Imperial College London

DrNazaninZounemat Kermani

Faculty of EngineeringDepartment of Computing

Research Associate
 
 
 
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n.kermani

 
 
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William Penney LaboratorySouth Kensington Campus

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Publications

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28 results found

Russell B, Beyer K, Lawlor A, Roobol MJ, Venderbos LDF, Remmers S, Briers E, MacLennan SJ, MacLennan S, Omar MI, Van Hemelrijck M, PIONEER Consortiumet al., 2024, Survivorship Data in Prostate Cancer: Where Are We and Where Do We Need To Be?, Eur Urol Open Sci, Vol: 59, Pages: 27-29

UNLABELLED: Cancer survivorship was recently identified as a prostate cancer (PCa) research priority by PIONEER, a European network of excellence for big data in PCa. Despite being a research priority, cancer survivorship lacks a clear and agreed definition, and there is a distinct paucity of patient-reported outcome (PRO) data available on the subject. Data collection on cancer survivorship depends on the availability and implementation of (validated) routinely collected patient-reported outcome measures (PROMs). There have been recent advances in the availability of such PROMs. For instance, the European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) is developing survivorship questionnaires. This provides an excellent first step in improving the data available on cancer survivorship. However, we propose that an agreed, standardised definition of (prostate) cancer survivorship must first be established. Only then can real-world data on survivorship be collected to strengthen our knowledge base. With more men than ever surviving PCa, this type of research is imperative to ensure that the quality of life of these men is considered as much as their quantity of life. PATIENT SUMMARY: As there are more prostate cancer survivors than ever before, research into cancer survivorship is crucial. We highlight the importance of such research and provide recommendations on how to carry it out. The first step should be establishing agreement on a standardised definition of survivorship. From this, patient-reported outcome measures can then be used to collect important survivorship data.

Journal article

Li C-X, Chen H, Zounemat-Kermani N, Adcock IM, Sköld CM, Zhou M, Wheelock ÅM, U-BIOPRED study groupet al., 2024, Consensus clustering with missing labels (ccml): a consensus clustering tool for multi-omics integrative prediction in cohorts with unequal sample coverage, Briefings in Bioinformatics, Vol: 25, ISSN: 1467-5463

Multi-omics data integration is a complex and challenging task in biomedical research. Consensus clustering, also known as meta-clustering or cluster ensembles, has become an increasingly popular downstream tool for phenotyping and endotyping using multiple omics and clinical data. However, current consensus clustering methods typically rely on ensembling clustering outputs with similar sample coverages (mathematical replicates), which may not reflect real-world data with varying sample coverages (biological replicates). To address this issue, we propose a new consensus clustering with missing labels (ccml) strategy termed ccml, an R protocol for two-step consensus clustering that can handle unequal missing labels (i.e. multiple predictive labels with different sample coverages). Initially, the regular consensus weights are adjusted (normalized) by sample coverage, then a regular consensus clustering is performed to predict the optimal final cluster. We applied the ccml method to predict molecularly distinct groups based on 9-omics integration in the Karolinska COSMIC cohort, which investigates chronic obstructive pulmonary disease, and 24-omics handprint integrative subgrouping of adult asthma patients of the U-BIOPRED cohort. We propose ccml as a downstream toolkit for multi-omics integration analysis algorithms such as Similarity Network Fusion and robust clustering of clinical data to overcome the limitations posed by missing data, which is inevitable in human cohorts consisting of multiple data modalities. The ccml tool is available in the R language (https://CRAN.R-project.org/package=ccml, https://github.com/pulmonomics-lab/ccml, or https://github.com/ZhoulabCPH/ccml).

Journal article

Asamoah K, Chung K, Bodinier B, Dahlen S-E, Djukanovic R, Bhavsar P, Adcock I, Vuckovic D, Chadeau Met al., 2024, Proteomic signatures of eosinophilic and neutrophilic asthma from serum and sputum, EBioMedicine, Vol: 99, ISSN: 2352-3964

BackgroundEosinophilic and neutrophilic asthma defined by high levels of blood and sputum eosinophils and neutrophils exemplifies the inflammatory heterogeneity of asthma, particularly severe asthma. We analysed the serum and sputum proteome to identify biomarkers jointly associated with these different phenotypes.MethodsProteomic profiles (N = 1129 proteins) were assayed in sputum (n = 182) and serum (n = 574) from two cohorts (U-BIOPRED and ADEPT) of mild-moderate and severe asthma by SOMAscan. Using least absolute shrinkage and selection operator (LASSO)-penalised logistic regression in a stability selection framework, we sought sparse sets of proteins associated with either eosinophilic or neutrophilic asthma with and without adjustment for established clinical factors including oral corticosteroid use and forced expiratory volume.FindingsWe identified 13 serum proteins associated with eosinophilic asthma, including 7 (PAPP-A, TARC/CCL17, ALT/GPT, IgE, CCL28, CO8A1, and IL5-Rα) that were stably selected while adjusting for clinical factors yielding an AUC of 0.84 (95% CI: 0.83–0.84) compared to 0.62 (95% CI: 0.61–0.63) for clinical factors only. Sputum protein analysis selected only PAPP-A (AUC = 0.81 [95% CI: 0.80–0.81]). 12 serum proteins were associated with neutrophilic asthma, of which 5 (MMP-9, EDAR, GIIE/PLA2G2E, IL-1-R4/IL1RL1, and Elafin) complemented clinical factors increasing the AUC from 0.63 (95% CI: 0.58–0.67) for the model with clinical factors only to 0.89 (95% CI: 0.89–0.90). Our model did not select any sputum proteins associated with neutrophilic status.InterpretationTargeted serum proteomic profiles are a non-invasive and scalable approach for subtyping of neutrophilic and eosinophilic asthma and for future functional understanding of these phenotypes.FundingU-BIOPRED has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115010, resources of which a

Journal article

Versi A, Ivan FX, Abdel-Aziz MI, Bates S, Riley J, Baribaud F, Kermani NZ, Montuschi P, Dahlen S-E, Djukanovic R, Sterk P, Maitland-Van Der Zee AH, Chotirmall SH, Howarth P, Adcock IM, Chung KF, U-BIOPRED consortiumet al., 2023, Haemophilus influenzae and Moraxella catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation, Allergy, Vol: 78, Pages: 2906-2920, ISSN: 0105-4538

BACKGROUND: Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. METHODS: Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs). RESULTS: α-diversity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α-diversity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis, respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella, Neisseria and Veillonella species and Haemophilus parainfluenzae. Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and β-diversities were stable at one year. CONCLUSIONS: Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.

Journal article

Yasinska V, Gomez C, Kolmert J, Ericsson M, Pohanka A, James A, Andersson LI, Sparreman-Mikus M, Sousa AR, Riley JH, Bates S, Bakke PS, Kermani NZ, Caruso M, Chanez P, Fowler SJ, Geiser T, Howarth PH, Horvath I, Krug N, Montuschi P, Sanak M, Behndig A, Shaw DE, Knowles RG, Dahlen B, Maitland-van der Zee A-H, Sterk PJ, Djukanovic R, Adcock IM, Chung KF, Wheelock CE, Dahlen S-E, Jonsson EWet al., 2023, Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids, ERJ Open Research, Vol: 9, ISSN: 2312-0541

Rationale 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. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure.Methods Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) 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.Measurements and main results 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 sulfate (DHEA-S) concentrations were <5% 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<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12–18 months.Conclusion The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.

Journal article

Bertels X, Edris A, Garcia-Aymerich J, Faner R, Meteran H, Sigsgaard T, Alter P, Vogelmeier C, Olvera N, Kermani NZ, Agusti A, Donaldson GC, Wedzicha JA, Brusselle GG, Backman H, Ronmark E, Lindberg A, Vonk JM, Chung KF, Adcock IM, van den Berge M, Lahousse Let al., 2023, Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration, BMJ Open Respiratory Research, Vol: 10, ISSN: 2052-4439

Background The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts.Methods This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV1/FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model.Results The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1

Journal article

Lee J-H, Dixey P, Bhavsar P, Raby K, Kermani N, Chadeau-Hyam M, Adcock IM, Song W-J, Kwon H-S, Lee S-W, Cho YS, Chung KF, Kim T-Bet al., 2023, Precision Medicine Intervention in Severe Asthma (PRISM) study: molecular phenotyping of patients with severe asthma and response to biologics, ERJ Open Research, Vol: 9, ISSN: 2312-0541

Severe asthma represents an important clinical unmet need despite the introduction of biologic agents. Although advanced omics technologies have aided researchers in identifying clinically relevant molecular pathways, there is a lack of an integrated omics approach in severe asthma particularly in terms of its evolution over time. The collaborative Korea–UK research project Precision Medicine Intervention in Severe Asthma (PRISM) was launched in 2020 with the aim of identifying molecular phenotypes of severe asthma by analysing multi-omics data encompassing genomics, epigenomics, transcriptomics, proteomics, metagenomics and metabolomics. PRISM is a prospective, observational, multicentre study involving patients with severe asthma attending severe asthma clinics in Korea and the UK. Data including patient demographics, inflammatory phenotype, medication, lung function and control status of asthma will be collected along with biological samples (blood, sputum, urine, nasal epithelial cells and exhaled breath condensate) for omics analyses. Follow-up evaluations will be performed at baseline, 1 month, 4–6 months and 10–12 months to assess the stability of phenotype and treatment responses for those patients who have newly begun biologic therapy. Standalone and integrated omics data will be generated from the patient samples at each visit, paired with clinical information. By analysing these data, we will identify the molecular pathways that drive lung function, asthma control status, acute exacerbations and the requirement for daily oral corticosteroids, and that are involved in the therapeutic response to biological therapy. PRISM will establish a large multi-omics dataset of severe asthma to identify potential key pathophysiological pathways of severe asthma.

Journal article

Mumby S, Kermani NZ, Garnett JP, Pavlidis S, Wilson SJ, Howarth PJ, Thomas MJ, Adcock IM, Lopez-Garcia Cet al., 2022, CEACAM5 is an IL-13-regulated epithelial gene that mediates transcription in type-2 (T2) high severe asthma, ALLERGY, Vol: 77, Pages: 3463-3466, ISSN: 0105-4538

Journal article

Pinkerton JW, Kim RY, Brown AC, Rae BE, Donovan C, Mayall JR, Carroll OR, Khadem Ali M, Scott HA, Berthon BS, Baines KJ, Starkey MR, Kermani NZ, Guo Y-K, Robertson AAB, O'Neill LAJ, Adcock IM, Cooper MA, Gibson PG, Wood LG, Hansbro PM, Horvat JCet al., 2022, Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma, Journal of Allergy and Clinical Immunology, Vol: 149, Pages: 1270-1280, ISSN: 0091-6749

BACKGROUND: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. OBJECTIVE: We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. METHODS: We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma. RESULTS: Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. CONCLUSION: We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors.

Journal article

Fricker M, Qin L, Sanchez-Ovando S, Simpson JL, Baines KJ, Riveros C, Scott HA, Wood LG, Wark PAB, Kermani NZ, Chung KF, Gibson PGet al., 2022, An altered sputum macrophage transcriptome contributes to the neutrophilic asthma endotype, ALLERGY, Vol: 77, Pages: 1204-1215, ISSN: 0105-4538

Journal article

Tiotiu A, Zounemat Kermani N, Badi Y, Pavlidis S, Hansbro PM, Guo Y-K, Chung KF, Adcock IM, U-BIOPRED consortium project teamet 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.

Journal article

Beyer K, Moris L, Lardas M, Haire A, Barletta F, Scuderi S, Vradi E, Gandaglia G, Omar MI, MacLennan S, Zong J, Farahmand B, Maclennan SJ, Devecseri Z, Asiimwe A, Collette L, Bjartell A, Ndow J, Briganti A, Van Hemelrijck M, PIONEER Consortiumet al., 2021, Diagnostic and prognostic factors in patients with prostate cancer: a systematic review protocol., BMJ Open, Vol: 11

INTRODUCTION: As part of the PIONEER (Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe) Consortium, we will explore which diagnostic and prognostic factors (DPFs) are currently being researched to previously defined clinical and patient-reported outcomes for prostate cancer (PCa). METHODS AND ANALYSIS: This research project will follow the following four steps: (1) a broad systematic literature review of DPFs for all stages of PCa, covering evidence from 2014 onwards; (2) discussion of systematic review findings by a multidisciplinary expert panel; (3) risk of bias assessment and applicability with Prediction model Risk Of Bias Assessment Tool criteria, Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and the Quality In Prognosis Studies tool (QUIPS) and (4) additional quantitative assessments if required. ETHICS AND DISSEMINATION: We aim to develop an online tool to present the DPFs identified in this research and make them available across all stakeholders. There are no ethical implications.

Journal article

Kermani NZ, Song W-J, Badi Y, Versi A, Guo Y, Sun K, Bhavsar P, Howarth P, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock IM, Chung KF, U-BIOPRED Consortiumet al., 2021, Correction to: Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma., Respiratory Research, Vol: 22, Pages: 1-3, ISSN: 1465-9921

Journal article

Kermani N, Song W-J, Badi Y, Versi A, Guo Y, Sun K, Bhavsar P, Howarth P, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock I, Chung KFet al., 2021, Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma, Respiratory Research, Vol: 22, ISSN: 1465-9921

BackgroundPatients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.MethodsWe examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels.ResultsACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes.ConclusionLevels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.

Journal article

Abdel-Aziz MI, Brinkman P, Vijverberg SJH, Neerincx AH, Riley JH, Bates S, Hashimoto S, Kermani NZ, Chung KF, Djukanovic R, Dahlén S-E, Adcock IM, Howarth PH, Sterk PJ, Kraneveld AD, Maitland-van der Zee AH, U-BIOPRED Study Groupet 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.

Journal article

Kermani NZ, Saqi M, Agapow P, Pavlidis S, Kuo C, Tan KS, Mumby S, Sun K, Loza M, Baribaud F, Sousa AR, Riley J, Wheelock AM, Wheelock CE, De Meulder B, Schofield J, Sánchez-Ovando S, Louise Simpson J, Baines KJ, Wark PA, Auffray C, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock IM, Guo Y-K, Chung KF, U-BIOPRED project teamet al., 2021, Type 2-low asthma phenotypes by integration of sputum transcriptomics and serum proteomics., Allergy, Vol: 76, Pages: 380-383, ISSN: 0105-4538

Journal article

Kermani NZ, Pavlidis S, Xie J, Sun K, Loza M, Baribaud F, Fowler SJ, Shaw DE, Fleming LJ, Howarth PH, Sousa AR, Corfield J, Auffray C, De Meulder B, Sterk PJ, Guo Y, Uddin M, Djukanovic R, Adcock IM, Chung KF, U-BIOPRED study groupet al., 2020, Instability of sputum molecular phenotypes in U-BIOPRED severe asthma, European Respiratory Journal, Vol: 57, Pages: 1-5, ISSN: 0903-1936

Journal article

Aliee H, Massip F, Qi C, de Biase MS, van Nijnatten J, Kersten ETG, Kermani NZ, Khuder B, Vonk JM, Vermeulen RCH, U-BIOPRED study group, Cambridge Lung Cancer Early Detection Programme, INER-Ciencias Mexican Lung Program, NHLBI LungMAP Consortium, Neighbors M, Tew GW, Grimbaldeston M, Ten Hacken NHT, Hu S, Guo Y, Zhang X, Sun K, Hiemstra PS, Ponder BA, Mäkelä MJ, Malmström K, Rintoul RC, Reyfman PA, Theis FJ, Brandsma CA, Adcock IM, Timens W, Xu CJ, van den Berge M, Schwarz RF, Koppelman GH, Nawijn MC, Faiz Aet al., 2020, Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways., Publisher: medRxiv

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. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.

Working paper

Omar MI, Roobol MJ, Ribal MJ, Abbott T, Agapow P-M, Araujo S, Asiimwe A, Auffray C, Balaur I, Beyer K, Bernini C, Bjartell A, Briganti A, Butler-Ransohoff J-E, Campi R, Cavelaars M, De Meulder B, Devecseri Z, Voss MD, Dimitropoulos K, Evans-Axelsson S, Franks B, Fullwood L, Horgan D, Smith EJ, Kiran A, Kivinummi K, Lambrecht M, Lancet D, Lindgren P, MacLennan S, MacLennan S, Nogueira MM, Moen F, Moinat M, Papineni K, Reich C, Reiche K, Rogiers S, Sartini C, van Bochove K, van Diggelen F, Van Hemelrijck M, Van Poppel H, Zong J, N'Dow J, PIONEER Consortiumet 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.

Journal article

Kermani NZ, Song W-J, Lunt A, Badi Y, Versi A, Guo Y, Sun K, Bhavsar P, Howarth P, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock IM, Chung KFet al., 2020, 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&

Journal article

Omar MI, Roobol MJ, Ribal MJ, Abbott T, Agapow P-M, Araujo S, Asiimwe A, Auffray C, Balaur I, Beyer K, Bernini C, Bjartell A, Briganti A, Butler-Ransohoff J-E, Campi R, Cavelaars M, De Meulder B, Devecseri Z, Voss MD, Dimitropoulos K, Evans-Axelsson S, Franks B, Fullwood L, Horgan D, Smith EJ, Kiran A, Kivinummi K, Lambrecht M, Lancet D, Lindgren P, MacLennan S, MacLennan S, Nogueira MM, Moen F, Moinat M, Papineni K, Reich C, Reiche K, Rogiers S, Sartini C, van Bochove K, van Diggelen F, Van Hemelrijck M, Van Poppel H, Zong J, N'Dow J, Andersson E, Arala H, Auvinen A, Bangma C, Burke D, Cardone A, Casariego J, Cuperus G, Dabestani S, Esperto F, Fossati N, Fridhammar A, Gandaglia G, Tandefelt DG, Horn F, Huber J, Hugosson J, Huisman H, Josefsson A, Kilkku O, Kreuz M, Lardas M, Lawson J, Lefresne F, Lejeune S, Longden-Chapman E, McVie G, Moris L, Mottet N, Murtola T, Nicholls C, Pang KH, Pascoe K, Picozzi M, Plass K, Pohjanjousi P, Reaney M, Remmers S, Robinson P, Schalken J, Schravendeel M, Seisen T, Servan A, Shiranov K, Snijder R, Steinbeisser C, Taibi N, Talala K, Tilki D, Van den Broeck T, Vassilev Z, Voima O, Vradi E, Waldeck R, Weistra W, Willemse P-P, Wirth M, Wolfinger R, Kermani NZet 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

Journal article

Ali MK, Kim RY, Brown AC, Mayall JR, Karim R, Pinkerton JW, Liu G, Martin KL, Starkey MR, Pillar A, Donovan C, Pathinayake PS, Carroll OR, Trinder D, Tay HL, Badi YE, Kermani NZ, Guo Y-K, Aryal R, Mumby S, Pavlidis S, Adcock IM, Weaver J, Xenaki D, Oliver BG, Holliday EG, Foster PS, Wark PA, Johnstone DM, Milward EA, Hansbro PM, Horvat JCet 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.

Journal article

Jolliffe DA, Stefanidis C, Wang Z, Kermani NZ, Dimitrov V, White JH, McDonough JE, Janssens W, Pfeffer P, Griffiths CJ, Bush A, Guo Y, Christenson S, Adcock IM, Chung KF, Thummel KE, Martineau ARet 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.

Journal article

Kermani NZ, Pavlidis S, Riley JH, Chung FK, Adcock IM, Guo Y-Ket al., 2019, Prediction of longitudinal inflammatory phenotypes using baseline sputum transcriptomics in UBIOPRED, EUROPEAN RESPIRATORY JOURNAL, Vol: 54, ISSN: 0903-1936

Journal article

Tiotiu A, Kermani NZ, Agapow P, Saqi M, Guo Y-K, Djukanovic R, Chung KF, Adcock IMet al., 2019, Differential macrophage activation in asthmatic sputum using U-BIOPRED transcriptomics, EUROPEAN RESPIRATORY JOURNAL, Vol: 54, ISSN: 0903-1936

Journal article

Kermani NZ, Pavlidis S, Saqi M, Guo Y, Agapow P, Kuo C-H, Loza M, Baribaud F, Rowe A, Sousa A, De Meulder B, Lefaudeux D, Fleming L, Corfield J, Knowles R, Auffray C, Djukanovic R, Sterk PJ, Adcock I, Chung Fet 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.

Conference paper

Zounemat Kermani N, 2017, dentifying Novel Peroxisomal Proteins by Multiple Kernel Learning (MKL) and likely Positive-Iterative Classification (LP-IC), NIPS workshos(LLD)

Conference paper

Chabok M, Nicolaides A, Aslam M, Farahmandfar M, Humphries K, Kermani NZ, Coltart J, Standfield Net 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

Journal article

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