MicroRNAs in lung cancer

Lung cancer (LC) is a serious public health problem responsible for the majority of cancer deaths and comorbidities in developed countries. Tobacco smoking is considered the main risk factor for LC; however, only a few smokers will be affected by this cancer. Current screening methods are focused on identifying the early stages of this malignancy. Thus, new data concerning the roles of microRNA alterations in inflammation, epithelial-mesenchymal transition and lung disease have increased hope about LC pathogenesis, diagnosis, treatment and prognosis. MicroRNA mechanisms include angiogenesis promotion, cell cycle regulation by modulating cellular proliferation and apoptosis, and migration and invasion inhibition. In this context, this manuscript reviews the current information about many important microRNAs as they relate to the initiation and progression of LC.info:eu-repo/semantics/publishedVersio

Occupational chemical exposures in combination with unusual working hours

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Effects of the combined exposure to chemicals and unusual working hours

Objective Both exposure to occupational chemicals and to unusual working hours have well documented effects on health. Determination of occupational exposure limits is, however, usually based on chemical-only exposure and assumes an 8-h workday, 5 days/week and a 40-h work week. A significant proportion of the workforce is exposed to chemicals while working in other work schedules. This review thus aimed to synthesize and evaluate the scientific support for a combined effect of unusual working hours and chemical exposure and, if possible, give recommendations for OEL adjustments to account for unusual working hours. Methods The search for articles was made as part of the preparation of a report for the Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals. In this report, unusual working hours were categorized as shift work or extended (>8 h) working hours. Inclusion criteria were observational studies in the English language published up to November 2021 in peer-reviewed journals, with explicit metrics of exposure (chemicals and unusual working hours) and of health outcome, and which explicitly tested the association between exposure and outcome. Search engines of seven databases were used. Results Of the initially 15 400 identified papers, 9 studies published between 1985 and 2021 met the inclusion criteria, 7 of which showed significant associations. Results from a few of the studies, i.e. regarding effects of dust and endotoxin on lung function, effects of acetone on sleep quality and tiredness, effects of carbon disulphide on coronary artery disease and effects of chemicals on spontaneous abortion, suggested more pronounced effects during night shifts compared to during day shifts. Discussion The reviewed data is considered insufficient to conclude on recommendations for OEL adjustment for shift work. Suggested areas of future studies are mentioned. Conclusion Further studies about the effects of the combined exposure to unusual working hours and chemical exposure are essential for risk assessment, and for recommendation of potential OEL adjustments. What is important about this paper? Effects of chemical agents at the workplace may depend not only on exposure level and duration but also on the time of exposure in relation to the circadian rhythm. This study reviewed the scientific support for a combined effect of unusual working hours and chemical exposure and revealed an obvious need for additional studies regarding the complex interplay of the two different exposures with respect to adverse health effects.publishedVersio

The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals

A significant proportion of the work force is employed in unusual work schedules. The combined effects of working hours and chemical agents at the workplace may depend on the duration and/or timing of exposure. However, occupational exposure limits (OELs) usually assume working day-time, an 8-hour workday, 5 days/week and a 40-hour work week. The aims of this document were to review the scientific support for a combined effect of unusual working hours (shift work or extended working hours) and chemical exposure and, to the extent possible provide recommendations for down-adjustment of the OEL to account for unusual working hours. Animal data from chronopharmacological studies suggest that the time of exposure (day-night) may affect the biotransformation and toxicity of chemicals. A few epidemiological studies, i.e. regarding effects of dust and endotoxin on lung function, effects of acetone on sleep quality and tiredness, effects of carbon disulphide on coronary artery disease and effects of chemicals on spontaneous abortion, suggest more pronounced effects during night shifts compared to day shift exposure. However, the reviewed data are considered insufficient to conclude on recommendations for OEL adjustment for shift work. The Quebec method is recommended to adjust for extended working hours. Each chemical is assigned in categories based on the toxic effect. No adjustment is applied for ceiling values, short-term exposure limits and limit values based on asphyxiation, irritation or malodour. For other substances producing effects following short- or long-term exposure, the method is based on Haber’s rule and the type of adverse effect

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic alteration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours with concordant deletion in the 4 most involved loci (3p21, 5q11–13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours without deletions at the corresponding loci (P< 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11–13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations. © 2001 Cancer Research Campaign http://www.bjcancer.co

Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies

Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×$10^{−9}$). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci

Replication of Lung Cancer Susceptibility Loci at Chromosomes 15q25, 5p15, and 6p21: A Pooled Analysis From the International Lung Cancer Consortium

Background Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. Methods Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided. Results Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, Ptrend = 2 × 10−26), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, Ptrend = 1 × 10−10) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, Ptrend = 5 × 10−8) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, Ptrend = 2 × 10−5; rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, Ptrend = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer. Conclusions In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histolog

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P= 1.2 × 10−4). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7–2.3 for lung cancer(LC;P= 4.0 × 10−4), chronic obstructive pulmonary disease (COPD;P= 9.3 × 10−4), peripheral artery disease (PAD;P= 0.090) and abdominal aortic aneurysms (AAAs; P= 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49,P= 2.2 × 10−4), COPD (OR = 3.22,P= 2.9 × 10−4), PAD (OR = 3.47,P= 9.2 × 10−3) and AAA (OR = 6.44, P= 6.3 × 10−3). Joint analysis of the four smoking-related diseases reveals significant association (P= 6.8 × 10−5), particularly for early-onset cases (P=2.1 × 10−7). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation

Effects of mild steel welding fume particles on pulmonary epithelial inflammation and endothelial activation

Welders have an increased risk for cardiovascular disease (CVD) following exposure to welding fumes. The underlying mechanisms are largely unknown; however, oxidative stress, systemic inflammation, and endothelial dysfunction have been suggested as contributing factors to particle-induced CVD. We investigated effects of mild steel welding fume (MSWF) on three target cell types: macrophages, pulmonary epithelial, and vascular endothelial cells. Cells were exposed to MSWF at nontoxic doses for 6 h/day, for five consecutive days. The expression of 40 genes involved in inflammation, fibrosis, and endothelial activation was analyzed. Moreover, changes in the reactive oxygen species production and migration capacity of cells were assessed. The expression of matrix metallopeptidase 1 (MMP1) was induced in both epithelial and endothelial cells following repeated exposure to MSWF. Although MMP1 is important in inflammatory responses in vivo, this effect was not concurrent with changes in the inflammatory status, cell proliferation, and migration capacities, nor did it induce oxidative stress in the cells. Thus, repeated exposure with low doses of MSWF was sufficient neither for inducing inflammatory stress in epithelial cells and macrophages nor for endothelial activation, and higher concentrations of MSWF or the nonparticle fraction of MSWF may be critical in causing the increased risk of CVD observed among welders.Effects of mild steel welding fume particles on pulmonary epithelial inflammation and endothelial activationpublishedVersio