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  • Journal article
    Harhay MO, Porcher R, Cantu E, Crowther MJ, Christie JD, Thabut G, Donaldson GCet al., 2018,

    An alternative approach for the analysis of time-to-event and survival outcomes in pulmonary medicine

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, ISSN: 1073-449X
  • Journal article
    Maneechotesuwan K, Yao X, Ito K, Jazrawi E, Usmani OS, Adcock IM, Barnes PJet al., 2018,

    Correction: Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease

    , PLoS Medicine, Vol: 15, ISSN: 1549-1277

    [This corrects the article DOI: 10.1371/journal.pmed.1000076.].

  • Journal article
    Baker J, Vuppusetty C, Colley T, Hassibi S, Fenwick P, Donnelly L, Ito K, Barnes Pet al., 2018,

    MicroRNA-570 is a novel regulator of cellular senescence and inflammaging

    , FASEB Journal, ISSN: 0892-6638

    Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs. Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases. Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells. These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease. Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1. MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1. Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16INK4a, p21Waf1, and p27Kip1), thereby restoring cellular growth by allowing progression through the cell cycle. MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1β, and IL-6). Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.—Baker, J. R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P. S., Donnelly, L. E., Ito, K., Barnes, P. J. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.

  • Journal article
    Willis-Owen SAG, Thompson AR, Kemp P, Moffatt MF, Polkey M, Cookson W, Natanek Set al., 2018,

    COPD is accompanied by co-ordinated transcriptional perturbation in the quadriceps affecting the mitochondria and extracellular matrix

    , Scientific Reports, Vol: 8, ISSN: 2045-2322

    Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.

  • Journal article
    Zafeiridou M, Hopkinson NS, Voulvoulis N, 2018,

    Cigarette Smoking: An assessment of tobacco's global environmental footprint across its entire supply chain.

    , Environmental Science and Technology, Vol: 52, Pages: 8087-8094, ISSN: 0013-936X

    While the health effects of cigarette smoking are well recognised and documented, the environmental impacts of tobacco are less appreciated and often overlooked. Here we evaluate tobacco's global footprint across its entire supply chain, looking at resources needs, wastes and emissions of the full cradle-to-grave life cycle of cigarettes. The cultivation of 32.4 Mt of green tobacco used for the production of 6.48 Mt of dry tobacco in the six trillion cigarettes manufactured worldwide in 2014, were shown to contribute almost 84 Mt CO2 eq emissions to climate change - approximately 0.2% of the global total, 490,000 tonnes 1,4 dichlorobenzene eq to ecosystem ecotoxicity levels, over 22 billion m3 and 21 Mt oil eq to water and fossil fuel depletion respectively. A typical cigarette was shown to have a water footprint of 3.7 litres, a climate change contribution of 14 g CO2 eq, and a fossil fuel depletion contribution of 3.5 g oil eq. Tobacco competes with essential commodities for resources and places significant pressures on the health of our planet and its most vulnerable inhabitants. Increased awareness as well as better monitoring and assessment of the environmental issues associated with tobacco should support the current efforts to reduce global tobacco use as an important element of sustainable development.

  • Journal article
    Chapman KR, Hurst JR, Frent S, Larbig M, Fogel R, Guerin T, Banerji D, Patalano F, Goyal P, Pfister P, Kostikas K, Wedzicha JAet al., 2018,

    Long-term triple therapy de-escalation to indacaterol/glycopyrronium in COPD patients (SUNSET): a randomized, double-blind, triple-dummy clinical trial

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 329-339, ISSN: 1073-449X

    Rationale: There are no studies on ICS withdrawal in patients on long-term triple therapy in the absence of frequent exacerbations. Objective: To evaluate the efficacy and safety of the direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in non-frequently exacerbating COPD patients. Methods: This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50μg once daily) or continuation of triple therapy (tiotropium 18μg once daily plus combination of salmeterol/fluticasone propionate [50/500μg] twice daily) in non-frequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was non-inferiority on change from baseline in trough forced expiratory volume in 1 second (FEV1). Moderate or severe exacerbations were predefined secondary endpoints. Measurements and Main Results: 527 patients were randomized to indacaterol/glycopyrronium and 526 to triple therapy. ICS withdrawal led to a reduction in trough FEV1 of −26mL (95% confidence interval [CI], −53 to 1 mL) with confidence limits exceeding the non-inferiority margin of −50 mL. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio 1.08; 95%CI, 0.83 to 1.40). Patients with ≥300 blood eosinophils/μL at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups. Conclusions: In COPD patients without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/µL suggests that these patients are likely to benefit from triple therapy. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02603393.

  • Journal article
    Ritchie AI, Polkey MI, Donaldson GC, Wedzicha JAet al., 2018,

    Is peer review still anonymous?

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 278-280, ISSN: 1073-449X
  • Journal article
    Schneider F, Waithe D, Galiani S, Bernardino de la Serna J, Sezgin E, Eggeling Cet al., 2018,

    Nanoscale spatiotemporal diffusion modes measured by simultaneous confocal and stimulated emission depletion nanoscopy imaging

    , Nano Letters, Vol: 18, Pages: 4233-4240, ISSN: 1530-6984

    The diffusion dynamics in the cellular plasma membrane provide crucial insights into molecular interactions, organization, and bioactivity. Beam-scanning fluorescence correlation spectroscopy combined with super-resolution stimulated emission depletion nanoscopy (scanning STED–FCS) measures such dynamics with high spatial and temporal resolution. It reveals nanoscale diffusion characteristics by measuring the molecular diffusion in conventional confocal mode and super-resolved STED mode sequentially for each pixel along the scanned line. However, to directly link the spatial and the temporal information, a method that simultaneously measures the diffusion in confocal and STED modes is needed. Here, to overcome this problem, we establish an advanced STED–FCS measurement method, line interleaved excitation scanning STED–FCS (LIESS–FCS), that discloses the molecular diffusion modes at different spatial positions with a single measurement. It relies on fast beam-scanning along a line with alternating laser illumination that yields, for each pixel, the apparent diffusion coefficients for two different observation spot sizes (conventional confocal and super-resolved STED). We demonstrate the potential of the LIESS–FCS approach with simulations and experiments on lipid diffusion in model and live cell plasma membranes. We also apply LIESS–FCS to investigate the spatiotemporal organization of glycosylphosphatidylinositol-anchored proteins in the plasma membrane of live cells, which, interestingly, show multiple diffusion modes at different spatial positions.

  • Journal article
    Chung K, 2018,

    "International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma." Kian Fan Chung, Sally E. Wenzel, Jan L. Brozek, Andrew Bush, Mario Castro, Peter J. Sterk, Ian M. Adcock, Eric D. Bateman, Elisabeth H. Bel, Eugene R. Bleecker, Louis-Philippe Boulet, Christopher Brightling, Pascal Chanez, Sven-Erik Dahlen, Ratko Djukanovic, Urs Frey, Mina Gaga, Peter Gibson, Qutayba Hamid, Nizar N. Jajour, Thais Mauad, Ronald L. Sorkness and W. Gerald Teague. Eur Respir J 2014; 43: 343-373.

    , Eur Respir J, Vol: 52
  • Journal article
    Barnes PJ, 2018,

    Targeting cytokines to treat asthma and chronic obstructive pulmonary disease

    , NATURE REVIEWS IMMUNOLOGY, Vol: 18, Pages: 454-466, ISSN: 1474-1733
  • Journal article
    Ellis T, Chiappi M, García-Trenco A, Al-Ejji M, Sarkar S, Georgiou TK, Shaffer MSP, Tetley TD, Schwander S, Ryan MP, Porter AEet al., 2018,

    Multimetallic microparticles increase the potency of rifampicin against intracellular mycobacterium tuberculosis

    , ACS Nano, Vol: 12, Pages: 5228-5240, ISSN: 1936-0851

    Mycobacterium tuberculosis ( M.tb) has the extraordinary ability to adapt to the administration of antibiotics through the development of resistance mechanisms. By rapidly exporting drugs from within the cytosol, these pathogenic bacteria diminish antibiotic potency and drive the presentation of drug-tolerant tuberculosis (TB). The membrane integrity of M.tb is pivotal in retaining these drug-resistant traits. Silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) are established antimicrobial agents that effectively compromise membrane stability, giving rise to increased bacterial permeability to antibiotics. In this work, biodegradable multimetallic microparticles (MMPs), containing Ag NPs and ZnO NPs, were developed for use in pulmonary delivery of antituberculous drugs to the endosomal system of M.tb-infected macrophages. Efficient uptake of MMPs by M.tb-infected THP1 cells was demonstrated using an in vitro macrophage infection model, with direct interaction between MMPs and M.tb visualized with the use of electron FIB-SEM tomography. The release of Ag NPs and ZnO NPs within the macrophage endosomal system increased the potency of the model antibiotic rifampicin by as much as 76%, realized through an increase in membrane disorder of intracellular M.tb. MMPs were effective at independently driving membrane destruction of extracellular bacilli located at the exterior face of THP1 macrophages. This MMP system presents as an effective drug delivery vehicle that could be used for the transport of antituberculous drugs such as rifampicin to infected alveolar macrophages, while increasing drug potency. By increasing M.tb membrane permeability, such a system may prove effectual in improving treatment of drug-susceptible TB in addition to M.tb strains considered drug-resistant.

  • Journal article
    Cowie MR, Gallagher AM, Simonds AK, 2018,

    The search for cardiovascular benefit from treating obstructive sleep apnoea with CPAP therapy

    , European Heart Journal, Vol: 39, Pages: 2298-2300, ISSN: 1522-9645
  • Journal article
    Martinez F, Han M, Allinson J, Barr G, Boucher R, Calverley PMA, Celli BR, Christenson SA, Crystal RG, Fageras M, Freeman CM, Groenke L, Hoffman EA, Kesimer M, Kostikas K, Paine III R, Rafii S, Rennard SI, Segal LN, Shaykhiev R, Stevenson C, Ruth T-S, Vestbo J, Woodruff P, Curtis J, Wedzicha Jet al., 2018,

    At the root: defining and halting progression of early chronic obstructive pulmonary disease

    , American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1540-1551, ISSN: 1073-449X

    Chronic obstructive pulmonary disease (COPD) is a prevalent, heterogeneous disorder with varying presentation and progression but with a limited number of disease-modifying therapies (1). This marked heterogeneity impedes identification of subpopulations at risk for accelerated progression, thwarting therapeutic advances. Most COPD studies have included populations with mean ages older than 60 years (2). However, it is increasingly evident that lung function trajectories in COPD differ significantly and that differences are detectable in young adulthood (3–5). In this Perspective, we highlight the need to distinguish “early disease” from late “mild disease,” propose an operational definition of early COPD for use in research studies, and attempt to unify current views on potential disease mechanisms. We focus on smoking, the chief etiologic factor for COPD in the industrialized world. Whether pathogenic mechanisms and effective treatments are shared with the sizable fraction of COPD in never-smokers or resulting from biomass fuel, electronic nicotine delivery systems, and other exposures, are separate, significant questions. We argue that refocusing investigation on early COPD could revolutionize understanding and therapies of this leading cause of worldwide death.

  • Journal article
    Singanayagam A, Glanville N, Girkin J, Ching YM, Marcellini A, Porter J, Toussaint M, Walton R, Finney L, Julia A, Zhu J, Trujillo-Torralbo M, Calderazzo M, Grainge C, Loo S-L, Veerati PC, Pathinayake P, Nichol K, Reid A, James P, Solari R, Wark P, Knight D, Moffatt M, Cookson W, Edwards M, Mallia P, Bartlett N, Johnston SLet al., 2018,

    Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.

  • Journal article
    Bhavsar PK, 2018,

    Role of humoral defense in severe asthma

    , American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1369-1371, ISSN: 1073-449X
  • Journal article
    Pereira M, Williams S, Restrick L, Cullinan P, Hopkinson NSet al., 2018,

    Response

    , Clinical Medicine, Vol: 18, Pages: 268-269, ISSN: 1470-2118
  • Conference paper
    Gallagher A, Simonds A, Cowie M, 2018,

    What is the prevalence of heart failure with preserved ejection fraction (HFPEF) in patients referred for sleep apnoea assessment?

    , Annual Conference of the British-Cardiovascular-Society on High Performing Teams, Publisher: BMJ Publishing Group, Pages: A38-A38, ISSN: 1355-6037
  • Journal article
    Pereira M, Williams S, Restrick L, Cullinan P, Hopkinson NSet al., 2018,

    Reponse to "Flu-related absence, a small proportion of all-causesickness absence"; Clin Med June 1, 2018 vol. 18 no. 3 268

    , Clinical Medicine, Vol: 18, Pages: 268-269, ISSN: 1470-2118
  • Journal article
    De Meulder B, Lefaudeux D, Bansal AT, Mazein A, Chaiboonchoe A, Ahmed H, Balaur I, Saqi M, Pellet J, Ballereau S, Lemonnier N, Sun K, Pandis I, Yang X, Batuwitage M, Kretsos K, van Eyll J, Bedding A, Davison T, Dodson P, Larminie C, Postle A, Corfield J, Djukanovic R, Chung KF, Adcock IM, Guo Y-K, Sterk PJ, Manta A, Rowe A, Baribaud F, Auffray C, U-BIOPRED Study Group and the eTRIKS Consortiumet al., 2018,

    A computational framework for complex disease stratification from multiple large-scale datasets

    , BMC Systems Biology, Vol: 12, ISSN: 1752-0509

    BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.

  • Journal article
    Meldrum K, Robertson SB, Roemer I, Marczylo T, Dean LSN, Rogers A, Gant TW, Smith R, Tetley TD, Leonard MOet al., 2018,

    Cerium dioxide nanoparticles exacerbate house dust mite induced type II airway inflammation

    , PARTICLE AND FIBRE TOXICOLOGY, Vol: 15, ISSN: 1743-8977

    BackgroundNanomaterial inhalation represents a potential hazard for respiratory conditions such as asthma. Cerium dioxide nanoparticles (CeO2NPs) have the ability to modify disease outcome but have not been investigated for their effect on models of asthma and inflammatory lung disease. The aim of this study was to examine the impact of CeO2NPs in a house dust mite (HDM) induced murine model of asthma.ResultsRepeated intranasal instillation of CeO2NPs in the presence of HDM caused the induction of a type II inflammatory response, characterised by increased bronchoalveolar lavage eosinophils, mast cells, total plasma IgE and goblet cell metaplasia. This was accompanied by increases in IL-4, CCL11 and MCPT1 gene expression together with increases in the mucin and inflammatory regulators CLCA1 and SLC26A4. CLCA1 and SLC26A4 were also induced by CeO2NPs + HDM co-exposure in air liquid interface cultures of human primary bronchial epithelial cells. HDM induced airway hyperresponsiveness and airway remodelling in mice were not altered with CeO2NPs co-exposure. Repeated HMD instillations followed by a single exposure to CeO2NPs failed to produce changes in type II inflammatory endpoints but did result in alterations in the neutrophil marker CD177. Treatment of mice with CeO2NPs in the absence of HDM did not have any significant effects. RNA-SEQ was used to explore early effects 24 h after single treatment exposures. Changes in SAA3 expression paralleled increased neutrophil BAL levels, while no changes in eosinophil or lymphocyte levels were observed. HDM resulted in a strong induction of type I interferon and IRF3 dependent gene expression, which was inhibited with CeO2NPs co-exposure. Changes in the expression of genes including CCL20, CXCL10, NLRC5, IRF7 and CLEC10A suggest regulation of dendritic cells, macrophage functionality and IRF3 modulation as key early events in how CeO2NPs may guide pulmonary responses to HDM towards type II inflammation.Conclusi

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