LRH1 as a driving factor in pancreatic cancer growth

Liver receptor homolog 1 (LRH1), directs the development and differentiation of embryonic pancreas, and is overexpressed in pancreatic cancer (PC). We hypothesized that LRH1 promotes PC growth. Cell proliferation and tumorigenicity in nude mice were compared between empty vector-transfected (control) and stable LRH1-overexpressed PC cell lines. The subsequent tumor burden, vasculature development, and histologic features were evaluated. LRH1 overexpression enhanced the expression of downstream target genes (cyclin D1/E1) and stimulated cell proliferation in PC cell lines. LRH1 upregulated cyclin E1 truncated T1/T2 isoforms expression which may occur through ERα–calpain1 signaling. Compared with the control, LRH1 overexpressing stable cells generated tumors with increased weight, proliferation index and enhanced angiogenesis. Cyclin D1/E1 and calpain1 were overexpressed in human PC tumors compared to adjacent normal pancreas. These observations demonstrate that LRH1 promotes PC growth and angiogenesis, suggesting that LRH1 is a driving factor in tumorigenesis and may serve as a potential therapeutic target

Long-Term Exposure to Silica Dust and Risk of Total and Cause-Specific Mortality in Chinese Workers: A Cohort Study

A retro-prospective cohort study by Weihong Chen and colleagues provides new estimates for the risk of total and cause-specific mortality due to long-term silica dust exposure among Chinese workers

Combined effect of silica dust exposure and cigarette smoking on total and cause-specific mortality in iron miners: a cohort study

Abstract Background Both cigarette smoking and long-term exposure to crystalline silica dust were reported to be associated with increased mortality. However, the combined effect of both factors has not been well evaluated. Methods We investigated a retro-prospective cohort of 7,665 workers from one Chinese iron mine with a median follow-up of 42.8 years. Cumulative silica exposure was estimated for each worker by linking work histories with a job-exposure matrix. Cigarette smoking information was collected through face-to-face questionnaires. Hazard ratios (HRs) for total and cause-specific mortality due to silica exposure and smoking were estimated using Cox proportional hazards models. Results A total of 2,814 deaths occurred during 315,772.9 person-years of follow-up. Significantly elevated mortality from all causes, cardiovascular disease, non-malignant respiratory disease and lung cancer was observed among silica-exposed workers, while elevated mortality from non-malignant respiratory disease and lung cancer was observed among smokers. Combined exposure to silica dust and cigarette smoking elevated the proportion of mortality and accounted for 21.2, 76.0, 35.7 and 81.4% of all causes, non-malignant respiratory disease, cardiovascular disease, and lung cancer, respectively. Significant additive joint effects of silica exposure and cigarette smoking on mortality from lung cancer (HR 1.893, 95% CI 0.628 to 3.441) and pneumoconiosis (6.457, 0.725 to 39.114), together with a significant multiplicative joint effect from all causes (1.002, 1.000 to 1.004) were observed. Conclusions The present findings indicated that silica exposure in combination with cigarette smoking accounted for a fraction of extra deaths in our cohort. Our research showed the urgent need for smoking cessation and silica control among iron miners

Effects of the Interactions between Dust Exposure and Genetic Polymorphisms in Nalp3, Caspase-1, and IL-1β on the Risk of Silicosis: A Case-Control Study.

To evaluate the effects of the interactions between polymorphisms in Nalp3, caspase-1, and interleukin(IL)-1β genes and occupational dust exposure on the risk of silicosis.We conducted a population-based case-control study in a large iron mine in China. Between January 2006 and December 2009, we identified 179 patients with silicosis to evaluate as cases and 201 individuals without silicosis to evaluate as controls. We estimated cumulative dust exposure (CDE) for all subjects and we genotyped polymorphisms in Nalp3, caspase-1, and IL-1β genes. We estimated odds ratios(ORs), 95% confidence intervals(95%CIs), and p-values using logistic regression models adjusted for selected confounders.After adjusting for age, smoking status, and CDE, subjects with the CT genotype of Ex4-849C>T in Nalp3 and the GA genotype of Ex2+37G>A in caspase-1 had increased risks of silicosis (adjusted ORs[95%CIs] = 2.40 [1.12-5.12] and 3.62 [1.63-8.02], respectively). Among subjects younger than 70 years old, those with the CC genotype of IVS8-7652A>C in Nalp3 had a lower risk of silicosis than those with other genotypes (adjusted OR[95%CI] = 0.24[0.06-0.88]). Among subjects aged 70 years and older, those with the CT genotype of Ex4-849C>T in Nalp3 and those with the GA genotype of Ex2+37G>A in caspase-1 had a higher risk of silicosis than those with other genotypes (adjusted ORs [95%CI] = 2.52[1.04-6.12] and 5.19[1.88-14.35], respectively). Among subjects with CDE greater than 120 mg/m3×year and among smokers, those with the GA genotype of Ex2+37G>A in caspase-1 had a higher risk of silicosis than those with other genotypes (adjusted ORs[95%CIs] = 26.37[3.35-207.39] and 3.47[1.40-8.64], respectively).Genetic polymorphisms in Nalp3 and caspase-1 may be associated with individual susceptibility to silicosis, especially when the polymorphisms interact with age, CDE, or smoking status

Occupational Hearing Loss among Chinese Municipal Solid Waste Landfill Workers: A Cross-Sectional Study.

Occupational hearing loss is an increasingly prevalent occupational condition worldwide, and has been reported to occur in a wide range of workplaces; however, its prevalence among workers from municipal solid waste landfills (MSWLs) remains less clear. This study aimed to investigate the occupational hearing loss among Chinese MSWL workers.A cross-sectional study of 247 workers from 4 Chinese MSWLs was conducted. Noise and total volatile organic compounds (TVOCs) levels at worksites were determined. We conducted hearing examinations to determine hearing thresholds. A worker was identified as having hearing loss if the mean threshold at 2000, 3000 and 4000 Hz in either ear was equal to or greater than 25 dB. Prevalence of occupational hearing loss was then evaluated. Using unconditional Logistic regression models, we estimated the odds ratios (ORs) of MSWL work associated with hearing loss.According to the job title for each worker, the study subjects were divided into 3 groups, including group 1 of 63 workers without MSWL occupational hazards exposure (control group), group 2 of 84 workers with a few or short-period MSWL occupational hazards exposure, and group 3 of 100 workers with continuous MSWL occupational hazards exposure. Both noise and TVOCs levels were significantly higher at worksites for group 3. Significantly poorer hearing thresholds at frequencies of 2000, 3000 and 4000 Hz were found in group 3, compared with that in group 1 and group 2. The overall prevalence rate of hearing loss was 23.5%, with the highest in group 3 (36.0%). The OR of MSWL work associated with hearing loss was 3.39 (95% confidence interval [CI]: 1.28-8.96).The results of this study suggest significantly higher prevalence of hearing loss among MSWL workers. Further studies are needed to explore possible exposure-response relationship between MSWL occupational hazards exposure and hearing loss

Stratification analysis for associations between genotypes of caspase-1 and the risk of silicosis.

<p>^*ORs were obtained from logistic regression models that were adjusted for age, smoking status, and CDE.</p><p>Stratification analysis for associations between genotypes of caspase-1 and the risk of silicosis.</p

Genotype frequencies and associated risks of silicosis in case and control subjects.

<p>^a Data were calculated using unconditional logistic regression and adjusting for age, smoking status, and CDE.</p><p>CI, confidence interval; OR, odds ratio.</p><p>Genotype frequencies and associated risks of silicosis in case and control subjects.</p

Summary of the single nucleotide polymorphisms(SNPs) among the 3 candidate genes.

<p>MAF, minor allele frequency.</p><p>RS#, reference SNP identification number.</p><p>Summary of the single nucleotide polymorphisms(SNPs) among the 3 candidate genes.</p

Stratification analysis for associations between genotypes of Nalp3 and the risk of silicosis.

<p>^*ORs were obtained from a logistic regression model that was adjusted for age, smoking status, and CDE.</p><p>Stratification analysis for associations between genotypes of Nalp3 and the risk of silicosis.</p

Stratification analysis for associations between genotypes of IL-1β and the risk of silicosis.

<p>^*ORs were obtained from a logistic regression model that was adjusted for age, smoking status, and CDE.</p><p>Stratification analysis for associations between genotypes of IL-1β and the risk of silicosis.</p