Resveratrol impairs the release of steroid-resistant inflammatory cytokines from human airway smooth muscle cells in chronic obstructive pulmonary disease.
Knobloch Jürgen,Sibbing Bernhard,Jungck David,Lin Yingfeng,Urban Katja,Stoelben Erich,Strauch Justus,Koch Andrea
The Journal of pharmacology and experimental therapeutics
Chronic obstructive pulmonary disease (COPD) therapy is complicated by corticosteroid resistance of the interleukin 8 (IL-8)-dependent and granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent chronic airway inflammation, for whose establishment human airway smooth muscle cells (HASMCs) might be crucial. It is unclear whether the release of inflammatory mediators from HASMCs is modulated by cigarette smoking and is refractory to corticosteroids in COPD. Resveratrol, an antiaging drug with protective effects against lung cancer, might be an alternative to corticosteroids in COPD therapy. Vascular endothelial growth factor (VEGF) might offer protection from developing emphysema. We tested the following hypotheses for HASMCs: 1) smoking with or without airway obstruction modulates IL-8, GM-CSF, and VEGF release; and 2) corticosteroids, but not resveratrol, fail to inhibit cytokine release in COPD. Cytokine release from HASMCs exposed to tumor necrosis factor α (TNFα), dexamethasone, and/or resveratrol was measured via enzyme-linked immunosorbent assay and compared between nonsmokers (NS), smokers without COPD (S), and smokers with COPD (all n = 10). In response to TNFα, IL-8 release was increased, but GM-CSF and VEGF release was decreased in S and COPD compared with NS. Dexamethasone and resveratrol inhibited concentration-dependently TNFα-induced IL-8, GM-CSF, and VEGF release. For IL-8 and GM-CSF efficiency of dexamethasone was NS > S > COPD. That of resveratrol was NS = S = COPD for IL-8 and NS = S < COPD for GM-CSF. For VEGF the efficiency of dexamethasone was NS = S = COPD, and that of resveratrol was NS = S > COPD. All resveratrol effects were partially based on p38 mitogen-activated protein kinase blockade. In conclusion, smoking modulates cytokine release from HASMCs. Corticosteroid refractoriness of HASMCs in COPD is cytokine-dependent. Resveratrol might be superior to corticosteroids in COPD therapy, because it more efficiently reduces the release of inflammatory mediators and has limited effects on VEGF in COPD.
10.1124/jpet.110.166843
Airflow limitation and survival after surgery for non-small cell lung cancer: Results from a systematic review and lung cancer screening trial (NLST-ACRIN sub-study).
Hopkins R J,Ko J,Gamble G D,Young R P
Lung cancer (Amsterdam, Netherlands)
OBJECTIVE:Lung cancer remains the single greatest cause of cancer mortality where surgery for early stage non-small cell lung cancer achieves the greatest survival. While there is growing optimism for better outcomes with screening using annual computed tomography, the impact of co-existing airflow limitation on survival remains unknown. To compare survival in non-small cell lung cancer patients undergoing surgery stratified according to the presence or absence of pre-surgery airflow limitation. MATERIALS AND METHODS:We undertook a systematic literature search of non-screen lung cancer that encompassed studies reported between January 1946 and January 2017. Full-text articles were identified following eligibility scoring, with data extracted and analysed using a standardised analytical method (PRISMA). The results of this systematic review in non-screen lung cancers were compared to real-world results from a lung cancer screening cohort (N = 10,054), where outcomes following surgery could be compared after stratification according to pre-surgery airflow limitation. RESULTS:In the systematic review, 6899 subjects were included from 10 studies; 7 were retrospective, 3 were prospective. Overall survival was 950 (44%) in 2144 people with COPD and 2597 (55%) from 4755 controls (unadjusted P value <0.001). However, the overall meta-analysed random effects odds ratio for overall survival (N = 10) and 5-year survival (N = 4) comparing those with and without COPD was 0.91 (95% CI = 0.84-1.00) and 0.99 (95% CI = 0.79-1.24) respectively. There were no signs of significant heterogeneity (I = 19.1%, P = 0.27) nor publication bias as assessed by funnel plot and Egger's test (P = 0.19). In the lung cancer screening sub-study of 10,054 screening participants we found no difference in 5-year survival in those with and without airflow limitation (84% and 81% respectively, P = 0.64). CONCLUSION:Survival after surgery for non-small cell lung cancer is comparable between those with and without spirometry evidence of airflow limitation. This finding was replicated in lung cancer diagnosed during screening.
10.1016/j.lungcan.2019.07.015
Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group.
Spiro Stephen G,Shah Pallav L,Rintoul Robert C,George Jeremy,Janes Samuel,Callister Matthew,Novelli Marco,Shaw Penny,Kocjan Gabrijela,Griffiths Chris,Falzon Mary,Booton Richard,Magee Nicholas,Peake Michael,Dhillon Paul,Sridharan Kishore,Nicholson Andrew G,Padley Simon,Taylor Magali N,Ahmed Asia,Allen Jack,Ngai Yenting,Chinyanganya Nyasha,Ashford-Turner Victoria,Lewis Sarah,Oukrif Dahmane,Rabbitts Pamela,Counsell Nicholas,Hackshaw Allan
The European respiratory journal
BACKGROUND:Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS:LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS:1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS:Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.
10.1183/13993003.00581-2019
Upregulation of miR-675-5p induced by lncRNA H19 was associated with tumor progression and development by targeting tumor suppressor p53 in non-small cell lung cancer.
Zheng Zi-Hui,Wu Dong-Mei,Fan Shao-Hua,Zhang Zi-Feng,Chen Gui-Quan,Lu Jun
Journal of cellular biochemistry
Lung cancer is the main cause of cancer-related death, and the proportion of non-small cell lung cancer (NSCLC) on lung cancer is 85%, while more than 80% lung cancer patients are diagnosed with chronic obstructive pulmonary disease (COPD). In this study, we aimed to explore the potential mechanism of COPD induced NSCLC. Luciferase assay and reverse transcription-polymerase chain reaction (RT-PCR) were conducted to study the regulatory relationship between P53 and microRNA-675 (miR-675). Real-time PCR, Western-blot analysis, and MTT assay were performed to explore the impact of H19 and miR-675 in the signaling pathway involved in COPD induced NSCLC. In NSCLC patients with COPD, H19 and miR-675 levels were strikingly upregulated while P53 level was significantly downregulated. P53 was identified as a target gene of miR-675, and H19 remarkably upregulated miR-675, while H19 siRNA notably inhibited miR-675. In addition, miR-675 and H19 dramatically suppressed the expression of P53 and Bax while inducing the expression of Bcl-2. Finally, H19 and miR-675 induced proliferation of A549 and MRC-5 cells. These finding indicated that COPD (hypoxia)-induced H19 promoted expression of miR-675 associated with NSCLC though target apoptosis-related protein P53, BAX, and Bcl-2.
10.1002/jcb.29182
Investigation of key miRNAs and potential mechanisms in non-small cell lung cancer development from chronic obstructive pulmonary disease.
Denkçeken Tuba,Pala Elif
General physiology and biophysics
Lung cancer (LC) is the prominent cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) represents approximately 85% of all diagnosed LC cases. It is stated that LC and chronic obstructive pulmonary disease (COPD) are directly linked at a molecular genetics level. Early diagnosis of LC is important for individuals affected by COPD. This study aims to construct a molecular network to discover molecules in NSCLC development from COPD. We downloaded the expression profiles of COPD patients from Gene Expression Omnibus database. The Database Annotation for Visualization and Integrated Discovery tool was utilized for enrichment analysis; STRING and Cytoscape were used for network construction. 15 hub genes were detected among 1517 differentially expressed genes (DEGs). Additionally, 20 differentially expressed miRNAswere identified from five datasets. We constructed miRNA-mRNA regulatory network between the groups of overlapping predicted target genes/DEGs and miRNAs that contained miRNA-mRNA pairs. UALCAN and OncomiR web-portals were used to validate hub genes and miRNAs in NSCLC. JUN, IL6, CD4 and hsa-miR-497-5p, hsa-miR-130b-5p were verified in both lung adenocarcinomas and lung squamous cell carcinomas. This study presents potential biomarkers and mechanisms underlying NSCLC development from COPD that would be targeted for early intervention.
10.4149/gpb_2019042
[Exploration of the treatment model for patients with advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease based on real-world data].
Wang F,Xie X H,Lin X Q,Qin Y Y,Xie Z H,Zhang J X,Ouyang M,Zhou C Z
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases
To explore whether combining treatment of chronic obstructive pulmonary disease (COPD) with anti-tumor therapy is better than that of tumor treatment alone in advanced non-small cell lung cancer (NSCLC) patients with COPD in the real world. The clinical data of 101 patients with advanced NSCLC complicated with COPD from January 1, 2015, to December 31, 2017, in the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively, including 99 males and two females, aged from 52 to 84 years[average (67±8) years]. Among the patients, 90 (89.1%) were smokers, with an average pack-year smoking index of (47±4) . The patients were divided into observation and control groups, depending on whether they received standardized anti-COPD supportive treatment. In the observation group, there were 36 patients, including 35 males and one female, aged from 54 to 84 years[ average (67±8) years], with an average pack-year of smoking (47±4). There were 65 patients in the control group, including 64 males and one female, aged from 52 to 83 years [average (67±8) years], with an average pack-year of smoking 47±4. There was no significant difference in the baseline data between the two groups. The primary outcome measures included the Objective response rate (ORR), disease control rate (DCR), disease-free survival (PFS), and overall survival (OS) of the two groups. An unpaired -test was used to compare continuous variables between the observation and control groups. The Pearson chi-square test was used to compare categorical variables between the two groups. Kaplan-Meier survival curves were used to evaluate the median PFS and median OS of patients, and the log-rank test was used to assess differences between groups. The ORR of the observation group and the control group was 22.6% (7 cases) and 22.2% (11 cases), respectively, with no significant difference (χ(2)=0.01, 0.971). The DCR between the observation group and the control group was 58.1% (19 cases) and 57.8% (27 cases), with no significant difference (χ(2)=0.02, 0.889). Median PFS in the observation group was 6.0 months, which was better than the 3.5 months in the control group (χ(2)=3.947, 0.05). The median OS of the observation group was 18.0 months, which was better than the 15.0 months of the control group (χ(2)=4.083, 0.05). Compared with the treatment of tumors alone, combination of anti-tumor therapy with anti-COPD therapy showed longer PFS and OS in patients with advanced NSCLC complicated with COPD.
10.3760/cma.j.cn112147-20200304-00241
Regional emphysema score is associated with tumor location and poor prognosis in completely resected NSCLC patients.
Heo Jung Won,Kang Hye Seon,Park Chan Kwon,Kim Sung Kyoung,Kim Ju Sang,Kim Jin Woo,Kim Seung Joon,Lee Sang Haak,Yeo Chang Dong
BMC pulmonary medicine
BACKGROUND:Lung cancer is a frequent comorbidity of chronic obstructive pulmonary disease (COPD). However, the local risk of developing lung cancer related to regional emphysema distribution and clinical outcome has not been investigated. Our aim was to evaluate the impact of regional emphysema score (RES) on tumor location and prognosis in non-small cell lung cancer (NSCLC) patients. METHODS:We enrolled 457 patients who underwent curative surgery for NSCLC at seven hospitals at The Catholic University of Korea from 2014 to 2018. Emphysema was visually assessed for each lobe, with the lingula as a separate lobe. Semi-quantitative emphysema scoring was classified as follows: 0 = none, 0.5 = 1 to 10%, 1 = 11 to 25%, 2 = 26 to 50%, 3 = 51 to 75%, and 4 = 76 to 100%. An RES was given to each of the six lung zone: the upper, middle, and lower lobes in the right and left lungs. RESULTS:There were 145 patients in the high RES (≥ 3) group and 312 in the low RES (< 3) group. The mean RES in each lobe with cancer was significantly higher than that in other lobes without cancer (0.51 vs. 0.37, P < 0.001). This group showed significantly shorter disease-free survival (P < 0.001), in addition, presence of COPD, low diffusing capacity of the lung for carbon monoxide (< 80), smoking status, and poor differentiation were more frequent in this group. Also, cancer in a lobe with a higher RES (odds ratio (OR) = 1.56; 95% confidence interval (CI:1.01-2.42; P = 0.04), pathologic stage ≥ III (OR = 2.23; 95% CI: 1.28-3.89; P < 0.001), and poor differentiation (OR = 1.99; 95% CI: 1.22-3.21; P < 0.001) were independent factors for tumor recurrence. CONCLUSIONS:The regional severity of emphysema by visual qualification was associated with the location of lung cancer, and was an independently poor prognostic factor for tumor recurrence in completely resected NSCLC patients.
10.1186/s12890-020-01268-7
Elective Nodal Irradiation for Non-small Cell Lung Cancer Complicated With Chronic Obstructive Pulmonary Disease Affects Immunotherapy Αfter Definitive Chemoradiotherapy.
Morimoto Masahiro,Nishino Kazumi,Wada Kentaro,Imamura Fumio,Konishi Koji,Kuhara Hanako,Tamiya Motohiro,Inoue Takako,Kunimasa Kei,Kimura Madoka,Hirata Takero,Kanayama Naoyuki,Toratani Masayasu,Kawachi Hayato,Ohira Kika,Nakanishi Erina,Ohira Shingo,Sagawa Tomohiro,Miyazaki Masayoshi,Matsunaga Takashi,Kumagai Toru,Teshima Teruki
Anticancer research
BACKGROUND/AIM:The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS:Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC. RESULTS:Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD- and ENI- group, and 16% (1/6 cases) in the COPD+ and ENI+ group. CONCLUSION:ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy.
10.21873/anticanres.14720