult-onset severe asthma is characterized by inflammatory pathways involving eosinophils, mast cells, and group 3 innate lymphoid cells. These pathways could represent useful targets for the treatment of adult-onset severe asthma.
Publisher: European Respiratory Society (ERS)
Date: 25-11-2021
Publisher: Wiley
Date: 12-11-2018
DOI: 10.1111/ALL.13629
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for dominick shaw.