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  • Journal article
    Compte M, Lykke Harwood S, Munoz IG, Navarro R, Zonca M, Perez-Chacon G, Erce-Llamazares A, Merino N, Tapia-Galisteo A, Cuesta AM, Mikkelsen K, Caleiras E, Nunez-Prado N, Aznar MA, Lykkemark S, Martinez-Torrecuadrada J, Melero I, Blanco FJ, Bernardino de la Serna J, Zapata JM, Sanz L, Alvarez-Vallina Let al., 2018,

    A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

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

    The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.

  • Journal article
    Simonds AK, 2018,

    Happy ever after? A new assessment tool for long-term noninvasive ventilation: the S-3-NIV questionnaire

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 52, ISSN: 0903-1936
  • Journal article
    Buttery S, Kemp S, Shah P, Waller D, Jordan S, Lee JL, Banya W, Steiner M, Hopkinson Net al., 2018,

    The CELEB trial: Comparative effectiveness of lung volume reduction surgery for emphysema and bronchoscopic lung volume reduction with valve placement. A protocol for a randomised controlled trial

    , BMJ Open, Vol: 8, ISSN: 2044-6055

    Introduction: Although lung volume reduction surgery and bronchoscopic lung volume reduction with endobronchial valves have both been shown to improve lung function, exercise capacity and quality of life in appropriately selected patients with emphysema, there are no direct comparison data between the two procedures to inform clinical decision making. Methods and Analysis: We describe the protocol of the CELEB study (ISRCTN19684749), a randomised controlled trial which will compare outcomes at 1 year between the two procedures, using a composite disease severity measure, the iBODE score, which includes body mass index, lung function, breathlessness and exercise capacity.Ethics and Dissemination: Ethical approval to conduct the study has been obtained from the Fulham Research Ethics Committee, London (16/LO/0286). The outcome of this trial will provide information to guide treatment choices in this population and will be presented at national and international meetings and published in peer-reviewed journals. We will also disseminate the main results to all participants in a letter.

  • Journal article
    Wang Y, Xu J, Meng Y, Adcock IM, Yao Xet al., 2018,

    Role of inflammatory cells in airway remodeling in COPD

    , International Journal of Chronic Obstructive Pulmonary Disease, Vol: 13, Pages: 3341-3348, ISSN: 1176-9106

    COPD is characterized by chronic bronchitis, chronic airway obstruction, and emphysema, leading to a progressive and irreversible decline in lung function. Inflammation is central for the development of COPD. Chronic inflammation in COPD mainly involves the infiltration of neutrophils, macrophages, lymphocytes, and other inflammatory cells into the small airways. The contribution of resident airway structural cells to the inflammatory process is also important in COPD. Airway remodeling consists of detrimental changes in structural tissues and cells including airway wall thickening, epithelial metaplasia, goblet cell hypertrophy, and smooth muscle hyperplasia. Persistent airway inflammation might contribute to airway remodeling and small airway obstruction. However, the underlying mechanisms remain unclear. In this review, we will provide an overview of recent insights into the role of major immunoinflammatory cells in COPD airway remodeling.

  • Conference paper
    Meldrum K, Robertson SB, Gant TW, Tetley TD, Smith R, Leonard MOet al., 2018,

    Transcriptional changes underlying cerium dioxide nanoparticle modulation of allergen induced type II airway inflammation

    , 54th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology Out of the Box, Publisher: ELSEVIER IRELAND LTD, Pages: S213-S213, ISSN: 0378-4274
  • Journal article
    Allinson JP, Hardy R, Donaldson GC, Wedzicha JAet al., 2018,

    Childhood exposures, asthma, smoking, interactions and the catch-up hypothesis

    , Annals of the American Thoracic Society, Vol: 15, Pages: 1241-1242, ISSN: 2329-6933
  • Journal article
    Visca D, Mori L, Tsipouri V, Fleming S, Firouzi A, Bonini M, Pavitt MJ, Alfieri V, Canu S, Bonifazi M, Boccabella C, De Lauretis A, Stock CJW, Saunders P, Montgomery A, Hogben C, Stockford A, Pittet M, Brown J, Chua F, George PM, Molyneaux PL, Margaritopoulos GA, Kokosi M, Kouranos V, Russell AM, Birring SS, Chetta A, Maher TM, Cullinan P, Hopkinson NS, Banya W, Whitty JA, Adamali H, Spencer LG, Farquhar M, Sestini P, Wells AU, Renzoni EAet al., 2018,

    Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial

    , Lancet Respiratory Medicine, Vol: 6, Pages: 759-770, ISSN: 2213-2600

    BACKGROUND: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was ass

  • Journal article
    Hoffmann C, Hanisch M, Heinsohn JAB, Dostal V, Jehn M, Liebers U, Pankow W, Donaldson GC, Witt Cet al., 2018,

    Increased vulnerability of COPD patient groups to urban climate in view of global warming

    , International Journal of Chronic Obstructive Pulmonary Disease, Vol: 13, Pages: 3493-3501, ISSN: 1176-9106

    Purpose: Patients with COPD show an increase in acute exacerbations (AECOPD) during the cold season as well as during heat waves in the summer months. Due to global climate changes, extreme weather conditions are likely to occur more frequently in the future. The goal of this study was to identify patient groups most at risk of exacerbations during the four seasons of the year and to determine at which temperature threshold the daily hospital admissions due to AECOPD increase during the summer.Patients and methods: We analyzed retrospective demographic and medical data of 990 patients, who were hospitalized for AECOPD in Berlin, Germany. The cases were grouped into the following cohorts: “spring” (admission between March and May), “summer” (June – August), “autumn” (September – November), and “winter” (December – February). AECOPD hospital admissions from 2006 and 2010 were grouped into a “hot summer” cohort and cases from 2011 and 2012 into a “cold summer” data-set. Climate data were obtained from the German Meteorological Office.Results: Patients hospitalized for a COPD exacerbation during winter were significantly older than summertime patients (P=0.040) and also thinner than patients exacerbating in spring (P=0.042). COPD exacerbations during hot summer periods happened more often to patients with a history of myocardial infarction (P=0.014) or active smokers (P=0.011). An AECOPD during colder summers occurred in patients with a higher Charlson index, who suffered in increased numbers from peripheral vascular diseases (P=0.016) or tumors (P=0.004). Summertime hospital admissions increased above a daily minimum temperature of 18.3°C (P=0.006).Conclusion: The identification of COPD patient groups most at risk for climate related exacerbations enables climate-adapted prevention through patient guidance and treatment. In view of global climate changes, discovering vulnerabi

  • Journal article
    Moroni-Zentgraf P, Usmani OS, Halpin DMG, 2018,

    Inhalation devices

    , Canadian Respiratory Journal, Vol: 2018, ISSN: 1198-2241
  • Journal article
    Belchamber KBR, Thomas C, Dunne A, Barnes P, Donnelly Let al., 2018,

    Comparison of fluticasone propionate and budesonide on COPD macrophage and neutrophil function

    , International Journal of COPD, Vol: 2018, Pages: 2883-2897, ISSN: 1176-9106

    Background: Inhaled corticosteroid (ICS) use is associated with increased rates of pneumonia in COPD patients. The underlying mechanism is unknown although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide. Macrophages and neutrophils from COPD patients are deficient in clearing bacteria and this might explain increased bacterial colonisation in COPD. ICS may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDM) and neutrophils.Methods: MDM from COPD patients (n=20-24) were pre-incubated with FP or budesonide for 1 or 18 h after which phagocytosis of fluorescently labelled inert beads or heat-killed Haemophilus influenzae or Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 h. Additionally, the following was measured: CXCL-8, IL-6 and TNFα concentrations in supernatants by ELISA, MDM scavenger receptor expression by flow cytometry, and the MDM ability to kill bacteria. Neutrophils from COPD patients (n=8) were pre-incubated with corticosteroids for 1 h, and phagocytosis of bacteria was measured by flow cytometry. Results: After 1 h pre-incubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10-7M) increased phagocytosis of S. pneumoniae by 23% (P<0.05). After 18 h pre-incubation, neither corticosteroid altered MDM phagocytosis of any prey, although phagocytosis of H. influenzae by budesonide was significantly greater compared to FP at 10-6 and 10-5M (P<0.05). The 1 h pre-incubation with either corticosteroid inhibited bacteria-induced CXCL-8 release (at 10-7 and 10-5M, P<0.05); however, this effect was lost at 18 h pre-incubation. There was no change in receptor expression, bacterial killing or neutrophil phagocytosis by either corticosteroid. Conclusions: These data suggest that dissolved FP an

  • Conference paper
    Garner J, Soni S, O'Dea K, Srikanthan K, Tenda E, Aboelhassan A, Singh S, Kemp SV, Wilson MR, Usmani OS, Shah PL, Takata Met al., 2018,

    Late Breaking Abstract - Intra-alveolar neutrophil-derived microvesicles: a biomarker of COPD severity

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Bolaji JA, Adcock JJ, Sandstrom T, Mudway I, Bloomberg A, Bosson J, Tetley TD, Birrell MA, Belvisi MGet al., 2018,

    Biodiesel: is it any safer to use?

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Price L, Kempny A, Mccabe C, Dimopoulos K, Kotecha J, Harries C, Barbosa J, Hopkinson N, Simonds A, Wells A, Wort Jet al., 2018,

    Sildenafil in Patients with Severe Group 3 Pulmonary Hypertension

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Wortley M, Bonvini SJ, Flajolet PLM, Belvisi MG, Birrell MAet al., 2018,

    The anti-tussive effects of an inhaled LABA are maintained after chronic treatment

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Finney L, Belchamber K, Fenwick P, Kemp S, Johnston S, Donnelly L, Wedzicha Jet al., 2018,

    Human rhinovirus impairs macrophage innate immune responses to bacteria via the interferon pathway in COPD

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Chen X, Bonvini SJ, Dubuis E, Birrell MA, Belvisi MGet al., 2018,

    Characterisation of TRPA1 activation on sensory nerves

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Journal article
    Bewley M, Budd R, Ryan E, Cole J, Collini P, Marshall J, Kolsum U, Beech G, Emes R, Tcherniaeva I, Berbers G, Walmsley S, Donaldson G, Wedzicha J, Kilty I, Rumsey W, Sanchez Y, Brightling C, Donnelly LE, Barnes P, Singh D, Whyte M, Dockrell Det al., 2018,

    Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 739-750, ISSN: 1073-449X

    Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AM) in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms and clinical consequences remain incompletely defined.Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences and potential for therapeutic manipulation of these defects.Methods: We isolated alveolar macrophages (AM) and monocyte-derived macrophages (MDM) from a cohort of COPD patients and controls within the MRC COPD-MAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.Measurements and Main Results: COPD AM and MDM have impaired phagocytosis of S. pneumoniae. COPD AM have a selective defect in uptake of opsonized bacteria, despite the presence of anti-pneumococcal antibodies in bronchoalveolar lavage, not observed in MDM or healthy donor’s AM. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria and health related quality of life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AM was not reduced. COPD AM have reduced transcriptional responses to opsonized bacteria, including cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2-regualted genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and Compound 7) reverse defects in phagocytosis of S. pneumoniae and non-type able Haemophilus influenzae by COPD AM. Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AM, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.

  • Journal article
    Mackay AJ, Kostikas K, Murray L, Martinez FJ, Miravitlles M, Donaldson G, Banerji D, Patalano F, Wedzicha JAet al., 2018,

    Patient reported outcomes for the detection, quantification and evaluation of chronic obstructive pulmonary disease exacerbations

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 730-738, ISSN: 1073-449X

    An exacerbation of Chronic Obstructive Pulmonary Disease (COPD) is an acute worsening of respiratory symptoms, accompanied by a variable degree of physiological deterioration. The traditional assessment of an exacerbation consists of the reporting of symptoms directly by the patient to a clinician and subsequent clinical assessment. It would be valuable to also gather symptom reports directly from patients and thus patient-reported outcome (PRO) tools should be ideally suited to the evaluation of COPD exacerbations. However, most pharmaceutical and large academic-sponsored studies have used a healthcare resource utilization definition alone based on sustained worsening of a patient's condition from the stable state that requires a change in regular medication. This review explores the use of PROs for the detection, quantification, and evaluation of COPD exacerbations. It examines symptom diary cards as exacerbation detection tools and their evolution into electronic diaries used in pharmaceutical trials. This paper also describes the development of specifically designed PROs that have been used in exacerbation settings, focusing on the Exacerbations and Symptoms in COPD (ESCO) e-Diary, EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT®), COPD Assessment Test™ (CAT) and Chronic Respiratory Disease Questionnaire (CRQ), highlighting the strengths and weaknesses of these instruments. We describe the effectiveness of these tools to enhance exacerbation reporting, quantify exacerbation characteristics, including the frequency, duration, and severity of events, and evaluate the outcome. We also explore the potential use of PROs in future studies to discriminate the effect of therapies on different exacerbation phenotypes and thus enhance personalized therapeutic approaches.

  • Journal article
    Morrell MJ, 2018,

    Controlling for Obesity in OSA: Results from Dynamic MR Imaging.

    , Am J Respir Crit Care Med
  • 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

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