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IL-6 pathway upregulation in subgroup of severe asthma is associated with neutrophilia and poor lung function.

In this study, we have used various types of datasets from  severe asthma non smoker patients and healthy participants from the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes  (Ubiopred) consortium(1). The study design and population has been previously described1 . The datasets that has been used include sputum microarray, sputum and blood somalogic proteomics, inflammatory mediators from blood measured with luminex techonology, serum IL6 levels measured with MDS and clinical data.

Authors: Turan N, Edwards MJ, Bates S, Shaw D, Chung KF, Loza MJ, James A, Van Oosterhout A, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2018
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Impaired innate immune gene profiling in airway smooth muscle cells from chronic cough patients

Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough. Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers. ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection. Supernatants were collected for multiplex analysis. Our results showed no significant differentially expressed genes (DEGs, false discovery rate (FDR) <0.05) between chronic cough and healthy non-cough ASMCs at baseline. Poly(I:C) stimulation resulted in 212 DEGs (>1.5 fold-change, FDR <0.05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers. The top up-regulated genes included chemokine (C-X-C motif) ligand (CXCL) 11 (CXCL11), CXCL10, chemokine (C-C motif) ligand (CCL) 5 (CCL5) and interferon-induced protein 44 like (IFI44L) corresponding with inflammation and innate immune response pathways. ASMCs from cough subjects had enhanced activation of viral response pathways in response to poly(I:C) compared with healthy non-cough subjects, reduced activation of pathways involved in chronic inflammation and equivalent activation of neuroregulatory genes. The poly(I:C)-induced release of inflammatory mediators, including CXCL8, interleukin (IL)-6 and CXCL1, from ASMCs from cough patients was significantly impaired compared with healthy non-cough subjects. Addition of fluticasone propionate (FP) to poly(I:C)-treated ASMCs resulted in greater gene expression changes in healthy non-cough ASMCs. FP had a differential effect on poly(I:C)-induced mediator release between chronic cough and healthy non-cough volunteers. In conclusion, altered innate immune and inflammatory gene profiles within ASMCs, rather than infiltrating cells or nerves, may drive the cough response following respiratory viral infection.

Authors: Rossios C, Pavlidis S, Gibeon D, Mumby S, Ojo O, Horowitz D, Loza MJ, Baribaud F, Rao NL, Chung KF, Adcock IM
Publication type: Academic Publication
Published: 2017

InfluenzeInduced exacerbation in Chronic House dust mite asthma model

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Author: Lutter R
Publication type: Academic Publication
Published: 2013
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Information for professionals

A slide presentation about the project aimed at professionals

Author: U-BIOPRED
Publication type: Project Resources
Published: 2011
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Information for the public

A slide presentation about the project aimed at the public 

Author: U-BIOPRED
Publication type: Project Resources
Published: 2011
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Integration of scientific review, ethical assessment and the patient perspective – a case from two European projects

The new European Clinical Trial Regulation536/2014 replaces the 2001 directive. Despite debates it remains a two-tier procedure and does not guarantee patient involvement. Using our experience in two European clinical projects, we provide support and recommendations to improve the new ethics assessment and monitoring procedure. The findings presented show that an integrated European-wide, multidisciplinary assessment from the ethical, safety, scientific and patients’ perspective is achievable.

Authors: Iy de Boer W, Gastmans C, Widdershoven GAM, Erzen D
Publication type: Academic Publication
Published: 2017
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Large-scale label-free quantitative mapping of the sputum proteome

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 HDMSE applied to 40 healthy nonsmoking participants, which provides an essential baseline from which to compare modulation of protein expression in respiratory diseases. The "core" sputum proteome (proteins detected in ≥40% of participants) was composed of 284 proteins, and the extended proteome (proteins detected in ≥3 participants) contained 1666 proteins. Quality control procedures were developed to optimize the accuracy and consistency of measurement of sputum proteins and analyze the distribution of sputum proteins in the healthy population. The analysis showed that quantitation of proteins by HDMSE is influenced by several factors, with some proteins being measured in all participants' samples and with low measurement variance between samples from the same patient. The measurement of some proteins is highly variable between repeat analyses, susceptible to sample processing effects, or difficult to accurately quantify by mass spectrometry. Other proteins show high interindividual variance. We also highlight that the sputum proteome of healthy individuals is related to sputum neutrophil levels, but not gender or allergic sensitization. We illustrate the importance of design and interpretation of disease biomarker studies considering such protein population and technical measurement variance.

Authors: Burg D, Schofield JPR, Brandsma J, Staycova D, Folisi C, Bansal AT, Nicholas B, Xian Y, Rowe A, Corfield J, Wilson SJ, Ward JA, Lutter R, Fleming LJ, Shaw DE, Bakke PS, Caruso M, Dahlen SE, Fowler SJ, Hashimoto S, Horvath I, Howarth PH, Krug N, Montuschi P, Sanak M, Sandstrom T, Singer F, Sun K, Pandis I, Auffray C, Sousa AR, Adcock IM, Chung F, Sterk PJ, Djukanovic R, Skipp P, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2018
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Lega Italiana Anti Fumo news article

A feature about the Italian anti-smoking organisation’s involvement in U-BIOPRED

Author: U-BIOPRED
Publication type: Project Resources
Published: 2012
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Lega Italiana Anti Fumo recruitment plan

The recruitment strategy of the Italian anti-smoking organisation LIAF

Author: Lega Italiana Anti Fumo
Publication type: Project Resources
Published: 2012
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lipid mediator metabolites in human urine from asthma patients

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Authors: Martin J, Morris R, Zolkipli Z
Publication type: Academic Publication
Published: 2013
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Lipid phenotyping of lung epithelial lining fluid in healthy human volunteers

Background

Lung epithelial lining fluid (ELF)—sampled through sputum induction—is a medium rich in cells, proteins and lipids. However, despite its key role in maintaining lung function, homeostasis and defences, the composition and biology of ELF, especially in respect of lipids, remain incompletely understood.

Objectives

To characterise the induced sputum lipidome of healthy adult individuals, and to examine associations between different ELF lipid phenotypes and the demographic characteristics within the study cohort.

Methods

Induced sputum samples were obtained from 41 healthy non-smoking adults, and their lipid compositions analysed using a combination of untargeted shotgun and liquid chromatography mass spectrometry methods. Topological data analysis (TDA) was used to group subjects with comparable sputum lipidomes in order to identify distinct ELF phenotypes.

Results

The induced sputum lipidome was diverse, comprising a range of different molecular classes, including at least 75 glycerophospholipids, 13 sphingolipids, 5 sterol lipids and 12 neutral glycerolipids. TDA identified two distinct phenotypes differentiated by a higher total lipid content and specific enrichments of diacyl-glycerophosphocholines, -inositols and -glycerols in one group, with enrichments of sterols, glycolipids and sphingolipids in the other. Subjects presenting the lipid-rich ELF phenotype also had significantly higher BMI, but did not differ in respect of other demographic characteristics such as age or gender.

Conclusions

We provide the first evidence that the ELF lipidome varies significantly between healthy individuals and propose that such differences are related to weight status, highlighting the potential impact of (over)nutrition on lung lipid metabolism.

Electronic supplementary material
The online version of this article (10.1007/s11306-018-1412-2) contains supplementary material, which is available to authorized users.

 

Authors: Brandsma J, Goss V, Yang X, Bakke PS, Caruso M, Chanez P, Dahlen SE, Fowler SJ, Horvath I, Krug N, Montuschi P, Sanak M, Sandstrom T, Shaw D, Chung KF, Singer F, Fleming LJ, Sousa AR, Pandis I, Bansal AT, Sterk PJ, Djukanovic R, Postle A, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2018
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Longitudinal characterisation of a model of chronic allergic lung inflammation in mice using imaging, functional and immunological methods

Role imaging could have for assessing lung inflammation in a mouse model of a HDM provoked allergic inflammation. Inflammation is usually assessed using terminal procedures such as bronchoalveolar lavage (BAL) and histopathology; however, magnetic resonance imaging (MRI) and computed tomography (CT) methods have the potential to allow longitudinal, repeated study of individual animals.

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Author: Knowles R
Publication type: Academic Publication
Published: 2013
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Methodological considerations for large-scale breath analysis studies: lessons from the U-BIOPRED severe asthma project

Methods for breath sampling and analysis require robust quality assessment to minimise the risk of false discoveries. Planning large-scale multi-site breath metabolite profiling studies also requires careful consideration of systematic and random variation as a result of sampling and analysis techniques. In this study we use breath sample data from the recent U-BIOPRED cohort to evaluate and discuss some important methodological considerations such as batch variation and correction, variation between sites, storage and transportation, as well as inter-instrument analytical differences. Based on this we provide a summary of recommended best practices for new large scale multi-site studies.

Authors: Ahmed WM, Brinkman P, Weda H, Knobel HH, Xu Y, Nijsen TM, Goodacre R, Rattray NJ, Vink TJ, Santonico M, Pennazza G, Montuschi P, Sterk PJ, Fowler SJ
Publication type: Academic Publication
Published: 2018
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Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study

BACKGROUND:

Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.

METHODS:

In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.

FINDINGS:

We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).

INTERPRETATION:

We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.

FUNDING:

Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.

Authors: Shrine N, Portelli M, John C, Soler Artigas M, Bennett N, Hall R, Lewis J, Henry A, Billington CK, Ahmad A, Packer RJ, Shaw D, Pogson ZEK, Fogerty A, McKeever T, Singapuri A, Heaney L, Mansur A, Chaudhuri R, Thomson N, Holloway J, Lockett G, Howarth PH, Djukanovic R, Hankinson J, Niven R, Simpson AJ, Chung KF, Sterk PJ, Blakey J, Adcock IM, Hu S, Guo YK, Obeidat M, Sin DD, Van den Berge M, Nickle DC, Bosse Y, Tobin M, Hall IP, Brightling C, Wain L, Sayers I
Publication type: Academic Publication
Published: 2019

Multi-Center breath metabolomics

Many (multi-centre) breath-analysis studies require transport and storage of samples. We aimed to test the effect of transportation and storage using sorbent tubes of exhaled breath samples for diagnostic accuracy of electronic nose (eNose) and GC-MS analysis.

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Authors: Fens N, van der Schee MP
Publication type: Academic Publication
Published: 2012
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Obesity-associated severe Asthma represents a distinct clinical phenotype

The researchers looked at obesity and severe asthma by comparing patient information for three weight categories, defined by body mass index (BMI), in a group of adults with severe asthma.

They found that the obese group needed greater amounts and different types of medication, had higher bone density, weaker lung function, and were more likely to report eczema than the normal and overweight groups. The findings also suggest that as BMI increases, people are at greater risk of developing asthma, they will experience more frequent exacerbations, with greater severity and frequency of symptoms.

The results show that obese people with severe asthma have specific characteristics as a group that could identify a sub-type of asthma. 

Author: Gibeon D
Publication type: Academic Publication
Published: 2013
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Pathway discovery using transcriptomic profiles in adult-onset severe asthma

BACKGROUND:

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 samples.

OBJECTIVE:

We sought to identify gene profiles associated with adult-onset severe asthma.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

Authors: Hekking PP, Loza MJ, Pavlidis S, Meulder B, Lefaudeux D, Baribaud F, Auffray C, Wagener A H, Brinkman P, Lutter R, Bansal AT, Sousa AR, Bates SA, Pandis I, Fleming LJ, Shaw D, Fowler SJ, Guo YK, Meiser A, Sun K, Corfield J, Howarth PH, Bel E H, Adcock IM, Chung KF, Djukanovic R, Sterk PJ, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2018

Poly:IC Causes Exacerbation In A Murine Allergic Inflammation Model Driven By House Dust Mite In Freund’s Complete Adjuvant

RNA viruses are major causes of respiratory infections and known to exacerbate asthma and other respiratory diseases. The objective of the study was to use poly I:C, a synthetic analogue dsRNA, to elicit exacerbation in a model of allergic inflammation driven by house dust mite (HDM) in Freund’s Complete Adjuvant (FCA). This HDM-CFA model is characterized by airway hyperresponsiveness (AHR) and a mixed T-helper phenotype (1)  

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Authors: Miralpeix P, De Alba J
Publication type: Academic Publication
Published: 2012
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