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Type 2 innate lymphoid cells (ILC2s) have been shown to produce large amounts of type 2 cytokines in a non–antigen-specific manner. These cytokines act upstream and downstream of ILC2 and are increasingly common in asthma drug development, thus warranting a closer investigation of the mechanism-related clinical manifestations of ILC2 in the selection of patients with asthma. We hypothesized that IL-13+ILC2s in the circulation might correlate with asthma control status as a result of persistent T-helper cell type 2 (Th2) inflammation in the lung. Furthermore, we aimed to explore ILC2s’ responsiveness to glucocorticoid. The percentages of ILC2s and IL-13+ILC2s in different asthma subgroups were checked, and correlation analyses between ILC2s and asthma-related clinical parameters were performed. Dexamethasone treatments in ILC2s and Th2 cells were performed to clarify their response properties. ILC2s were identified as a Lin-CD45hiIL-7Rα+CRTH2+ cell population distinct from human peripheral blood mononuclea...

Background American College of Chest Physicians (CHEST) clinical practice guidelines on the evaluation of pulmonary nodules may have low adoption among clinicians in Asian countries. Unique patient characteristics of Asian patients affect the diagnostic evaluation of pulmonary nodules. The objective of these clinical practice guidelines was to adapt those of CHEST to provide consensus-based recommendations relevant to practitioners in Asia. Methods A modified ADAPTE process was used by a multidisciplinary group of pulmonologists and thoracic surgeons in Asia. An initial panel meeting analyzed all CHEST recommendations to achieve consensus on recommendations and identify areas that required further investigation before consensus could be achieved. Revised recommendations were circulated to panel members for iterative review and redrafting to develop the final guidelines. Results Evaluation of pulmonary nodules in Asia broadly follows those of the CHEST guidelines with important caveats. Practitioners should be aware of the risk of lung cancer caused by high levels of indoor and outdoor air pollution, as well as the high incidence of adenocarcinoma in female nonsmokers. Furthermore, the high prevalence of granulomatous disease and other infectious causes of pulmonary nodules need to be considered. Therefore, diagnostic risk calculators developed in non-Asian patients may not be applicable. Overall, longer surveillance of nodules than those recommended by CHEST should be considered. Conclusions TB in Asia favors lesser reliance on PET scanning and greater use of nonsurgical biopsy over surgical diagnosis or surveillance. Practitioners in Asia are encouraged to use these adapted consensus guidelines to facilitate consistent evaluation of pulmonary nodules.

Aim High-resolution magic-angle spinning proton nuclear magnetic resonance (HRMAS 1H NMR) spectroscopy technique was employed to analyze the metabonomic characterizations of lung cancer tissues in hope to identify potential diagnostic biomarkers for malignancy detection and staging research of lung tissues. Methods HRMAS 1H NMR spectroscopy technique can rapidly provide important information for accurate diagnosis and staging of cancer tissues owing to its noninvasive nature and limited requirement for the samples, and thus has been acknowledged as an excellent tool to investigate tissue metabolism and provide a more realistic insight into the metabonomics of tissues when combined with multivariate data analysis (MVDA) such as component analysis and orthogonal partial least squares-discriminant analysis in particular. Results HRMAS 1H NMR spectra displayed the metabonomic differences of 32 lung cancer tissues at the different stages from 32 patients. The significant changes (P < 0.05) of some important metabolites such as lipids, aspartate and choline-containing compounds in cancer tissues at the different stages had been identified. Furthermore, the combination of HRMAS 1H NMR spectroscopy and MVDA might potentially and precisely provided for a high sensitivity, specificity, prediction accuracy in the positive identification of the staging for the cancer tissues in contrast with the pathological data in clinic. Conclusion This study highlighted the potential of metabonomics in clinical settings so that the techniques might be further exploited for the diagnosis and staging prediction of lung cancer in future.

Background and objective The TIOtropium Safety and Performance In Respimat (TIOSPIR) trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat and HandiHaler in patients with COPD. The TIOSPIR results for patients in Asia are presented here. Methods TIOSPIR evaluated once-daily tiotropium Respimat 5 and 2.5 µg with HandiHaler 18 µg in patients with COPD. Primary endpoints included time to death and time to first COPD exacerbation. Safety and exacerbation efficacy profiles were determined for the Asian region, and for Asia (all treatment arms pooled) versus the rest of the world (RoW). Results In Asia (n = 2356), time to death was similar for Respimat 5 and 2.5 µg versus HandiHaler 18 µg (hazard ratio (HR) (95% CI): 0.96 (0.67, 1.38) and 1.23 (0.87, 1.73)). Risk of COPD exacerbation was similar for Respimat 5 µg, but increased for 2.5 µg versus HandiHaler 18 µg (HR (95% CI): 0.99 (0.85, 1.15) and 1.17 (1.00, 1.35)). Time to death in Asia and RoW was similar (HR (95% CI): 1.15 (0.99, 1.35)). Time to first COPD exacerbation was longer (HR (95% CI): 0.84 (0.78, 0.89)) and exacerbation rates were lower in Asia, but severe exacerbations were more frequent than in the RoW. Risk of major adverse cardiovascular events was similar for both regions. Conclusion Similar safety and exacerbation efficacy profiles were observed for tiotropium Respimat 5 µg and HandiHaler 18 µg in patients with COPD from Asia, analogous to the global analysis. Asian patients had lower risk of, and fewer exacerbations overall, but a higher proportion of severe exacerbations than in the RoW.

Background The combination of NMR spectroscopy and multivariate data analysis (MVDA), such as orthogonal partial least squares-discriminant analysis (OPLS-DA), has been collectively acknowledged as an excellent tool to investigate tissue metabolism and provide metabolite information for the diagnosis of disease, and become an important metabonomic platform for studies in biological tissues so far. Methods Both ex vivo high resolution magic-angle spinning1H NMR and in vitro1H NMR spectroscopy technique were synchronously employed to analyze the metabonomic characteristics of 102 lung tissues from 34 patients with lung cancer in hope to identify potential diagnostic biomarkers for malignancy detection in lung tissues. Results Significant elevations in the levels of lipids and lactate and significant reductions in the levels of myo-inositol and valine in the cancer tissues had been identified when compared with the adjacent non-involved tissues. Furthermore, the OPLSDA models calculated by two1H NMR spectra provided for relatively high sensitivity, specificity and good prediction accuracy in the identification of class membership regardless of the number of metabolites involved. Conclusions MVDA in combination with1H NMR spectra highlighted the potential of metabonomics in clinical settings so that the techniques might be further exploited for future lung cancer biomarker research or identification.

e15536 Background: Recent screening trial results using low-dose computed tomography (LDCT) have been shown to reduce lung cancer mortality in high-risk patients. However, high false-positive rates, inter-grader variability, and radiation injuries are challenging, and therefor highlight the necessity for complementary biomarkers. The diagnostic performance of circulating genetically abnormal cells (CACs) was respectively evaluated in samples collected from patients with pulmonary nodules before and after lung lobectomy within the Multicenter Chinese Pulmonary Nodule Detection (MCPND) trial. We also propose a deep learning that detects related genetically abnormal cells in excisions of symptomatic lesions to identify the source of CACs. Methods: 269 plasma samples (n = 179, before surgery; n = 90, after surgery) from 179 participants, including 125 patients with lung cancer and 54 donors with benign nodular lesions, were analyzed by using a FISH–based assay for 3p22.1, 3q29, 10q22_3 and CEP10. Diagnostic performance of CAC was evaluated in a blinded validation group. 109 paraffin-embedded specimens (45 benign nodular lesions, 64 malignancies) obtained from participants were tested in the same way to identify the genetically abnormal cells. Results: The diagnostic performance of CACs for lung cancer detection was 91% for sensitivity and 81% for specificity. For all participants, CACs had a positive predictive value of 92% and 80% for negative predictive value, respectively. Area under the ROC curve was 0.89 (P < 0.01; 95%CI (0.82, 0.96)). 90 plasma samples were drawn from patients within 10 days after surgery. Of these samples, 58 participants’ CACs level reduced and 25 of them remained stable. Moreover, of 64 malignant specimens, genetically abnormal cells were detected in 60 specimens. However, only 4 specimens were detected having genetically abnormal cells in 45 benign nodular lesions. Conclusions: This validation study indicated that the number of genetically abnormal cells in circulation decreased after surgical resection, which suggested CACs could be released from lung cancer. CACs have diagnostic and prognostic value and could assist to improve the diagnostic accuracy in early stage lung cancer after low-dose computed tomography. Clinical trial information: ChiCTR1900026233.

e21055 Background: The ability to diagnose earlier stages of carcinogenesis using less invasive presurgical tissue samples is especially desirable, but is often inconclusive because of insufficient morphological evidences of cancer. Many of the epigenetic biomarkers are involved in lung cancer, but are challenging to clinically evaluate. In this study, Quantitative Chromogenic Imprinting Gene In-Situ Hybridization (QCIGISH) was applied to directly visualize and quantitatively assess the biallelic and multiallelic alterations of imprinted gene expressions in order to characterize lung cancer carcinogenesis and progression. We updated an imprinted gene panel and developed an accurate lung cancer diagnostic grading model from minimally invasive biopsies using the QCIGISH method. Methods: 225 surgical (151 lung cancer, 74 benign lung lesion) and 95 pre-surgical samples (77 lung cancer, 18 benign lung lesion) were collected from 320 patients under clinical trial NCT03882684 involving five medical centers between 2015 and 2019. The QCIGISH method was applied to detect the allelic expression status of the GNAS, GRB10, SNRPN and HM13 imprinted gene panel. A diagnostic grading model for lung cancer progression was trained using 225 retrospectively collected surgical tissue set with known diagnosis, refined using 25 presurgical samples, and blindly validated using 70 presurgical samples. Results: The diagnostic grading model collectively achieved high sensitivity (98.7%) which is significantly higher than standard presurgical bronchoscopy diagnostic methods including transbronchial brushing (58-74%), transbronchial biopsy (61-75%), alveolar lavage (35-64%) and the combination of the aforementioned three methods (64-80%). Thus, epigenetic imprinted gene biomarkers significantly improve bronchoscopy diagnostic accuracy by 18.7% (98.7% vs 80%), while demonstrating even higher specificity (100% vs 94-96%). Conclusions: Epigenetic imprinted gene biomarkers are shown to be highly accurate in effectively differentiating benign lesions and malignant lung cancer cases. In addition, the improved accuracy demonstrated by QCIGISH over standard presurgical bronchoscopy diagnostic procedures makes it a viable and revolutionary epigenetics-based cancer detection method for practical clinical applications especially for small samples and less advanced grades of lung cancer.

Highlights Air pollution is responsible for a wide variety of health problems and 4.2 million premature deaths annually and is a health risk even in “low” pollution areas. Air pollution exposures can be reduced by using portable room air purifiers, wearing face masks, recirculating automobile cabin air, using air conditioning, and by closing windows. Clinicians can determine appropriate interventions to reduce personal exposures by following the algorithm developed in Figure 3.

OBJECTIVE: In the era of fast track surgery, early and accurately estimating whether postoperative length of stay (p-LOS) will be prolonged after lung cancer surgery is very important, both for patient’s discharge planning and hospital bed management. Pulmonary function tests (PFTs) are very valuable routine examinations which should not be underutilized before lung cancer surgery. Thus, this study aimed to establish an accurate but simple prediction tool, based on PFTs, for achieving a personalized prediction of prolonged p-LOS in patients following lung resection. METHODS: The medical information of 1257 patients undergoing lung cancer surgery were retrospectively reviewed and served as the training set. p-LOS exceeding the third quartile value was considered prolonged. Using logistic regression analyses, potential predictors of prolonged p-LOS were identified among various preoperative factors containing PFTs and intraoperative factors. A nomogram was constructed and subjected to internal and external validation. RESULTS: Five independent risk factors for prolonged p-LOS were identified, including older age, being male, and ratio of residual volume to total lung capacity (RV/TLC) ≥ 45.0% which is the only modifiable risk factor, more invasive surgical approach, and surgical type. The nomogram comprised of these five predictors exhibited sufficient predictive accuracy, with the area under the receiver operating characteristic curve (AUC) of 0.76 [95% confidence interval (CI) 0.73–0.79] in the internal validation. Also its predictive performance remained fine in the external validation, with the AUC of 0.70 (95% CI 0.60–0.79). The calibration curves showed satisfactory agreements between the model predicted probability and the actually observed probability. CONCLUSIONS: Preoperative amelioration of RV/TLC may prevent lung cancer patients from unnecessary prolonged p-LOS. The integrated nomogram we developed could provide personalized risk prediction of prolonged p-LOS. This prediction tool may help patients perceive expected hospital stays and enable clinicians to achieve better bed management after lung cancer surgery. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13167-019-00168-z) contains supplementary material, which is available to authorized users.

To investigate the efficacy and safety of nintedanib versus placebo in Chinese patients with idiopathic pulmonary fibrosis (IPF).The INPULSISA total of 101 Chinese patients (nintedanib/placebo: 61/40) were treated. The demographic characteristics were generally balanced between treatment arms. Over 52 weeks, the rate of decline in FVC was lower in nintedanib-treated patients compared with placebo-treated patients in the Chinese subgroup [- 126.43 vs. - 229.82 mL/year; ∆ = 103.39 mL/year (95% confidence interval, CI: - 19.40 to 226.18)]. The proportion of patients with adverse events (AEs) over 52 weeks was similar between treatment arms. The most commonly reported AEs with nintedanib treatment were gastrointestinal symptoms (diarrhoea, nausea, and vomiting).Nintedanib is clinically efficacious in Chinese patients with IPF with approximately 50% reductions in the rate of decline in FVC, demonstrating slowed disease progression. Similar to the overall INPULSISNCT01335464, NCT01335477.Boehringer Ingelheim. Plain language summary available for this article.

Jinfang Ma,1 Jinping Zheng,1 Nanshan Zhong,1 Chunxue Bai,2 Haoyan Wang,3 Juan Du,4 Fenglei Li,5 Yanwei Chen,6 Zhe Shi,7 Xin Li,8 Pingyan Chen9 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, People’s Republic of China; 4Department of Respiratory Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 5Department of Respiratory Medicine, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 6Department of Respiratory Medicine, Nanshan People’s Hospital, Shenzhen, People’s Republic of China; 7Department of Respiratory Medicine, The First People’s Hospital, Huizhou, People’s Republic of China; 8Department of Respiratory Medicine, China Resource and Wisco General Hospital, Wuhan, People’s Republic of China; 9Department of Biostatistics, Southern Medical University, Guangzhou, People’s Republic of China Purpose: Recurrence of acute exacerbations has a major impact on patients with COPD. Therefore, effective prevention and treatment of exacerbation is crucial in the management of COPD, especially for patients with moderate to severe disease. This study evaluated the effectiveness of YuPingFeng granule administration in preventing exacerbation and improving symptom score, as well as its long-term (1 year) safety profile, in patients with COPD. Patients and methods: This was a randomized, double-blind, parallel, placebo-controlled study of 240 patients from eight centers in China. Participants were eligible if they had mild to severe COPD as defined by Global Initiative for Chronic Obstructive Lung Disease, had a history of at least two COPD exacerbations or one hospitalization within the previous year, and had remained clinically stable for over 4weeks before the study. They were randomly assigned to receive 5g of YuPingFeng or placebo, three times per day, for 1year. The primary end point was the exacerbation rate over 1year, and the analysis was by intention to treat. Secondary end points included symptom score, which was assessed by COPD assessment test (CAT) score and safety profiles. This trial was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn; registration number: ChiCTR-IPR-15007023). Results: The YuPingFeng group had a significantly lower exacerbation rate than the placebo group (1.15 vs 1.55; risk ratio=0.677 [95% CI 0.531–0.863]; P=0.002) and a significantly reduced risk of second exacerbation (95% CI 0.326–0.772; P=0.002). After treatment, the mean change in the CAT score in the YuPingFeng group (-4.41±7.01) differed significantly from that in the placebo group (-2.49±5.31; P=0.001). YuPingFeng was well tolerated. Conclusion: YuPingFeng granules can be considered as a treatment option for COPD; this treatment prevents acute exacerbations of COPD and has a good safety profile. Keywords: COPD, exacerbation, treatment, YuPingFeng

Gefitinib, an epidermal growth factor receptor (EGFR)-specific drug, is effective for ~1 year, after which resistance is inevitable. Calpain 2 (CAPN2) is known to serve a role in the drug response and resistance in certain cancer therapies. However, the full function of CAPN2, particularly in non-small cell lung cancer, has not yet been elucidated. In the present study, CAPN2 expression in gefitinib-resistant lung adenocarcinoma cells was investigated. CAPN2 function in these cells was further evaluated using gene knockdown both in vitro and in vivo. The results demonstrated that CAPN2 was strongly associated with gefitinib-resistance, and CAPN2 mRNA and protein expression levels were significantly increased in gefitinib-resistant cell lines. Furthermore, CAPN2 knockdown inhibited gefitinib-resistant cell proliferation in vitro and in vivo. CAPN2 conferred gefitinib-resistance by inhibiting cell apoptosis and arresting the cell cycle. CAPN2 knockdown also induced caspase activation and mitochondrial dysfunction, and its function in gefitinib resistance appeared to be largely mediated by EGFR/protein kinase B/survivin signaling pathway activation. These results suggest that CAPN2 is responsible for EGFR-tyrosine kinase inhibitor resistance, and CAPN2 inhibition may be used to provide therapeutic benefits in the treatment of gefitinib resistance.

Background The aim of present study was to investigate the effects and mechanisms of peroxiredoxin (Prdx) 6 on cecal ligation and puncture (CLP) induced acute lung injury (ALI) in mice. Methods The cecal of male Prdx 6 knockout and wildtype C57BL/6J mice were ligated and perforated. Stool was extruded to ensure wound patency. Two hours, 4 h, 8 h and 16 h after stimulation, the morphology, wet/dry ratio, protein concentration in bronchial alveolar lavage fluid (BALF) were measured to evaluate lung injury. Myeloperoxidase (MPO) activity, hydrogen peroxide (H2O2), malondialdehyde (MDA), total superoxide dismutase (SOD), xanthine oxidase (XOD), CuZn-SOD, total anti-oxidative capability (TAOC), glutathione peroxidase (GSH-PX), catalase (CAT) in lungs were measured by assay kits. The mRNA expression of lung tumor necrosis factor (TNF-α), interleukin (IL)-1β, and matrix metalloproteinases (MMP) 2 and 9 were tested by real-time RT-PCR. The nuclear factor (NF)-κB activity was measured by TransAM kit. Results CLP-induced ALI was characterized by inflammation in morphology, increased wet/dry ratio, elevated protein concentration in BALF and higher level of MPO activity. The levels of H2O2, MDA, and XOD were significantly increased and SOD, CuZn-SOD, GSH-PX, CAT, and T-AOC were significantly decreased in lungs after CLP. The activity of NF-κB was significantly increased and subsequently, the mRNA expression of TNF-α, IL-1β and MMP2 and MMP9 were significantly increased after CLP. Those above injury parameters were more severe in Prdx 6 knockout mice than those in wildtype mice. Conclusions Prdx 6 knockout aggravated the CLP induced lung injury by augmenting oxidative stress, inflammation and matrix degradation partially through NF-κB pathway.

Patients with toxic epidermal necrolysis (TEN) are known to experience various complications. Although pulmonary complications are commonly observed, they typically manifest in an acute form. By contrast, chronic complications are quite rare, and little is known with regard to their incidences or clinical manifestations. The present study reports the case of a 29-year-old female patient who suffered from TEN. At the onset of the disease, the patient exhibited no pulmonary impairment; however, 1 month after recovering from TEN, the patient developed severe obstruction and a mild diffusion defect. A diagnosis of bronchiolitis obliterans was determined, and the patient was treated with antibiotics, inhaled corticosteroids, anticholinergic agents, and bronchodilators. At the last follow-up, the patient was alive, but with a stable airway obstruction.

Acute lung injury (ALI) is a severe inflammatory disease, for which no specific treatment exists. The decreased ratio of regulatory T cells (CD4+ CD25+ FoxP3 Tregs) and Th17 cells is implicated in ALI and inflammation. We here investigated whether maintaining the balance of CD4+ CD25+ Foxp3+ Tregs and Th17 cells can alleviate lung injury. For CD4+ CD25+ FoxP3 Treg depletion, 200 μg of an anti-CD25 antibody was administered intraperitoneally per mouse on days -3 and -1 before lipopolysaccharide (LPS) instillation. And 150 μg of TGF-β was administered intraperitoneally per mouse on day 0 after LPS instillation. To down-regulate of Th17 cells, 200 μg per mouse of isotype, IL-17 or IL-22 antibodies were injected intraperitoneally into mice at days 0 after LPS instillation. We detected lung morphology; lung wet-to-dry weight ratio; protein concentration, the count of total cells, neutrophils and macrophages, and cytokines in bronchoalveolar lavage fluid (BALF). And we also evaluated the percentage of CD4+ CD25+ Foxp3+ Tregs in lung, and Th17 cells in lung. CD4+ CD25+ Foxp3+ Tregs depletion via anti-CD25 treatment or TGF-β neutralization delayed recovery of ALI. The prolonged inflammation was mainly dominated by neutrophils, macrophages and Th17 cells. Furthermore, inhibition of Th17 cells via monoclonal antibodies against IL-17 and IL-22 alleviated ALI inflammation by inhibiting the recruitment of neutrophils and macrophages, increasing the number of CD4+ CD25+ Foxp3+ Tregs. Our findings support a critical role for CD4+ CD25+ Foxp3+ Tregs in regulating from ALI pathophysiology, and a potential therapeutic role for the inhibition of Th17 cells in ALI treatment. These findings provide a rationale for treating patients with ALI by modulating CD4+ CD25+ Foxp3+ Tregs and Th17 cells.

Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer. Gefitinib is one of the most accepted therapies against NSCLC in those carrying EGFR mutations, but it is only effective in approximately 20% of patients with NSCLC. Thus, alternative therapeutic interventions are urgently needed to overcome gefitinib resistance. Glutaredoxin (GLRX) plays a key role in oxidative stress. However, whether GLRX inhibition could enhance gefitinib efficacy in the gefitinib-resistant NSCLC cells is unknown. In this study, we aimed to determine whether combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells. Real-time PCR and western blotting were used to examine the mRNA and protein levels of GLRX in gefitinib-sensitive PC9 and HCC827 and -resistant human lung adenocarcinoma PC9R, HCC827R, and H1975 cells. Cell Counting Kit-8, flow cytometry, JC-1 staining, and reactive oxygen species (ROS) assays were used to evaluate cell proliferation, cell cycle progression, mitochondrial membrane potential, and ROS generation, respectively. Mouse tumor xenografts were used to assess the effect of GLRX in vivo. We found that GLRX was upregulated in gefitinib-resistant PC9R, HCC827R, and H1975 cells. GLRX inhibition enhanced the effects of geftinib in gefitinib-resistant cell proliferation in vitro and in vivo and promoted apoptosis and cell cycle arrest via the EGFR/Forkhead Box M1 (FoxM1) signaling pathway, indicating that combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells. Our results suggest that GLRX inhibition enhances the effects of geftinib in EGFR-TKI-resistant NSCLC cells. Thus, GLRX may represent a therapeutic target for increasing the efficiency of gefitinib treatment.

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, including gefitinib, are first-line drugs against advanced non-small cell lung cancer with activating EGFR mutations. However, the development of resistance to such drugs is a major clinical challenge. Methods The role of annexin A5 in resistance to EGFR tyrosine kinase inhibitors was investigated by qPCR and western blot of relevant molecules, by CCK8 and EdU assay of cell proliferation and viability, by annexin V/propidium iodide assay of apoptosis and cell cycle distribution, by JC-1 assay of mitochondrial integrity, and by xenograft assay of tumorigenicity. Results We found that annexin A5 is upregulated in gefitinib-resistant cell lines, as well as in clinical specimens resistant to EGFR tyrosine kinase inhibitors. Accordingly, knockdown of the gene from gefitinib-resistant cells restores gefitinib sensitivity in vitro and in vivo by downregulating polo-like kinase 1 signal pathway, thereby inducing mitochondrial damage, caspase activation, cell cycle arrest at G2/M, and, finally, apoptosis. Conclusions The data indicate that annexin A5 confers gefitinib resistance in lung cancer by inhibiting apoptosis and G2/M cell cycle arrest, and is thus a potential therapeutic target in non-small cell lung cancers resistant to EGFR tyrosine kinase inhibitors.

Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31+ cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti-hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.

Pemetrexed (PEM) is a novel and multi-targeted antifolate used as an antineoplastic agent for non-small cell lung cancer (NSCLC) and pleural mesothelioma. Although glucocorticoid was often used with PEM to reduce toxicity during the chemotherapy, it is not clear yet whether glucocorticoid co-administration could affect PEM efficacy in NSCLC. Here we established NSCLC cell lines and examined the effects of dexamethasone (DEX) on PEM sensitivity in vitro and in xenograft models. DEX co-administration reduced chemotherapy sensitivity to PEM in xenograft models. DEX co-administration promoted cell growth and weakened senescence growth arrest, such as altered secretions of proinflammatory and mitogenic cytokines, reminiscent of a senescence associate secretory phenotype (SASP). CSCs in DEX co-administration group were subsequently found to be less sensitive towards PEM treatment as measured by cell proliferation and generation of tumor spheres in the presence of PEM. Survival molecule B-cell lymphoma-2 (Bcl-2) may involve in this process and blockage of Bcl-2 could reverse altered senescence and CSCs abilities, thus alleviated PEM insensitivity. As such, DEX might suppress the antitumor activity of PEM through altered SASP level that had induced traits similar to CSCs.

Introduction Bronchiectasis is a common disabling respiratory disease in China. However, the literatures that focused on the long-term prognosis and the risk factors for mortality are limited. Objective The aim of this study was to identify risk factors for 5-year mortality in patients with bronchiectasis. Methods A retrospective study was conducted. Patients who were newly diagnosed with bronchiectasis by thoracic conventional CT scans from January 2003 to March 2008 were assessed. Baseline characteristics, symptoms, radiographic extent, pulmonary function tests data and comorbidities were recorded through chart review. The vital status of the patients was obtained by telephone contact and record of hospital admission. Multivariate cox regression analysis was used to determine the independent risk factors for 5-year mortality. Results Eighty-nine patients newly diagnosed with bronchiectasis were included in our cohort. The mean age of the cohort was 55.29 ± 16.15 and 49.4% of the patients were female. At the end of the study, 12 patients (13.5%) died and the mean survival time was 57.05 ± 1.09 months. Multivariate analysis revealed that long-term mortality was significantly associated with emphysema (HR, 5.62; 95% confidence interval [CI], 1.35-23.46; P = 0.02) and radiographic extent (HR, 1.62; 95% CI, 1.02-2.58; P = 0.04). Conclusion The main finding of our study was that emphysema might be a risk factor for mortality in patients with bronchiectasis.

Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Author(s): Li, Jinghong; Li, Willis X; Bai, Chunxue; Song, Yuanlin | Abstract: Background and aimsLung cancer is the leading cause of cancer death worldwide. Cigarette smoking is the well-known risk factor for lung cancer. Epidemiological studies suggest that air pollution, especially particulate matter (PM) exposure, is associated with increased lung cancer risk and mortality independent of cigarette smoking.MethodsEnglish-language publications focusing on PM, epigenetic changes, and lung cancer were reviewed. The epigenome serves as an interface between the environment and the genome. PM is one of the environmental factors that can cause epigenetic changes. The epigenome serves as an interface between the environment and the genome. Some of the epigenetic changes lead to increased disease susceptibility and progression. In cardiovascular disease and asthma, the association between PM exposure and the disease specific epigenetic changes has been identified. In lung cancer, the epigenetic changes in DNA methylation, histone modification and microRNA expression are commonly found, but the specific link between PM exposure and lung cancer remains incompletely understood.ResultsThe results of epidemiological studies indicate the important effects of PM exposure on lung cancer. PM2.5 is consistently associated with the increased lung cancer risk and mortality. Based on the epidemiological associations between PM exposure and lung cancer, PM-induced epigenetic changes may play important roles in the pathogenesis of lung cancer.ConclusionIn this review, we focus on the current knowledge of epigenetic changes associated with PM exposure and lung cancer. Better understanding of the link between PM exposure and lung cancer at the epigenomic level by comprehensive comparison approach may identify lung cancer early detection biomarkers and novel therapeutic targets.

The incidence and mortality of lung cancer in China have rapidly increased. Lung cancer is the leading cause of cancer death in China, possibly because of the inadequate early diagnosis of lung cancer. Reaching a consensus on early diagnostic strategies for lung cancer in China is an unmet needed. Recently, much progress has been made in lung cancer diagnosis, such as screening in high-risk populations, the application of novel imaging technologies, and the use of minimally invasive techniques for diagnosis. However, systemic reviews of disease history, risk assessment, and patients' willingness to undergo invasive diagnostic procedures also need to be considered. A diagnostic strategy for lung cancer should be proposed and developed by a multidisciplinary group. A comprehensive evaluation of patient factors and clinical findings should be completed before treatment.

Lung cancer is the leading cause of cancer-related death worldwide. In China, the incidence of lung cancer has grown rapidly, resulting in a large social and economic burden. Several researchers have devoted their studies to lung cancer and have demonstrated that there are many risk factors for lung cancer in China, including tobacco use, environmental pollution, food, genetics, and chronic obstructive pulmonary disease. However, the lung cancer incidence is still growing rapidly in China, and there is an even higher incidence among the younger generation. One explanation may be the triple-neglect situation, in which medical policies that neglect prevention, diagnosis, and supportive care have increased patients' mortality and reduced their quality of life. Therefore, it is necessary to enhance the efficiency of prevention and early diagnosis not only by focusing more attention on treatment but also by drawing more attention to supportive care for patients with lung cancer.

China is the largest producer and consumer of tobacco in the world. Consequently, the burden of tobacco-related diseases in China is enormous. Implementation of the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) may lead to a significant reduction in tobacco-related morbidity and mortality both in China and globally. In this review, the authors summarize the epidemic of tobacco use and the progress made in implementing the WHO FCTC, including the promotion of legislation for smoke-free public places; smoking-cessation assistance; labeling of tobacco packaging; enforcement of bans on tobacco advertising, promotion, and sponsorship; increased taxes on tobacco products; increased tobacco prices; improvements in public awareness of the dangers of smoking; and identifying the barriers to implementing effective tobacco-control measures in China. Since the WHO FCTC officially took effect in China on January 9, 2006, China has taken some important steps, especially in promoting legislation for smoke-free public places. Because tobacco permeates the fabric of society, business, commerce, and politics in China, commitments and actions from the government are crucial, and implementing the WHO FCTC in China will be an arduous and long-term task.

BACKGROUND This study applied a combined cancer biomarker panel to clinically identify small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) in a high-risk population. METHODS The serum levels of 4 biomarkers (progastrin-releasing peptide [ProGRP], carcinoembryonic antigen [CEA], squamous cell carcinoma antigen [SCC], and cytokeratin 19 fragment [CYFRA21-1]) were determined in 153 patients with a high risk of lung cancer (12 with a new diagnosis of SCLC, 52 with NSCLC, and 89 without lung cancer). Information about diagnosis delays was collected through interviews of all participants. RESULTS Significantly higher serum levels of ProGRP (P

Autophagy, a type II programmed cell death, is essential for cell survival under stress, e.g. lung injury, and bone marrow-derived mesenchymal stem cells (BM-MSCs) have great potential for cell therapy. However, the mechanisms underlying the BM-MSC activation of autophagy to provide a therapeutic effect in ischaemia/reperfusion-induced lung injury (IRI) remain unclear. Thus, we investigate the activation of autophagy in IRI following transplantation with BM-MSCs. Seventy mice were pre-treated with BM-MSCs before they underwent lung IRI surgery in vivo. Human pulmonary micro-vascular endothelial cells (HPMVECs) were pre-conditioned with BM-MSCs by oxygen-glucose deprivation/reoxygenation (OGD) in vitro. Expression markers for autophagy and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signalling pathway were analysed. In IRI-treated mice, administration of BM-MSCs significantly attenuated lung injury and inflammation, and increased the level of autophagy. In OGD-treated HPMVECs, co-culture with BM-MSCs attenuated endothelial permeability by decreasing the level of cell death and enhanced autophagic activation. Moreover, administration of BM-MSCs decreased the level of PI3K class I and p-Akt while the expression of PI3K class III was increased. Finally, BM-MSCs-induced autophagic activity was prevented using the inhibitor LY294002. Administration of BM-MSCs attenuated lung injury by improving the autophagy level via the PI3K/Akt signalling pathway. These findings provide further understanding of the mechanisms related to BM-MSCs and will help to develop new cell-based therapeutic strategies in lung injury.

Background Understanding the role and underlying regulation mechanism of autophagy in ischemia/reperfusion (I/R)-induced lung injury may provide potentially new pharmacologic targets for treatment of acute lung injury. The aim of this study was to adjust autophagy with pharmacologic agents to determine its functional significance in I/R-induced lung injury. Methods Human pulmonary microvascular endothelial cells (HPMVECs) and mice were pre-conditioned with autophagy inhibitor chloroquine or promoter rapamycin before they were challenged with oxygen–glucose deprivation/oxygen–glucose restoration (OGD) and lung I/R, respectively. Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 was pre-injected into I/R-induced mice to test the role of ERK1/2 in regulating autophagy. Results OGD caused tight conjunction damage and cell death in HPMVECs, which was further aggravated by blocking autophagy, yet ameliorated through promoting autophagy. On a consistent basis, inhibiting autophagy aggravated I/R-induced lung edema and tissue inflammation, which was significantly alleviated by promoting autophagy with rapamycin. In addition, inhibition of ERK1/2 increased expression of active mammalian target-of-rapamycin and thus decreased I/R-induced autophagy. Conclusions It appears that autophagy plays a protective role in I/R-induced lung injury and this effect may be enhanced by moderately improving autophagy level. Meanwhile, the ERK1/2 signal pathway has a positively regulating role in lung I/R-induced autophagy.

Background and Aims Primary ciliary dyskinesia (PCD) is a rare, genetic disorder featured with dysfunctional motility of cilia. Clinical presentations of PCD include situs inversus, repeated respiratory tract infections, otitis media, sinusitis and infertility. This study aims to provide clinical strategies on diagnosis and treatment of PCD. Methods Clinical data of seven patients diagnosed as PCD in Zhongshan Hospital, Fudan University were analyzed. We also extracted data from other cases in mainland China from the China Academic Journals Full-Text Database by the end of 2012. A total of 127 cases of PCD were summarized and analyzed in this study. Results Seven patients in Zhongshan Hospital, Fudan University were finally confirmed to have PCD. All of them had clinical history of recurrent respiratory infection. Imaging analysis showed varying degrees of bronchiectasis. Pulmonary function tests in four patients showed combined obstructive and restrictive patterns. Three cases were confirmed to have PCD by electron microscopy. We then further extracted information from literature for those 127 PCD patients in mainland China. All of them had chronic respiratory infection. Seven cases were complicated with recurrent otitis media and 15 cases were complicated with infertility. A total of 119 patients were diagnosed with situs inversus totalis (94%). Among those 127 patients, only 9 patients' diagnosis was confirmed by electron microscopy. Four patients received sinus resection, and one patient received pulmonary lobectomy due to recurrent hemoptysis. One patient died of massive hemoptysis. Conclusions Being a rare disease and easily confused with uncomplicated bronchiectasis, PCD diagnosis warrants particular attention. Recurrent respiratory infection, especially situs inversus could be the most important indicator of this disease.

Cryptococcal infection primarily affects the lung or the central nervous system and rare cases have been reported involving the gastrointestinal tract. However, among patients with HIV/AIDS, the gastrointestinal involvement is increasing. According to the PubMed search results, there were seven cases reported involving duodenal cryptococcosis combined with AIDS in five reports. Here, we report the case of a patient found to have AIDS combined with duodenal, pulmonary, and subsequent neurological cryptococcal infection simultaneously. The duodenal cryptococcosis was diagnosed on the basis of PET/computed tomography, which showed intense captation of glucose metabolism in duodenum (maximum standardized uptake value 16.53); a positive serum cryptococcal latex agglutination test; and upper gastrointestinal endoscopy-guided duodenal biopsy that confirmed Cryptococcus neoformans yeast. The patient's HIV screen test was positive. Because of refusal of lumbar puncture and the difficulty of performing transbronchial lung biopsy, the pulmonary and neurological involvements were the only clinical diagnoses. This case indicates that when cryptococcosis exists in a rare location, AIDS should be considered and when cryptococcosis occurs in the HIV-infected patient, disseminated disease is more common.

At the end of March 2013, the first case of human infection with avian influenza A(H7N9) virus was confirmed in Shanghai. From April to May 2013, 18 patients with avian influenza A(H7N9) virus infection were hospitalized in Shanghai Public Health Clinical Center, and finally, 12 of them survived. The short-term prognosis of these patients had been described previously,[1] but the long-term prognosis remained unclear.

Prospective epidemiological studies, observational cross-sectional studies and some randomised prevention trials have demonstrated inconsistent findings of the impact of vitamin E on asthma risk. The goals of this study were to explore whether this differing association of vitamin E on asthma risk is due to an interaction of vitamin E isoforms. To address this question, in a population-based asthma incidence study we assessed the interaction between the plasma concentrations of vitamin E isoforms α-tocopherol and γ-tocopherol on asthma risk. Second, to understand the mechanisms of any interaction of these isoforms, we conducted experimental supplementation of α-tocopherol and γ-tocopherol isoforms in mice on the outcome of allergic airway inflammation. We found that in the highest γ-tocopherol tertile, low levels of α-tocopherol were associated with increased asthma risk, while highest tertile α-tocopherol levels trended to be protective. Similarly, in a mouse model of asthma, diet supplementation with α-tocopherol decreased lung inflammation in response to house dust mite (HDM) challenge. In contrast, diet supplementation with γ-tocopherol increased lung inflammation in response to HDM. These human and animal studies provide evidence for the competing effects of the vitamin E isoforms, in physiological concentrations, on asthma and allergic airway disease.

Host antioxidant defense, consisting of enzymatic antioxidant activity and nonenzymatic antioxidant micronutrients, is implicated in asthma pathogenesis. Studies of antioxidant defense and adult incident asthma have either used measures of antioxidants estimated from questionnaires or not considered enzymatic aspects of host defense.We conducted the first study designed and powered to investigate the association of antioxidant defenses on adult incident asthma.In a nested case-control study, we followed Shanghai women (aged 40-70 years) without prevalent asthma at baseline, over 8 years. Subjects with incident asthma were ascertained prospectively by gold standard testing of symptomatic women and matched to two asymptomatic control subjects.Baseline urinary F2-isoprostanes, plasma concentrations of antioxidant micronutrients (tocopherols, xanthines, carotenes, and lycopene), and antioxidant enzyme activity (platelet-activating factor acetylhydrolase [PAF-AH] and superoxide dismutase) were measured from samples collected before disease onset. Among 65,372 women, 150 (0.24%) developed asthma. F2-isoprostane levels before asthma onset were not different between cases and control subjects. Doubling of α-tocopherol concentrations and PAF-AH activity was associated with 50 and 37% decreased risk of incident asthma (α-tocopherol: adjusted odds ratio = 0.52; 95% confidence interval, 0.32-0.84; PAF-AH: adjusted odds ratio = 0.63; 95% confidence interval, 0.42-0.93).In this prospective study, α-tocopherol, within normal reference ranges, and PAF-AH enzymatic activity were associated with decreased asthma development. These modifiable risk factors may be an effective strategy to test for primary asthma prevention.

Kryptokokkosen weisen weltweit eine signifikante Morbidität und Mortalität auf. Die pulmonale Kryptokokkose ist eine subakute oder chronische Pilzerkrankung der Lunge. Wir stellen hier einen Fall von Kryptokokkose der Lunge mit karzinomähnlicher Invasion der Trachealwand bei einem immunkompetenten Patienten vor und geben einen Literaturüberblick. Der 44-jährige Nichtraucher klagte über leichte Dyspnoe und weißes Sputum, zeitweilig mit Blutspuren. In der Computertomographie (CT) des Thorax imponierten zwei potenziell maligne Läsionen im rechten Lungenhilus und im rechten Oberfeld der Lunge, die auch im Positronen-Emissions-Tomographie/CT-Scan (PET/CT-Scan) eine erhöhte Aufnahme von Fluordesoxyglucose zeigten. Die pathologische Untersuchung einer Lungenbiopsie-Probe ergab disseminierte Pilzsporen; die Perjodsäure-Schiff(PAS)-Färbung war positiv. Immunstatus und Blut-Tumormarker des Patienten waren durchgängig normal. Der Cryptococcus-Antigentiter betrug laut Latex-Agglutinationstest 1:1,280. In der Fiberbronchoskopie zeigte sich an der rechten Trachealwand eine prominente neue Raumforderung, die den rechten Hauptbronchus weitgehend blockierte. Um die Symptome der Atemwegsobstruktion zu lindern, wurde eine bronchoskopische Behandlung mit Ablation und endotrachealer Stent-Implantation durchgeführt. Da sich unter Itraconazol die Symptome verschlechterten, wurde auf Amphotericin-B-Liposome als Antimykotikum umgestellt. Durch diese Maßnahmen verbesserte sich der Befund. Wir gelangen zu der Schlussfolgerung, dass eine Kryptokokkose der Lunge im radiologischen und bronchoskopischen Erscheinungsbild einer Tumorerkrankung der Lunge ähneln und sogar bei immunkompetenten Patienten auftreten kann.

Background Sample quality is critical for biomarker detection in oncology, and platelet degradation and contamination in plasma have a remarkable impact on the ability to accurately quantify many blood-based biomarkers. Platelet factor 4 (PF4) can be used as an indicator to monitor sample quality. This multicenter study aimed to determine the impact of critical components of the blood sample handling process on platelet degradation/contamination and to establish an optimal method for collecting platelet-poor plasma samples. Methods At each of six participating centers, blood samples were drawn from 12-13 healthy volunteers. Serum and plasma samples were prepared from whole blood samples using nine different methods that have been commonly used in ongoing multicenter trials. PF4 levels in the prepared samples were measured by enzyme-linked immunosorbent assay (ELISA). Paired t-tests were used for statistical analysis. Results Blood samples were collected from 74 subjects enrolled in six centers. PF4 levels were significantly higher in serum samples than in plasma samples (P

Objectives Early and accurate diagnosis of lung cancer is crucial for effective treatment. This study aimed to identify plasma microRNAs for diagnosis of lung cancer and for further discrimination of small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC). Materials and methods Plasma microRNA expression was investigated using three independent cohorts including 1132 participants recruited between October 2008 and September 2014 from five medical centers. The subjects were healthy individuals and patients with NSCLC or SCLC. Microarrays were used to screen 723 human microRNAs in 106 plasma samples for candidate selection. Quantitative reverse-transcriptase PCR was applied to evaluate the expression of selected microRNAs. Two logistic regression models were constructed based on a training cohort (n = 565) and then validated using an independent cohort (n = 461). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. Results Plasma panel A with six microRNAs (miR-17, miR-190b, miR-19a, miR-19b, miR-26b, and miR-375) provided high diagnostic accuracy in discriminating lung cancer patients from healthy individuals (AUC 0.873 and 0.868 for training and validation cohort, respectively). Moreover, plasma panel B with three microRNAs (miR-17, miR-190b, and miR-375) demonstrated high diagnostic accuracy in discriminating SCLC from NSCLC (AUC 0.878 and 0.869 for training and validation cohort, respectively). Conclusion We constructed and validated two plasma microRNA panels that have considerable clinical value in diagnosis of lung cancer, and could play an important role in determining optimal treatment strategies based on discrimination between SCLC and NSCLC.

Background: Particulate matter (PM) is a high risk factor for various respiratory diseases and triggers an inflammatory response in lung tissues. However, the molecular mechanism of the PM-induced inflammatory response is incompletely understood. Methods: Human bronchial epithelial cells (HBECs) were treated with the urban PM 1649b for assessment of the inflammatory response. The intracellular level of reactive oxygen species (ROS) was measured by flow cytometry. PM-activated signaling pathways were addressed with specific inhibitors. In vivo, the C57 mice model of PM-induced acute lung inflammation was established with intratracheal instillation of PM for 2 consecutive days. The oxidant stress in lung tissues was assessed with dihydroethidium (DHE) staining, and malondialdehyde (MDA) activity and hydrogen peroxide (H2O2) assays. The histopathologic changes in lung tissues and number of inflammatory cells in bronchoalveolar lavage fluid (BALF) were examined. Expression of pro-inflammatory cytokines in BALF was measured by ELISA. Results: PM increased the expression of interleukin (IL)-1β, IL-6, IL-8, matrix metalloproteinase (MMP)- 9 and cyclooxygenase (COX)-2 in a dose-dependent manner. ROS generation and activation of MAPK (ERK, JNK, p38 MAPK) and NF-κB pathways were detected in PM-exposed HBECs. Pretreatment with N-acetylcysteine (NAC) led to the inflammatory response, ROS level and activation of the MAPK and NF-κB pathways to be attenuated. Blockade of ERK, JNK or p38 MAPK pathway with specific inhibitor prevented the release of pro-inflammatory cytokines and activation of the NF-κB pathway. Inhibition of the NF-κB pathway reduced the expression of pro-inflammatory cytokines. In vivo, PM exposure increased oxidant stress in lung tissues, infiltration of inflammatory cells around PM in lung tissues, the number of total cells and inflammatory cells in BALF, and the concentrations of IL-1β, IL-6, IL-8 and MMP-9 in BALF, all of which were reversed partially upon NAC treatment. Conclusions: PM exposure enhanced the airway inflammatory response significantly through ROSmediated activation of MAPK (ERK, JNK, p38 MAPK) and downstream NF-κB signaling pathways. Oxidative stress appeared to be the key regulator for PM-induced lung inflammation. These results suggested the molecular mechanism of lung inflammation caused by PM.

BackgroundPatients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. MethodsIn a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 μg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in...

The REACH study is the first multicenter randomized controlled trial conducted in China assessing the safety and effectiveness of endobronchial valve treatment for severe emphysema patients with complete fissures. The study objectives were target lobe volume reduction (TLVR) and significant improvement in lung function. 101 subjects, 66 treatment and 35 control, were enrolled at 12 study sites. Target lobe selection, based on visual HRCT identified an upper lobe in 55% and a lower lobe in 45% of patients. Treatment consisted of target lobe occlusion utilizing the Spiration Valve System (Olympus, USA). The control group received optimal medical management. 64.6% of patients at 12 months showed evidence of significant (TLVR at 350 ml MCID). Mean TLVR in treatment patients was 781 ml at 12 months. Compared to control, the treatment group achieved a significant and clinically meaningful improvement in FEV1 at the 1, 3, 6 and 12 month visits (16.8%, 14.2%, 20.7%, 22.8%) with a responder rate of approximately 39.8% at 12 months. Significant improvements were also observed for quality of life measures and 6MWT. Between the 6 and 12 month follow-up visits, there were 8 serious adverse events in the treatment group consisting primarily of acute COPD exacerbations (6), lung abscess (1) and pneumothorax (1). There was one control and no treatment group deaths. In conclusion, this is the first multicenter study comparing endobronchial valve therapy to medical arm control that has demonstrated 12 month sustained clinically meaningful benefit with acceptable adverse events for severe emphysema patients selected only by HRCT.

Background and objective Chemotherapy drugs, such as cisplatin (DDP), improve the survival of patients with lung cancer by inducing apoptosis in cancer cells, which quickly develop resistance to DDP through uncharacterized mechanisms. Glioma Pathogenesis-Related Protein 1 (GLIPR1) plays an important role in cell proliferation, migration and apoptosis. However, the expression and function of GLIPR1 in mediating DDP resistance in human lung adenocarcinoma A549/DDP and human large cell lung cancer H460/DDP cells has not yet been reported. Methods In this study, real-time PCR (RT-PCR) and western blot were used to examine the mRNA and protein expression of GLIPR1, respectively. Bright-field microscopy, the cell counting kit-8 (CCK-8) assay, flow cytometry analysis and JC-1 dye were used to measure the cellular morphology, proliferation, apoptosis and mitochondrial membrane potential, respectively. Results Compared to human lung adenocarcinoma A549 cells, the mRNA and protein expression of GLIPR1 were significantly increased in DDP-resistant A549/DDP cells (p < 0.05). Similarly, the mRNA level of GLIPR1 in DDP-resistant H460/DDP cells was also significantly higher than that in DDP-sensitive H460 cells (p < 0.05). Silencing of GLIPR1 in A549/DDP and H460/DDP cells led to increased apoptosis via a mitochondrial signaling pathway following incubation with various concentrations of DDP. Furthermore, GLIPR1 downregulation markedly reduced the protein expression of Bcl-2, and increased the cleaved Poly (ADP-Ribose) Polymerase (PARP) and cleaved caspase-3 in DDP-resistant A549/DDP cells. Conclusion In this study, we demonstrated for the first time that GLIPR1 could modulate the response of DDP-resistant A549/DDP and H460/DDP cells to cisplatin. Therefore, GLIPR1 deserves further investigation in the context of none-small lung cancer (NSCLC).

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p

Aquaporins (AQPs ) are water channel proteins supposed to facilitating fluid transport in alveolar space, airway humidification, pleural fluid absorption, and submucosal gland secretion . In this chapter, we mainly focus on the expression of 4 AQPs in the lungs which include AQP1, AQP2 , AQP4 and AQP5 in normal and disease status, and the experience of AQPs function from various model and transgenic mice were summarized in detail to improve our understanding of the role of AQPs in fluid balance of respiratory system. It has been suggested that AQPs play important roles in various physiology and pathophysiology conditions of different lung diseases. There still remains unclear the exact role of AQPs in lung diseases, and thus continuous efforts on elucidating the roles of AQPs in lung physiological and pathophysilogical processes are warranted.

Background Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. Patients with chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), are exposed to a higher risk of developing lung cancer. Chronic inflammation may play an important role in the lung carcinogenesis among those patients. The present study aimed at identifying candidate biomarker predicting lung cancer risk among patients with chronic respiratory diseases. Methods We applied clinical bioinformatics tools to analyze different gene profile datasets with a special focus on screening the potential biomarker during chronic inflammation-lung cancer transition. Then we adopted an in vitro model based on LPS-challenged A549 cells to validate the biomarker through RNA-sequencing, quantitative real time polymerase chain reaction, and western blot analysis. Results Bioinformatics analyses of the 16 enrolled GSE datasets from Gene Expression Omnibus online database showed myocyte enhancer factor 2D (MEF2D) level significantly increased in COPD patients coexisting non-small-cell lung carcinoma (NSCLC). Inflammation challenge increased MEF2D expression in NSCLC cell line A549, associated with the severity of inflammation. Extracellular signal-regulated protein kinase inhibition could reverse the up-regulation of MEF2D in inflammation-activated A549. MEF2D played a critical role in NSCLC cell bio-behaviors, including proliferation, differentiation, and movement. Conclusions Inflammatory conditions led to increased MEF2D expression, which might further contribute to the development of lung cancer through influencing cancer microenvironment and cell bio-behaviors. MEF2D might be a potential biomarker during chronic inflammation-lung cancer transition, predicting the risk of lung cancer among patients with chronic respiratory diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1168-x) contains supplementary material, which is available to authorized users.

Background Early diagnosis of COPD is often not achieved due to limited recognition and limited access to the pulmonary function test. Our hypothesis was that lung function decline may be different between populations with mild COPD and those who are at high risk and do not receive treatment. Patients and methods Subjects with mild COPD and those from a high-risk COPD population were recruited from a community-based COPD epidemiological study after obtaining consent. Baseline clinical characteristics, symptom questionnaire, spirometry, low-dose computed tomography (LDCT) chest scan, and blood plasma biomarker data were collected initially and then 1 year later. Results A total of 617 participants were recruited, and 438 eventually completed the first-year follow-up visit; 72 participants (46 males) were in the mild COPD group, and 225 participants (165 males) were in the high-risk group. The mean forced expiratory volume in the first second of expiration (FEV1) decline in the mild COPD group was 129 mL, which was significantly higher than the 30 mL decline in the high-risk population group (P=0.005). Group category (odds ratio [OR] =0.230) and COPD Assessment Test (CAT) score (OR =9.912) were independent risk factors for an FEV1% predicted decline of >15% for all participants. In the mild COPD group, patients with a higher CAT (OR =5.310) and Emphysema Index (OR =5.681) were associated with a FEV1% predicted decline of >15% at the first-year follow-up. No factor showed a significantly predictive effect on FEV1 decline in the high-risk COPD group. Conclusion Group category was an independent influential factor associated with FEV1 decline.