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Journal articleShim JM, Lee JS, Russell KE, et al., 2017,
BET proteins are a key component of immunoglobulin gene expression
, Epigenomics, Vol: 9, Pages: 393-406, ISSN: 1750-192XAims:Bromo and extraterminal domain (BET) proteins have been shown to regulate gene expression including inflammatory genes. Methods:In order to investigate the role of the BET proteins in immunoglobulin production we treated the human B cell line CLNH11.4 and primary human B cells and ozone exposed mice with BET inhibitors (JQ1 or IBET151). Results:Both proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription. In vivo treatment of ozone-exposed mice with the BET inhibitor IBET151 similarly inhibited ozone induced immunoglobulin production. JQ1 did not reduce the protein levels of Brd4 or Oct2 per se but reduced the ability of Brd4 and Oct2 to co-immunoprecipitate and of Oct2 to bind to immunoglobulin gene promoters.Conclusions:Our results indicate that BET proteins including Brd4 play a crucial role regulation B cell specific gene expression and immunoglobulin production.
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Journal articleVogelmeier CF, Criner GJ, Martinez FJ, et al., 2017,
Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease 2017 Report GOLD Executive Summary
, RESPIROLOGY, Vol: 22, Pages: 575-601, ISSN: 1323-7799 -
Journal articleMitchell S, Riha RL, Rohde G, et al., 2017,
Continuing professional development: introducing the ERS International Certificate in Respiratory Sleep Medicine
, BREATHE, Vol: 13, Pages: 11-14, ISSN: 1810-6838 -
Journal articleVogelmeier CF, Criner GJ, Martinez FJ, et al., 2017,
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary
, ARCHIVOS DE BRONCONEUMOLOGIA, Vol: 53, Pages: 128-149, ISSN: 0300-2896 -
Journal articlePolley A, Orlowski A, Danne R, et al., 2017,
Glycosylation and lipids working in concert direct CD2 ectodomain orientation and presentation
, Journal of Physical Chemistry Letters, Vol: 8, Pages: 1060-1066, ISSN: 1948-7185Proteins embedded in the plasma membrane mediate interactions with the cell environment and play decisiveroles in many signaling events. For cell−cell recognition molecules, it is highly likely that their structures and behavior have beenoptimized in ways that overcome the limitations of membrane tethering. In particular, the ligand binding regions of theseproteins likely need to be maximally exposed. Here we show by means of atomistic simulations of membrane-bound CD2, a smallcell adhesion receptor expressed by human T-cells and natural killer cells, that the presentation of its ectodomain is highlydependent on membrane lipids and receptor glycosylation acting in apparent unison. Detailed analysis shows that the underlyingmechanism is based on electrostatic interactions complemented by steric interactions between glycans in the protein and themembrane surface. The findings are significant for understanding the factors that render membrane receptors accessible forbinding and signaling.
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Journal articleVogelmeier CF, Criner GJ, Martinez FJ, et al., 2017,
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary
, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 557-582, ISSN: 1073-449XThis Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 report focuses primarily on the revised and novel parts of the document. The most significant changes include: (1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; (2) for each of the groups A to D, escalation strategies for pharmacologic treatments are proposed; (3) the concept of deescalation of therapy is introduced in the treatment assessment scheme; (4) nonpharmacologic therapies are comprehensively presented; and (5) the importance of comorbid conditions in managing chronic obstructive pulmonary disease is reviewed.
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Journal articleVogelmeier CF, Criner GJ, Martinez FJ, et al., 2017,
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary
, EUROPEAN RESPIRATORY JOURNAL, Vol: 49, ISSN: 0903-1936- Author Web Link
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Journal articlePignataro FS, Bonini M, Forgione A, et al., 2017,
Asthma and gender: the female lung
, Pharmacological Research, Vol: 119, Pages: 384-390, ISSN: 1043-6618Asthma is a common chronic disease that affects over 300 million people worldwide, resulting in a considerable socio-economic burden.Literature data suggest that asthma has a higher incidence in females, particularly at certain stages of pubertal development. Moreover, women seem to experience more asthma symptoms than men and to use more rescue medications, resulting in a reduced quality of life.Although several mechanisms have been proposed to explain these differences, there are not yet final data available in the literature on the role of gender in the pathogenesis of asthma and different behavior in females.Some study suggested a more prevalent hyper-responsiveness in women than in men. Nevertheless, in the literature definitive data on a possible different response to drugs used for asthma between males and females are not described.Understanding the mechanisms that underlie these gender differences in clinical history of asthma patients could give inspiration to new areas of research to obtain a more specific diagnostic and therapeutic approach gender-oriented.
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Conference paperShen C, Bernardino de la Serna J, Struth B, et al., 2017,
Azobenzene-Cholesterol as a Photoactivator in Biomimetic Membranes: 2. Membrane Structure
, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 319A-319A, ISSN: 0006-3495 -
Journal articleKuo CS, Pavlidis S, Loza M, et al., 2017,
A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED
, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 443-455, ISSN: 1535-4970RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes. METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement. RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity.
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Journal articleDonaldson GC, Wedzicha JA, 2017,
Prediction of Chronic Obstructive Pulmonary Disease Exacerbation Frequency Clinical Parameters Are Still Better Than Biomarkers
, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 415-416, ISSN: 1073-449X -
Conference paperChan K-L, Gonzalez EG, Padilla-Parra S, et al., 2017,
Well-Characterised Time-Gated Detector Photon Flux Resolves the Ultrastructure of DNA-Damage Nuclear Bodies with G-STED Nanoscopy
, 61st Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 141A-141A, ISSN: 0006-3495 -
Journal articleMcFarlane AJ, McSorley HJ, Davidson DJ, et al., 2017,
Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota.
, Journal of Allergy and Clinical Immunology, Vol: 140, Pages: 1068-1078.e6, ISSN: 0091-6749BACKGROUND: Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. OBJECTIVE: Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. METHODS: A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV-inactivated RSV. RESULTS: H polygyrus-infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH2 responses, were not essential because protection against RSV was maintained in Rag1(-/-) and Il4rα(-/-) mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon-stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1(-/-) and germ-free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus-induced protection against RSV. CONCLUSION: These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota-dependent type I interferon response.
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Journal articleCalderon L, Han TT, McGilvery CM, et al., 2017,
Release of airborne particles and Ag and Zn compounds from nanotechnology-enabled consumer sprays: Implications for inhalation exposure
, ATMOSPHERIC ENVIRONMENT, Vol: 155, Pages: 85-96, ISSN: 1352-2310The increasing prevalence and use of nanotechnology-enabled consumer products have increased potential consumer exposures to nanoparticles; however, there is still a lack of data characterizing such consumer exposure. The research reported here investigated near-field airborne exposures due to the use of 13 silver (Ag)-based and 5 zinc (Zn)-based consumer sprays. The products were sprayed into a specially designed glove box, and all products were applied with equal spraying duration and frequency. Size distribution and concentration of the released particles were assessed using a Scanning Mobility Particle Sizer and an Aerodynamic Particle Sizer. Inductively coupled plasma mass spectrometry (ICP-MS) was used to investigate the presence of metals in all investigated products. Spray liquids and airborne particles from select products were examined using transmission electron microscopy (TEM) and Energy Dispersive X-ray Spectroscopy (EDS). We found that all sprays produced airborne particles ranging in size from nano-sized particles (<100 nm) to coarse particles (>2.5 μm); however, there was a substantial variation in the released particle concentration depending on a product. The total aerosol mass concentration was dominated by the presence of coarse particles, and it ranged from ∼30 μg/m3 to ∼30,000 μg/m3. The TEM verified the presence of nanoparticles and their agglomerates in liquid and airborne states. The products were found to contain not only Ag and Zn compounds - as advertised on the product labeling - but also a variety of other metals including lithium, strontium, barium, lead, manganese and others. The results presented here can be used as input to model population exposures as well as form a basis for human health effects studies due to the use nanotechnology-enabled products.
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Journal articleKuo C-HS, Pavlidis S, Loza M, et al., 2017,
T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED
, European Respiratory Journal, Vol: 49, ISSN: 0903-1936Asthma is characterised by heterogeneous clinical phenotypes. Our objective was to determine molecular phenotypes of asthma by analysing sputum cell transcriptomics from 104 moderate-to-severe asthmatic subjects and 16 nonasthmatic subjects.After filtering on the differentially expressed genes between eosinophil- and noneosinophil-associated sputum inflammation, we used unbiased hierarchical clustering on 508 differentially expressed genes and gene set variation analysis of specific gene sets.We defined three transcriptome-associated clusters (TACs): TAC1 (characterised by immune receptors IL33R, CCR3 and TSLPR), TAC2 (characterised by interferon-, tumour necrosis factor-α- and inflammasome-associated genes) and TAC3 (characterised by genes of metabolic pathways, ubiquitination and mitochondrial function). TAC1 showed the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2 (Th2) and innate lymphoid cell type 2. TAC1 had the highest sputum eosinophilia and exhaled nitric oxide fraction, and was restricted to severe asthma with oral corticosteroid dependency, frequent exacerbations and severe airflow obstruction. TAC2 showed the highest sputum neutrophilia, serum C-reactive protein levels and prevalence of eczema. TAC3 had normal to moderately high sputum eosinophils and better preserved forced expiratory volume in 1 s. Gene–protein coexpression networks from TAC1 and TAC2 extended this molecular classification.We defined one Th2-high eosinophilic phenotype TAC1, and two non-Th2 phenotypes TAC2 and TAC3, characterised by inflammasome-associated and metabolic/mitochondrial pathways, respectively.
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Journal articleAtalla A, Carlisle TW, Simonds AK, et al., 2017,
Sleepiness and activity in heart failure patients with reduced ejection fraction and central sleep-disordered breathing
, SLEEP MEDICINE, Vol: 34, Pages: 217-223, ISSN: 1389-9457 -
Journal articleKemp P, Natanek A, 2017,
Epigenetics and susceptibility to muscle wasting in COPD
, Archivos de Bronconeumología, Vol: 53, Pages: 364-365, ISSN: 0300-2896 -
Journal articleDhariwal J, Cameron A, Trujillo-Torralbo MB, et al., 2017,
Mucosal type 2 innate lymphoid cells are a key component of the allergic response to aeroallergen
, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1586-1596, ISSN: 1535-4970RATIONALE: Newly characterised type 2 innate lymphoid cells display potent type 2 effector functionality, however their contribution to allergic airways inflammation and asthma is poorly understood. Mucosal biopsy used to characterise the airway mucosa is invasive, poorly tolerated and does not allow sequential sampling. OBJECTIVES: To assess the role of type 2 innate lymphoid cells during nasal allergen challenge in subjects with allergic rhinitis, using novel non-invasive methodology. METHODS: We used a human experimental allergen challenge model, with flow cytometric analysis of nasal curettage samples, to assess the recruitment of type 2 innate lymphoid cells and granulocytes to the upper airways of atopic and healthy subjects following allergen provocation. Soluble mediators in the nasal lining fluid were measured using nasosorption. MEASUREMENTS AND MAIN RESULTS: Following allergen challenge, atopic subjects displayed rapid induction of upper airway symptoms, an enrichment of type 2 innate lymphoid cells, eosinophils and neutrophils, along with increased production of interleukin-5, prostaglandin D2, and eosinophil and T-helper type 2 cell chemokines compared to healthy subjects. The most pronounced type 2 innate lymphoid cell recruitment was observed in patients with elevated serum IgE and airway eosinophilia. CONCLUSIONS: The rapid recruitment of type 2 innate lymphoid cells to the upper airways of allergic rhinitis patients, and their association with key type 2 mediators, highlights their likely important role in the early allergic response to aeroallergen in the airways. The novel methodology described herein enables the analysis of rare cell populations from non-invasive, serial tissue sampling.
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Journal articleSpina G, Spruit MA, Alison J, et al., 2017,
Analysis of nocturnal actigraphic sleep measures in patients with COPD and their association with daytime physical activity.
, Thorax, Vol: 72, Pages: 694-701, ISSN: 0040-6376BACKGROUND: Sleep disturbances are common in patients with chronic obstructive pulmonary disease (COPD) with a considerable negative impact on their quality of life. However, factors associated with measures of sleep in daily life have not been investigated before nor has the association between sleep and the ability to engage in physical activity on a day-to-day basis been studied. AIMS: To provide insight into the relationship between actigraphic sleep measures and disease severity, exertional dyspnoea, gender and parts of the week; and to investigate the association between sleep measures and next day physical activity. METHODS: Data were analysed from 932 patients with COPD (66% male, 66.4±8.3 years, FEV1% predicted=50.8±20.5). Participants had sleep and physical activity continuously monitored using a multisensor activity monitor for a median of 6 days. Linear mixed effects models were applied to investigate the factors associated with sleep impairment and the association between nocturnal sleep and patients' subsequent daytime physical activity. RESULTS: Actigraphic estimates of sleep impairment were greater in patients with worse airflow limitation and worse exertional dyspnoea. Patients with better sleep measures (ie, non-fragmented sleep, sleeping bouts ≥225 min, sleep efficiency ≥91% and time spent awake after sleep onset <57 min) spent significantly more time in light (p<0.01) and moderate-to-vigorous physical activity (p<0.01). CONCLUSIONS: There is a relationship between measures of sleep in patients with COPD and the amount of activity they undertake during the waking day. Identifying groups with specific sleep characteristics may be useful information when designing physical activity-enhancing interventions.
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Journal articleO'Byrne PM, FitzGerald JM, Zhong N, et al., 2017,
The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials
, Trials, Vol: 18, ISSN: 1745-6215Background: In many patients with mild asthma, the low frequency of symptoms and the episodic nature ofexacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance onshort-acting β2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poorcontrol of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol ‘as needed’ inresponse to symptoms may represent an alternative treatment option for patients with mild asthma.Methods/design: The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week,double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with aclinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaledcorticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid)plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-neededbudesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthmaweeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versusmaintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, orbudesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate thenoninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured bythe annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recordedelectronically using Turbuhaler® Usage Monito
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