Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells:Implications for co-ordinated airway and vascular branching in lung development

This work was supported by a Wellcome Trust project grant 088032/Z/08/Z to SCL.Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3′ sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.Publisher PDFPeer reviewe

Bacterial biogeography of adult airways in atopic asthma

Abstract Background Perturbations to the composition and function of bronchial bacterial communities appear to contribute to the pathophysiology of asthma. Unraveling the nature and mechanisms of these complex associations will require large longitudinal studies, for which bronchoscopy is poorly suited. Studies of samples obtained by sputum induction and nasopharyngeal brushing or lavage have also reported asthma-associated microbiota characteristics. It remains unknown, however, whether the microbiota detected in these less-invasive sample types reflect the composition of bronchial microbiota in asthma. Results Bacterial microbiota in paired protected bronchial brushings (BB; n = 45), induced sputum (IS; n = 45), oral wash (OW; n = 45), and nasal brushings (NB; n = 27) from adults with mild atopic asthma (AA), atopy without asthma (ANA), and healthy controls (HC) were profiled using 16S rRNA gene sequencing. Though microbiota composition varied with sample type (p < 0.001), compositional similarity was greatest for BB-IS, particularly in AAs and ANAs. The abundance of genera detected in BB correlated with those detected in IS and OW (r median [IQR] 0.869 [0.748–0.942] and 0.822 [0.687–0.909] respectively), but not with those in NB (r = 0.004 [− 0.003–0.011]). The number of taxa shared between IS-BB and NB-BB was greater in AAs than in HCs (p < 0.05) and included taxa previously associated with asthma. Of the genera abundant in NB, only Moraxella correlated positively with abundance in BB; specific members of this genus were shared between the two compartments only in AAs. Relative abundance of Moraxella in NB of AAs correlated negatively with that of Corynebacterium but positively with markers of eosinophilic inflammation in the blood and BAL fluid. The genus, Corynebacterium, trended to dominate all NB samples of HCs but only half of AAs (p = 0.07), in whom abundance of this genus was negatively associated with markers of eosinophilic inflammation. Conclusions Induced sputum is superior to nasal brush or oral wash for assessing bronchial microbiota composition in asthmatic adults. Although compositionally similar to the bronchial microbiota, the microbiota in induced sputum are distinct, reflecting enrichment of oral bacteria. Specific bacterial genera are shared between the nasal and the bronchial mucosa which are associated with markers of systemic and bronchial inflammation.https://deepblue.lib.umich.edu/bitstream/2027.42/144218/1/40168_2018_Article_487.pd

Respiratory Symptoms Items from the COPD Assessment Test Identify Ever-Smokers with Preserved Lung Function at Higher Risk for Poor Respiratory Outcomes

Rationale: Ever-smokers without airflow obstruction scores greater than or equal to 10 on the COPD Assessment Test (CAT) still have frequent acute respiratory disease events (exacerbation-like), impaired exercise capacity, and imaging abnormalities. Identification of these subjects could provide new opportunities for targeted interventions. Objectives: We hypothesized that the four respiratory-related items of the CAT might be useful for identifying such individuals, with discriminative ability similar to CAT, which is an eight-item questionnaire used to assess chronic obstructive pulmonary disease impact, including nonrespiratory questions, with scores ranging from 0 to 40. Methods: We evaluated ever-smoker participants in the Subpopulations and Intermediate Outcomes in COPD Study without airflow obstruction (FEV1/FVC≥0.70; FVC above the lower limit of normal). Using the area under the receiver operating characteristic curve, we compared responses to both CAT and the respiratory symptom–related CAT items (cough, phlegm, chest tightness, and breathlessness) and their associations with longitudinal exacerbations. We tested agreement between the two strategies (k statistic), and we compared demographics, lung function, and symptoms among subjects identified as having high symptoms by each strategy. Results: Among 880 ever-smokers with normal lung function (mean age, 61 yr; 52% women) and using a CAT cutpoint greater than or equal to 10, we classified 51.8% of individuals as having high symptoms, 15.3% of whom experienced at least one exacerbation during 1-year follow-up. After testing sensitivity and specificity of different scores for the first four questions to predict any 1-year followup exacerbation, we selected cutpoints of 0–6 as representing a low burden of symptoms versus scores of 7 or higher as representing a high burden of symptoms for all subsequent comparisons. The four respiratory-related items with cutpoint greater than or equal to 7 selected 45.8% participants, 15.6% of whom experienced at least one exacerbation during follow-up. The two strategies largely identified the same individuals (agreement, 88.5%; k = 0.77; P \u3c 0.001), and the proportions of high-symptoms subjects who had severe dyspnea were similar between CAT and the first four CAT questions (25.9% and 26.8%, respectively), as were the proportions reporting impaired quality of life (66.9% and 70.5%, respectively) and short walking distance (22.4% and 23.1%, respectively). There was no difference in area under the receiver operating characteristic curve to predict 1-year follow-up exacerbations (CAT score ≥10, 0.66; vs. four respiratory items from CAT ≥ 7 score, 0.65; P = 0.69). Subjects identified by either method also hadmore depression/anxiety symptoms, poor sleep quality, and greater fatigue. Conclusions: Four CAT items on respiratory symptoms identified high-risk symptomatic ever-smokers with preserved spirometry as well as the CAT did. These data suggest that simpler strategies can be developed to identify these high-risk individuals in primary care

I am hiQ—a novel pair of accuracy indices for imputed genotypes

Background: Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand. Results: Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2). Conclusion: We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data

Sleep study, respiratory mechanics, chemosensitive response and quality of life in morbidly obese patients undergoing bariatric surgery: a prospective, randomized, controlled trial

<p>Abstract</p> <p>Background</p> <p>Obesity is a major public health problem in both developed and developing countries alike and leads to a series of changes in respiratory physiology. There is a strong correlation between obesity and cardiopulmonary sleep disorders. Weight loss among such patients leads to a reduction in these alterations in respiratory physiology, but clinical treatment is not effective for a long period of time. Thus, bariatric surgery is a viable option.</p> <p>Methods/Design</p> <p>The present study involves patients with morbid obesity (BMI of 40 kg/m²or 35 kg/m²to 39.9 kg/m²with comorbidities), candidates for bariatric surgery, screened at the Santa Casa de Misericórdia Hospital in the city of Sao Paulo (Brazil). The inclusion criteria are grade III morbid obesity, an indication for bariatric surgery, agreement to participate in the study and a signed term of informed consent. The exclusion criteria are BMI above 55 kg/m², clinically significant or unstable mental health concerns, an unrealistic postoperative target weight and/or unrealistic expectations of surgical treatment. Bariatric surgery candidates who meet the inclusion criteria will be referred to Santa Casa de Misericórdia Hospital and will be reviewed again 30, 90 and 360 days following surgery. Data collection will involve patient records, personal data collection, objective assessment of HR, BP, neck circumference, chest and abdomen, collection and analysis of clinical preoperative findings, polysomnography, pulmonary function test and a questionnaire on sleepiness.</p> <p>Discussion</p> <p>This paper describes a randomised controlled trial of morbidly obese patients. Polysomnography, respiratory mechanics, chemosensitive response and quality of life will be assessed in patients undergoing or not undergoing bariatric surgery.</p> <p>Trial Registration</p> <p>The protocol for this study is registered with the Brazilian Registry of Clinical Trials - ReBEC (RBR-9k9hhv).</p

Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Background Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant x variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13-1.27; p = 5.6 x 10(-10)) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19-1.35; p = 1.0 x 10(-12)). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers