279 results found
Willis-Owen S, Domingo Sabugo C, Starren E, et al., 2021, Y disruption, autosomal hypomethylation and poor male lung cancer survival, Scientific Reports, Vol: 11, ISSN: 2045-2322
Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA–IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40–10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4–2.0, P = 1.2 × 10–10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.
Cuthbertson L, Felton I, James P, et al., 2021, The fungal airway microbiome in cystic fibrosis and non-cystic fibrosis bronchiectasis, Journal of Cystic Fibrosis, Vol: 20, Pages: 295-302, ISSN: 1569-1993
BackgroundThe prevalence of fungal disease in cystic fibrosis (CF) and non-CF bronchiectasis is increasing and the clinical spectrum is widening. Poor sensitivity and a lack of standard diagnostic criteria renders interpretation of culture results challenging. In order to develop effective management strategies, a more accurate and comprehensive understanding of the airways fungal microbiome is required. The study aimed to use DNA sequences from sputum to assess the load and diversity of fungi in adults with CF and non-CF bronchiectasis.MethodsNext generation sequencing of the ITS2 region was used to examine fungal community composition (n = 176) by disease and underlying clinical subgroups including allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, non-tuberculous mycobacteria, and fungal bronchitis. Patients with no known active fungal disease were included as disease controls.ResultsITS2 sequencing greatly increased the detection of fungi from sputum. In patients with CF fungal diversity was lower, while burden was higher than those with non-CF bronchiectasis. The most common operational taxonomic unit (OTU) in patients with CF was Candida parapsilosis (20.4%), whereas in non-CF bronchiectasis sputum Candida albicans (21.8%) was most common. CF patients with overt fungal bronchitis were dominated by Aspergillus spp., Exophiala spp., Candida parapsilosis or Scedosporium spp.ConclusionThis study provides a framework to more accurately characterize the extended spectrum of fungal airways diseases in adult suppurative lung diseases.
Feng Y-CA, Guo Y, Pain L, et al., 2020, Estimating cell-type-specific DNA methylation effects in heterogeneous cellular populations, EPIGENOMICS, Vol: 13, Pages: 87-97, ISSN: 1750-1911
Habibi M, Thwaites R, Chang M, et al., 2020, Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection, Science, Vol: 370, Pages: 1-15, ISSN: 0036-8075
INTRODUCTIONEven with intimate exposure to a virus, some people fail to become infected. Variable transmission partly depends on the dose and duration of exposure but is also governed by the immune status of the host, such as the presence of specific protective antibodies or T cells. However, for some infections, the reasons for erratic transmission are largely unknown. For example, respiratory syncytial virus (RSV) can repeatedly reinfect individuals throughout their lives despite the presence of specific immunity. Additionally, antibodies and T cells have limited efficacy against newly emergent pathogens with pandemic potential. However, the intrinsic and innate mechanisms underlying protection when people are exposed to these viruses are poorly understood.RATIONALEWe reasoned that the prior state of the respiratory mucosa’s innate defenses may contribute to the variable outcome of RSV inoculation. By performing experimental challenge of adult volunteers, we were able to measure variations in the status of the nasal mucosa before inoculation and in mucosal responses during the presymptomatic phase of infection. Neither of these phases is easily observable during natural spontaneous transmission. Our observations could then be validated using specific interventional studies in a well-established mouse model of RSV infection.RESULTSAfter nasal administration of RSV, 57% of inoculated volunteers became infected. The uptake of infection was poorly explained by specific B or T cell immunity. However, transcriptomic profiling of the nasal tissue before inoculation demonstrated a neutrophilic inflammatory signal in those destined to develop symptomatic infection, and this was associated with suppression of an early interleukin-17 (IL-17)–dominated immune response during the presymptomatic period. This was followed by symptomatic infection associated with the expression of proinflammatory cytokines. By contrast, those who resisted infection showed a transient
Zhang YZ, Brambilla C, Molyneaux PL, et al., 2020, Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade, Histopathology, Vol: 77, Pages: 423-436, ISSN: 0309-0167
AIMS: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (1) externally validate the prognostic role of pleomorphic features in E-MPM and (2) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. METHODS AND RESULTS: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared those without (5.4 months vs 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 months vs. 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. CONCLUSIONS: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.
Cookson WOCM, Moffatt MF, 2020, In the Wrong Place at the Wrong Time: Microbial Misplacement and Acute Respiratory Distress Syndrome, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 201, Pages: 506-507, ISSN: 1073-449X
Zhang YZ, Brambilla C, Molyneaux PL, et al., 2020, Utility of nuclear grading system in epithelioid malignant pleural mesothelioma in biopsy-heavy setting, The American Journal of Surgical Pathology, Vol: 44, Pages: 347-356, ISSN: 0147-5185
Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P<0.001 except 2-tier nuclear grade, P=0.001). In the scenario of a single- site biopsy with tissue dimension ≤10 mm, none but age (P=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum tissue dimension of at least 20 mm from a single site is optimal for nuclear grade assessment. In conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy cohort provided the tissue sample met minimum dimensional criteria.
Groves HT, Higham SL, Moffatt MF, et al., 2020, Respiratory viral infection alters the gut microbiota by inducing inappetence, mBio, Vol: 11, ISSN: 2150-7511
Respiratory viral infections are extremely common, but their impacts on the composition and function of the gut microbiota are poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here, we show that weight loss during respiratory syncytial virus (RSV) or influenza virus infection was due to decreased food consumption, and that the fasting of mice altered gut microbiota composition independently of infection. While the acute phase tumor necrosis factor alpha (TNF-α) response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, the depletion of CD8+ cells increased food intake and prevented weight loss, resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the fecal gut metabolome, with a significant shift in lipid metabolism. Sphingolipids, polyunsaturated fatty acids (PUFAs), and the short-chain fatty acid (SCFA) valerate were all increased in abundance in the fecal metabolome following RSV infection. Whether this and the impact of infection-induced anorexia on the gut microbiota are part of a protective anti-inflammatory response during respiratory viral infections remains to be determined.
Zhu Z, Guo Y, Shi H, et al., 2020, Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 145, Pages: 537-549, ISSN: 0091-6749
Hoang LT, Domingo-Sabugo C, Starren ES, et al., 2019, Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non-small-cell lung cancer, Molecular Oncology, Vol: 13, Pages: 2406-2421, ISSN: 1574-7891
Lung cancer is the leading cause of cancer‐related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non‐small‐cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5‐year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesized that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate in promoting cancer metastasis through platelet activation and angiogenesis suggest this metabolite could be a potential therapeutic target.
Cuthbertson L, Oo SWC, Cox MJ, et al., 2019, Viral respiratory infections and the oropharyngeal bacterial microbiota in acutely wheezing children, PLOS ONE, Vol: 14, ISSN: 1932-6203
Domingo-Sabugo C, Starren E, Mandal A, et al., 2019, Comprehensive Molecular Profiling and Comparison of Common and Rarer Subtypes of Lung Cancer, Publisher: ELSEVIER SCIENCE INC, Pages: S686-S686, ISSN: 1556-0864
Januszewski A, Zhang YZ, Brambilla C, et al., 2019, Correlation of Mutations in TP53, CDKN2A and PIK3CA with VISTA Expression in Pleomorphic Lung Carcinoma, Publisher: ELSEVIER SCIENCE INC, Pages: S465-S466, ISSN: 1556-0864
Nastase A, Mandal A, Lu SK, et al., 2019, Low Number of Mutations and Frequent Co-Deletions of CDKN2A and IFN Type I Characterize Malignant Pleural Mesothelioma, Publisher: ELSEVIER SCIENCE INC, Pages: S345-S345, ISSN: 1556-0864
Mandal A, Nastase A, Lu SK, et al., 2019, Analysis of Immune Phenotype Composition in Malignant Pleural Mesothelioma (MPM) Using Bulk RNA Sequencing, Publisher: ELSEVIER SCIENCE INC, Pages: S345-S346, ISSN: 1556-0864
Zhang YZ, Brambilla C, Rice A, et al., 2019, WDPM-Like but Not Cribriform as Secondary Growth Patterns Modify Survival in Epithelioid Malignant Pleural Mesothelioma, Publisher: ELSEVIER SCIENCE INC, Pages: S480-S481, ISSN: 1556-0864
Zhang YZ, Brambilla C, Rice A, et al., 2019, Growth Patterns in Epithelioid Malignant Pleural Mesothelioma: A Clinicopathological Review of 614 Cases Over 15 Years, Publisher: ELSEVIER SCIENCE INC, Pages: S295-S296, ISSN: 1556-0864
Hoang L, Domingo-Sabugo C, Starren E, et al., 2019, Integrative Omics Analysis Reveals Important Roles of Adenosine Diphosphate in Haemostasis and Platelet Activation in NSCLC, Publisher: ELSEVIER SCIENCE INC, Pages: S419-S419, ISSN: 1556-0864
Sugier P-E, Sarnowski C, Granell R, et al., 2019, Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood, Clinical and Experimental Allergy, Vol: 49, Pages: 1342-1351, ISSN: 0954-7894
BACKGROUND: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. OBJECTIVE: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. METHODS: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totaling 8,273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analyzed. RESULTS: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P=4.3x10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P<5x10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P=4.9x10-7 ), 14q22 (rs7493885 near NIN; P=2.9x10-6 ) and 2p22 (rs232542 near CYP1B1; P=4.1x10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. CONCLUSION AND CLINICAL RELEVANCE: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms. This article is protected by copyright. All rights reserved.
Singanayagam A, Glanville N, Cuthbertson L, et al., 2019, Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease, Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234
Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.
Wilkinson S, Hodgson U, Honti F, et al., 2019, The application of targeted sequencing and whole exome analysis to identify disease-causing variants in familial pulmonary fibrosis, 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Publisher: NATURE PUBLISHING GROUP, Pages: 83-84, ISSN: 1018-4813
Ciano M, Mantellato G, Connolly M, et al., 2019, EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype, Scientific Reports, Vol: 9, ISSN: 2045-2322
A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.
Groves H, Higham S, Moffatt M, et al., 2019, Respiratory viral infection alters the gut microbiota by inducing inappetence, Publisher: bioRxiv
Abstract The gut microbiota has an important role in health and disease. Respiratory viral infections are extremely common but their impact on the composition and function of the gut microbiota is poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here we show that weight loss during Respiratory Syncytial Virus (RSV) or influenza virus infection was due to decreased food consumption, and that fasting mice independently of infection altered gut microbiota composition. While the acute phase TNF-α response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, depleting CD8 + cells increased food intake and prevented weight loss resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the faecal gut metabolome during RSV infection, with a significant shift in lipid metabolism. Sphingolipids, poly-unsaturated fatty acids (PUFAs) and the short-chain fatty acid (SCFA) valerate all increased in abundance in the faecal metabolome following RSV infection. Whether this, and the impact of infection-induced anorexia on the gut microbiota, are part of a protective, anti-inflammatory response during respiratory viral infections remains to be determined.
Januszewski A, Zhang YZ, Chang W-C, et al., 2019, Impact of MET variants on PD-L1 expression in pleomorphic lung carcinoma, European Lung Cancer Congress (ELCC), Publisher: OXFORD UNIV PRESS, Pages: 1-1, ISSN: 0923-7534
Ahmed B, Cox M, Cuthbertson L, et al., 2019, Longitudinal development of the airway microbiota in infants with cystic fibrosis, Scientific Reports, Vol: 9, ISSN: 2045-2322
The pathogenesis of airway infection in cystic fibrosis (CF) is poorly understood. We performed a longitudinal study coupling clinical information with frequent sampling of the microbiota to identify changes in the airway microbiota in infancy that could underpin deterioration and potentially be targeted therapeutically. Thirty infants with CF diagnosed on newborn screening (NBS) were followed for up to two years. Two hundred and forty one throat swabs were collected as a surrogate for lower airway microbiota (median 35 days between study visits) in the largest longitudinal study of the CF oropharyngeal microbiota. Quantitative PCR and Illumina sequencing of the 16S rRNA bacterial gene were performed. Data analyses were conducted in QIIME and Phyloseq in R. Streptococcus spp. and Haemophilus spp. were the most common genera (55% and 12.5% of reads respectively) and were inversely related. Only beta (between sample) diversity changed with age (Bray Curtis r2 = 0.15, P = 0.03). Staphylococcus and Pseudomonas were rarely detected. These results suggest that Streptococcus spp. and Haemophilus spp., may play an important role in early CF. Whether they are protective against infection with more typical CF micro-organisms, or pathogenic and thus meriting treatment needs to be determined.
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Normal airway microbial communities play a central role in respiratory health but are poorly characterized. Cigarette smoking is the dominant global environmental influence on lung function, and asthma has become the most prevalent chronic respiratory disease worldwide. Both conditions have major microbial components that are also poorly defined.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We investigated airway bacterial communities in a general population sample of 529 Australian adults. Posterior oropharyngeal swabs were analysed by sequencing of the 16S rRNA and methionine aminopeptidase genes. The microbiota were characterised according to their prevalence, abundance, and network memberships.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Microbial communities were similar across the population and were strongly organized into co-abundance networks. Smoking associated with diversity loss, negative effects on abundant taxa, profound alterations to network structure and expansion of <jats:italic>Streptococcus</jats:italic> spp. By contrast, the asthmatic microbiota were selectively affected by an increase in <jats:italic>Neisseria</jats:italic> spp. and by reduced numbers of low abundance but prevalent organisms.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Our study shows healthy airway microbiota are contained within a highly structured ecosystem, indicating balanced relationships between the microbiome and human host factors. The marked abnormalities in smokers may be pathogenic for chronic obstructive pulmonary disease (COPD) and lung cancer. The narrow spectrum of abnormalities in asthmatics encourages investigation of damaging and
Dunning J, Blankley S, Hoang LT, et al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908
In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.
Wootton DG, Cox MJ, Gloor GB, et al., 2019, A haemophilus sp. dominates the microbiota of sputum from UK adults with non-severe community acquired pneumonia and chronic lung disease, Scientific Reports, Vol: 9, ISSN: 2045-2322
The demographics and comorbidities of patients with community acquired pneumonia (CAP) vary enormously but stratified treatment is difficult because aetiological studies have failed to comprehensively identify the pathogens. Our aim was to describe the bacterial microbiota of CAP and relate these to clinical characteristics in order to inform future trials of treatment stratified by co-morbidity. CAP patients were prospectively recruited at two UK hospitals. We used 16S rRNA gene sequencing to identify the dominant bacteria in sputum and compositional data analysis to determine associations with patient characteristics. We analysed sputum samples from 77 patients and found a Streptococcus sp. and a Haemophilus sp. were the most relatively abundant pathogens. The Haemophilus sp. was more likely to be dominant in patients with pre-existing lung disease, and its relative abundance was associated with qPCR levels of Haemophilus influenzae. The most abundant Streptococcus sp. was associated with qPCR levels of Streptococcus pneumoniae but dominance could not be predicted from clinical characteristics. These data suggest chronic lung disease influences the microbiota of sputum in patients with CAP. This finding could inform a trial of stratifying empirical CAP antibiotics to target Haemophilus spp. in addition to Streptococcus spp. in those with chronic lung disease.
Zhang Y, Willis-Owen S, Spiegel S, et al., 2019, The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 478-488, ISSN: 1073-449X
Rationale: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. Objectives: To investigate the role of ORMDL3 in cellular inflammation. Methods: We modelled time-series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the SPT inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial (NHBE) cells. Cytokine and metabolite levels were analysed by ANOVA. Transcript abundances were analysed by group means parameterisation, controlling the false discovery rate (FDR) below 0.05. Measurements and Main Results: Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced ER stress after IL1B. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses and ubiquitination: in particular ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-P (S1P) were also observed. Conclusions: The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.
Januszewski A, Chang W, Zhang Y, et al., 2019, Intratumoral heterogeneity in PD-L1 expression in pleomorphic lung carcinoma: implications for management of stage III disease, British Thoracic Oncology Group, Publisher: Elsevier, ISSN: 0169-5002
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