Showing papers in "Lung in 2016"
TL;DR: A poor sensitivity and insufficient specificity of high ACE for diagnosis of sarcoidosis is demonstrated suggesting a limited role of ACE in clinical practice.
Abstract: Sarcoidosis is a disease with heterogenous clinical presentations. Diagnosis of sarcoidosis is often challenging with the lack of gold standard tests. In this study, we investigated the diagnostic utility of angiotensin-converting enzyme (ACE) for diagnosis of sarcoidosis. A cohort of Olmsted County, Minnesota residents who were diagnosed with sarcoidosis between January 1, 1984 and December 31, 2013 was identified based on individual medical record review. ACE levels recorded in the medical records of all subjects at the time of diagnosis were extracted. Comparator subjects were residents of Olmsted County, Minnesota who had ACE levels tested the same time period but did not have a diagnosis of sarcoidosis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the c-statistic of high versus low/normal ACE to diagnose sarcoidosis were calculated. A total of 3277 Olmsted County residents age ≥18 years had at least one ACE test in 1984–2013. The sarcoidosis incidence cohort contained 295 Olmsted County residents diagnosed with sarcoidosis in 1984–2013. Of these, ACE tests were obtained in 251. The sensitivity and specificity of high ACE for diagnosis of sarcoidosis were 41.4 % (95 % CI 35.3–47.8 %) and 89.9 % (95 % CI 88.8–91.0 %), respectively. The PPV and NPV in this population were 25.4 % (95 % CI 21.3–29.9 %) and 94.9 % (95 % CI 85.0–87.4 %). This study demonstrated a poor sensitivity and insufficient specificity of high ACE for diagnosis of sarcoidosis suggesting a limited role of ACE in clinical practice.
130 citations
TL;DR: The decline in FVC in INPULSIS®-ON in both subgroups by baseline FVC % predicted was similar to that in IN PULSIS®, suggesting that nintedanib may have a similar effect on disease progression in patients with advanced disease as in less advanced disease.
Abstract: In the Phase III INPULSIS® trials, 52 weeks’ treatment with nintedanib reduced decline in forced vital capacity (FVC) versus placebo in patients with idiopathic pulmonary fibrosis (IPF). Patients who completed the INPULSIS® trials could receive nintedanib in an open-label extension trial (INPULSIS®-ON). Patients with FVC 50 % predicted at the start of INPULSIS®-ON, the absolute mean change in FVC from baseline to week 48 of INPULSIS®-ON was −62.3 and −87.9 mL, respectively (n = 24 and n = 558, respectively). No new safety signals were identified in INPULSIS®-ON compared with INPULSIS®. The decline in FVC in INPULSIS®-ON in both subgroups by baseline FVC % predicted was similar to that in INPULSIS®, suggesting that nintedanib may have a similar effect on disease progression in patients with advanced disease as in less advanced disease.
100 citations
TL;DR: The results suggest that ILD remains an important and significant source of mortality in patients with inflammatory myopathies and as such should be screened for and treated aggressively.
Abstract: Among patients with autoimmune myositis, associated interstitial lung disease (MA-ILD) is a known contributor of excess morbidity and mortality. Recent data on survival in idiopathic inflammatory myopathies originate primarily in Asia and Europe and vary widely. We sought to examine mortality in a large U.S. myositis cohort focusing in particular on the impact of associated ILD. A cross-sectional analysis of participants from the Johns Hopkins Myositis Center with autoimmune myositis (polymyositis [PM], dermatomyositis [DM], or clinically amyopathic dermatomyositis [CADM]) was conducted. The primary outcome assessed was all-cause mortality. Cumulative mortality rates were estimated using the Kaplan–Meier test; the Cox proportional hazards model was used to compare group differences in survival. Eight hundred and thirty-one participants were included with a median follow-up time of 4.5 years. Four hundred thirty-eight (53 %) had PM, 362 (43 %) had DM, and 31 (4 %) had CADM. Ninety-four (11 %) participants had clinically evident ILD. Overall, 51 participants died (6 %). In those without ILD, the survival rates at 1, 5, and 10 years were 99, 95, and 90 %, respectively. In those with ILD, the survival rates at 1, 5, and 10 years were 97, 91, and 81 %, respectively. The risk of death was statistically significantly higher among participants with ILD compared to those without ILD (HR 2.13. 95 % CI 1.06–4.25; p = 0.03). We analyzed one of the largest known cohorts of patients with autoimmune myositis and found significantly higher mortality rates among those with clinically evident ILD compared to those without clinically evident ILD. Our results suggest that ILD remains an important and significant source of mortality in patients with inflammatory myopathies and as such should be screened for and treated aggressively.
93 citations
TL;DR: People with IPF report substantial deficits in HRQOL across a range of PROMIS domains, and deficits vary by dyspnea and cough severity, which warrant monitoring in clinical practice and consideration when investigating new therapies.
Abstract: Idiopathic pulmonary fibrosis (IPF) produces symptoms and activity limitations that impair health-related quality of life (HRQOL). The Patient-Reported Outcomes Measurement Information System® (PROMIS®) includes measures of self-reported health and HRQOL for a range of conditions. This study evaluated the HRQOL of individuals with IPF using PROMIS measures and examined associations between HRQOL and key symptoms or supplemental oxygen need. Individuals who reported being told by a doctor that they have IPF completed an online battery of measures at baseline and 7–10 days later (for test–retest reliability). Measures included a brief survey of demographic and health-related questions, the PROMIS-29 profile, the Modified Medical Research Council Dyspnea Scale (MMRC), PROMIS dyspnea severity short form, A Tool to Assess Quality of life in IPF (ATAQ-IPF) and one cough item from the Functional Assessment of Chronic Illness Therapy (FACIT). 220 individuals were included in the final sample. Except for sleep disturbance, all PROMIS domain scores significantly (p 0.7) for all scales, but was lower for sleep disturbance (0.64). People with IPF report substantial deficits in HRQOL across a range of PROMIS domains, and deficits vary by dyspnea and cough severity. These deficits warrant monitoring in clinical practice and consideration when investigating new therapies. Further research is required to further evaluate the psychometric performance of the PROMIS-29 in IPF.
84 citations
TL;DR: Diaphragm US is a valid predictor of extubation success at some but not all PS settings, and using a ∆tdi% of 20 % on PS levels up to 10/5 cm of H2O may reduce both unnecessarily prolonged intubations and prevent emergent reintubations.
Abstract: Ultrasonographic assessment of diaphragm function with patients on low levels of pressure support (PS) predicts extubation outcomes, but similar information regarding extubation success under other conditions is lacking. The purpose of this study was to determine whether ultrasound (US) measurements of the diaphragm made on various levels of PS can predict time until successful extubation. Fifty-six intubated patients underwent ultrasound of the right hemidiaphragm during a PS wean at varying levels of pressure support (PS 5/5 cm of H2O, 10/5 cm of H2O, and 15/5 cm of H2O). The diaphragm was visualized using a 7.5–10 mHz transducer in the zone of apposition of the diaphragm to the lower rib cage. The percent change in diaphragm thickness between end-expiration and end-inspiration (∆tdi%) was calculated at each level of PS. ∆tdi% >20 is a robust predictor of extubation success within 48 h of US at PS 5/5 cm of H2O and 10/5 cm of H2O (sensitivity 84.6 and 88.9 % and specificity 79.0 and 75.0 %, respectively). At PS greater than 10/5 cm of H2O, its predictive power was greatly diminished. Of nine patients who were extubated with ∆tdi% below the cutoff, 66.6 % required emergent reintubation in the next two days. Diaphragm US is a valid predictor of extubation success at some but not all PS settings. Using a ∆tdi% of 20 % on PS levels up to 10/5 cm of H2O may reduce both unnecessarily prolonged intubations and prevent emergent reintubations.
63 citations
TL;DR: 3-dimensional cell culture is currently a major area of development, where cells are cultured in a matrix or in a manner that they develop ECM-like scaffolds between them, thus mimicking the in vivo phenotype more faithfully.
Abstract: The pulmonary epithelium is divided into upper, lower, and alveolar (or small) airway epithelia and acts as the mechanical and immunological barrier between the external environment and the underlying submucosa. Of these, the small airway epithelium is the principal area of gas exchange and has high immunological activity, making it a major area of cell biology, immunology, and pharmaceutical research. As animal models do not faithfully represent the human pulmonary system and ex vivo human lung samples have reliability and availability issues, cell lines, and primary cells are widely used as small airway epithelial models. In vitro, these cells are mostly cultured as monolayers (2-dimensional cultures), either media submerged or at air–liquid interface. However, these 2-dimensional cultures lack a three dimension—a scaffolding extracellular matrix, which establishes the intercellular network in the in vivo airway epithelium. Therefore, 3-dimensional cell culture is currently a major area of development, where cells are cultured in a matrix or are cultured in a manner that they develop ECM-like scaffolds between them, thus mimicking the in vivo phenotype more faithfully. This review focuses on the commonly used small airway epithelial cells, their 2-dimensional and 3-dimensional culture techniques, and their comparative phenotype when cultured under these systems.
62 citations
TL;DR: The aim of this review is to describe the main clinical, imaging, and pathological aspects of Niemann–Pick disease, with a focus on pulmonary involvement.
Abstract: Niemann–Pick disease is a rare autosomal recessive lysosomal storage disease with three subtypes. Types A and B result from a deficiency of acid sphingomyelinase activity, associated with the accumulation of lipid-laden macrophages (so-called Niemann–Pick cells) in various tissues, especially the liver and spleen. Type A is a fatal neurodegenerative disorder of infancy. Type B Niemann–Pick disease is a less severe form with milder neurological involvement, characterized by hepatosplenomegaly, hyperlipidemia, and pulmonary involvement; most patients live into adulthood. Type C Niemann–Pick disease is a complex lipid storage disorder caused by defects in cholesterol trafficking, resulting in a clinical presentation dominated by neurological involvement. Pulmonary involvement occurs in all three types of Niemann–Pick disease, but most frequently in type B. Respiratory manifestations range from a lack of symptoms to respiratory failure. Progression of respiratory disease is slow, but inexorable, due to the accumulation of Niemann–Pick cells in the alveolar septa, bronchial walls, and pleura, potentially leading to a progressively worsening restrictive pattern on pulmonary function testing. Bronchoalveolar lavage has important diagnostic value because it shows the presence of characteristic Niemann–Pick cells. Radiographic findings consist of a reticular or reticulonodular pattern and, eventually, honeycombing, involving mainly the lower lung zones. The most common changes identified by high-resolution computed tomography are ground-glass opacities, mild smooth interlobular septal thickening, and intralobular lines. The aim of this review is to describe the main clinical, imaging, and pathological aspects of Niemann–Pick disease, with a focus on pulmonary involvement.
55 citations
TL;DR: The cut-off level for serum LDH: pleural fluid ADA ratio of >20 is highly predictive of malignancy in patients with exudative pleural effusion (whether lymphocytic or neutrophilic) with high sensitivity and specificity.
Abstract: Aim
We studied the diagnostic potential of serum lactate dehydrogenase (LDH) in malignant pleural effusion.
55 citations
TL;DR: The two IGRAs showed better performance than TST for the diagnosis of the tuberculosis, however, neither of them showed stability in the diagnoses of TB.
Abstract: We conducted a systematic review and meta-analysis to compare the accuracy of the interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) for the diagnosis of Mycobacterium tuberculosis infection. We systematically searched PubMed, Embase, Cochrane library, and Web of Science databases for relevant published studies in recent decades and calculated pooled estimated sensitivities, specificities, DOR, and SROC curve of the QFT-IT, T-SPOT and TST. Random-effects models were used to assess estimates from studies with significant heterogeneity. Moreover, area under the curve was used to evaluate the accuracy of the tests. Overall, 9 studies for QFT-IT, 12 studies for T-SPOT, and 16 studies for TST involving 3586 participants were included in this analysis. We found that sensitivities of the QFT-IT, T-SPOT, and TST were respectively 0.842 (95 % CI 0.811–0.870), 0.840 (95 % CI 0.814–0.864), and 0.665 (CI 0.635–0.693); specificities were respectively 0.745 (95 % CI 0.715–0.775), 0.658 (95 % CI 0.621–0.693), and 0.633 (CI 0.605–0.661); positive likelihood ratios were respectively 3.652 (95 % CI 2.180–6.117), 2.196 (95 % CI 1.727–2.794), and 1.825 (95 % CI 1.351–2.464); negative likelihood ratios were respectively 0.212 (95 % CI 0.109–0.414), 0.246 (95 % CI 0.161–0.377), and 0.556 (95 % CI 0.385–0.804); the SROC curves were 19.205, 10.397, and 3.810. The two IGRAs showed better performance than TST for the diagnosis of the tuberculosis. However, neither of them showed stability in the diagnosis of TB.
49 citations
TL;DR: The results showed the clinical benefits of OM-85 in reducing RTIs and exacerbations of the underlying medical condition, in patients with allergic rhinitis, asthma, or COPD.
Abstract: The aim of this study was to evaluate the efficacy of OM-85 in reducing the incidence of respiratory tract infections (RTIs) in patients with allergic rhinitis, asthma, or chronic obstructive pulmonary disease (COPD), and its effect on immunological parameters, namely serum and secretory IgA levels. This was an open-label, prospective, sequential study which included 84 consecutive patients aged 16–65 years, who presented with recurrent (three or more) respiratory infections during the year prior to study entry. In the first year of the study, patients received standard optimized care (SOC), according to their underlying disease condition (asthma, allergic rhinitis, or COPD). In the following year, patients received treatment with OM-85 oral bacterial lysate (one 7 mg capsule daily for ten consecutive days per month, for 3 months), with a 6-month follow-up. Medical history, clinical symptoms, serum, and secretory IgA levels, and the number of infections and exacerbations were evaluated before and after treatment. There was a decrease in the total number of RTIs before the OM-85 treatment period (SOC only) compared to the year before the study start [69/266 (corresponding to a 74 % reduction)] and an additional decrease [38/69 (corresponding to a 45 % reduction)] after OM-85 treatment; p < 0.05. There was also a significant reduction in the total number of exacerbations related to the patients’ underlying medical conditions, which decreased from 55 to 35 during OM-85 (+SOC) treatment, corresponding to a reduction of 36 %. In addition, an increase in serum and secretory IgA levels which coincided with the administration of OM-85 was observed. Our results showed the clinical benefits of OM-85 in reducing RTIs and exacerbations of the underlying medical condition, in patients with allergic rhinitis, asthma, or COPD.
46 citations
TL;DR: Endoscopic therapy, associated with a conservative treatment, is a safe and useful option in the management of the postoperative bronchopleural fistula.
Abstract: Bronchopleural fistula is a rare but potentially fatal complication of pulmonary resections and proper management is essential for its resolution. In this study, we analyzed the incidence of fistula after pulmonary resection and reported data about endoscopic and conservative treatments of this complication. From January 2003 to December 2013, 835 patients underwent anatomic lung resections: 786 (94.1 %) had a lobectomy and 49 (5.9 %) a pneumonectomy. Bronchopleural fistula was suspected by clinical signs and confirmed by endoscopic visualization. Eighteen patients (2.2 %) developed a bronchopleural fistula, 11 in lobectomy group (1.4 %) and 7 in pneumonectomy group (14.3 %). The fistula size ranged between <1 mm and 6 mm and mean time of fistula onset was 33.9 ± 54.9 days after surgery. Of 18 patients who developed fistula, one died due to acute respiratory failure and another one was reoperated and then died to causes unrelated to the treatment. All the remaining 16 patients were treated with a conservative therapy that consisted in keeping or replacing a drainage chest tube. Nine of them underwent also endoscopic closure of the fistula using biological or synthetic glues. The mean period of time elapsed for the resolution of this complication was shorter with combined (conservative + endoscopic) than with conservative treatment alone (15.4 ± 13.2 vs. 25.8 ± 13.2 days, respectively), but without significant difference between the two methods (p: 0.299). Endoscopic therapy, associated with a conservative treatment, is a safe and useful option in the management of the postoperative bronchopleural fistula.
TL;DR: Nearly one-quarter of the patients with COPD in this study presented clinically significant depression associated with worse quality of life, reduced exercise capacity, greater dyspnea, and a higher score in the BODE index.
Abstract: Introduction
Depression is a prevalent comorbidity in COPD and has an impact on the prognosis of these patients, thereby making it important to study the factors associated with depression in patients with COPD.
TL;DR: The results suggest that muscular dysfunction in patients with COPD differs in different muscular compartments, and the main factor for a reduced exercise capacity was a reduction in inspiratory capacity.
Abstract: Muscular dysfunction has been described as one of the systemic manifestations of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate muscular strength of the different anatomical compartments in patients with severe COPD compared with healthy controls. We performed a cross-sectional study in patients with severe COPD. We evaluated the muscular strength of the respiratory muscles, flexors and extensors of the cervical spine and knee, as well as handgrip force. The 6-min walking test (6MWT) and serum inflammatory markers were also analysed. Twenty-eight male patients with COPD (mean age 67.8 years, mean FEV1 (%) 39 %) and 24 male healthy controls (mean age 70.2 years) were studied. The strength of the flexors and extensors of the knee was significantly reduced in patients with COPD (p < 0.001 and p = 0.003). No differences were observed in the flexors and extensors of the cervical spine and handgrip force between groups. No correlation was observed between the muscular strength in the different anatomic compartments and the concentrations of blood inflammatory biomarkers or the metres walked in the 6MWT in COPD patients. However, a significant negative linear correlation was observed between the 6MWT and IL-6 and IL-8 levels (rho = −0.67, p = 0.001; rho = −0.57, p = 0.008). In addition, we found a negative correlation between the 6MWT and inspiratory capacity (rho = −0.755, p = 0.031). Our results suggest that muscular dysfunction in patients with COPD differs in different muscular compartments. The main factor for a reduced exercise capacity was a reduction in inspiratory capacity.
TL;DR: Serum biomarkers may be helpful for early diagnosis of MPM in asbestos-exposed cases, and SMRP and TRX increased in a graded fashion from the controls to asbestos exposure and MPM groups.
Abstract: The purpose of this study was to investigate the potential value of certain biomarkers in predicting the presence of malignant pleural mesothelioma (MPM) in individuals environmentally exposed to asbestos. This prospective study investigated three groups; a control group composed of 41 healthy subjects, an asbestos exposure group consisting of 48 individuals, and a MPM group consisting of 42 patients. Serum levels of soluble mesothelin-related peptide (SMRP), thioredoxin-1 (TRX), epidermal growth factor receptor (EGFR), fibulin-3, syndecan-1 (SDC-1), and mesothelin were determined. Benign pleural plaques were present in 27 (58.3 %) of the individuals in the asbestos exposure group. The asbestos exposure group had significantly higher mean TRX, SMRP, and mesothelin levels compared to the control group (p = 0.023, p = 0.011, and p < 0.001, respectively). Compared to the asbestos exposure group, the MPM group had significantly higher mean EGFR, TRX, SMRP, and fibulin-3 levels (p = 0.041, p = 0.023, p = 0.002, and p = 0.001, respectively), and significantly lower mean SDC-1 levels (p = 0.002). Unlike the other biomarkers, SMRP and TRX levels increased in a graded fashion among the control, asbestos exposure, and MPM groups, respectively. Area under the curve values for SMRP and TRX were 0.86 and 0.72, respectively (95 % CI 0.79–0.92 and p < 0.001 for SMRP, and 95 % CI 0.62–0.81 and p < 0.001 for TRX). The cut-off value for SMRP was 0.62 nmol/l (sensitivity: 97.6 %, specificity: 68.9 %, positive predictive value (PPV): 56.2 %, and negative predictive value (NPV): 98.3 %) and for TRX was 156.67 ng/ml (sensitivity: 92.9 %, specificity: 77.6 %, PPV: 41.4 %, and NPV: 92.1 %). The combination of the biomarkers reached a sensitivity of 100 %, but had lower specificity (as high as 27.7 %). Serum biomarkers may be helpful for early diagnosis of MPM in asbestos-exposed cases. SMRP and TRX increased in a graded fashion from the controls to asbestos exposure and MPM groups. These two seem to be the most valuable biomarkers for the diagnosis of MPM, both individually and in combination.
TL;DR: Based on this review, heavy dosing sedation strategy with benzodiazepines contributes to cognitive dysfunction and outcome for mental health dysfunction is mixed in regard to newer sedatives agents such as dexmedetomidine and propofol.
Abstract: The practice of sedation dosing strategy in mechanically ventilated patient has a profound effect on cognitive function. We conducted a comprehensive review of outcome of sedation on mental health function in critically ill patients on mechanical ventilation in the intensive care unit (ICU). We specifically evaluated current sedative dosing strategy and the development of delirium, post-traumatic stress disorders (PTSDs) and agitation. Based on this review, heavy dosing sedation strategy with benzodiazepines contributes to cognitive dysfunction. However, outcome for mental health dysfunction is mixed in regard to newer sedatives agents such as dexmedetomidine and propofol. Moreover, studies that examine the impact of sedatives for persistence of PTSD/delirium and its long-term cognitive and functional outcomes for post-ICU patients are frequently underpowered. Most studies suffer from low sample sizes and methodological variations. Therefore, larger randomized controlled trials are needed to properly assess the impact of sedation dosing strategy on cognitive function.
TL;DR: Intermittent hypoxia contributes to the lung damage by increased oxidative stress, inflammation, and disbalance in protease/antiprotease system and the application of anti-inflammatory infliximab und anti-oxidative l-glutathione prevented at least partly the above-observed Hypoxia-associated changes.
Abstract: Intermittent hypoxia as a surrogate of obstructive sleep apnea is associated with different cardiovascular complications. However, the effects of intermittent hypoxia on the lung tissue are less known. Therefore, the aim of our present study was to investigate if intermittent hypoxia may influence oxidative stress, inflammation, and protease/antiprotease system in the lung. Additionally, potential protective properties of anti-inflammatory and anti-oxidative drugs have been evaluated. 32 mice were divided into four groups: (1) intermittent hypoxia, (2) intermittent hypoxia with infliximab, (3) intermittent hypoxia with l-glutathione, and (4) normoxia. After 4 weeks, lungs and blood were collected. Levels of reactive oxygen species in the lung were calculated by L-O12-enhanced chemiluminescence. CD68-positive lung macrophages were detected by immunofluorescence. Concentrations of elastase and desmosine in lung and of alpha-1-antitrypsin in blood were calculated by means of enzyme-linked immunosorbent assay. Compared to a control, intermittent hypoxia augmented the release of free oxygen radicals, expression of CD68+ macrophages, and concentration of elastase in the lung tissue. Despite increased blood levels of protective alpha-1-antitrypsin, concentrations of desmosine—degradation product of elastin were higher versus control. The application of anti-inflammatory infliximab und anti-oxidative l-glutathione prevented at least partly the above-observed hypoxia-associated changes. Intermittent hypoxia contributes to the lung damage by increased oxidative stress, inflammation, and disbalance in protease/antiprotease system. Infliximab and l-glutathione may prevent adverse hypoxia-induced lung alternations.
TL;DR: A mechanism of Ply-mediated platelet activation involving sub-lytic pore formation, Ca2+ influx, and mobilization of CD62P-expressing α-granules, which, if operative in vivo, may contribute to the pathogenesis of associated acute lung and myocardial injury during invasive pneumococcal disease.
Abstract: This study has explored the role of the pneumococcal toxin, pneumolysin (Ply), in activating human platelets. Following exposure to Ply (10-80 ng/ml), platelet activation and cytosolic Ca(2+) concentrations were measured flow cytometrically according to the level of expression of CD62P (P-selectin) and spectrofluorimetrically, respectively. Exposure to Ply resulted in marked upregulation of expression of platelet CD62P, achieving statistical significance at concentrations of 40 ng/ml and higher (P < 0.05), in the setting of increased influx of Ca(2+). These potentially pro-thrombotic actions of Ply were attenuated by depletion of Ca(2+) from the extracellular medium or by exposure of the cells to a pneumolysoid devoid of pore-forming activity. These findings are consistent with a mechanism of Ply-mediated platelet activation involving sub-lytic pore formation, Ca(2+) influx, and mobilization of CD62P-expressing α-granules, which, if operative in vivo, may contribute to the pathogenesis of associated acute lung and myocardial injury during invasive pneumococcal disease.
TL;DR: Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1, and INPP4A, which could possibly serve as candidate genes for alterations associated withbestos exposure.
Abstract: Asbestos is a carcinogen linked to malignant mesothelioma (MM) and lung cancer. Some gene aberrations related to asbestos exposure are recognized, but many associated mutations remain obscure. We performed exome sequencing to determine the association of previously known mutations (driver gene mutations) with asbestos and to identify novel mutations related to asbestos exposure in lung adenocarcinoma (LAC) and MM. Exome sequencing was performed on DNA from 47 tumor tissues of MM (21) and LAC (26) patients, 27 of whom had been asbestos-exposed (18 MM, 9 LAC). In addition, 9 normal lung/blood samples of LAC were sequenced. Novel mutations identified from exome data were validated by amplicon-based deep sequencing. Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM. In asbestos-exposed MM patients, previously non-described NF2 frameshift mutation (one) and BAP1 mutations (four) were detected. Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1. BAP1 and COPG1 mutations were seen exclusively in MM. Pathogenic KRAS mutations were common in LAC patients (42 %), both in non-exposed (n = 5) and exposed patients (n = 6). Pathogenic BRAF mutations were found in two LACs. BAP1 mutations occurred in asbestos-exposed MM. MRPL1, SDK1, SEMA5B, and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure. KRAS mutations in LAC were not associated with asbestos exposure.
TL;DR: It is suggested that ANGPTL4 was essential for proliferation and metastasis of lung cancer cells and might serve as a novel target for the treatment of Lung cancer.
Abstract: Purpose Lung cancer remains the leading cause of cancer deaths with intricate mechanisms. In the present study, we evaluated the clinical significance and biological role of ANGPTL4 in non-small cell lung cancer (NSCLC), the most common lung cancer subtype. Methods Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for examining the mRNA level of ANGPTL4 in NSCLC tissues and adjacent non-tumor tissues, NSCLC cell lines, and the immortalized human bronchial epithelial cell line HBE, respectively. A tissue microarray was used for analyzing the relationship between ANGPTL4 expression and the clinicopathological parameters of NSCLC patients. Commercial lentivirus expressing shRNAs was used for silencing ANGPTL4. Cell Counting Kit-8 (CCK-8) was employed for evaluating the cell proliferation ability and transwell with or without matrigel was used for cell migration and invasion assay. Results As the result, ANGPTL4 was over-expressed in NSCLC tissues compared with benign lung tissues. Silencing ANGPTL4 expression strongly inhibited the proliferation, migration, and invasion of A549 and H520 cells, which was in accordance with the increase of epithelial marker E-cadherin and decrease of mesenchymal marker vimentin. By screening the ERK, AKT, EGFR, and STAT3 pathways, we found that cell growth, migration, and invasion arrest induced by loss of ANGPTL4 expression was partially attributable to down-regulation of ERK signaling. Conclusion These results suggested that ANGPTL4 was essential for proliferation and metastasis of lung cancer cells and might serve as a novel target for the treatment of lung cancer.
TL;DR: Evidence supports the idea that changes occur in the physiology of both the sensory and autonomic innervation during viral infection, which can lead to underlying airway pathologies such as asthma and COPD and hospitalization.
Abstract: Respiratory virus infections leads to coughing, sneezing, and increases in reflex parasympathetic bronchoconstriction and secretions. These responses to viral infection are exclusively or largely secondary to changes in the function of the nervous system. For many with underlying airway pathologies such as asthma and COPD, this neuroplasticity can lead to disease exacerbations and hospitalization. Relatively little is understood about the cellular and molecular mechanisms that underlie the changes in neuronal control of the respiratory tract during viral infection, but the evidence supports the idea that changes occur in the physiology of both the sensory and autonomic innervation. Virus infection can lead to acute increases in the activity of sensory nerves as well as to genetic changes causing alterations in sensory nerve phenotype. In addition, respiratory viral infections are associated with changes in the control of neurotransmitter release from cholinergic nerve endings terminating at the level of the airway smooth muscle.
TL;DR: The main inflammatory mediators and oxidative stress markers analyzed were TNF-α, IL-8,IL-6, IL,1β, nuclear factor kappa β, MDA, and MPO, and it is necessary to increase the rigor of study design and data, in order to have studies that are more homogeneous and with appropriate methodological quality.
Abstract: Background
The inhalation injury is usually initiated by uninhibited absorption of smoke, favoring the release of cytokines and other lipid mediators from inflammatory cells in lung airways and parenchyma.
TL;DR: Cardiac involvement in sarcoidosis was diagnosed in the similar percentage as in previously published data but was significantly more frequently in men.
Abstract: Introduction
Sarcoidosis is a systemic granulomatous disease which predominantly affects the lungs, although granulomas can also involve all other organs, including the heart. Cardiac sarcoidosis (CS) may occur at any stage of the disease and may be the cause of sudden cardiac death, even in a previously asymptomatic patient. The aim of this study was to evaluate the incidence of CS in a large group of patients diagnosed or followed up due to sarcoidosis.
TL;DR: The HRCT patterns of PR3-ANCA-positive IIP patients varied more than those of the IPF patients, but the clinical features of high IIP-onset age and male predominance were similar between the groups.
Abstract: The clinical significance of proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity is not well established in idiopathic interstitial pneumonia (IIP) patients. We aimed to determine the clinical features of PR3-ANCA-positive IIP patients. We retrospectively reviewed 377 consecutive IIP patients; of these, 360 patients had PR3-ANCA and myeloperoxidase-antineutrophil cytoplasmic antibody test results available. The clinical features of PR3-ANCA-positive IIP patients and control ANCA-negative idiopathic pulmonary fibrosis patients (ANCA-negative IPF) were compared. Sixteen patients (4.4 %) were PR3-ANCA-positive IIP and 94 (26 %) were ANCA-negative IPF. The median age at diagnosis (72 vs. 70 years, P = 0.17) and proportion of males (75 vs. 89 %, P = 0.12) in PR3-ANCA-positive IIP and ANCA-negative IPF patients, respectively, were not significantly different. Radiologically, the HRCT patterns of PR3-ANCA-positive IIP patients varied (UIP, n = 3, 18.8 %; possible UIP, n = 3, 18.8 %; NSIP, n = 5, 31.3 %; unclassifiable CT pattern, n = 5, 31.3 %) more than those of ANCA-negative IPF patients (UIP, n = 69, 73.4 %; possible UIP, n = 25, 26.6 %; P < 0.001). No PR3-ANCA-positive IIP patients developed ANCA-associated vasculitis. The 5-year survival rate was 50 % in PR3-ANCA-positive IIP patients and 52 % in ANCA-negative IPF patients with no significant difference (P = 0.96 by log-rank test). The HRCT patterns of PR3-ANCA-positive IIP patients varied more than those of the IPF patients, but the clinical features of high IIP-onset age and male predominance were similar between the groups. Furthermore, PR3-ANCA-positive IIP patients had a poor prognosis similar to that of IPF patients.
TL;DR: Investigation of epithelial–mesenchymal transition induced by MTX and by transforming growth factor (TGF)-β1 in the human alveolar epithelial cell line A549 demonstrated that phenotypic changes of A549 cells induced byMTX are partly mediated by a TGF-β1-related intracellular signaling pathway, although TGF -β1 itself is not directly involved in this process.
Abstract: Methotrexate (MTX) therapy of certain cancers and rheumatoid arthritis often induces serious interstitial lung complications including pulmonary fibrosis. In this study, we investigated the epithelial–mesenchymal transition (EMT) induced by MTX and by transforming growth factor (TGF)-β1 in the human alveolar epithelial cell line A549 in order to develop new strategies for the prevention of EMT. First, we examined the effect of TGF-β1 and MTX on cell morphology and the expression of EMT-related mRNAs in A549 cells. Then, the effects of SB431542 (SB), a potent inhibitor of TGF-β receptor kinase, and a neutralizing antibody for TGF-β1 on the phenotypic changes of A549 cells induced by TGF-β1 and MTX were examined. After incubation with TGF-β1 and MTX, the mRNA expression of epithelial markers such as cytokeratin 19 was reduced, while that of mesenchymal markers such as α-smooth muscle actin was increased. SB suppressed the development of morphological changes and partially rescued alterations in mRNA expression of EMT markers induced by MTX. In addition, the enhancement of SMAD2 phosphorylation by MTX was also prevented by SB. On the other hand, EMT-related changes induced by MTX were not affected by a neutralizing antibody for TGF-β1. We have demonstrated that phenotypic changes of A549 cells induced by MTX are partly mediated by a TGF-β1-related intracellular signaling pathway, although TGF-β1 itself is not directly involved in this process.
TL;DR: In moderate stable COPD, fatigue may be a central driver of functional disability, to the same extent as dyspnoea.
Abstract: Fatigue is one of the most disabling symptoms in COPD, but little is known about the impact of fatigue on functional disability. We explored the impact of fatigue and fatigue intensity on exercise tolerance after adjusting for other factors using multivariate analysis and compared it to that of dyspnoea. A total of 119 patients with mainly moderate–severe stable COPD (38 % women, mean age 66 years) were enrolled. We used the Medical Research Council dyspnoea scores (MRC), Manchester COPD fatigue scale (MCFS) and its three dimensions, Borg scales for fatigue and dyspnoea, six-minute walk distance (6MWD), St George’s Respiratory Questionnaire, the BODE index, and the Centre for Epidemiological Study on Depression scale (CES-D), and we measured spirometry, blood gases, systemic inflammatory markers and fat-free mass index (FFMI). Fatigue measured using the MCFS was associated with 6MWD and explained 22 % of the variability in 6MWD (p < 0.001). Fatigue remained associated with 6MWD after adjusting for MRC dyspnoea, FFMI and FEV1, FVC, PaO2, PaCO2, CES-D, TNF-alpha, smoking status, age and gender. We found that 33, 50 and 23 % of patients reported an increase by 2 scores on Borg scales for fatigue, dyspnoea or both at the end of the 6MWT. Fatigue scores (both before and after the 6MWT) were negatively correlated with 6MWD after adjusting for FEV1, FFMI, CES-D score and age (p = 0.007 and 0.001, respectively). In moderate stable COPD, fatigue may be a central driver of functional disability, to the same extent as dyspnoea.
TL;DR: It is indicated that autophagy protected human lung cancer cells from gemcitabine-induced apoptosis, and the combined use of gem citabine and an autophagic inhibitor in lung cancer patients may be an effective therapeutic strategy.
Abstract: Gemcitabine has been used as a therapeutic drug combined with cisplatin for the treatment of lung cancer patients. However, the prognosis is poor due to acquired resistance. Accumulating studies have revealed that autophagy may contribute to the drug resistance. Therefore, the present study is aimed to clarify the mechanisms underlying gemcitabine-acquired resistance. SPC-A1 and A549 cells were incubated with gemcitabine followed by assessment of cell viability with MTT assays. GFP-LC3 transient transfection, MDC staining, and transmission electron microscopy were used to detect the change of autophagy at morphological level. Flow cytometry was used to monitor the effect of 3-MA on gemcitabine-induced apoptosis. Western blot analysis was used to detect the expression of p62, LC3, Beclin-1, ATG5, activated caspase 3, Bax, BNIP3, BNIP3L, and Bcl-2. Our study showed that gemcitabine significantly induced both autophagy and apoptosis in human lung cancer cells SPC-A1 and A549. Of interest was that when autophagy was inhibited by 3-MA, the gemcitabine-induced apoptosis was effectively enhanced, suggesting that gemcitabine can activate autophagy to impair the chemosensitivity of lung cancer cells. Furthermore, the inhibition of autophagy by 3-MA further increased the expression of activated caspase 3, Bax, BNIP3, and BNIP3L, all are critical apoptotic mediators. Contrarily, 3-MA treatment further decreased the expression of Bcl-2, which is an important anti-apoptotic protein. Our study indicated that autophagy protected human lung cancer cells from gemcitabine-induced apoptosis, and the combined use of gemcitabine and an autophagic inhibitor in lung cancer patients may be an effective therapeutic strategy.
TL;DR: Findings could help identify COPD patient subsets who may benefit from therapies targeting IL-1β pathway and reaffirm association between IL- 1β pathway activation and airway bacterial infection in COPD.
Abstract: Activation of the interleukin-1β (IL-1β) signaling pathway has been implicated in COPD, but the proportion of COPD subjects whose disease is principally driven by activation of this pathway is poorly understood. In this study, we sought to differentiate an IL-1β-associated sputum signature from other inflammation-associated COPD phenotypes. Luminex-multiplex assays were used to study IL-1β-mediated signature proteins within airway epithelium, smooth muscle, and vascular endothelial cell cultures. The IL-1β-mediated signature was tested in a longitudinal study comprising of 35 paired stable-COPD and acute exacerbation (AECOPD) sputum samples. The presence of respiratory pathogens (H. influenzae, M. catarrhalis, S. pneumoniae, and P. aeruginosa) was evaluated by sputum cultures. Five proteins namely TNF-α, GCSF, IL-6, CD-40L, and MIP-1β were found to be IL-1β-regulated across all donors and cell types. All five of these IL-1β-mediated proteins were significantly increased (p 0.05, spearman) with known markers of other major COPD inflammation phenotypes. In addition, there was a significant association with bacterial presence in sputum culture with an odds ratio of 9 (95 % CI 1.56, 51.9) in IL-1β+ events versus IL-1β− events. Our findings provide insights into potential markers of IL-1β-associated AECOPD, and reaffirm association between IL-1β pathway activation and airway bacterial infection in COPD. Taken together, our findings could help identify COPD patient subsets who may benefit from therapies targeting IL-1β pathway.
TL;DR: Results indicated that simvastatin and BMSC combination therapy was superior to simVastatin therapy and B MSC therapy alone in reduction of airway remodeling and lung inflammation in the ovalbumin-induced asthma model in mouse.
Abstract: The effect of bone marrow-derived mesenchymal stem cells (BMSCs) on asthma treatment was shown in our previous study. Several studies have shown the effect of statins on BMSC preservation and migration to sites of inflammation. In this study, the effects of simvastatin and BMSC combination therapy in an ovalbumin-induced asthma model in mouse were examined. Four groups of BALB/c mice were studied including control group (animals were not sensitized), asthma group (animals were sensitized by ovalbumin), asthma + simvastatin group (asthmatic animals were treated with simvastatin), and asthma + BMSC + simvastatin group (asthmatic animals were treated with simvastatin and BMSCs). BMSCs were isolated, characterized, labeled with BrdU, and transferred into asthmatic mice. BMSC migration, airways histopathology, and total and differential white blood cell (WBC) count in bronchoalveolar lavage (BAL) fluid were evaluated. A significant increase in the number of BrdU-BMSCs was found in the lungs of mice treated with simvastatin + BMSCs compared to mice treated with BMSCs. The histopathological changes, BAL total WBC counts, and the percentage of neutrophils and eosinophils were increased in asthma group compared to the control group. Treatment with simvastatin significantly decreased airway inflammation and inflammatory cell infiltration. Combination therapy improved all measured parameters higher than simvastatin. Goblet cell hyperplasia and subepithelial fibrosis were also decreased in combination therapy group. These results indicated that simvastatin and BMSC combination therapy was superior to simvastatin therapy and BMSC therapy alone in reduction of airway remodeling and lung inflammation in the ovalbumin-induced asthma model in mouse.
TL;DR: The findings indicate that smoking is closely related to the risk of squamous-cell and small-cell carcinoma among women as well as men, but the magnitude of smoking-related lung cancer risk is likely to differ between men and women.
Abstract: Using nationwide cancer incidence data, we examined whether the strength of the association of cigarette smoking with lung cancer risk differs according to major histological type and gender, taking account of other risk factors in the Korean population. The study population derived from government employees and teachers aged 20 years and over who participated in a national health examination program in 1998 or 1999. Total study subjects were 1,357,447. After excluding 1556 subjects who were treated with lung cancer during 1998–2000, we restricted our analysis to 1,355,891 cases. We followed up those 1,355,891 subjects who were cancer-free at baseline until December 31, 2010. The incident cancer cases were identified from the Korea Central Cancer Registry, which is a nationwide hospital-based cancer registry system that includes 94 % of the university hospitals and 96 % of the resident training hospitals of the country. A higher risk for having ever smoked was observed for squamous-cell and small-cell carcinoma in both men and women. Heavy and long-term smokers were at higher risk for these carcinomas. Significant associations with quantity and duration-related factors were observed mainly among men. These findings indicate that smoking is closely related to the risk of squamous-cell and small-cell carcinoma among women as well as men. However, the magnitude of smoking-related lung cancer risk is likely to differ between men and women. The hazard ratios for all types of lung cancer were significantly higher in male current smokers than in male never smokers. In case of women, the hazard ratios for adenocarcinoma were not different between current smokers and never smokers. The hazard ratios we found, however, were lower than those reported in Western countries and in Korea, but consistent with those reported in North-eastern Asian countries.
TL;DR: Nonsmoker COPD patients presented with impaired mobility, pain/discomfort, and anxiety/depression functions as well as a lower mean EuroQol Five-Dimension Questionnaire utility score, which showed HRQoL.
Abstract: Chronic obstructive pulmonary disease (COPD) is increasing in prevalence and mortality. This study evaluated the prevalence, risk factors, characteristics, and health-related quality of life (HRQoL) of COPD among nonsmokers in Korea. This was a population-based cross-sectional study using data obtained from the Fourth and Fifth Korean National Health and Nutrition Examination Survey, which was conducted from 2007 to 2011. A total of 15,063 participants completely answered the questionnaire and performed the spirometry. Among them, 59.6 % were nonsmokers and 40.4 % were smokers. The prevalence of nonsmoker COPD was 7.1 %. On multivariate analysis, age ≥65 years (OR, 2.93; 95 % CI, 2.44–3.51), male sex (OR, 2.98; 95 % CI, 2.40–3.71), living in rural area (OR, 1.26; 95 % CI, 1.05–1.51), lower body mass index (BMI) (<18.5 kg/m2) (OR, 3.00; 95 % CI, 1.78–5.01), self-reported asthma (OR, 2.72; 95 % CI, 2.05–3.60), and self-reported tuberculosis (OR, 4.73; 95 % CI, 3.63–6.17) showed a significantly higher risk of nonsmoker COPD. Analysis of nonsmoker and smoker COPD revealed that there are more females in nonsmoker COPD patients (73.9 vs. 6.9 %, P < 0.001). Nonsmoker COPD patients presented with impaired mobility, pain/discomfort, and anxiety/depression functions as well as a lower mean EuroQol Five-Dimension Questionnaire utility score, which showed HRQoL. The burden of nonsmoker COPD was considerable. Older age, male sex, lower BMI, self-reported asthma, and self-reported tuberculosis were risk factors for nonsmoker COPD and there were differences between nonsmoker and smoker COPD in terms of sex, comorbidities, and HRQoL.