15 results found
Tiotiu A, Zounemat Kermani N, Badi Y, et al., 2021, Sputum macrophage diversity and activation in asthma: role of severity and inflammatory phenotype, Allergy, Vol: 76, Pages: 775-788, ISSN: 0105-4538
BACKGROUND: Macrophages control innate and acquired immunity but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort. METHODS: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically- and alternatively-activated macrophages: M1 and M2 respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome-associated clusters (TACs). RESULTS: Macrophage numbers were significantly decreased in severe asthma compared to mild-moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll-like receptors via NF-κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL-2 biosynthesis (all p<0.01). Sputum macrophage number and the ES for most macrophage signatures were higher in the TAC3 group compared to TAC1 and TAC2 asthmatics. However, a high enrichment was found in TAC1 for 3 modules showing inflammatory pathways linked to Toll-like and TNF receptor activation and arachidonic acid metabolism (p<0.001) and in TAC2 for the inflammasome- and interferon-signalling pathways (p<0.001). Data was validated in the ADEPT cohort. Module analysis provides additional information compared to conventional M1 and M2 classification. TR-Mφ were enriched in TAC3 and associated with mitochondrial function. CONCLUSIONS: Macrophage activation is attenuated in severe granulocytic asthma highlighting defective innate immunity except for specific subsets characterised by distinct inflammatory pathways.
Abdel-Aziz MI, Brinkman P, Vijverberg SJH, et al., 2021, Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12-18 months, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 123-134, ISSN: 0091-6749
BACKGROUND: Asthma is a heterogeneous disease characterized by distinct phenotypes with associated microbial dysbiosis. OBJECTIVES: To identify severe asthma phenotypes based on sputum microbiome profiles and assess their stability after 12-18 months. Furthermore, to evaluate clusters' robustness after inclusion of an independent mild-to-moderate asthmatics. METHODS: In this longitudinal multicenter cohort study, sputum samples were collected for microbiome profiling from a subset of the U-BIOPRED adult patient cohort at baseline and after 12-18 months of follow-up. Unsupervised hierarchical clustering was performed using the Bray-Curtis β-diversity measure of microbial profiles. For internal validation, partitioning around medoids, consensus cluster distribution, bootstrapping and topological data analysis were applied. Follow-up samples were studied to evaluate within-patient clustering stability in severe asthmatics. Cluster robustness was evaluated by an independent mild-moderate asthma cohort. RESULTS: Data were available for 100 severe asthma subjects (median age: 55 yrs, 42% males). Two microbiome-driven clusters were identified, characterized by differences in asthma onset, smoking status, residential locations, percentage of blood and/or sputum neutrophils and macrophages, lung spirometry, and concurrent asthma medications (all p-values <.05). Cluster 2 patients displayed a commensal-deficient bacterial profile which was associated with worse asthma outcomes compared to cluster 1. Longitudinal clusters revealed high relative stability after 12-18 months in the severe asthmatics. Further inclusion of 24 independent mild-to-moderate asthmatics was consistent with the clustering assignments. CONCLUSION: Unbiased microbiome-driven clustering revealed two distinct robust severe asthma phenotypes, which exhibited relative overtime stability. This suggests that the sputum microbiome may serve as a biomarker for better characterizing asthma phenotypes.
Kermani NZ, Saqi M, Agapow P, et al., 2021, Type 2-low asthma phenotypes by integration of sputum transcriptomics and serum proteomics., Allergy, Vol: 76, Pages: 380-383, ISSN: 0105-4538
Kermani NZ, Pavlidis S, Xie J, et al., 2020, Instability of sputum molecular phenotypes in U-BIOPRED severe asthma, European Respiratory Journal, Vol: 57, Pages: 1-5, ISSN: 0903-1936
Omar MI, Roobol MJ, Ribal MJ, et al., 2020, Author Correction: Introducing PIONEER: a project to harness big data in prostate cancer research., Nat Rev Urol, Vol: 17
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Omar MI, Roobol MJ, Ribal MJ, et al., 2020, Introducing PIONEER: a project to harness big data in prostate cancer research, NATURE REVIEWS UROLOGY, Vol: 17, Pages: 351-361, ISSN: 1759-4812
Ali MK, Kim RY, Brown AC, et al., 2020, Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma., European Respiratory Journal, Vol: 55, Pages: 1-14, ISSN: 0903-1936
Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FEV1/FVC). The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma with TFR1 expression correlating with reduced lung function and increased type 2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma, including airway hyper-responsiveness and fibrosis and T2 inflammatory responses, in vivoTogether these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
Jolliffe DA, Stefanidis C, Wang Z, et al., 2020, Vitamin D metabolism is dysregulated in asthma and chronic obstructive pulmonary disease., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 371-382, ISSN: 1073-449X
RATIONALE: Vitamin D deficiency is common in patients with asthma and COPD. Low 25-hydroxyvitamin D (25[OH]D) levels may represent a cause or a consequence of these conditions. OBJECTIVE: To determine whether vitamin D metabolism is altered in asthma or COPD. METHODS: We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D3, administered over one year, differed between those with asthma or COPD vs. controls. Serum concentrations of vitamin D3, 25(OH)D3 and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) were determined pre- and post-supplementation in 93 adults with asthma, COPD or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed fourteen datasets to compare expression of 1α,25[OH]2D3-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD vs. controls. MEASUREMENTS AND MAIN RESULTS: The mean post-supplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in controls (39.8 nmol/L; P=0.001). Compared with controls, patients with asthma and COPD had lower molar ratios of 25(OH)D3-to-vitamin D3 and higher molar ratios of 1α,25(OH)2D3-to-25(OH)D3 both pre- and post-supplementation (P≤0.005). Inter-group differences in 1α,25[OH]2D3-inducible gene expression signatures were modest and variable where statistically significant. CONCLUSIONS: Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D3-to-vitamin D3 and increased molar ratios of 1α,25(OH)2D3-to-25(OH)D3 in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.
Kermani NZ, Pavlidis S, Riley JH, et al., 2019, Prediction of longitudinal inflammatory phenotypes using baseline sputum transcriptomics in UBIOPRED, EUROPEAN RESPIRATORY JOURNAL, Vol: 54, ISSN: 0903-1936
Tiotiu A, Kermani NZ, Agapow P, et al., 2019, Differential macrophage activation in asthmatic sputum using U-BIOPRED transcriptomics, EUROPEAN RESPIRATORY JOURNAL, Vol: 54, ISSN: 0903-1936
Kermani NZ, Pavlidis S, Saqi M, et al., 2018, Further resolution of non-T2 asthma subtypes from high-throughput sputum transciptomics data in U-BIOPRED, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: European Respiratory Society, Pages: 1-3, ISSN: 0903-1936
Background: Precision medicine of asthma requires understanding of its heterogeneity and molecular pathophysiology.Aim: Three sputum-derived transcriptomic clusters (TACs) were previously identified [Kuo at al. Eur Respir J.2017, 49] in the U-BIOPRED cohort: TAC1 consisting of T2 high patients with eosinophilia, TAC2 with neutrophilia and inflammasome activation and TAC3, a more heterogeneous cluster with mostly paucigranulocytic patients. We further refine TAC3.Methods: Gaussian mixture modelling for model-based clustering was applied to sputum gene expression of 104 asthmatic participants from the adult cohort to substructure TAC3. Gene set variation analysis (GSVA) was used to explore the enrichment of gene signatures across the TACs.Results: We again produce the three TACs (TAC1 N=23, TAC2 N=24) but TAC3 was further split into two groups (TAC3a N=28, TAC3b N=29), distinguished by distinct neutrophils and macrophages density and enrichment of IL13 stimulation, inflammasome activation and OXPHOS gene signatures (Figure), as well as IL-4 and LPS-stimulated macrophage gene signatures. However, there were no distinguishing clinical features.Conclusion: Identification of sub-structure of sputum TACs, particularly of TAC3, will help towards improved targeted therapies.
Zounemat Kermani N, 2017, dentifying Novel Peroxisomal Proteins by Multiple Kernel Learning (MKL) and likely Positive-Iterative Classification (LP-IC), NIPS workshos(LLD)
Chabok M, Nicolaides A, Aslam M, et al., 2016, Risk factors associated with increased prevalence of abdominal aortic aneurysm in women, BRITISH JOURNAL OF SURGERY, Vol: 103, Pages: 1132-1138, ISSN: 0007-1323
Aliee H, Massip F, Qi C, et al., Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. A subset of COVID-19 patients progresses to severe disease, with high mortality and limited treatment options. Detailed knowledge of the expression regulation of genes required for viral entry into respiratory epithelial cells is urgently needed.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Here we assess the expression patterns of genes required for SARS-CoV-2 entry into cells, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi).</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Genes encoding viral receptors and activating protease are increased in the nose compared to the bronchi in matched samples and associated with the proportion of secretory epithelial cells in cellular deconvolution analyses. Current or ex-smoking was found to increase expression of these genes only in lower airways, which was associated with a significant increase in the predicted proportion of goblet cells. Both acute and second hand smoke exposure were found to increase ACE2 expression while inhaled corticosteroids decrease ACE2 expression in the lower airways. A strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Genes associated with SARS-CoV-2 viral entry into cells are high in upper airways, but strongly increased in lower airways by smoke exposure. In contrast, ICS decreases ACE2 expression, indicating tha
Kermani NZ, Song W-J, Lunt A, et al., Airway expression of SARS-CoV-2 receptor, ACE2, and proteases, TMPRSS2 and furin, in severe asthma
<jats:title>Summary</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Patients with severe asthma may have a greater risk of dying from COVID-19 disease caused by SARS-CoV-2 virus. Angiotensin converting enzyme 2 (ACE2) receptor and enzyme proteases, transmembrane protease, serine 2 (TMPRSS2) and furin are needed for the attachment and invasion of the virus into host cells. We determined whether their expression in the airways of severe asthma patients is increased.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We examined the microarray mRNA expression of ACE2, TMPRSS2 and furin in the sputum, bronchial brush and bronchial biopsies of participants in the European U-BIOPRED cohort.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>ACE2 and furin sputum gene expression was significantly increased in severe non-smoking asthma compared to mild-moderate asthma and healthy volunteers. By contrast, TMPRSS2 expression in bronchial biopsy and bronchial brushings was increased in severe smoking and ex-smoking asthmatics, and so was furin expression in bronchial brushings. Several clinical parameters including male gender, oral steroid use and nasal polyps were positively associated with ACE2, TMPRSS2 and furin expression levels. There was a higher expression of ACE2 and furin in the sputum neutrophilic molecular phenotype with inflammasome activation compared to the eosinophilic Type2-high or paucigranulocytic phenotypes. The enrichment score of the IL-13-Type2 gene signature was positively correlated with ACE2, TMPRSS2 and furin levels.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These key determinants of virus entry into the lungs may contribute to the poorer outcomes from COVID-19 disease in patients with severe asthma.</jats:p></jats:sec&
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