Causal effect of immune cells on idiopathic pulmonary fibrosis: A mendelian randomization study.

BACKGROUND: A key component of idiopathic pulmonary fibrosis (IPF) is the involvement of immune cells. However, the causal interaction between different immune cell signatures and IPF remain inconclusive. OBJECTIVES: Based on publicly accessible data, our study utilized the Mendelian randomization (MR) approach to determine the causative relevance of complex immune cell phenotypes in IPF. METHODS: We deployed a two-sample Mendelian randomization approach to evaluate the causal interaction between immune cell markers and IPF. All data regarding 731 immune signatures and IPF were acquired from two genome-wide association studies (GWAS) that are accessible to the public. The original study adopted the inverse variance weighted (IVW) method, followed by sensitivity analyses aimed at eliminating heterogeneity and pleiotropy. Additionally, Multivariate Mendelian randomization (MVMR) was utilized to identify the independent risk factors in our study. RESULTS: The summary dataset for IPF was accessed from the Finnish Genetic Consortium R9, comprising 2018 patients and 373,064 controls. And the dataset for immune signatures was conducted in 3,757 Sardinian individuals. By conducting IVW and extensive sensitivity analyses, univariate Mendelian randomization (UVMR) identified one immunophenotype that remained causally associated with IPF after false discovery rate (FDR) correction: CD39 on CD39+ CD8+T cells (odd ratio [OR] = 0.850, 95 % confidence interval [CI] = 0.787-0.918, P = 3.68 × 10-5). The causal association with IPF was further validated using MVMR. CONCLUSIONS: Based on rigorous MR analysis methods and FDR correction, our study demonstrated that CD39 on CD39+ CD8+T cells showed a protective effect against IPF, providing effective insights for preventing and diagnosing pulmonary fibrosis.

Dietary fiber intake and its association with diabetic kidney disease in American adults with diabetes: A cross-sectional study.

BACKGROUND: Dietary fiber (DF) intake may have a protective effect against type 2 diabetes (T2D); however, its relationship with diabetic kidney disease (DKD) remains unclear. AIM: To investigate the potential association between DF intake and the prevalence of DKD in individuals diagnosed with T2D. METHODS: This cross-sectional study used data from the National Health and Nutrition Examination Survey collected between 2005 and 2018. DF intake was assessed through 24-h dietary recall interviews, and DKD diagnosis in individuals with T2D was based on predefined criteria, including albuminuria, impaired glomerular filtration rate, or a combination of both. Logistic regression analysis was used to assess the association between DF intake and DKD, and comprehensive subgroup and sensitivity analyses were performed. RESULTS: Among the 6032 participants, 38.4% had DKD. With lower DF intake-T1 (≤ 6.4 g/1000 kcal/day)-as a reference, the adjusted odds ratio for DF and DKD for levels T2 (6.5-10.0 g/1000 kcal/day) and T3 (≥ 10.1 g/1000 kcal/day) were 0.97 (95%CI: 0.84-1.12, P = 0.674) and 0.79 (95%CI: 0.68-0.92, P = 0.002), respectively. The subgroup analysis yielded consistent results across various demographic and health-related subgroups, with no statistically significant interactions (all P > 0.05). CONCLUSION: In United States adults with T2D, increased DF intake may be related to reduced DKD incidence. Further research is required to confirm these findings.

Pattern of multiple human papillomavirus infection and type competition: An analysis in healthy Chinese women aged 18-45 years.

To assess the pattern of multiple human papillomavirus infection to predict the type replacement postvaccination. A total of 7372 women aged 18-45y from a phase III trial of an Escherichia coli-produced HPV-16/18 vaccine were analyzed at enrollment visit before vaccination. Hierarchical multilevel logistic regression was used to evaluate HPV vaccine type and nonvaccine-type interactions with age as a covariate. Binary logistic regression was construed to compare multiple infections with single infections to explore the impact of multiple-type infections on the risk of cervical disease. Multiple HPV infections were observed in 25.2% of HPV-positive women and multiple infections were higher than expected by chance. Statistically significant negative associations were observed between HPV16 and 52, HPV18 and HPV51/52/58, HPV31 and HPV39/51/52/53/54/58, HPV33 and HPV52/58, HPV58 and HPV52, HPV6 and HPV 39/51/52/53/54/56/58. Multiple HPV infections increased the risk of CIN2+ and HSIL+, with the ORs of 2.27(95%CI: 1.41, 3.64) and 2.26 (95%CI: 1.29, 3.95) for multiple oncogenic HPV infection separately. However, no significant evidence for the type-type interactions on risk of CIN2+ or HSIL+. There is possibility of type replacement between several pairs of vaccine and nonvaccine HPV type. Multiple HPV infection increased the risk of cervical disease, but coinfection HPV types seem to follow independent disease processes. Continued post-vaccination surveillance for HPV 51/52/58 types and HPV 39/51 types separately was essential after the first and second generation of HPV vaccination implementation in China.

The role of macrophage polarization and cellular crosstalk in the pulmonary fibrotic microenvironment: a review.

Pulmonary fibrosis (PF) is a progressive interstitial inflammatory disease with a high mortality rate. Patients with PF commonly experience a chronic dry cough and progressive dyspnoea for years without effective mitigation. The pathogenesis of PF is believed to be associated with dysfunctional macrophage polarization, fibroblast proliferation, and the loss of epithelial cells. Thus, it is of great importance and necessity to explore the interactions among macrophages, fibroblasts, and alveolar epithelial cells in lung fibrosis, as well as in the pro-fibrotic microenvironment. In this review, we discuss the latest studies that have investigated macrophage polarization and activation of non-immune cells in the context of PF pathogenesis and progression. Next, we discuss how profibrotic cellular crosstalk is promoted in the PF microenvironment by multiple cytokines, chemokines, and signalling pathways. And finally, we discuss the potential mechanisms of fibrogenesis development and efficient therapeutic strategies for the disease. Herein, we provide a comprehensive summary of the vital role of macrophage polarization in PF and its profibrotic crosstalk with fibroblasts and alveolar epithelial cells and suggest potential treatment strategies to target their cellular communication in the microenvironment.

Parental willingness of HPV vaccination in Mainland China: A meta-analysis.

This meta-analysis aimed to systematically review and analyze parental awareness of human papillomavirus (HPV) and its vaccine, as well as parental willingness of the HPV vaccine in China. The literature search selected studies that met the following criteria: study published between 2009 and 2023, study design involving parents with at least one child aged ≤ 18 years, sample sizes exceeding 300, availability of data on parental willingness of the HPV vaccine or sufficient information to calculate effect sizes, and studies published in either English or Chinese. Studies that did not meet one of the above points were excluded. From an initial pool of 660 papers, 33 studies were included, encompassing a total sample size of 92,802. The analysis revealed that the pooled awareness rates of HPV and the HPV vaccine among Chinese parents were 45.0% (95% CI: 36.1-54.0%) and 41.4% (95%CI: 30.7-52.5%), respectively. The overall parental willingness for vaccinating children against HPV was 61.0% (95% CI: 53.5-68.3%). Both parental awareness and willingness of the HPV vaccine in China were found to remain low when compared to other countries.

A novel necroptosis related gene signature and regulatory network for overall survival prediction in lung adenocarcinoma.

We downloaded the mRNA expression profiles of patients with LUAD and corresponding clinical data from The Cancer Genome Atlas (TCGA) database and used the Least Absolute Shrinkage and Selection Operator Cox regression model to construct a multigene signature in the TCGA cohort, which was validated with patient data from the GEO cohort. Results showed differences in the expression levels of 120 necroptosis-related genes between normal and tumor tissues. An eight-gene signature (CYLD, FADD, H2AX, RBCK1, PPIA, PPID, VDAC1, and VDAC2) was constructed through univariate Cox regression, and patients were divided into two risk groups. The overall survival of patients in the high-risk group was significantly lower than of the patients in the low-risk group in the TCGA and GEO cohorts, indicating that the signature has a good predictive effect. The time-ROC curves revealed that the signature had a reliable predictive role in both the TCGA and GEO cohorts. Enrichment analysis showed that differential genes in the risk subgroups were associated with tumor immunity and antitumor drug sensitivity. We then constructed an mRNA-miRNA-lncRNA regulatory network, which identified lncRNA AL590666. 2/let-7c-5p/PPIA as a regulatory axis for LUAD. Real-time quantitative PCR (RT-qPCR) was used to validate the expression of the 8-gene signature. In conclusion, necroptosis-related genes are important factors for predicting the prognosis of LUAD and potential therapeutic targets.

Network pharmacology and molecular docking to explore the pharmacological mechanism of Yifei Tongluo granules in treating idiopathic pulmonary fibrosis: A review.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that leads to progressive dyspnea and dry cough, with extracellular matrix deposition as the main pathological feature. Yifei Tongluo granules (YTG) are a traditional Chinese medicine formula that could nourish Qi-Yin, clear phlegm, and invigorate blood circulation. In this research, network pharmacology and molecular docking were used to elucidate the potential mechanism of YTG for treating IPF. A total of 278 biologically active compounds were included in YTG, and 16 compounds were selected for pharmacological analysis and molecular docking through "drugs-compounds-intersecting targets of YTG and IPF" network construction. Protein-protein interaction network was constructed using 330 YTG-IPF intersecting targets. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. A total of 10 core targets were screened by protein-protein interaction, and molecular docking was used to further validate the binding ability of the compounds to the core targets. The network pharmacology and molecular docking results showed that Danshenol A, isorhamnetin, Ginsenoside-Rh4, quercetin, and kaempferol might be the main active compounds in the treatment of IPF by YTG, whereas MAPK1, MAPK3, EGFR, and SRC are the core targets while PI3K/AKT pathway and MAPK pathway are the main signaling pathways through which YTG regulates relevant biological processes to intervene in IPF. This study shows that YTG can treat IPF by inhibiting the epithelial-mesenchymal transit process, fibroblast proliferation, fibroblast-to-myofibroblast conversion, myofibroblast anti-apoptosis, collagen expression, and other mechanisms.YTG can be widely used as an adjuvant therapy for IPF in clinical practice, and this study provides the basis for subsequent experimental studies.

Safety of hepatitis E vaccination for pregnancy: a post-hoc analysis of a randomized, double-blind, controlled phase 3 clinical trial.

Special attention has been paid to Hepatitis E (HE) prophylaxis for pregnant women due to poor prognosis of HE in this population. We conducted a post-hoc analysis based on the randomized, double-blind, HE vaccine (Hecolin)-controlled phase 3 clinical trial of human papillomavirus (HPV) vaccine (Cecolin) conducted in China. Eligible healthy women aged 18-45 years were randomly assigned to receive three doses of Cecolin or Hecolin and were followed up for 66 months. All the pregnancy-related events throughout the study period were closely followed up. The incidences of adverse events, pregnancy complications, and adverse pregnancy outcomes were analysed based on the vaccine group, maternal age, and interval between vaccination and pregnancy onset. During the study period, 1263 Hecolin receivers and 1260 Cecolin receivers reported 1684 and 1660 pregnancies, respectively. The participants in the two vaccine groups showed similar maternal and neonatal safety profiles, regardless of maternal age. Among the 140 women who were inadvertently vaccinated during pregnancy, the incidences of adverse reactions had no statistical difference between the two groups (31.8% vs 35.1%, p = 0.6782). The proximal exposure to HE vaccination was not associated with a significantly higher risk of abnormal foetal loss (OR 0.80, 95% CI 0.38-1.70) or neonatal abnormality (OR 2.46, 95% CI 0.74-8.18) than that to HPV vaccination, as did distal exposure. Significant difference was not noted between pregnancies with proximal and distal exposure to HE vaccination. Conclusively, HE vaccination during or shortly before pregnancy is not associated with increased risks for both the pregnant women and pregnancy outcomes.

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.

A comprehensive review of emodin in fibrosis treatment.

Emodin is the main pharmacodynamic components of rhubarb, with significant pharmacological effects and clinical efficacy.Emodin has a variety of therapy effects, such as anti-cancer, anti-fibrosis effects, and is widely used to treat encephalitis, diabetic cataract and organ fibrosis. Several studies have shown that emodin has a good treatment effect on organ fibrosis, but the mechanism is complex. Moreover, the evidence of some studies is conflicting and confusing. This paper reviewed the mechanism, pharmacokinetics and toxicology of emodin in fibrosis treatment, and briefly discussed relevant cutting-edge new formulations to improve the efficacy, the result can provide some reference for future study.

Efficacy of prophylactic human papillomavirus vaccines on cervical cancer among the Asian population: A meta-analysis.

Objective: We conducted a meta-analysis to assess the efficacy of prophylactic human papillomavirus (HPV) vaccines against cervical cancer precursors and HPV persistent infection among Asian populations. Methods: Randomized controlled clinical trials conducted in Asian countries were identified from three electronic databases (PubMed, EMBASE and the Cochrane Library). Publication retrieval was performed on September 1, 2022 and only those written in English were included. The data were analyzed with Cochrane Review Manager (version 5.3) and Stata/SE (15.1). Effect sizes were presented as risk ratios (RRs) and 95% confidence intervals (CIs). Results: Ten articles were considered in the meta-analysis, without significant heterogeneity among them. The fixed-effect RRs and 95% CIs for cervical intraepithelial neoplasia grade 1 (CIN1+) and CIN2+ were 0.10 (0.05-0.21) and 0.11 (0.04-0.27), respectively. Positive effect of HPV vaccination on 6- and 12-month persistent infection were observed, with the respective pooled RRs of 0.05 (95% CI: 0.03-0.09) and 0.09 (95% CI: 0.05-0.15). HPV vaccination has a positive effect on the incidence of cytological abnormalities associated with HPV 16/18 (RR, 0.13; 95% CI (0.09-0.20)). Positive effects of HPV vaccination were also observed for HPV 16- and 18-specific immunogenicity (RR, 235.02; 95% CI (82.77-667.31) and RR, 98.24; 95% CI (50.36-191.67), respectively). Females receiving an initial vaccination showed significant decreased incidences of cervical intraepithelial neoplasia, HPV persistent infection and cytological abnormalities and a significantly higher antibody positive conversion rate compared with non-vaccination counterparts. Conclusion: Prophylactic HPV vaccines are highly efficacious in preventing cervical cancer in Asian females. The government should accelerate the processes of vaccine introduction and vaccination implementation by prioritizing them in public health policies, which should be helpful to enhance Asian females' awareness of receiving HPV vaccination volitionally.

Comparison of the performance of HPV DNA chip test and HPV PCR test in cervical cancer screening in rural China.

Background: This study aimed to evaluate the performance of two different principles of HPV testing in primary cervical cancer screening and ASC-US triage in rural areas. Methods: 3,328 and 3,913 women were enrolled in Shanxi, China in 2017 and 2018, respectively, and screened using liquid-based cytology and different HPV tests with a 4-year follow-up. Different screening methods commonly used in clinical practice were evaluated. Results: In the HPV PCR test cohort, the prevalence of HPV infection was 14.90%. A total of 38 cases of CIN2+ were identified at baseline, 2 of which were in the HPV-negative cohort and the rest in the HPV-positive cohort (2 = 186.85, p < 0.001). Fifty-three cases of CIN2+ were accumulated over 4 years. The HPV infection rate in the HPV DNA chip test cohort was 21.10%. A total of 26 CIN2+ cases were identified at baseline, all in the HPV-positive population (2 = 92.96, p < 0.001). 54 CIN2+ cases were cumulative over 4 years. At 4-year follow-up, HPV-negative results were significantly more protective against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) than normal cytologic results at baseline. HPV screening was more sensitive and specific than cytologic screening (using ASC-US as the threshold) and performed better on the HPV DNA microarray test. In addition, compared with HPV 16/18 testing, sensitivity increases and specificity decreases when using HPV testing for cytologic ASC-US triage, regardless of which HPV test is used. Conclusion: In the rural areas where we implemented the study, HPV tests performed well for screening than LBC and HPV DNA chip testing performed better than HPV PCR testing in the screening cohort. Optimal screening was achieved technically when used in combination with LBC for ASC-US population triage, without thinking the feasibility for resource availability.

Comparison of primary cytology, primary HPV testing and co-testing as cervical cancer screening for Chinese women: a population-based screening cohort.

OBJECTIVES: We compared clinical performance of three strategies of primary human papillomavirus (HPV) testing, primary cytology and co-testing for cervical cancer screening. DESIGN: A population-based prospective cohort study of clinical performance of screening strategy. SETTING: Patients recruited from community in Changzhi County, Shanxi Province, China. PATIENT: 3209 women aged 30-64 years without gynaecological issues. PRIMARY AND SECONDARY OUTCOME MEASURES: The performance of different screening strategies for detecting cervical intraepithelial neoplasia grade 2 or more severe (CIN2+). RESULTS: A total of 53 CIN2+ and 31 CIN3+ cases are detected. For CIN2+, sensitivity of primary HPV (95.9%) and co-testing (98.0%) are not statistically different, but significantly higher than primary cytology (48.0%). Specificity (86.8%), colposcopy referral rate (7.8%) and number of colposcopies required to detect one case (9.8) for primary HPV are better than co-testing (79.8%, 11.9%, 14.3%, respectively). For CIN3+, primary HPV, co-testing have 100% of sensitivity and specificity, which is significantly higher than primary cytology (56.7% and 90.2%). Number of colposcopies required to detect one case for primary HPV (15.9) is better than co-testing (23.8). CONCLUSIONS: Compared with co-testing, HPV primary screening had comparable sensitivity and higher specificity for CIN2+ detection, and both of them showed better performance than cytology primary screening in cervical cancer screening.

Cation Bridge Mediating Homo- and Cross-Coupling in Copper-Catalyzed Reductive Coupling of Benzaldehyde and Benzophenone.

A novel mechanism of organobase-mediated Brook rearrangement and C-C coupling in the copper-catalyzed reductive coupling of benzaldehyde and benzophenone is proposed. The results demonstrate that this reaction proceeds mainly through five sequential elementary steps: transmetalation, carbonyl addition, σ-bond metathesis, Brook rearrangement, and C-C coupling. The organobases played a significant role not only in forming the active catalyst but also in mediating the Brook rearrangement and chemoselectivity in homo- and cross-coupling. Brook rearrangement mediated by organobases is more favored than that without organobases. In the C-C coupling step, the cation bridge combines two O atoms with the same electronegativity to form a pre-reaction complex. Moreover, a significant charge difference is a major factor in the selectivity of carbonyl addition and C-C coupling.

Role of TRPV1 in respiratory disease and association with traditional Chinese medicine: A literature review.

Transient receptor potential vanilloid type 1 (TRPV1), involved in multiple pathophysiological processes including inflammation, is a thermally activated, non-selective cation channel. It has been identified that TRPV1 is highly involved in some common respiratory diseases including allergic rhinitis, asthma, chronic obstructive pulmonary disease, and pulmonary infection by participating in neurogenic and immunogenic inflammation, sensitization, and oxidative stress. In recent years, the hypothesis of transient receptor potential (TRP) has been introduced in studies on the theory of five flavors and four properties of Chinese medicinal. However, the hypothesis is undetermined due to the multi-component and multi-target characteristics of Chinese medicinal. This study describes the relations between TRPV1 and four types of respiratory diseases based on the literature in recent five years. In the meantime, the therapeutic effect of Chinese medicinal by intervening TRPV1 was reviewed, in an attempt to provide certain evidence for future studies on the medicinal property-effect relationship, mechanism of drug action, the syndrome differentiation in traditional Chinese medicine (TCM) for respiratory diseases and to help for new drug development.

The Role and Mechanisms of Traditional Chinese Medicine for Airway Inflammation and Remodeling in Asthma: Overview and Progress.

Asthma as an individual disease has blighted human health for thousands of years and is still a vital global health challenge at present. Though getting much progress in the utilization of antibiotics, mucolytics, and especially the combination of inhaled corticosteroids (ICS) and long-acting ß-agonists (LABA), we are confused about the management of asthmatic airway inflammation and remodeling, which directly threatens the quality of life for chronic patients. The blind addition of ICS will not benefit the remission of cough, wheeze, or sputum, but to increase the risk of side effects. Thus, it is necessary to explore an effective therapy to modulate asthmatic inflammation and airway remodeling. Traditional Chinese Medicine (TCM) has justified its anti-asthma effect in clinical practice but its underlying mechanism and specific role in asthma are still unknown. Some animal studies demonstrated that the classic formula, direct exacts, and natural compounds isolated from TCM could significantly alleviate airway structural alterations and exhibit the anti-inflammatory effects. By investigating these findings and data, we will discuss the possible pathomechanism underlined airway inflammation and remodeling in asthma and the unique role of TCM in the treatment of asthma through regulating different signaling pathways.

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.

[Progress of Research on the Relationship between Lung Microbiome and Lung Cancer].

The microbiota plays an important role in the biological functions of the human body and is associated with various disease states such as inflammation (gastritis, hepatitis) and cancer (stomach, cervical, liver). The Human Microbiome Project painted a panorama of human microorganisms in its first phase, incorporating body parts such as the nasal cavity, oral cavity, intestine, vagina and skin, while the lungs were considered a sterile environment. However, studies in recent years have confirmed the presence of a rich microbial community in the lung, and the association of this lung microbiota with lung disease has become a hot topic of research. Current research has found that patients with lung cancer have a specific microbiota compared to healthy individuals or patients with lung disease. Even in patients with lung cancer, a lung microbiota specific to the tumor site is present. In addition, different pathological types and metastatic status of lung cancer can lead to differences in microbiota. Mechanistic studies have found that the lung microbiota may influence lung cancer development by affecting the immune response. Clinical studies on lung microbiota and immunotherapy are still in the preliminary stage. More relevant studies are needed in the future to provide high-quality evidence to further understand the oncogenic mechanisms of lung microbiota and provide new ideas for clinical treatment. This paper briefly reviews the progress of lung microbiota research in terms of its relevance to lung cancer, possible molecular mechanisms and applications in clinical treatment, and provides an outlook for future research.
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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.

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.