ResearchPad - environmental-and-occupational-lung-diseases https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Possible risk factors for poor asthma control assessed in a cross-sectional population-based study from Telemark, Norway]]> https://www.researchpad.co/article/elastic_article_13801 This cross-sectional study of the general population of Telemark County, Norway, aimed to identify risk factors associated with poor asthma control as defined by the Asthma Control Test (ACT), and to determine the proportions of patients with poorly controlled asthma who had undergone spirometry, used asthma medication, or been examined by a pulmonary physician. In 2014–2015, the study recruited 326 subjects aged 16–50 years who had self-reported physician-diagnosed asthma and presence of respiratory symptoms during the previous 12 months. The clinical outcome measures were body mass index (BMI), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), fractional exhaled nitric oxide (FeNO), immunoglobulin E (IgE) in serum and serum C-reactive protein (CRP). An ACT score ≤ 19 was defined as poorly controlled asthma. Overall, 113 subjects (35%) reported poor asthma control. The odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with poorly controlled asthma were: self-reported occupational exposure to vapor, gas, dust, or fumes during the previous 12 months (OR 2.0; 95% CI 1.1–3.6), body mass index ≥ 30 kg/m2 (OR 2.2; 95% CI 1.2–4.1), female sex (OR 2.6; 95% CI 1.5–4.7), current smoking (OR 2.8; 95% CI 1.5–5.3), and past smoking (OR 2.3; 95% CI 1.3–4.0). Poor asthma control was also associated with reduced FEV1 after bronchodilation (β –3.6; 95% CI –7.0 to –0.2). Moreover, 13% of the participants with poor asthma control reported no use of asthma medication, 51% had not been assessed by a pulmonary physician, and 20% had never undergone spirometry. Because these data are cross-sectional, further studies assessing possible risk factors in general and objectively measured occupational exposure in particular are needed. However, our results suggest that there is room for improvement with regards to use of spirometry and pulmonary physician referrals when a patient’s asthma is inadequately controlled.

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<![CDATA[Correlation of Apical Fluid-Regulating Channel Proteins with Lung Function in Human COPD Lungs]]> https://www.researchpad.co/article/5989da9bab0ee8fa60ba3dc9

Links between epithelial ion channels and chronic obstructive pulmonary diseases (COPD) are emerging through animal model and in vitro studies. However, clinical correlations between fluid-regulating channel proteins and lung function in COPD remain to be elucidated. To quantitatively measure epithelial sodium channels (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR), and aquaporin 5 (AQP5) proteins in human COPD lungs and to analyze the correlation with declining lung function, quantitative western blots were used. Spearman tests were performed to identify correlations between channel proteins and lung function. The expression of α and β ENaC subunits was augmented and inversely associated with lung function. In contrast, both total and alveolar type I (ATI) and II (ATII)-specific CFTR proteins were reduced. The expression level of CFTR proteins was associated with FEV1 positively. Abundance of AQP5 proteins and extracellular superoxide dismutase (SOD3) was decreased and correlated with spirometry test results and gas exchange positively. Furthermore, these channel proteins were significantly associated with severity of disease. Our study demonstrates that expression of ENaC, AQP5, and CFTR proteins in human COPD lungs is quantitatively associated with lung function and severity of COPD. These apically located fluid-regulating channels may thereby serve as biomarkers and potent druggable targets of COPD.

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<![CDATA[Critical Role of VCP/p97 in the Pathogenesis and Progression of Non-Small Cell Lung Carcinoma]]> https://www.researchpad.co/article/5989d9efab0ee8fa60b6df9e

Background

Valosin-containing protein (VCP)/p97 is an AAA ATPase molecular chaperone that regulates vital cellular functions and protein-processing. A recent study indicated that VCP expression levels are correlated with prognosis and progression of non-small cell lung carcinoma (NSCLC). We not only verified these findings but also identified the specific role of VCP in NSCLC pathogenesis and progression.

Methodology/Principal Findings

Our results show that VCP is significantly overexpressed in non-small cell lung carcinoma (NSCLC) as compared to normal tissues and cell lines (p<0.001). Moreover, we observed the corresponding accumulation of ubiquitinated-proteins in NSCLC cell lines and tissues as compared to the normal controls. VCP inhibition by si/shRNA or small-molecule (Eeyarestatin I, EerI) significantly (p<0.05, p<0.00007) suppressed H1299 proliferation and migration but induced (p<0.00001) apoptosis. Cell cycle analysis by flow cytometry verified this data and shows that VCP inhibition significantly (p<0.001, p<0.003) induced cell cycle arrest in the G0/G1 phases. We also found that VCP directly regulates p53 and NFκB protein levels as a potential mechanism to control tumor cell proliferation and progression. Finally, we evaluated the therapeutic potential of VCP inhibition and observed significantly reduced NSCLC tumor growth in both in vitro and xenograft murine (athymic-nude) models after EerI treatment (p<0.05).

Conclusions/Significance

Thus, targeting VCP in NSCLC may provide a novel strategy to restore p53 and NFκB levels and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes.

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<![CDATA[Region-Specific Sensitivity of Anemophilous Pollen Deposition to Temperature and Precipitation]]> https://www.researchpad.co/article/5989dae1ab0ee8fa60bbbd71

Understanding relations between climate and pollen production is important for several societal and ecological challenges, importantly pollen forecasting for pollinosis treatment, forensic studies, global change biology, and high-resolution palaeoecological studies of past vegetation and climate fluctuations. For these purposes, we investigate the role of climate variables on annual-scale variations in pollen influx, test the regional consistency of observed patterns, and evaluate the potential to reconstruct high-frequency signals from sediment archives. A 43-year pollen-trap record from the Netherlands is used to investigate relations between annual pollen influx, climate variables (monthly and seasonal temperature and precipitation values), and the North Atlantic Oscillation climate index. Spearman rank correlation analysis shows that specifically in Alnus, Betula, Corylus, Fraxinus, Quercus and Plantago both temperature in the year prior to (T-1), as well as in the growing season (T), are highly significant factors (TApril rs between 0.30 [P<0.05[ and 0.58 [P<0.0001]; TJuli-1 rs between 0.32 [P<0.05[ and 0.56 [P<0.0001]) in the annual pollen influx of wind-pollinated plants. Total annual pollen prediction models based on multiple climate variables yield R2 between 0.38 and 0.62 (P<0.0001). The effect of precipitation is minimal. A second trapping station in the SE Netherlands, shows consistent trends and annual variability, suggesting the climate factors are regionally relevant. Summer temperature is thought to influence the formation of reproductive structures, while temperature during the flowering season influences pollen release. This study provides a first predictive model for seasonal pollen forecasting, and also aides forensic studies. Furthermore, variations in pollen accumulation rates from a sub-fossil peat deposit are comparable with the pollen trap data. This suggests that high frequency variability pollen records from natural archives reflect annual past climate variability, and can be used in palaeoecological and -climatological studies to bridge between population- and species-scale responses to climate forcing.

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<![CDATA[Exhaled Air Dispersion during Coughing with and without Wearing a Surgical or N95 Mask]]> https://www.researchpad.co/article/5989da0aab0ee8fa60b7763f

Objectives

We compared the expelled air dispersion distances during coughing from a human patient simulator (HPS) lying at 45° with and without wearing a surgical mask or N95 mask in a negative pressure isolation room.

Methods

Airflow was marked with intrapulmonary smoke. Coughing bouts were generated by short bursts of oxygen flow at 650, 320, and 220L/min to simulate normal, mild and poor coughing efforts, respectively. The coughing jet was revealed by laser light-sheet and images were captured by high definition video. Smoke concentration in the plume was estimated from the light scattered by smoke particles. Significant exposure was arbitrarily defined where there was ≥ 20% of normalized smoke concentration.

Results

During normal cough, expelled air dispersion distances were 68, 30 and 15 cm along the median sagittal plane when the HPS wore no mask, a surgical mask and a N95 mask, respectively. In moderate lung injury, the corresponding air dispersion distances for mild coughing efforts were reduced to 55, 27 and 14 cm, respectively, p < 0.001. The distances were reduced to 30, 24 and 12 cm, respectively during poor coughing effort as in severe lung injury. Lateral dispersion distances during normal cough were 0, 28 and 15 cm when the HPS wore no mask, a surgical mask and a N95 mask, respectively.

Conclusions

Normal cough produced a turbulent jet about 0.7 m towards the end of the bed from the recumbent subject. N95 mask was more effective than surgical mask in preventing expelled air leakage during coughing but there was still significant sideway leakage.

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<![CDATA[NOTCH1, HIF1A and Other Cancer-Related Proteins in Lung Tissue from Uranium Miners—Variation by Occupational Exposure and Subtype of Lung Cancer]]> https://www.researchpad.co/article/5989daf6ab0ee8fa60bc2ee7

Background

Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners.

Methodology/Principal Findings

Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (rs). Occupational exposure was associated with an up-regulation of NOTCH1 (radon rs = 0.18, 95% CI 0.02–0.33; arsenic: rs = 0.23, 95% CI 0.07–0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%.

Conclusions/Significance

These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.

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<![CDATA[Comparison of Gene Expression Profiles in Chromate Transformed BEAS-2B Cells]]> https://www.researchpad.co/article/5989da46ab0ee8fa60b8be05

Background

Hexavalent chromium [Cr(VI)] is a potent human carcinogen. Occupational exposure has been associated with increased risk of respiratory cancer. Multiple mechanisms have been shown to contribute to Cr(VI) induced carcinogenesis, including DNA damage, genomic instability, and epigenetic modulation, however, the molecular mechanism and downstream genes mediating chromium's carcinogenicity remain to be elucidated.

Methods/Results

We established chromate transformed cell lines by chronic exposure of normal human bronchial epithelial BEAS-2B cells to low doses of Cr(VI) followed by anchorage-independent growth. These transformed cell lines not only exhibited consistent morphological changes but also acquired altered and distinct gene expression patterns compared with normal BEAS-2B cells and control cell lines (untreated) that arose spontaneously in soft agar. Interestingly, the gene expression profiles of six Cr(VI) transformed cell lines were remarkably similar to each other yet differed significantly from that of either control cell lines or normal BEAS-2B cells. A total of 409 differentially expressed genes were identified in Cr(VI) transformed cells compared to control cells. Genes related to cell-to-cell junction were upregulated in all Cr(VI) transformed cells, while genes associated with the interaction between cells and their extracellular matrices were down-regulated. Additionally, expression of genes involved in cell proliferation and apoptosis were also changed.

Conclusion

This study is the first to report gene expression profiling of Cr(VI) transformed cells. The gene expression changes across individual chromate exposed clones were remarkably similar to each other but differed significantly from the gene expression found in anchorage-independent clones that arose spontaneously. Our analysis identified many novel gene expression changes that may contribute to chromate induced cell transformation, and collectively this type of information will provide a better understanding of the mechanism underlying chromate carcinogenicity.

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<![CDATA[Increased Virulence of an Epidemic Strain of Mycobacterium massiliense in Mice]]> https://www.researchpad.co/article/5989da39ab0ee8fa60b873ef

Background

Chronic pulmonary disease and skin/soft tissue infections due to non-tuberculous mycobacteria (NTM) of the Mycobacterium chelonae-abscessus-massiliense group is an emerging health problem worldwide. Moreover, the cure rate for the infections this group causes is low despite aggressive treatment. Post-surgical outbreaks that reached epidemic proportions in Brazil recently were caused by M. massiliense isolates resistant to high-level disinfection with glutaraldehyde (GTA). Understanding the differences in the virulence and host immune responses induced by NTM differing in their sensitivity to disinfectants, and therefore their relative threat of causing outbreaks in hospitals, is an important issue.

Methodology/Principal Finding

We compared the replication and survival inside macrophages of a GTA-susceptible reference Mycobacterium massiliense clinical isolate CIP 108297 and an epidemic strain from Brazil, CRM-0019, and characterized the immune responses of IFNγ knockout mice exposed to a high dose aerosol with these two isolates. CRM-0019 replicated more efficiently than CIP 108297 inside mouse bone marrow macrophages. Moreover, the animals infected with CRM-0019 showed a progressive lung infection characterized by a delayed influx of CD4+ and CD8+ T cells, culminating in extensive lung consolidation and demonstrated increased numbers of pulmonary CD4+ Foxp3+ regulatory T cells compared to those infected with the reference strain. Immunosuppressive activity of regulatory T cells may contribute to the progression and worsening of NTM disease by preventing the induction of specific protective immune responses.

Conclusions/Significance

These results provide the first direct evidence of the increased virulence in macrophages and mice and pathogenicity in vivo of the Brazilian epidemic isolate and the first observation that NTM infections can be associated with variable levels of regulatory T cells which may impact on their virulence and ability to persist in the host.

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<![CDATA[Immunogenic Properties of Archaeal Species Found in Bioaerosols]]> https://www.researchpad.co/article/5989da05ab0ee8fa60b75858

The etiology of bioaerosol-related pulmonary diseases remains poorly understood. Recently, archaea emerged as prominent airborne components of agricultural environments, but the consequences of airway exposure to archaea remain unknown. Since subcomponents of archaea can be immunogenic, we used a murine model to study the pulmonary immune responses to two archaeal species found in agricultural facilities: Methanobrevibacter smithii (MBS) and Methanosphaera stadtmanae (MSS). Mice were administered intranasally with 6.25, 25 or 100 µg of MBS or MSS, once daily, 3 days a week, for 3 weeks. MSS induced more severe histopathological alterations than MBS with perivascular accumulation of granulocytes, pronounced thickening of the alveolar septa, alveolar macrophages accumulation and increased perivascular mononucleated cell accumulation. Analyses of bronchoalveolar lavage fluids revealed up to 3 times greater leukocyte accumulation with MSS compared to MBS. Instillation of 100 µg of MBS or MSS caused predominant accumulation of monocyte/macrophages (4.5×105 and 4.8×105 cells/ml respectively) followed by CD4+ T cells (1.38×105 and 1.94×105 cells/ml respectively), B cells (0.73×105 and 1.28×105 cells/ml respectively), and CD8+ T cells (0.20×105 and 0.31×105 cells/ml respectively) in the airways. Both archaeal species induced similar titers of antigen-specific IgGs in plasma. MSS but not MBS caused an accumulation of eosinophils and neutrophils in the lungs, which surprisingly, correlated inversely with the size of the inoculum. Stronger immunogenicity of MSS was confirmed by a 3 fold higher accumulation of myeloid dendritic cells in the airways, compared to MBS. Thus, the dose and species of archaea determine the magnitude and nature of the pulmonary immune response. This is the first report of an immunomodulatory role of archaeal species found in bioaerosols.

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<![CDATA[Diagnostic Performance of Ultra-Low-Dose Computed Tomography for Detecting Asbestos-Related Pleuropulmonary Diseases: Prospective Study in a Screening Setting]]> https://www.researchpad.co/article/5989db4dab0ee8fa60bdacc8

Objective

To evaluate the diagnostic performance of Ultra-Low-Dose Chest CT (ULD CT) for the detection of any asbestos-related lesions (primary endpoint) and specific asbestos-related abnormalities, i.e. non-calcified and calcified pleural plaques, diffuse pleural thickening, asbestosis and significant lung nodules (secondary endpoints).

Material and Methods

55 male patients (55.7±8.1 years old) with occupational asbestos exposure for at least 15 years and where CT screening was indicated were prospectively included. They all underwent a standard unenhanced chest CT (120kV, automated tube current modulation), considered as the reference, and an ULD CT (135kV, 10mA), both with iterative reconstruction.

Two chest radiologists independently and blindly read the examinations, following a detailed protocol. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy and error rate of ULD CT were calculated using the exact method of Pearson with a confidence interval of 95%.

Results

Radiation dose was 17.9±1.2mGy.cm (0.25mSv) for the ULD-CT versus 288.8 ±151mGy.cm (4mSv); p <2.2e-16.

Prevalence of abnormalities was 20%. The ULD CT’s diagnostic performance in joint reading was high for the primary endpoint (sensitivity = 90.9%, specificity = 100%, positive predictive value = 100%, negative predictive value = 97.8%), high for lung nodules, diffuse pleural thickening and calcified pleural plaques (sensitivity, specificity, PPV and NPV = 100%) and fair for asbestosis (sensitivity = 75%, specificity = 100%, PPV = 00%, NPV = 98.1%).

Intra-reader accuracy between the ULD CT and the reference CT for the primary endpoint was 98% for the senior and 100% for the junior radiologist. Inter-reader agreement for the primary endpoint was almost perfect (Cohen’s Kappa of 0.81).

Conclusion

ULD CT in the screening of asbestos exposure related diseases has 90.9% sensitivity and 100% specificity, and could therefore be proposed as a first line examination.

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<![CDATA[Age-Dependent Decline in Mouse Lung Regeneration with Loss of Lung Fibroblast Clonogenicity and Increased Myofibroblastic Differentiation]]> https://www.researchpad.co/article/5989da2bab0ee8fa60b82822

While aging leads to a reduction in the capacity for regeneration after pneumonectomy (PNX) in most mammals, this biological phenomenon has not been characterized over the lifetime of mice. We measured the age-specific (3, 9, 24 month) effects of PNX on physiology, morphometry, cell proliferation and apoptosis, global gene expression, and lung fibroblast phenotype and clonogenicity in female C57BL6 mice. The data show that only 3 month old mice were fully capable of restoring lung volumes by day 7 and total alveolar surface area by 21 days. By 9 months, the rate of regeneration was slower (with incomplete regeneration by 21 days), and by 24 months there was no regrowth 21 days post-PNX. The early decline in regeneration rate was not associated with changes in alveolar epithelial cell type II (AECII) proliferation or apoptosis rate. However, significant apoptosis and lack of cell proliferation was evident after PNX in both total cells and AECII cells in 24 mo mice. Analysis of gene expression at several time points (1, 3 and 7 days) post-PNX in 9 versus 3 month mice was consistent with a myofibroblast signature (increased Tnc, Lox1, Col3A1, Eln and Tnfrsf12a) and more alpha smooth muscle actin (αSMA) positive myofibroblasts were present after PNX in 9 month than 3 month mice. Isolated lung fibroblasts showed a significant age-dependent loss of clonogenicity. Moreover, lung fibroblasts isolated from 9 and 17 month mice exhibited higher αSMA, Col3A1, Fn1 and S100A expression, and lower expression of the survival gene Mdk consistent with terminal differentiation. These data show that concomitant loss of clonogenicity and progressive myofibroblastic differentiation contributes to the age-dependent decline in the rate of lung regeneration.

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<![CDATA[20-HETE Mediates Ozone-Induced, Neutrophil-Independent Airway Hyper-Responsiveness in Mice]]> https://www.researchpad.co/article/5989db26ab0ee8fa60bd042c

Background

Ozone, a pollutant known to induce airway hyper-responsiveness (AHR), increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways.

Methodology/Principal Findings

Male BALB/c mice were exposed to ozone (3 or 6 ppm) or filtered air (controls) for 2 h. Precision cut lung slices (PCLS; 250 µm thickness) containing an intrapulmonary airway (∼0.01 mm2 lumen area) were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh). Log EC50 and Emax values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg), or 1-aminobenzotriazol (ABT) (50 mg/kg) were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg) was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS) for lipid analysis were assessed in bronchoalveolar lavage (BAL) fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL)-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment.

Conclusions/Significance

These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX) inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in oxidized lipids. 20-HETE plays a pivotal role in mediating acute ozone-induced AHR.

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<![CDATA[MicroRNA-218 Is Deleted and Downregulated in Lung Squamous Cell Carcinoma]]> https://www.researchpad.co/article/5989da04ab0ee8fa60b75213

MicroRNAs (miRNAs) are a family of small, non-coding RNA species functioning as negative regulators of multiple target genes including tumour suppressor genes and oncogenes. Many miRNA gene loci are located within cancer-associated genomic regions. To identify potential new amplified oncogenic and/or deleted tumour suppressing miRNAs in lung cancer, we inferred miRNA gene dosage from high dimensional arrayCGH data. From miRBase v9.0 (http://microrna.sanger.ac.uk), 474 human miRNA genes were physically mapped to regions of chromosomal loss or gain identified from a high-resolution genome-wide arrayCGH study of 132 primary non-small cell lung cancers (NSCLCs) (a training set of 60 squamous cell carcinomas and 72 adenocarcinomas). MiRNAs were selected as candidates if their immediately flanking probes or host gene were deleted or amplified in at least 25% of primary tumours using both Analysis of Copy Errors algorithm and fold change (≥±1.2) analyses. Using these criteria, 97 miRNAs mapped to regions of aberrant copy number. Analysis of three independent published lung cancer arrayCGH datasets confirmed that 22 of these miRNA loci showed directionally concordant copy number variation. MiR-218, encoded on 4p15.31 and 5q35.1 within two host genes (SLIT2 and SLIT3), in a region of copy number loss, was selected as a priority candidate for follow-up as it is reported as underexpressed in lung cancer. We confirmed decreased expression of mature miR-218 and its host genes by qRT-PCR in 39 NSCLCs relative to normal lung tissue. This downregulation of miR-218 was found to be associated with a history of cigarette smoking, but not human papilloma virus. Thus, we show for the first time that putative lung cancer-associated miRNAs can be identified from genome-wide arrayCGH datasets using a bioinformatics mapping approach, and report that miR-218 is a strong candidate tumour suppressing miRNA potentially involved in lung cancer.

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<![CDATA[Apoptosis Induced by Piroxicam plus Cisplatin Combined Treatment Is Triggered by p21 in Mesothelioma]]> https://www.researchpad.co/article/5989daa4ab0ee8fa60ba6d26

Background

Malignant mesothelioma (MM) is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase.

Methodology/Principal Findings

We analyzed, at molecular level, the apoptotic increase caused by piroxicam/cisplatin treatment in MM cell lines. By means of genome wide analyses, we analyzed transcriptional gene deregulation both after the single piroxicam or cisplatin and the combined treatment. Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing.

Conclusions/Significance

Piroxicam/cisplatin combined treatment determines an apoptosis increase in MM cells, which is dependent on the p21 expression. The results provided suggest that piroxicam/cisplatin combination might be tested in clinical settings in tumor specimens that express p21.

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<![CDATA[Transient Receptor Potential Ankyrin 1 Channel Localized to Non-Neuronal Airway Cells Promotes Non-Neurogenic Inflammation]]> https://www.researchpad.co/article/5989db47ab0ee8fa60bd8c1e

Background

The transient receptor potential ankyrin 1 (TRPA1) channel, localized to airway sensory nerves, has been proposed to mediate airway inflammation evoked by allergen and cigarette smoke (CS) in rodents, via a neurogenic mechanism. However the limited clinical evidence for the role of neurogenic inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway inflammation is promoted by non-neuronal TRPA1.

Methodology/Principal Findings

By using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1), a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists), or the neuropeptide substance P (SP), which is released from sensory nerve terminals by capsaicin, acrolein or CS), produced neurogenic inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue) in bronchoalveolar lavage (BAL) fluid of wild-type mice. This effect of TRPA1 agonists was attenuated by TRPA1 antagonism or in TRPA1-deficient mice, but not by pharmacological ablation of sensory nerves.

Conclusions

Our results demonstrate that, although either TRPV1 or TRPA1 activation causes airway neurogenic inflammation, solely TRPA1 activation orchestrates an additional inflammatory response which is not neurogenic. This finding suggests that non-neuronal TRPA1 in the airways is functional and potentially capable of contributing to inflammatory airway diseases.

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<![CDATA[Access Rate to the Emergency Department for Venous Thromboembolism in Relationship with Coarse and Fine Particulate Matter Air Pollution]]> https://www.researchpad.co/article/5989daeeab0ee8fa60bc06ef

Particulate matter (PM) air pollution has been associated with cardiovascular and respiratory disease. Recent studies have proposed also a link with venous thromboembolism (VTE) risk. This study was aimed to evaluate the possible influence of air pollution-related changes on the daily flux of patients referring to the Emergency Department (ED) for VTE, dissecting the different effects of coarse and fine PM. From July 1st, 2007, to June 30th, 2009, data about ED accesses for VTE and about daily concentrations of PM air pollution in Verona district (Italy) were collected. Coarse PM (PM10-2.5) was calculated by subtracting the finest PM2.5 from the whole PM10. During the index period a total of 302 accesses for VTE were observed (135 males and 167 females; mean age 68.3±16.7 years). In multiple regression models adjusted for other atmospheric parameters PM10-2.5, but not PM2.5, concentrations were positively correlated with VTE (beta-coefficient = 0.237; P = 0.020). During the days with high levels of PM10-2.5 (≥75th percentile) there was an increased risk of ED accesses for VTE (OR 1.69 with 95%CI 1.13–2.53). By analysing days of exposure using distributed lag non-linear models, the increase of VTE risk was limited to PM10-2.5 peaks in the short-term period. Consistently with these results, in another cohort of subjects without active thrombosis (n = 102) an inverse correlation between PM10-2.5 and prothrombin time was found (R = −0.247; P = 0.012). Our results suggest that short-time exposure to high concentrations of PM10-2.5 may favour an increased rate of ED accesses for VTE through the induction of a prothrombotic state.

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<![CDATA[Increased Expression of SVCT2 in a New Mouse Model Raises Ascorbic Acid in Tissues and Protects against Paraquat-Induced Oxidative Damage in Lung]]> https://www.researchpad.co/article/5989dacfab0ee8fa60bb5a87

A new transgenic mouse model for global increases in the Sodium Dependent Vitamin C transporter 2 (SVCT2) has been generated. The SVCT2-Tg mouse shows increased SVCT2 mRNA levels in all organs tested and correspondingly increased ascorbic acid (ASC) levels in all organs except liver. The extent of the increase in transporter mRNA expression differed among mice and among organs. The increased ASC levels did not have any adverse effects on behavior in the SVCT2-Tg mice, which did not differ from wild-type mice on tests of locomotor activity, anxiety, sensorimotor or cognitive ability. High levels of SVCT2 and ASC were found in the kidneys of SVCT2-Tg mice and urinary albumin excretion was lower in these mice than in wild-types. No gross pathological changes were noted in kidneys from SVCT2-Tg mice. SVCT2 immunoreactivity was detected in both SVCT2 and wild-type mice, and a stronger signal was seen in tubules than in glomeruli. Six treatments with Paraquat (3x10 and 3x15 mg/kg i.p.) were used to induce oxidative stress in mice. SVCT2-Tg mice showed a clear attenuation of Paraquat-induced oxidative stress in lung, as measured by F2-isoprostanes. Paraquat also decreased SVCT2 mRNA signal in liver, lung and kidney in SVCT2-Tg mice.

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<![CDATA[Leveraging Big Data for Exploring Occupational Diseases-Related Interest at the Level of Scientific Community, Media Coverage and Novel Data Streams: The Example of Silicosis as a Pilot Study]]> https://www.researchpad.co/article/5989daa6ab0ee8fa60ba77e7

Objective

Silicosis is an untreatable but preventable occupational disease, caused by exposure to silica. It can progressively evolve to lung impairment, respiratory failure and death, even after exposure has ceased. However, little is known about occupational diseases-related interest at the level of scientific community, media coverage and web behavior. This article aims at filling in this gap of knowledge, taking the silicosis as a case study.

Methods

We investigated silicosis-related web-activities using Google Trends (GT) for capturing the Internet behavior worldwide in the years 2004–2015. GT-generated data were, then, compared with the silicosis-related scientific production (i.e., PubMed and Google Scholar), the media coverage (i.e., Google news), the Wikipedia traffic (i.e, Wikitrends) and the usage of new media (i.e., YouTube and Twitter).

Results

A peak in silicosis-related web searches was noticed in 2010–2011: interestingly, both scientific articles production and media coverage markedly increased after these years in a statistically significant way. The public interest and the level of the public engagement were witnessed by an increase in likes, comments, hashtags, and re-tweets. However, it was found that only a small fraction of the posted/uploaded material contained accurate scientific information.

Conclusions

GT could be useful to assess the reaction of the public and the level of public engagement both to novel risk-factors associated to occupational diseases, and possibly related changes in disease natural history, and to the effectiveness of preventive workplace practices and legislative measures adopted to improve occupational health. Further, occupational clinicians should become aware of the topics most frequently searched by patients and proactively address these concerns during the medical examination. Institutional bodies and organisms should be more present and active in digital tools and media to disseminate and communicate scientifically accurate information. This manuscript should be intended as preliminary, exploratory communication, paving the way for further studies.

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<![CDATA[Bronchoalveolar Lavage Results Are Independent of Season, Age, Gender and Collection Site]]> https://www.researchpad.co/article/5989da15ab0ee8fa60b7adca

Background

Clinical interpretation of bronchoalveolar lavage fluid results is dependent on the availability of reference values for healthy individuals. Only a few studies have published such reference values and the applicability of results is restricted by small sample sizes and the limited representativeness of the study population. We aim to investigate the influence of age, gender, collection site and season on bronchoalveolar lavage fluid results and to establish reference values for use in clinical practice.

Methodology/Principal Findings

Bronchoalveolar lavage fluid data from 295 healthy never-smoking volunteers, investigated during 1990–2009, were analyzed retrospectively. 47 volunteers had 2–5 repeat lavages during the course of several years. Fluid recovery, total number of cells, cell concentration, and differential cell counts on cytospin prepared slides were recorded. Reference values, as represented by the 5th to the 95th percentile, were 72–96% for macrophages, 2–26% for lymphocytes, 0–4% for neutrophils and 0–1% for eosinophils. Basophils and mast cells were rare. When repeat lavages were performed, there was a relatively large intra-individual variability, mainly for macrophages and lymphocytes. An age dependent decrease of lavage fluid return was present, but there was no age dependent correlation with any of the other BALF parameters. The BALF cell parameters were independent of gender, season and site (lingula vs. middle lobe).

Conclusions/Significance

Our data show that bronchoalveolar lavage fluid cell differential count is independent of age, gender, season and collection site (RML or lingua). It therefore seems acceptable to use the same reference values for all never-smoking individuals.

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<![CDATA[Effects of a mixture of chloromethylisothiazolinone and methylisothiazolinone on peripheral airway dysfunction in children]]> https://www.researchpad.co/article/5989db59ab0ee8fa60bdf17c

Background

Children who were only exposed to a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) as humidifier disinfectant (HD) components were evaluated for humidifier disinfectant-associated lung injury (HDLI) from 2012. This study was to evaluate the pulmonary function using, impulse oscillometry (IOS) for children exposed to a mixture of CMIT/MIT from HD.

Methods

Twenty-four children who were only exposed to a mixture of CMIT/MIT, with no previous underlying disease, were assessed by IOS. Diagnostic criteria for HDLI were categorized as definite, probable, possible, or unlikely. Home visits and administration of a standardized questionnaire were arranged to assess exposure characteristics.

Results

Definite and probable cases showed higher airborne disinfectant exposure intensity during sleep (32.4 ± 8.7 μg/m3) and younger age at initial exposure (3.5 ± 3.3 months) compared with unlikely cases (17.3 ± 11.0 μg/m3, p = 0.026; 22.5 ± 26.2 months, p = 0.039, respectively). Reactance at 5 Hz was significantly more negative in those with high-density exposure during sleep (mean, -0.463 kPa/L/s vs. low density, -0.296, p = 0.001). The reactance area was also higher with high-density exposure during sleep (mean, 3.240 kPa/L vs. low density, 1.922, p = 0.039). The mean bronchodilator response with high-density exposure was within the normal range for reactance.

Conclusions

Significant peripheral airway dysfunction were found in children with high levels of inhalation exposure to a mixture of CMIT/MIT during sleep. Strict regulation of a mixture of CMIT/MIT exposure were associated with positive effects on lung function of children.

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