Impact of lifetime air pollution exposure patterns on the risk of chronic disease.

Long-term exposure to air pollution can lead to cardiovascular disease, metabolic syndrome, and chronic respiratory disease. However, from a lifetime perspective, the critical period of air pollution exposure in terms of health risk is unknown. This study aimed to evaluate the impact of air pollution exposure at different life stages. The study participants were recruited from community centers in Northern Taiwan between October 2018 and April 2021. Their annual averages for fine particulate matter (PM2.5) exposure were derived from a national visibility database. Lifetime PM2.5 exposures were determined using residential address information and were separated into three stages (<20, 20-40, and >40 years). We employed exponentially weighted moving averages, applying different weights to the aforementioned life stages to simulate various weighting distribution patterns. Regression models were implemented to examine associations between weighting distributions and disease risk. We applied a random forest model to compare the relative importance of the three exposure life stages. We also compared model performance by evaluating the accuracy and F1 scores (the harmonic mean of precision and recall) of late-stage (>40 years) and lifetime exposure models. Models with 89% weighting on late-stage exposure showed significant associations between PM2.5 exposure and metabolic syndrome, hypertension, diabetes, and cardiovascular disease, but not gout or osteoarthritis. Lifetime exposure models showed higher precision, accuracy, and F1 scores for metabolic syndrome, hypertension, diabetes, and cardiovascular disease, whereas late-stage models showed lower performance metrics for these outcomes. We conclude that exposure to high-level PM2.5 after 40 years of age may increase the risk of metabolic syndrome, hypertension, diabetes, and cardiovascular disease. However, models considering lifetime exposure showed higher precision, accuracy, and F1 scores and lower equal error rates than models incorporating only late-stage exposures. Future studies regarding long-term air pollution modelling are required considering lifelong exposure pattern. .1.

Discrimination of vascular aging using the arterial pulse spectrum and machine-learning analysis.

Aging contributes to the progression of vascular dysfunction and is a major nonreversible risk factor for cardiovascular disease. The aim of this study was to determine the effectiveness of using arterial pulse-wave measurements, frequency-domain pulse analysis, and machine-learning analysis in distinguishing vascular aging. Radial pulse signals were measured noninvasively for 3 min in 280 subjects aged 40-80 years. The cardio-ankle vascular index (CAVI) was used to evaluate the arterial stiffness of the subjects. Forty frequency-domain pulse indices were used as features, comprising amplitude proportion (Cn), coefficient of variation of Cn, phase angle (Pn), and standard deviation of Pn (n = 1-10). Multilayer perceptron and random forest with supervised learning were used to classify the data. The detected differences were more prominent in the subjects aged 40-50 years. Several indices differed significantly between the non-vascular-aging group (aged 40-50 years; CAVI <9) and the vascular-aging group (aged 70-80 years). Fivefold cross-validation revealed an excellent ability to discriminate the two groups (the accuracy was >80%, and the AUC was >0.8). For subjects aged 50-60 and 60-70 years, the detection accuracies of the two trained algorithms were around 80%, with AUCs of >0.73 for both, which indicated acceptable discrimination. The present method of frequency-domain analysis may improve the index reliability for further machine-learning analyses of the pulse waveform. The present noninvasive and objective methodology may be meaningful for developing a wearable-device system to reduce the threat of vascular dysfunction induced by vascular aging.

Influence of intradialytic systolic blood pressure changes on arteriovenous access thrombosis in maintenance hemodialysis patients.

BACKGROUND: Arteriovenous access (AV) thrombosis is an important and preventable problem amongst chronic hemodialysis (HD) patients. Systolic blood pressure (SBP) fluctuation relates to higher cardiovascular mortality amongst these patients. We proposed there is a close relation between SBP changes and arteriovenous (AV) access thrombosis. We also determined other risk factors and biochemical parameters related to AV access failure. METHODS: 50 HD patients with thrombosis and 50 HD patients without thrombosis were included in the study. Odds ratios and 95% confidence intervals were estimated with multivariate-adjusted logistic regression models to determine the association between potential thrombosis-related risk factors and thrombosis risk. RESULTS: Elder adults, women, and patients with AV grafts, lower intradialytic SBP and higher SBP variations during HD sessions had higher incidence of AV access thrombosis. AV access infection and decreased blood flow (BF) velocity were associated with an increased incidence of thrombotic events, whereas the use of anti-thrombotic agents was associated with a decreased incidence of thrombotic events. Further, anaemia, hypoalbuminemia, hyperlipidemia, and impaired mineral metabolism parameters were also found to be associated with AV access thrombosis. CONCLUSIONS: Close monitoring and management of intradialytic hypotension and SBP fluctuation in every HD session are important. Some important and novel modifiable risk factors related to AV access thrombosis were identified in this study (eg, AV access infection, decreased BF and abnormal biochemical parameters, etc). Earlier surveillance and modification of these risk factors is crucial to prevent AV access failure in HD patients.

Association between VEGF gene promoter polymorphisms and bladder cancer: An updated meta-analysis.

BACKGROUND: Vascular endothelial growth factor (VEGF) is the key regulator of angiogenesis in the development of various cancers. Previous studies have examined the relationship between VEGF gene promoter polymorphisms such as -2578C/A and -460C/T and bladder cancer risk; however, these results are inconclusive. Therefore, we performed this meta-analysis to investigate the association between VEGF gene promoter polymorphisms and bladder cancer risk. METHODS: PubMed, Embase, Cochrane Library and Web of Science databases were searched for studies published before September 2018. The methodological quality assessment of included studies was performed based on the Newcastle-Ottawa Quality Scale (NOS). We conducted a systematic review and meta-analysis using both fixed- and random-effect model. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the relationship. In addition, the stability of our analysis was evaluated by heterogeneity, sensitivity, subgroup of ethnicity, and publication bias analysis. RESULTS: We finally included 7 case-control studies with a total of 2412 bladder cancer patients and 3157 cancer-free controls. In Asian population with the VEGF -2578C/A polymorphism, significantly higher bladder cancer risks of 1.55 (95% CI = 1.25-1.93) and 1.53 (95% CI = 1.11-2.10) were found in the heterozygous model (AC vs CC) and the dominant model (AA + AC vs CC), respectively. Though there was no statistical association between VEGF -460C/T polymorphism and bladder cancer, a tendency to higher bladder cancer risk was observed in various genetic models (T vs C; TT vs CC; TC vs CC and TT + TC vs CC). CONCLUSIONS: Our findings suggest that VEGF -2578C/A polymorphism might be a risk factor with a modest significance for bladder cancer only in Asian population. Further studies with a larger sample size and other functional polymorphisms are needed to explore the effects of VEGF gene on the risk of bladder cancer.

Association of rs2651899 Polymorphism in the Positive Regulatory Domain 16 and Common Migraine Subtypes: A Meta-Analysis.

BACKGROUND: Migraine is a neurovascular disease with recurrent headache attacks. A polymorphism (rs2651899) of the PRDM16 gene, which is associated with migraine, was identified in recent genome-wide association studies. The potential role of the PRDM16 rs2651899 polymorphism in migraine is still unknown. Therefore, we conducted this systematic review and meta-analysis to examine this issue. METHODS: We performed a comprehensive literature search of the PubMed, Embase, and Google Scholar databases to identify eligible studies published before October 2018. Individual odds ratio and 95% confidence interval was used to estimate the pooled strength of the association between the PRDM16 rs2651899 polymorphism and common migraine subtypes, including migraine with aura (MA) and migraine without aura (MO). RESULTS: Six studies with 2853 cases and 9319 controls that fulfilled the inclusion and exclusion criteria were selected for this meta-analysis. Of the 6 included studies, 4 studies had available data for MWA and another 4 studies had data for MWoA. Overall, significant migraine risks of 1.257, 1.305, and 1.419 were found under allele model (C vs T), dominant model (C/C+T/C vs T/T), and recessive model (C/C vs T/C+T/T), respectively. In the recessive model, significantly increased risks of 1.454 and 1.546 were found for MA and MO, respectively. CONCLUSION: Our major findings suggest that PRDM16 rs2651899 polymorphism is associated with the risk of migraine. Furthermore, we found that PRDM16 rs2651899 polymorphism is significantly related to common migraine subtypes (MA and MO).

Association between interleukin-8 rs4073 polymorphism and prostate cancer: A meta-analysis.

BACKGROUND/PURPOSE: Interleukin-8 (IL-8) is an inflammatory cytokine and plays important role in development of cancers. We conducted a meta-analysis to explore the association between IL-8 rs4073 polymorphism and risk of prostate cancer. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were searched for only case-control studies published before February 2019. The methodological quality assessment of included studies was performed based on Newcastle-Ottawa Quality Scale (NOS). Based on the heterogeneity, we conducted a meta-analysis using random-effect models. Pooled odds ratios (ORs) with a 95% confidence interval (CI) were calculated using the allele (T vs. A), homozygous (TT vs. AA), heterozygous (TA vs. AA), dominant (TT + TA vs. AA), and recessive (TT vs. TA + AA) genetic models to assess the strength of the relationship between IL-8 rs4073 polymorphism and prostate cancer risk. In addition, the stability of our analysis was evaluated by heterogeneity, sensitivity, subgroup of ethnicity and study design, and publication bias analysis. RESULTS: We included 6 case-control studies with a total of 1752 cases and 1982 controls. Significantly higher prostate cancer risk of 1.12 (95% CI = 1.01-1.25), 1.26 (95% CI = 1.03-1.55), and 1.20 (95% CI = 1.02-1.41) were found for the allele, homogeneous, and recessive model, respectively. Though there was no statistical association with other genetic models in our meta-analyses, a tendency of higher prostate cancer risk was observed in all five genetic models. CONCLUSION: The major findings of this meta-analysis suggested that IL-8 rs4073 polymorphism is significantly associated with risk of prostate cancer.

Associations of gene polymorphisms in interferon-alpha signature-related genes with autoimmune thyroid diseases.

Interferon (IFN)-α treatment predisposes patients to the occurrence of autoimmune thyroid disease (AITD). METHODS: We investigated associations of single nucleotide polymorphisms (SNPs) of molecules participating in the IFN-α signature, including rs2304204 and rs2304206 of IFN regulatory factor 3 (IRF3), rs1061501 of IRF7, and rs7708392 of TNFA1P3-interacting protein 1 with serum IFN-α levels and AITD in an ethnic Chinese (ie Taiwanese) population. Totally, 319 patients with Graves' disease (GD), 83 patients with Hashimoto's thyroiditis (HT) and 351 healthy controls were recruited. RESULTS: There were increased percentages of the C allele, and CC and TC + CC genotypes of rs1061501 in GD patients compared to the controls. HT patients had higher serum IFN-α levels compared to the controls, while there was no difference in serum IFN-α levels between patients with GD and controls. However, patients with GD in a remission status had lower serum IFN-α levels than those without remission. On the other hand, the C allele of rs1061501 was only associated with serum IFN-α levels in patients with HT. CONCLUSIONS: The SNP rs1061501 of IRF7 was associated with the development of GD. Serum IFN-α levels were associated with HT, while they might modify the disease status of GD. Moreover, a genetic effect of rs1061501 on regulating serum IFN-α production was observed in HT.

Associations of secreted phosphoprotein 1 and B lymphocyte kinase gene polymorphisms with autoimmune thyroid disease.

BACKGROUND: Dysregulation of the type 1 interferon (IFN)-related signalling pathway predisposes one to autoimmune diseases. Possible associations of single-nucleotide polymorphisms (SNPs) of secreted phosphoprotein 1 (SPP1) and B lymphocyte kinase (BLK) of the type 1 IFN-related signalling pathway with autoimmune thyroid disease (AITD) in an ethnic Chinese (ie Taiwanese) population were tested. METHODS: Totally, 83 Hashimoto's thyroiditis (HT) patients, 319 Graves' disease (GD) patients and 369 controls were enrolled. Genotypes of the two SNPs (rs1126772 and rs1126616) of SPP1 and two SNPs (rs13277113 and rs2736340) of BLK were determined. RESULTS: Our results showed reduced percentages of the G allele of rs13277113 of BLK in GD (P = 0.037, odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.62-0.99) and HT (P = 0.002, OR = 0.54, 95% CI = 0.36-0.81), compared to the controls. At the same time, lower frequencies of the C allele of rs2736340 of BLK in GD (P = 0.025, OR = 0.76, 95% CI = 0.60-0.97) and HT (P = 0.003, OR = 0.53, 95% CI = 0.35-0.81) than the controls were also observed. There were significantly higher AT haplotype frequencies of rs1327713 and rs2736340 in GD and HT patients than in the controls (P = 0.025, OR = 1.31, 95% CI = 1.03-1.67, and P = 0.003, OR = 1.89, 95% CI = 1.24-2.87, respectively). Moreover, the anti-microsomal antibody titre was associated with rs2736340. CONCLUSIONS: Genetic variants of rs13277113 and rs2736340 of BLK were associated with susceptibility to GD, HT and AITD in an ethnic Chinese population. Our results suggest the BLK may participate in the pathogenesis of GD, HT and AITD.

Arsenic Exposure From Drinking Water and the Incidence of CKD in Low to Moderate Exposed Areas of Taiwan: A 14-Year Prospective Study.

BACKGROUND: Arsenic exposure is associated with decreased kidney function. The association between low to moderate arsenic exposure and kidney disease has not been fully clarified. STUDY DESIGN: The association between arsenic exposure from drinking water and chronic kidney disease (CKD) was examined in a long-term prospective observational study. SETTING & PARTICIPANTS: 6,093 participants 40 years and older were recruited from arseniasis-endemic areas in northeastern Taiwan. Arsenic levels were 28.0, 92.8, and 295.7µg/L at the 50th, 75th, and 90th percentiles, respectively. PREDICTOR: Well-water arsenic and urinary total arsenic (inorganic plus methylated arsenic species) concentrations, adjusted for urinary creatinine concentration. OUTCOMES: Kidney diseases (ICD-9 codes: 250.4, 274.1, 283.11, 403.*1, 404.*2, 404.*3, 440.1, 442.1, 447.3, or 580-589) and CKD (ICD-9 code: 585) ascertained using Taiwan's National Health Insurance database 1998 to 2011. MEASUREMENTS: HRs contrasting CKD risk across arsenic exposure levels were estimated using Cox regression. Prevalence ORs for proteinuria (protein excretion ≥ 200mg/g) comparing quartiles of total urinary arsenic concentrations were estimated using logistic regression. RESULTS: We identified 1,104 incident kidney disease cases, including 447 CKD cases (incidence rates, 166.5 and 67.4 per 104 person-years, respectively). A dose-dependent association between well-water arsenic concentrations and kidney diseases was observed after adjusting for age, sex, education, body mass index, cigarette smoking, alcohol consumption, and analgesic use. Using arsenic concentration ≤ 10.0µg/L as reference, multivariable-adjusted HRs for incident CKD were 1.12 (95% CI, 0.88-1.42), 1.33 (95% CI, 1.03-1.72), and 1.33 (95% CI, 1.00-1.77) for arsenic concentrations of 10.1 to 49.9, 50.0 to 149.9, and ≥150.0µg/L, respectively (P for trend=0.02). The association between arsenic concentration and kidney diseases was stronger for women (P for interaction=0.06). Arsenic values in the range of 50th to 75th and 75th to 100th percentiles of total urinary arsenic concentrations were associated with 50% and 67% higher prevalences, respectively, of proteinuria. LIMITATIONS: Kidney diseases and CKD outcomes were based on diagnostic codes. Glomerular filtration rates were not available. Other heavy metals were not measured. CONCLUSIONS: This study describes the temporal relationship between arsenic concentrations ≥ 10µg/L in drinking water and CKD. A dose-dependent association between well-water arsenic concentration and kidney diseases was observed. Higher creatinine-adjusted urinary total arsenic concentrations were associated with a higher prevalence of proteinuria.

Outcome Analysis of Patients with Gallstone Disease Receiving Cholecystectomy: A Population-Based Cohort Study.

BACKGROUND/AIMS: Cholecystectomy is generally performed to treat patients with gallstone disease (GSD) in clinical practice. The present study aimed to investigate whether type 2 diabetes mellitus (T2DM) may influence the overall survival of GSD patients. METHODS: The National Health Insurance Research Database, a population-based registry data in Taiwan, was used to identify GSD patients from 2001 to 2008. The risk of cancers and effects of T2DM on the overall survival of GSD patients receiving cholecystectomy were estimated by hazards ratios (HRs) and 95% CIs using the Cox proportional hazard model. RESULTS: Among 392,028 eligible GSD patients, 81,971 underwent cholecystectomy, whereas 310,057 did not. After cholecystectomy, the HR for developing cancer was 1.14. The HR for the overall survival was 0.74-fold lower for patients who underwent cholecystectomy than that for patients who did not. GSD patients without T2DM who underwent cholecystectomy (0.78-fold lower risk) had a longer survival, whereas those with T2DM had shorter survival (1.64-fold higher risk without cholecystectomy and 1.13-fold higher risk with cholecystectomy) compared with those without T2DM who did not undergo cholecystectomy. CONCLUSIONS: Our major findings suggest that T2DM may worsen the prognosis of GSD patients after cholecystectomy, which provides useful insight into the treatment of T2DM among GSD patients in clinical settings.

Effects of Arsenic in Drinking Water on Risk of Hepatitis or Cirrhosis in Persons With and Without Chronic Viral Hepatitis.

BACKGROUND & AIMS: Arsenic in drinking water is associated with hepatomegaly and death from liver cancer. However, confounding factors related to liver diseases have not been carefully studied. We examined associations between exposure of arsenic in drinking water and risk of hepatitis and cirrhosis, and the interaction with chronic viral hepatitis, in people living in the Lanyang Basin of northeastern Taiwan, where well water has an arsenic content that ranges from undetectable to 3590 µg/L. METHODS: We tested blood samples from 4387 people who lived in arseniasis-endemic areas in northeastern Taiwan from 1991 through 1994 for hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), and antibodies against hepatitis C virus (anti-HCV). We measured arsenic concentrations in well water and collected information on residents' histories of major chronic diseases. Reports of chronic hepatitis or cirrhosis were ascertained using the Taiwan National Health Insurance database. Reports of liver cancer were ascertained using the Taiwan National Cancer Registry. RESULTS: Prevalence odds ratios in the overall study population for chronic hepatitis or cirrhosis for well water arsenic concentrations of ≤10 µg/L were 1.00 (reference), 0.93 for 10.1-49.9 µg/L (95% confidence interval [CI], 0.57-1.52), 1.24 for 50.0-99.9 µg/L (95% CI, 0.68-2.23), 0.98 for 100.0-299.9 (95% CI, 0.52-1.85), and 1.86 for ≥300.0 µg/L (95% CI, 1.08-3.20). Increasing levels of arsenic in drinking water were associated with increasing prevalence of chronic hepatitis or cirrhosis in residents who were seronegative for HBsAg and seronegative for anti-HCV, but not for seropositive for either HBsAg or anti-HCV. In individuals who were seropositive for HBsAg or anti-HCV, we observed an inverse association between hepatitis or cirrhosis and consumption of water with levels of arsenic ≥100.0 µg/L. Among participants who were seropositive for HBsAg or anti-HCV, consumption of water with levels of arsenic ≥100.0 µg/L was associated with a reduced risk of liver cancer (multivariate-adjusted hazard ratio, 0.29; 95% CI, 0.09-0.95; P < .05). A higher proportion of individuals exposed to cumulative arsenic level >14,000 µg/L ×year were carriers of inactive hepatitis B virus (DNA <10,000 copies/mL) and were positive for HBsAg (60%) than individuals exposed to water below this arsenic level (35%). CONCLUSIONS: Concentrations of arsenic concentration in drinking water ≥300.0 µg/L significantly increase risk of hepatitis or cirrhosis in people without chronic viral hepatitis. However, in people with chronic viral hepatitis, levels of arsenic ≥100.0 µg/L in drinking water significantly reduce the risk of chronic hepatitis or cirrhosis.

Glycated Albumin Predicts Long-term Survival in Patients Undergoing Hemodialysis.

BACKGROUND: In patients with advanced renal dysfunction undergoing maintenance hemodialysis, glycated albumin (GA) levels may be more representative of blood glucose levels than hemoglobin A1C levels. The aim of this study was to determine the predictive power of GA levels on long-term survival in hemodialysis patients. METHODS: A total of 176 patients with a mean age of 68.2 years were enrolled. The median duration of follow-up was 51.0 months. Receiver-operating characteristic curve analysis was utilized to determine the optimal cutoff value. We examined the cumulative survival rate by Kaplan-Meier estimates and the influence of known survival factors with the multivariate Cox proportional-hazard regression model. RESULTS: In the whole patient group, cumulative survival in the low GA group was better than in the high GA group (p=0.030), with more prominence in those aged <70 years (p=0.029). In subgroup analysis, both diabetic (DM) and non-DM patients with low GA had a better cumulative survival compared with those with high GA. The risk of mortality increased by 3.0% for each 1% increase in serum GA level in all patients undergoing hemodialysis. CONCLUSIONS: In addition to serving as a glycemic control marker, GA levels may be useful for evaluating the risk of death in both DM and non-DM patients on hemodialysis.

Association of IRF8 gene polymorphisms with autoimmune thyroid disease.

BACKGROUND: The occurrence of autoimmune thyroid disease (AITD) is known to have a major adverse effect on interferon (INF)-α treatment. The genetic variant of the INF regulatory factor 8 (IRF8), a type 1 INF regulator, is associated with susceptibility to systemic lupus erythematosus and multiple sclerosis. In this study, we investigated possible associations of the IRF8 polymorphisms, rs17445836 and rs2280381, with AITD in an ethnic Chinese population. MATERIAL AND METHODS: In total, 278 patients with Graves' disease (GD) and 55 patients with Hashimoto's thyroiditis (HT), and 252 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing were used for genotyping. RESULTS: Significantly lower frequencies of the GA genotype and A allele of rs17445836 were found in the HT group than in the control group (P = 0·028, odds ratio (OR) = 4·71 and P = 0·022, OR = 4·40, respectively). Both rs17445836 and rs2280381 were associated with the presence of an antimicrosomal antibody (AmiA), and rs2280381 was also associated with the presence of an antithyroglobulin antibody (ATA) in AITD. Moreover, rs17445836 was associated with the level of AmiA in AITD. CONCLUSIONS: rs17445836 of IRF8 is a possible genetic variant associated with the development of HT. rs17445836 was associated with the production of thyroid antibody, and the GG genotype of rs17445836 was associated with a higher AmiA titre than the GA genotype.

Heatstroke Effect on Brain Heme Oxygenase-1 in Rats.

Exposure to high environmental temperature leading to increased core body temperature above 40°C and central nervous system abnormalities such as convulsions, delirium, or coma is defined as heat stroke. Studies in humans and animals indicate that the heat shock responses of the host contribute to multiple organ injury and death during heat stroke. Heme oxygenase-1 (HO-1)-a stress-responsive enzyme that catabolizes heme into iron, carbon monoxide, and biliverdin-has an important role in the neuroprotective mechanism against ischemic stroke. Here, we investigated the role of endogenous HO-1 in heat-induced brain damage in rats. RT-PCR results revealed that levels of HO-1 mRNA peaked at 0 h after heat exposure and immunoblot analysis revealed that the maximal protein expression occurred at 1 h post-heat exposure. Subsequently, we detected the HO-1 expression in the cortical brain cells and revealed the neuronal cell morphology. In conclusion, HO-1 is a potent protective molecule against heat-induced brain damage. Manipulation of HO-1 may provide a potential therapeutic approach for heat-related diseases.

Association between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer: a meta-analysis.

Several previous studies have investigated the association between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer in various populations. However, these results remain inconsistent. Therefore, we performed this meta-analysis to evaluate the relationship between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer. An extensive literature search was performed to identify all eligible studies regarding this association. The odds ratios (ORs) with 95 % confidence intervals (CIs) were used to estimate the strength of risk under fixed and random effects models. We identified and included eight case-control studies including 2,036 cases and 2,273 controls. No significant association was found between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer under the dominant model; however, those with the SULT1A1 Arg/Arg genotype had a significantly increased risk (OR = 1.218, 95 % CI = 1.067-1.392, P = 0.0044) under the recessive model. In the subgroup analysis of ethnicity, a significant association was observed in Caucasians under the recessive model (OR = 1.269, 95 % CI = 1.069-1.506, P = 0.007). Furthermore, an increased risk of bladder cancer was observed between the Arg213His polymorphism and never smokers in the recessive model (OR = 1.428, 95 % CI = 1.079-1.890, P = 0.013). The results of this meta-analysis indicate that the SULT1A1 Arg213His polymorphism is associated with the risk bladder cancer under a recessive model; however, a possibly higher risk for Caucasians with the Arg/Arg genotype and never smokers needs further investigation.

The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer.

Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer.

Comparison of genome-wide DNA methylation in urothelial carcinomas of patients with and without arsenic exposure.

BACKGROUND: Arsenic is a well-documented carcinogen of human urothelial carcinoma (UC) with incompletely understood mechanisms. OBJECTIVES: This study aimed to compare the genome-wide DNA methylation profiles of arsenic-induced UC (AsUC) and non-arsenic-induced UC (Non-AsUC), and to assess associations between site-specific methylation levels and cumulative arsenic exposure. METHODS: Genome-wide DNA methylation profiles in 14 AsUC and 14 non-AsUC were analyzed by Illumina Infinium methylation27 BeadChip and validated by bisulfite pyrosequencing. Mean methylation levels (߯) in AsUC and non-AsUC were compared by their ratio (߯ ratio) and difference (Δ߯). Associations between site-specific methylation levels in UC and cumulative arsenic exposure were examined. RESULTS: Among 27,578 methylation sites analyzed, 231 sites had ߯ ratio >2 or <0.5 and 45 sites had Δ߯ >0.2 or <-0.2. There were 13 sites showing statistically significant (q<0.05) differences in ߯ between AsUC and non-AsUC including 12 hypermethylation sites in AsUC and only one hypermethylation site in non-AsUC. Significant associations between cumulative arsenic exposure and DNA methylation levels of 28 patients were observed in nine CpG sites of nine gens including PDGFD (Spearman rank correlation, 0.54), CTNNA2 (0.48), KCNK17 (0.52), PCDHB2 (0.57), ZNF132 (0.48), DCDC2 (0.48), KLK7 (0.48), FBXO39 (0.49), and NPY2R (0.45). These associations remained statistically significant for CpG sites in CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 in 20 non-smoking women after adjustment for tumor stage and age. CONCLUSIONS: Significant associations between cumulative arsenic exposure and methylation level of CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 were found in smoking-unrelated urothelial carcinoma. Arsenic exposure may cause urothelial carcinomas through the hypermethylation of genes involved in cell adhesion, proteolysis, transcriptional regulation, neuronal pathway, and ion transport. The findings of this study, which are limited by its small sample size and moderate dose-response relation, remain to be validated by further studies with large sample sizes.

Combined effects of GSTO1 and SULT1A1 polymorphisms and cigarette smoking on urothelial carcinoma risk in a Taiwanese population.

BACKGROUND/PURPOSE: Cigarette smoking is the main risk factor for urothelial carcinoma of the bladder (UCB). Glutathione S-transferase omega 1 (GSTO1) and sulfotransferase 1A1 (SULT1A1) have been reported to be associated with the metabolism of polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. The aim of the present study was to investigate the combined effects of polymorphisms in GSTO1 and SULT1A1 genes and cigarette smoking on UCB risk in a Taiwanese population. METHODS: A total of 300 patients with histopathologically confirmed UCB and 233 cancer-free controls were recruited from the Department of Urology of Tung's Taichung Metro Harbor Hospital and Taipei Medical University Hospital. A comprehensive interview was conducted to collect personal information, including demographic characteristics and cigarette smoking status. A multivariate-adjusted logistic regression was performed to estimate the risk of UCB. RESULTS: A significantly increased risk of UCB was observed in ever smokers [odds ratio (OR) = 2.3]. The Ala/Ala genotype of the GSTO1 gene and the Arg/Arg genotype of the SULT1A1 gene were associated with a significantly increased risk of UCB, with ORs of 1.8 [95% confidence interval (CI) = 1.2-2.6] and 2.1 (95% CI = 1.6-4.5), respectively. Significantly increased UCB risks were found in heavy smokers with the Ala/Ala genotype of the GSTO1 gene (OR = 4.2) and the Arg/Arg genotype of the SULT1A1 gene (OR = 6.8). Furthermore, a significant synergistic effect in an additive model (OR = 3.5) between the GSTO1 Ala/Ala genotype and the SULT1A1 Arg/Arg genotype on UCB risk was observed. CONCLUSION: The present study provided epidemiological evidence for a significantly increased risk of UCB in ever smokers with the Ala/Ala genotype of the GSTO1 gene and the Arg/Arg genotype of the SULT1A1 gene.

Use of arsenic-induced palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent internal malignancy.

Hyperpigmentation, hyperkeratoses, and Bowen's disease are hallmarks of chronic arsenic exposure. The association between arsenic-induced skin lesions and subsequent internal cancers is examined by using a community-based prospective study. The cohort was enrolled from an arseniasis-endemic area in southwestern Taiwan, where 2,447 residents participated in skin examinations during the late 1980s. The number of participants diagnosed with hyperpigmentation was 673; with hyperkeratosis, 243; and with skin cancer (Bowen's disease or non-melanoma skin cancer), 378. Newly diagnosed internal cancers were ascertained through linkage with National Cancer Registry profiles. Cox regression was performed to estimate hazard ratios with 95% confidence intervals for potential risk predictors. Compared with participants without skin lesions, patients affected with skin cancers had a significantly increased risk of lung cancer (hazard ratio = 4.64, 95% confidence interval: 2.92, 7.38) and urothelial carcinoma (hazard ratio = 2.02, 95% confidence interval: 1.23, 3.30) after adjustment for potential confounders and cumulative arsenic exposure. Hyperkeratosis is significantly associated with an increased lung cancer risk (hazard ratio = 2.76, 95% confidence interval: 1.35, 5.67). A significant interactive effect on lung cancer risk between hyperkeratosis and cigarette smoking was identified, which suggests that patients with hyperkeratosis who have been exposed to arsenic should cease smoking.

MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells.

MicroRNAs (miRNAs) can regulate cell survival and death by targeting apoptosis-related gene expression. miR-210 is one of the most hypoxia-sensitive miRNAs. In this study, we evaluated the roles of miR-210 in hypoxia-induced insults to neural cells. Treatment of neuro-2a cells with oxygen/glucose deprivation (OGD) induced cell apoptosis in a time-dependent manner. In parallel, OGD time-dependently increased cellular miR-210 levels. Knocking down miR-210 expression using specific antisenses significantly attenuated OGD-induced neural apoptosis. Concurrently, OGD increased hypoxia-inducible factor (HIF)-1α mRNA and protein syntheses. Pretreatment with YC-1, an inhibitor of HIF-1α, reduced OGD-caused cell death. Sequentially, OGD specifically decreased antiapoptotic Bcl-2 mRNA and protein levels in neuro-2a cells. A search by a bioinformatic approach revealed that miR-210-specific binding elements exist in the 3'-untranslated region of Bcl-2 mRNA. Application of miR-210 antisenses simultaneously alleviated OGD-involved inhibition of Bcl-2 mRNA expression. In comparison, overexpression of miR-210 synergistically diminished OGD-caused inhibition of Bcl-2 mRNA expression and consequently induced greater cellular insults. Taken together, this study shows that OGD can induce miR-210 expression through activating HIF-1α. And miR-210 can mediate hypoxia-induced neural apoptosis by targeting Bcl-2.