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Journal articleGutowska-Owsiak D, Bernardino de la Serna J, Fritzsche M, et al., 2018,
Orchestrated control of filaggrin-actin scaffolds underpins cornification
, Cell Death and Disease, Vol: 9, ISSN: 2041-4889Epidermal stratification critically depends on keratinocyte differentiation and programmed death by cornification, leading to formation of a protective skin barrier. Cornification is dynamically controlled by the protein filaggrin, rapidly released from keratohyalin granules (KHGs). However, the mechanisms of cornification largely remain elusive, partly due to limitations of the observation techniques employed to study filaggrin organization in keratinocytes. Moreover, while the abundance of keratins within KHGs has been well described, it is not clear whether actin also contributes to their formation or fate. We employed advanced (super-resolution) microscopy to examine filaggrin organization and dynamics in skin and human keratinocytes during differentiation. We found that filaggrin organization depends on the cytoplasmic actin cytoskeleton, including the role for α- and β-actin scaffolds. Filaggrin-containing KHGs displayed high mobility and migrated toward the nucleus during differentiation. Pharmacological disruption targeting actin networks resulted in granule disintegration and accelerated cornification. We identified the role of AKT serine/threonine kinase 1 (AKT1), which controls binding preference and function of heat shock protein B1 (HspB1), facilitating the switch from actin stabilization to filaggrin processing. Our results suggest an extended model of cornification in which filaggrin utilizes actins to effectively control keratinocyte differentiation and death, promoting epidermal stratification and formation of a fully functional skin barrier.
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Journal articleAndersson C, Bonvini SJ, Horvath P, et al., 2018,
Research highlights from the 2017 ERS International Congress: airway diseases in focus
, ERJ Open Research, Vol: 4, ISSN: 2312-0541For another year, high-quality research studies from around the world transformed the annual ERS International Congress into a vivid platform to discuss trending research topics, to produce new research questions and to further push the boundaries of respiratory medicine and science. This article reviews only some of the high-quality research studies on asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and chronic cough that were presented during the congress through the Airway Diseases Assembly (ERS Assembly 5) and places them into the context of current knowledge and research challenges.
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Journal articleYanagisawa S, Baker JR, Vuppusetty C, et al., 2018,
The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure
, PLoS ONE, Vol: 13, ISSN: 1932-6203SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.
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Journal articleSantos AM, Ponjavic A, Fritzsche M, et al., 2018,
Capturing resting T cells: the perils of PLL
, Nature Immunology, Vol: 19, Pages: 203-205, ISSN: 1529-2908 -
Journal articleCowie MR, Woehrle H, Wegscheider K, et al., 2018,
Adaptive servo-ventilation for central sleep apnoea in systolic heart failure: results of the major substudy of SERVE-HF
, European Journal of Heart Failure, Vol: 20, Pages: 536-544, ISSN: 1388-9842AIMS: The SERVE-HF trial investigated the impact of treating central sleep apnoea (CSA) with adaptive servo-ventilation (ASV) in patients with systolic heart failure. A preplanned substudy was conducted to provide insight into mechanistic changes underlying the observed effects of ASV, including assessment of changes in left ventricular function, ventricular remodelling, and cardiac, renal and inflammatory biomarkers. METHODS AND RESULTS: In a subset of the 1325 randomised patients, echocardiography, cardiac magnetic resonance imaging (cMRI) and biomarker analysis were performed at baseline, and 3 and 12 months. In secondary analyses, data for patients with baseline and 12-month values were evaluated; 312 patients participated in the substudy. The primary endpoint, change in echocardiographically determined left ventricular ejection fraction from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between-group differences for changes in left ventricular dimensions, wall thickness, diastolic function or right ventricular dimensions and ejection fraction (echocardiography), and on cMRI (in small patient numbers). Plasma N-terminal pro B-type natriuretic peptide concentration decreased in both groups, and values were similar at 12 months. There were no significant between-group differences in changes in cardiac, renal and systemic inflammation biomarkers. CONCLUSION: In patients with systolic heart failure and CSA, addition of ASV to guideline-based medical management had no statistically significant effect on cardiac structure and function, or on cardiac biomarkers, renal function and systemic inflammation over 12 months. The increased cardiovascular mortality reported in SERVE-HF may not be related to adverse remodelling or worsening heart failure.
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Journal articlePolsek D, Gildeh N, Cash D, et al., 2018,
Obstructive sleep apnoea and Alzheimer's disease: in search of shared pathomechanisms
, Neuroscience and Biobehavioral Reviews, Vol: 86, Pages: 142-149, ISSN: 0149-7634Alzheimer’s disease (AD) is a significant public health concern. The incidence continues to rise, and it is set to be over one million in the UK by 2025. The processes involved in the pathogenesis of AD have been shown to overlap with those found in cognitive decline in patients with Obstructive Sleep Apnoea (OSA). Currently, the standard treatment for OSA is Continuous Positive Airway Pressure. Adherence to treatment can, however, be an issue, especially in patients with dementia. Also, not all patients respond adequately, necessitating the use of additional treatments. Based on the body of data, we here suggest that excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA in the absence of appropriately structured sleep. Further, we argue that external factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain, and further promote disease progression. If this hypothesis is proven in future studies, it could have far-reaching clinical translational implications, as well as implications for future treatment strategies in OSA.
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Journal articleMoskwa S, Piotrowski W, Marczak J, et al., 2018,
Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients
, ALLERGY ASTHMA & IMMUNOLOGY RESEARCH, Vol: 10, Pages: 144-154, ISSN: 2092-7355PurposeIn order to gain an insight into determinants of reported variability in immune responses to respiratory viruses in human bronchial epithelial cells (HBECs) from asthmatics, the responses of HBEC to viral infections were evaluated in HBECs from phenotypically heterogeneous groups of asthmatics and in healthy controls.MethodsHBECs were obtained during bronchoscopy from 10 patients with asthma (6 atopic and 4 non-atopic) and from healthy controls (n=9) and grown as undifferentiated cultures. HBECs were infected with parainfluenza virus (PIV)-3 (MOI 0.1) and rhinovirus (RV)-1B (MOI 0.1), or treated with medium alone. The cell supernatants were harvested at 8, 24, and 48 hours. IFN-α, CXCL10 (IP-10), and RANTES (CCL5) were analyzed by using Cytometric Bead Array (CBA), and interferon (IFN)-β and IFN-λ1 by ELISA. Gene expression of IFNs, chemokines, and IFN-regulatory factors (IRF-3 and IRF-7) was determined by using quantitative PCR.ResultsPIV3 and RV1B infections increased IFN-λ1 mRNA expression in HBECs from asthmatics and healthy controls to a similar extent, and virus-induced IFN-λ1 expression correlated positively with IRF-7 expression. Following PIV3 infection, IP-10 protein release and mRNA expression were significantly higher in asthmatics compared to healthy controls (median 36.03-fold). No differences in the release or expression of RANTES, IFN-λ1 protein and mRNA, or IFN-α and IFN-β mRNA between asthmatics and healthy controls were observed. However, when asthmatics were divided according to their atopic status, HBECs from atopic asthmatics (n=6) generated significantly more IFN-λ1 protein and demonstrated higher IFN-α, IFN-β, and IRF-7 mRNA expressions in response to PIV3 compared to non-atopic asthmatics (n=4) and healthy controls (n=9). In response to RV1B infection, IFN-β mRNA expression was lower (12.39-fold at 24 hours and 19.37-fold at 48 hours) in non-atopic asthmatics com
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Journal articleFinkel RS, Mercuri E, Meyer OH, et al., 2018,
Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics
, NEUROMUSCULAR DISORDERS, Vol: 28, Pages: 197-207, ISSN: 0960-8966- Author Web Link
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- Citations: 303
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Conference paperWrench C, Belchamber K, Bercusson A, et al., 2018,
Reduced Clearance of Fungal Spores by Chronic Obstructive Pulmonary Disease GM-CSF- and M-CSF-derived Macrophages
, Publisher: American Thoracic Society, Pages: 271-273, ISSN: 1044-1549 -
Journal articleMercuri E, Finkel RS, Muntoni F, et al., 2018,
Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care
, NEUROMUSCULAR DISORDERS, Vol: 28, Pages: 103-115, ISSN: 0960-8966- Author Web Link
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- Citations: 440
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Journal articleDelgado-Eckert E, Fuchs O, Kumar N, et al., 2018,
Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants
, THORAX, Vol: 73, Pages: 107-115, ISSN: 0040-6376- Author Web Link
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- Citations: 15
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Journal articleSinharay R, Gong J, Barratt B, et al., 2018,
Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants older than 60 years with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study (vol 391, pg 339, 2017)
, LANCET, Vol: 391, Pages: 308-308, ISSN: 0140-6736- Author Web Link
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- Citations: 1
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Journal articleLiu S, Grigoryan H, Edmands WMB, et al., 2018,
Cys34 Adductomes Differ between Patients with Chronic Lung or Heart Disease and Healthy Controls in Central London
, Environmental Science and Technology (Washington), Vol: 52, Pages: 2307-2313, ISSN: 0013-936XOxidative stress generates reactive species that modify proteins, deplete antioxidant defenses, and contribute to chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD). To determine whether protein modifications differ between COPD or IHD patients and healthy subjects, we performed untargeted analysis of adducts at the Cys34 locus of human serum albumin (HSA). Biospecimens were obtained from nonsmoking participants from London, U.K., including healthy subjects (n = 20) and patients with COPD (n = 20) or IHD (n = 10). Serum samples were digested with trypsin and analyzed by liquid chromatography-high resolution mass spectrometry. Effects of air pollution on adduct levels were also investigated based on estimated residential exposures to PM2.5, O3 and NO2. For the 39 adducts with sufficient data, levels were essentially identical in blood samples collected from the same subjects on two consecutive days, consistent with the 28 day residence time of HSA. Multivariate linear regression revealed 21 significant associations, mainly with the underlying diseases but also with air-pollution exposures (p-value < 0.05). Interestingly, most of the associations indicated that adduct levels decreased with the presence of disease or increased pollutant concentrations. Negative associations of COPD and IHD with the Cys34 disulfide of glutathione and two Cys34 sulfoxidations, were consistent with previous results from smoking and nonsmoking volunteers and nonsmoking women exposed to indoor combustion of coal and wood.
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Journal articleUsmani OS, Lavorini F, Marshall J, et al., 2018,
Critical inhaler errors in asthma and COPD: a systematic review of impact on health outcomes
, Respiratory Research, Vol: 19, ISSN: 1465-9921Background:Inhaled drug delivery is the cornerstone treatment for asthma and chronic obstructive pulmonary disease (COPD). However, use of inhaler devices can be challenging, potentially leading to critical errors in handling that can significantly reduce drug delivery to the lungs and effectiveness of treatment.Methods:A systematic review was conducted to define ‘critical’ errors and their impact on health outcomes and resource use between 2004 and 2016, using key search terms for inhaler errors in asthma and COPD (Search-1) and associated health-economic and patient burden (Search-2).Results:Search-1 identified 62 manuscripts, 47 abstracts, and 5 conference proceedings (n = 114 total). Search-2 identified 9 studies. We observed 299 descriptions of critical error. Age, education status, previous inhaler instruction, comorbidities and socioeconomic status were associated with worse handling error frequency. A significant association was found between inhaler errors and poor disease outcomes (exacerbations), and greater health-economic burden.Conclusions:We have shown wide variations in how critical errors are defined, and the evidence shows an important association between inhaler errors and worsened health outcomes. Given the negative impact diminished disease outcomes impose on resource use, our findings highlight the importance of achieving optimal inhaler technique, and a need for a consensus on defining critical and non-critical errors.
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Journal articleSimonds AK, 2018,
Influenza news from the frontline: what's happening?
, ERJ OPEN RESEARCH, Vol: 4 -
Journal articleRitchie AI, Singanayagam A, Wiater E, et al., 2018,
beta(2)-agonists enhance asthma-relevant inflammatory mediators in human airway epithelial cells
, American Journal of Respiratory Cell and Molecular Biology, Vol: 58, Pages: 128-132, ISSN: 1044-1549 -
Journal articleMalhotra A, Morrell MJ, Eastwood PR, 2018,
Update in respiratory sleep disorders: Epilogue to a modern review series
, RESPIROLOGY, Vol: 23, Pages: 16-17, ISSN: 1323-7799- Author Web Link
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- Citations: 4
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Conference paperSinharay R, Mithra S, Patel P, et al., 2018,
EGFR mutation specific immunohistochemistry revolutionises time to treatment with tyrosine kinase inhibitors (TKIs)
, Publisher: ELSEVIER IRELAND LTD, Pages: S24-S24, ISSN: 0169-5002 -
Conference paperMa J, Bonvini SJ, Dubuis E, et al., 2018,
Investigation into the Mechanisms Driving Hypo-Osmotic Stress-Triggered Activation of Airway Sensory Nerves
, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Conference paperBolaji J, Bonvini SJ, Adcock JJ, et al., 2018,
Cleaning Agent Surfactant, 4-Octylphenol, Activates Airway Sensory Nerves and Triggers Respiratory Symptoms: Role in Occupational Asthma?
, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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