Arsenic, tobacco use, and lung cancer: An occupational cohort with 27 follow-up years.

BACKGROUND: We explored the shape of the exposure-response relationship of arsenic-related lung cancer and the interaction between arsenic and tobacco use. METHODS: A total of 3278 tin miners with at least 10 years of arsenic exposure were enrolled since 1992 and followed up for 27 years. After excluding radon-exposed miners and former smokers, 1620 miners were included into the sub-cohort. Lung cancer risks were estimated by modeling total exposure and intensity of arsenic exposure. RESULTS: The cohort experienced 73,866 person-years and 414 lung cancer cases. Firstly, the ERR/mg/m3-year was 0.0033 (95% CI: 0.0014-0.0045) in arsenic concentration <3 mg/m3 and 0.0056 (95% CI: 0.0035-0.0073) in arsenic concentration ≥3 mg/m3. After adjusting for cumulative arsenic exposure, and the ERR/mg/m3 increased with increasing intensity (0.129 (95% CI: 0.039, 0.189)). Secondly, an unique aspect of this population was the early age at first arsenic exposure for workers. Results showed that lung cancer incidence risk from exposed in childhood (<13 years) was non-significantly greater than those in other age groups (13-17 and ≥ 18 years). Finally, the most likely joint effects of inhaled arsenic and tobacco use was sub-multiplicative. CONCLUSION: This study enlightened us that for fixed cumulative arsenic exposure, higher concentration over shorter duration might be more deleterious than lower concentration over longer duration. Substantial reductions in the lung cancer burden of smokers exposed to arsenic could be achieved by reductions in either exposure.

Quantitative evaluation of radon, tobacco use and lung cancer association in an occupational cohort with 27 follow-up years.

BACKGROUND: Occupational radon cohorts provide important information about exposure at residential level, which are difficult to observe prospectively. However, evidence about radon-related lung cancer risks from initial exposure in childhood or interaction between radon and smoking is still limited. METHODS: A total of 6017 tin miners with at least 10 years of underground radon exposure were enrolled beginning in 1992 and followed for up to 27 years. Lung cancer risks were estimated by modeling total and intensity of radon exposure. RESULTS: A total of 933 lung cancer cases occurred in this cohort over 89,092 person-years of follow up. Excess relative risk increased by 0.96% per cumulative working level month (WLM). A unique aspect of this population was the early age at first radon exposure for workers. Results showed that lung cancer risk from initial radon exposure in childhood (<13 years old) was greater than risk when first exposure occurred at later ages (13-17, 18-24, and ≥ 25 years old). Moreover, risk declined with years since last exposure and attained age, but increased with age at last exposure. Importantly, these patterns were stable after adjustment for tobacco use or arsenic exposure. For joint effects of radon and other agents, our results support sub-multiplicative as the most likely model for interaction between radon and tobacco use or arsenic exposure. CONCLUSION: This study highlights the possible importance of radon exposure in childhood in cancer etiology and suggests another potential strategy to mitigate the global lung cancer burden.

Benzyl isothiocyanate induces protective autophagy in human lung cancer cells through an endoplasmic reticulum stress-mediated mechanism.

Isothiocyanates, such as allyl isothiocya¬nate (AITC), benzyl isothiocyanate (BITC), phenethyl isothio¬cyanate (PEITC) and sulforaphane (SFN), are natural compounds abundant in cruciferous vegetables, which have substantial chemopreventive activities against various human malignancies. However, the mechanisms underlying the inhibition of tumor cell growth by isothiocyanates are not fully understood. Since autophagy has dual functions in cancer, in the present study we investigated the effects of BITC on autophagy induction in human lung cancer cells in vitro and in vivo. BITC (1-100 µmol/L) dose-dependently inhibited the growth of 3 different human lung cancer cell lines A549 (adenocarcinoma), H661 (large cell carcinoma) and SK-MES-1 (squamous cell carcinoma) with IC50 values of 30.7±0.14, 15.9±0.22 and 23.4±0.11 µmol/L, respectively. BITC (10-40 µmol/L) induced autophagy in the lung cancer cells, evidenced by the formation of acidic vesicular organelles (AVOs), the accumulation of LC3-II, the punctate pattern of LC3, and the expression of Atg5. Pretreatment with the autophagy inhibitor 3-MA (5 mmol/L) significantly enhanced the BITC-caused growth inhibition in the lung cancer cells. Furthermore, BITC (20-40 µmol/L) activated ER stress, as shown by the increased cytosolic Ca2+ level and the phosphorylation of the ER stress marker proteins PERK and eIF2α in the lung cancer cells. Pretreatment with the ER stress inhibitor 4-PBA (5 mmol/L) attenuated the autophagy induction and potentiated the BITC-induced cell growth inhibition. In nude mice bearing A549 xenografts, administration of BITC (100 mg·kg-1·d-1, ip) for 8 weeks markedly suppressed the lung tumor growth, and significantly enhanced both autophagy and ER stress in the tumor tissues. Our results demonstrate that BITC inhibits human lung cancer cell growth in vitro and in vivo. In addition, BITC induces autophagy in the lung cancer cells, which protects the cancer cells against the inhibitory action of BITC; the autophagy induction is mediated by the ER stress response.

The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer.

Long non-coding RNAs (lncRNAs) are associated with the occurrence, development and prognoses of non-small cell lung cancer (NSCLC). In the present study, we investigated the functional mechanisms of the lncRNA XIST in two human NSCLC cell lines, A549 and NCI-H1299. In all the 5 NSCLC cell lines (NL9980, NCI-H1299, NCI-H460, SPC-A-1 and A549) tested, the expression levels of XIST were significantly elevated, as compared with those in normal human bronchial epithelial cell line BEAS-2B. In A549 and NCI-H1299 cells, knockdown of XIST by siRNA significantly inhibited the cell proliferation, migration and invasion, and promoted cell apoptosis. Furthermore, XIST knockdown elevated the expression of E-cadherin, and suppressed the expression of Bcl-2. Moreover, knockdown of XIST significantly suppressed the tumor growth in NSCLC A549 xenograft mouse model. Bioinformatic analysis and luciferase reporter assays revealed that XIST was negatively regulated by miR-449a. We further identified reciprocal repression between XIST and miR-449a, which eventually influenced the expression of Bcl-2: XIST functioned as a miRNA sponge of miR-449a, which was a negative regulator of Bcl-2. These data show that expression of the lncRNA XIST is associated with an increased growth rate and metastatic potential in NSCLC A549 and NCI-H1299 cells partially through miR-449a, and suggest that XIST may be a potential prognostic factor and therapeutic target for patients with NSCLC.

HapMap-based study on the association between MPO and GSTP1 gene polymorphisms and lung cancer susceptibility in Chinese Han population.

AIM: Myeloperoxidase (MPO) and glutathione S-transferase pi 1 (GSTP1) are important carcinogen-metabolizing enzymes. The aim of this study was to investigate the association between the common polymorphisms of MPO and GSTP1 genes and lung cancer risk in Chinese Han population. METHODS: A total of 266 subjects with lung cancer and 307 controls without personal history of the disease were recruited in this case control study. The tagSNPs approach was used to assess the common polymorphisms of MOP and GSTP1 genes and lung cancer risk according to the disequilibrium information from the HapMap project. The tagSNP rs7208693 was selected as the polymorphism site for MPO, while the haplotype-tagging SNPs rs1695, rs4891, rs762803 and rs749174 were selected as the polymorphism sites for GSTP1. The gene polymorphisms were confirmed using real-time PCR, cloning and sequencing. RESULTS: The four GSTP1 haplotype-tagging SNPs rs1695, rs4891, rs762803 and rs749174, but not the MPO tagSNP rs7208693, exhibited an association with lung cancer susceptibility in smokers in the overall population and in the studied subgroups. When Phase 2 software was used to reconstruct the haplotype for GSTP1, the haplotype CACA (rs749174+rs1695 + rs762803+rs4891) exhibited an increased risk of lung cancer among smokers (adjust odds ratio 1.53; 95%CI 1.04-2.25, P=0.033). Furthermore, diplotype analyses demonstrated that the significant association between the risk haplotype and lung cancer. The risk haplotypes co-segregated with one or more biologically functional polymorphisms and corresponded to a recessive inheritance model. CONCLUSION: The common polymorphisms of the GSTP1 gene may be the candidates for SNP markers for lung cancer susceptibility in Chinese Han population.

[A standardization study of Meta-analyses on nephropathy published in Chinese journals].

OBJECTIVE: To evaluate the standardization of Meta-analyses on nephropathy published in Chinese journals. METHODS: By searching in WANFANG, VIP, CNKI databases and Chinese Biomedical Literature Database (CBM) as well as related Chinese journals, eligible Meta-analyses were enrolled and analyzed according to the PRISMA(Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement and the MOOSE (Meta-analysis of Observational Studies in Epidemiology) Checklist. RESULTS: A total of 217 Meta-analyses were enrolled with 166 on randomized controlled trials (RCT) and 51 on observational studies. Based on the PRSIMA Statement, of the 166 Meta-analyses on RCT, 51.8% (86 papers) were found with the complete research hypothesis, 13.9% (23) with the literature screening flow chart, 15.7% (26) with the subgroup analysis, 53.0% (88) with the publication bias analysis and 28.3% (47) with the sensitivity analysis. According to the MOOSE Checklist, of the 51 Meta-analyses on observational studies, only 9.8% (5) had done the statistical stability calculation, 54.9% (28) with the outlook of application, 45.1% (23) with the limitation of the study, 2.0% (1) with the quantitative analysis on potential bias and 17.6% (9) with the suggestion for future studies. CONCLUSIONS: Unclear hypothesis, limited methodological description, lack of in-depth analysis on heterogeneity and bias are the common defects in Meta-analyses published in Chinese journals on nephrology.

Effect of Arsenic Exposure and Cigarette Smoking on Total and Cause-Specific Mortality: An Occupational Cohort With 27 Follow-up Years.

BACKGROUND: The relationship between arsenic exposure and all-cause mortality and the joint effects of arsenic exposure and smoking have been poorly described in previous studies. METHODS: After 27 years of follow-up, a total of 1738 miners were included in the analysis. Different statistical methods were used to explore the relationship between arsenic exposure and smoking and the risk of all-cause mortality and various causes of death. RESULTS: A total of 694 deaths occurred during the 36,199.79 person-years of follow-up. Cancer was the leading cause of death, and arsenic-exposed workers had significantly higher mortality rates for all-cause, cancer, and cerebrovascular disease. All-cause, cancer, cerebrovascular disease, and respiratory disease increased with cumulative arsenic exposure. CONCLUSIONS: We demonstrated the negative effects of smoking and arsenic exposure on all-cause mortality. More effective actions should be taken to reduce arsenic exposure in miners.

Additional new species of the genus Hexarhopalus Fairmaire, 1891 (Coleoptera, Tenebrionidae: Cnodalonini) from China.

Three new species of the genus Hexarhopalus Fairmaire, 1891, all of the nominate subgenus, are described and figured from China: Hexarhopalus (Hexarhopalus) ferreri sp. nov. from Yunnan, H. (H.) tianbaoyanensis sp. nov. from Fujian, and H. (H.) yeziyangi sp. nov. from Jiangxi.

Effect of Time Since Smoking Cessation on Lung Cancer Incidence: An Occupational Cohort With 27 Follow-Up Years.

Background: This special cohort reveals the effect of smoking cessation in occupational miners exposed to radon and arsenic. Methods: A total of 9,134 tin miners with at least 10 years of underground radon and arsenic exposure were enrolled beginning in 1992 and followed for up to 27 years. Detailed smoking information was collected at baseline, and information on smoking status was consecutively collected from 1992 to 1996. The Cox proportional hazards model was used to explore the relationship between time since smoking cessation and lung cancer. Results: A total of 1,324 lung cancer cases occurred in this cohort over 167,776 person-years of follow-up. Among populations exposed to radon and arsenic, miners after quitting smoking for 10 years or more had almost halved their lung cancer risk [adjusted hazard ratio (HR) = 0.55, 95% CI: 0.38-0.79], compared with current smokers. Among miners after quitting smoking for 5 years or more, lung cancer incidence approximately halved (HR = 0.52, 95% CI: 0.30-0.92) for squamous cell lung carcinoma, while it showed no significant decline for adenocarcinoma (HR = 0.79, 95% CI: 0.34-1.85). Conclusion: Smoking cessation for 10 years or more halved lung cancer incidence among miners exposed to radon and arsenic, and the benefit was more pronounced among squamous cell lung carcinoma.