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Wyświetlanie 1-10 z 11
Tytuł:
U-BIOPRED clinical adult asthma clusters linked to a subset of sputum -omics
Autorzy:
Shaw, Dominic E.
Fleming, Louise J.
Lefaudeux, Diane
Horvath, Ildiko
Chung, Kian. F.
Dahlen, Sven-Erik
Sandstrom, Thomas
Bakke, Per S.
Bansal, Aruna T.
Djukanovic, Ratko
Sousa, Ana R.
Montuschi, Paolo
Loza, Matthew J.
Chanez, Pascal
Sanak, Marek
Baribaud, Frédéric
Lutter, Rene
Krug, Norbert
Auffray, Charles
Caruso, Massimo
Pandis, Ioannis
De Meulder, Bertrand
Corfield, Julie
Adcock, Ian M.
Rowe, Anthony
Sterk, Peter J.
Roberts, Graham
Peffer, Nancy
Singer, Florian
Fowler, Stephen J.
Opis:
Background: 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. Objectives: We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. Methods: 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 clinicphysiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. Results: 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. Conclusion: Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.
Dostawca treści:
Repozytorium Uniwersytetu Jagiellońskiego
Artykuł
Tytuł:
Clinical and transcriptomic features of persistent exacerbation-prone severe asthma in U-BIOPRED cohort
Autorzy:
Shaw, Dominic E.
Rossios, Christos
Fleming, Louise J.
Loza, Matthew
Lefaudeux, Diane
Horvath, Ildiko
Dahlen, Sven-Erik
Sun, Kai
Musiał, Jacek
Pavlidis, Stelios
Sandstrom, Thomas
Bansal, Aruna T.
Djukanovic, Ratko
Dahlen, Barbro
Sousa, Ana R.
Montuschi, Paolo
Chanez, Pascal
Chung, Kian Fan
Lutter, Rene
Krug, Norbert
Hoda, Uruj
Caruso, Massimo
Auffray, Charles
Hu, Sile
Corfield, Julie
de Meulder, Bertrand
Baribaud, Frederic
Bhavsar, Pankaj
Adcock, Ian M.
Takahashi, Kentaro
Sterk, Peter J.
Guo, Yike
Singer, Florian
Ng Kee Kwong, Francois
Howarth, Peter H.
Fowler, Stephen J.
Opis:
Background: Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. Objectives: To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U-BIOPRED cohort. Methods: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. Results: Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short-acting beta-agonist use and asthma control index. CEA cell adhesion molecule 5 (CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T-helper type-17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. Conclusion: The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.
Dostawca treści:
Repozytorium Uniwersytetu Jagiellońskiego
Artykuł
Tytuł:
Stratification of asthma phenotypes by airway proteomic signatures
Autorzy:
Nicholas, Ben
Lefaudeux, Diane
Horvath, Ildiko
Riley, John
Dahlen, Sven-Erik
Sun, Kai
Sandstrom, Thomas
Bakke, Per S.
Bansal, Aruna T.
Djukanovic, Ratko
Sousa, Ana R.
Montuschi, Paolo
Sanak, Marek
Chung, Kian Fan
Lutter, Rene
Krug, Norbert
Auffray, Charles
Caruso, Massimo
Xian, Yang
Staykova, Doroteya
Shaw, Dominick E.
Pandis, Ioannis
Corfield, Julie
De Meulder, Bertrand
Folisi, Caterina
Howarth, Peter
Adcock, Ian M.
Rowe, Anthony
Sterk, Peter J.
Wilson, Susan
Guo, Yike
Burg, Dominic
Skipp, Paul J.
Strazzeri, Fabio
Ward, Jonathan
Brandsma, Joost
Schofield, James P.R.
Fowler, Stephen J.
Opis:
neutrophils
proteomics
biomarkers
asthma
Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.
eosinophils
Dostawca treści:
Repozytorium Uniwersytetu Jagiellońskiego
Artykuł
Wyświetlanie 1-10 z 11

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