[Show abstract][Hide abstract] ABSTRACT: Endometrial cancers (ECs) are the most common form of gynecologic malignancy. Recent studies have reported that ECs reveal distinct markers for molecular pathogenesis, which in turn is linked to the various histological types of ECs. To understand further the molecular events contributing to ECs and endometrial tumorigenesis in general, a more precise identification of cancer-associated molecules and signaling networks would be useful for the detection and monitoring of malignancy, improving clinical cancer therapy, and personalization of treatments.
ECs-specific gene co-expression networks were constructed by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Important pathways and putative cancer hub genes contribution to tumorigenesis of ECs were identified. An elastic-net regularized classification model was built using the cancer hub gene signatures to predict the phenotypic characteristics of ECs. The 19 cancer hub gene signatures had high predictive power to distinguish among three key principal features of ECs: grade, type, and stage. Intriguingly, these hub gene networks seem to contribute to ECs progression and malignancy via cell-cycle regulation, antigen processing and the citric acid (TCA) cycle.
The results of this study provide a powerful biomarker discovery platform to better understand the progression of ECs and to uncover potential therapeutic targets in the treatment of ECs. This information might lead to improved monitoring of ECs and resulting improvement of treatment of ECs, the 4th most common of cancer in women.
[Show abstract][Hide abstract] ABSTRACT: Bisphenol A (BPA) is a ubiquitous endocrine disrupting chemical in our daily life, and its health effect in response to prenatal exposure is still controversial. Early-life BPA exposure may impact brain development and contribute to childhood neurological disorders. The aim of the present study was to investigate molecular target genes of neuronal development in trans-placental exposure to BPA.
PLoS ONE 01/2014; 9(7):e100576. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inorganic arsenic (iAs) is an established transplacental agent known to affect fetal development in animal studies. However, iAs has not been adequately studied in the general population with respect to iAs exposure during pregnancy and its impact on the health status of newborns. The aims of this study were to 1) elucidate the association between arsenic exposure and oxidative/methylated DNA damage in pregnant women, and 2) determine the association with birth outcomes. A birth cohort study of 299 pregnant mother-newborn pairs was recruited during 2001-2002 in Taiwan. We collected maternal urine samples during the 3(rd) trimester for measuring iAs and its metabolites. We used high-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC-ICP-MS) for quantifications of the arsenic species. Liquid chromatography/tandem mass spectrometer (LC-MS/MS) was used to measure the 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and N(7)-methylguanosine (N(7)-MeG) DNA damage biomarkers. Birth outcomes were collected to assess the associations with maternal arsenic exposure and the DNA damage biomarkers. Multiple regression analyses showed that maternal urinary iAs had positive associations with the methylated N(7)-MeG (beta = 0.35, p<0.001) and oxidative 8-oxodG (beta = 0.24, p<0.001) DNA damage biomarkers, and a decreased one-minute (1-min) Apgar score (beta = -0.23, p = 0.041). Maternal N(7)-MeG was also associated with a decreased 1-min Apgar score (beta = -0.25, p = 0.042). Mutual adjustment for iAs and N(7)-MeG showed an independent and significant prediction for a decreased 1-min Apgar score of iAs (beta = -0.28, p = 0.036). Maternal iAs exposure was associated with both maternal DNA damage and adverse newborn health. Maternal N(7)-MeG levels might be a novel biomarker for monitoring fetal health related to iAs.
PLoS ONE 01/2014; 9(2):e86398. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The composting procedure in food waste plants generates airborne bioaerosols that have the potential to damage human airway epithelial cells. Persistent inflammation and repair responses induce airway remodeling and damage to the respiratory system. This study elucidated the expression changes of airway remodeling genes in human lung mucoepidermoid NCI-H292 cells exposed to bioaerosols from a composting plant. Different types of microorganisms were detectable in the composting plant, using the agar culture method. Real-time polymerase chain reaction was used to quantify the level of Aspergillus fumigatus and the profile of remodeling genes. The real-time PCR results indicated that the amount of A. fumigatus in the composting hall was less than 102 conidia. The endotoxins in the field bioaerosols were determined using a limulus amebocyte lysate test. The endotoxin levels depended on the type of particulate matter (PM), with coarse particles (2.5-10 μm) having higher endotoxin levels than did fine particles (0.5-2.5 μm). After exposure to the conditioned medium of field bioaerosol samples, NCI-H292 cells showed increased pro-inflammatory interleukin (IL)-6 release and activated epidermal growth factor receptor (EGFR), transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1 (p21WAF1/CIP1) gene expression, but not of matrix metallopeptidase (MMP)-9. Airborne endotoxin levels were higher inside the composting hall than they were in other areas, and they were associated with PM. This suggested that airborne bioaerosols in the composting plant contained endotoxins and microorganisms besides A. fumigatus that cause the inflammatory cytokine secretion and augment the expression of remodeling genes in NCI-H292 cells. It is thus necessary to monitor potentially hazardous materials from bioaerosols in food composting plants, which could affect the health of workers.
International Journal of Environmental Research and Public Health 01/2013; 11(1):337-354. · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study evaluated emergency room visit (ERV) risks for all causes and cardiopulmonary diseases associated with temperature and long-lasting extreme temperatures from 2000 to 2009 in four major cities in Taiwan. The city-specific daily average temperatures at the high 95th, 97th, and 99th percentiles, and the low 10th, 5th, and 1st percentiles were defined as extreme heat and cold. A distributed lag non-linear model was used to estimate the cumulative relative risk (RR) of ERV for morbidities associated with temperatures (0 to 3-day lags), extreme heat and cold lasting for 2 to 9 days or longer, and with the annual first extreme heat or cold event after controlling for covariates. Low temperatures were associated with slightly higher ERV risks than high temperatures for circulatory diseases. After accounting for 4-day cumulative temperature effect, the ERV risks for all causes and respiratory diseases were found to be associated with extreme cold at the 5th percentile lasting for >8 days and 1st percentile lasting for >3 days. The annual first extreme cold event of 5th percentile or lower temperatures was also significantly associated with ERV, with RRs ranging from 1.09 to 1.12 for all causes and from 1.15 to 1.26 for respiratory diseases. The annual first extreme heat event of 99th percentile temperature was associated with higher ERV for all causes and circulatory diseases. Annual first extreme temperature event and intensified prolonged extreme cold events are associated with increased ERVs in Taiwan.
Science of The Total Environment 02/2012; 416:97-104. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-αvβ3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK)) and bi-cyclic RGD (E[c(RGDyK)](2)) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis.
Human glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvβ3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK)](2) peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells.
This study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment.
PLoS ONE 01/2012; 7(5):e37935. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bisphenol A (BPA) is a sealant and flux of plastic materials and has been determined to be an endocrine-disrupting chemical. Prenatal exposure to BPA can lead to substantial adverse effects on fetal growth and development. This study was conducted to assess BPA concentration in pregnant women and umbilical cord blood, and to investigate whether maternal BPA exposure affected fetal outcomes including lower birth weight (LBW), smaller size for gestational age (SGA), and high leptin (HLP) and low adiponectin (LAD) secretion.
We measured the BPA levels of maternal blood (n = 97) and umbilical cord blood (n = 97) with a high-performance liquid chromatography/UV detector. The protein secretion of leptin and adiponectin were separately determined using enzyme-linked immunosorbent assay. A logistic regression was performed to estimate the effects of maternal exposure to BPA on LBW, SGA, and adverse action of adipokines in newborns.
The geometric means of BPA concentration in maternal blood and fetal cord blood were 2.5 ng/ml and 0.5 ng/ml, respectively. Elevated risks of LBW (OR 2.42, 95% confidence interval (CI) 1.72-3.36), SGA (OR 2.01, 95% CI 1.39-3.01), and adverse action of leptin (OR 1.67, 95% CI 1.12-2.25) and adiponectin (OR 1.25, 95% CI 1.52-3.97) were observed in male neonates in the highest quartile of maternal BPA exposure.
Elevated prenatal BPA exposure increased the risk of LBW, SGA, and adverse actions of adipokines in neonates, especially in male infants. These results provide further evidence that maternal exposure is correlated with adverse birth outcomes.
Environmental Health 11/2011; 10:94. · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diarrhea is an important public health problem in Taiwan. Climatic changes and an increase in extreme weather events (extreme heat, drought or rainfalls) have been strongly linked to the incidence of diarrhea-associated disease. This study investigated and quantified the relationship between climate variations and diarrhea-associated morbidity in subtropical Taiwan. Specifically, this study analyzed the local climatic variables and the number of diarrhea-associated infection cases from 1996 to 2007. This study applied a climate variation-guided Poisson regression model to predict the dynamics of diarrhea-associated morbidity. The proposed model allows for climate factors (relative humidity, maximum temperature and the numbers of extreme rainfall), autoregression, long-term trends and seasonality, and a lag-time effect. Results indicated that the maximum temperature and extreme rainfall days were strongly related to diarrhea-associated morbidity. The impact of maximum temperature on diarrhea-associated morbidity appeared primarily among children (0-14years) and older adults (40-64years), and had less of an effect on adults (15-39years). Otherwise, relative humidity and extreme rainfall days significantly contributed to the diarrhea-associated morbidity in adult. This suggested that children and older adults were the most susceptible to diarrhea-associated morbidity caused by climatic variation. Because climatic variation contributed to diarrhea morbidity in Taiwan, it is necessary to develop an early warning system based on the climatic variation information for disease control management.
Science of The Total Environment 10/2010; 409(1):43-51. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bronchial epithelial cells exposed to allergens typically secrete chemokines to recruit eosinophils. Persistent inflammation and repair responses result in airway remodeling and irreversible airflow limitation. House dust mite (HDM) is a common allergen causing allergic disorders. Thioredoxin (TRX) is a redox protein that scavenges reactive oxygen species (ROS). This study was to elucidate how TRX mediates gene expression of remodeling factors of human bronchial epithelial cells in response to HDM stimuli interacting with eosinophils. This study cultured normal human bronchial epithelial (BEAS-2B) cells with eosinophils exposed to 0.5 microg/ml recombinant Dermatophagoides pteronyssinus 1 (rDer p1) protease to mimic the allergen-immune reaction. Eosinophils were induced by rDer p1 protease to secrete tumor necrosis factor (TNF)-alpha and generate ROS. When cultured with rDer p1-stimulated eosinophils, BEAS-2B cells released interleukin-6 and underwent apoptosis. The HDM-stimulated eosinophils applied oxidative stress and apoptosis to BEAS-2B cells through the release of mediators. Damaged BEAS-2B cells interfered with gene expression of remodeling factors, such as transforming growth factor (TGF)-beta 1, epidermal growth factor receptor (EGFR), cyclin dependent kinase inhibitor (p21(waf)) and matrix metalloproteinase (MMP) 9, relevant to inflammatory response and epithelial repair in airway remodeling. Notably, BEAS-2B cells over-expressing TRX reduced eosinophil-derived apoptosis and suppressed underlying airway remodeling via attenuation of TGF-beta1, EGFR and p21(waf) and up-regulation of MMP9 expression. Results of this study indicated TRX-over-expressing bronchial epithelial cells attenuated TGF-beta1 and activated MMP9 expression to prevent airway remodeling from HDM-induced inflammation. The finding can be as a reference for further therapeutic studies of TRX.
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoke (CS) generates reactive oxygen species (ROS) to produce oxidative damage of bronchial epithelial cells. Prolonged repair responses lead to airway remodeling and irreversible airflow limitation. Thioredoxin (TRX) is a redox protein that scavenges ROS to prevent oxidative stress. The aim of this study was to investigate the mechanisms underlying TRX-mediated CS-induced stress relevant to airway remodeling. Results showed that CS stimulated ROS generation and apoptosis in normal human bronchial epithelial (BEAS-2B) cells, and interfered with gene expression of remodeling factors, such as activation of transforming growth factor (TGF)-beta1, epidermal growth factor receptor (EGFR), and cyclin-dependent kinase inhibitor (p21), but repressed matrix metalloproteinases (MMP)-9. In particular, TRX-overexpressing bronchial epithelial (TRX-TD) cells reduced CS-induced apoptosis, and suppressed airway remodeling through attenuation of TGF-beta1, EGFR, and p21 and upregulation of MMP-9 expression. TGF-beta1 was shown to regulate MMP-9 as evidenced by suppression of MMP-9 protein induction by TGF-beta1 antibody. In addition, CS produced apoptosis of BEAS-2B cells via TRX oxidation, which activated signal transduction factors, including apoptosis signal-regulating kinase (ASK) 1 and c-Jun N-terminal kinase (JNK). In contrast, TRX-TD cells exposed to CS retained reduced-form TRX, and inactivated ASK1 and JNK to attenuate apoptosis. This study indicated TRX overexpression was involved in CS-induced apoptosis and prevented airway remodeling through ASK1-JNK inactivation and MMP-9 augmentation.
Journal of Toxicology and Environmental Health Part A 02/2008; 71(22):1490-8. · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The occurrence of childhood asthma has been associated with air pollution in studies. However, it remains unclear as of the specific air components associated with the disease among children. We conducted a study in Taipei attempting to identify air pollution markers that may have association with the disease. Based on the daily traffic density, this subproject divided Taipei metropolitan into 3 areas: high, moderate and low density areas. From each area, 3 primary schools were randomly selected for a questionnaire screening survey to identify students with the complaint of asthma. The parents of 4952 students from 7 Schools responded to this study. Among the students responded to the study, 17.7% (432/2440) boys and 11.5% (289/2512) girls had been diagnosed with asthma. Students at schools in moderate traffic areas were most prevalent with asthma (16.5%) and students at schools in low traffic areas the least (13.4%). The prevalence increased from 11.8% among students living in areas with the least air pollution to 25.0% in areas with the highest pollution; the corresponding odds ratio increased from 1.33, (95% CI =1.04~1.70) to 2.13, (95% CI =1.17~3.89). We also found that maternal smoking during pregnancy was strongly associated with an increased risk of asthma (smoking over 20 cigarettes per day, OR=7.49, 95% CI=1.51-37.2). In conclusion, this study has demonstrated that the asthma prevalence among school children may be associated with the traffic pollution. Key words: air pollution, childhood asthma, primary school students, traffic density, Taiwan
135st APHA Annual Meeting and Exposition 2007; 11/2007
[Show abstract][Hide abstract] ABSTRACT: Polycyclic aromatic hydrocarbons (PAH) are common air pollutants generated from incomplete combustion. The inhalation of exhaust fumes in urban areas has been suggested to be an additional contributing factor. This study investigated the influence of urban traffic exposure, personal lifestyle factors and metabolic enzyme polymorphisms on the urinary 1-hydroxypyrene (1-OHP) level, approximating exposure to PAH. With consents, 95 male taxi drivers exposed to vehicle exhaust in traffic and 75 male office employees received health interviews and provided urine samples. The results showed taxi drivers had higher urinary 1-OHP than the office employees (mean +/- standard deviation were 0.17 +/- 0.10 vs. 0.10 +/- 0.07 mol/mol creatinine, p<0.001). The average urinary 1-OHP level increased from 0.07 micromol/mol creatinine for non-smoking office employees to 0.17 micromol/mol creatinine for those who smoked more than 20 cigarettes daily. The values for taxi drivers with similar smoking statuses were 0.12 and 0.25 micromol/mol creatinine, respectively. Among non-smokers, taxi drivers still had higher 1-OHP level than office employees (0.12 +/- 0.05 vs. 0.07 +/- 0.03 micromol/mol creatinine). The subjects with the m1/m2 or m2/m2 genotype of CYP1A1 MspI or GSTM1 deficiency had significantly higher urinary 1-OHP levels than those with other CYP1A1 MspI and GSTM1 genotypes. Multivariate logistic regression analysis showed that taxi drivers (adjusted odds ratio (OR)=5.1, 95% confidence interval (CI)=1.1-13.6), smokers (OR=5.5, 95% CI=1.6-18.4) and subjects with the m1/m2 or m2/m2 genotype of CYP1A1 MspI (OR=9.7, 95% CI=2.7-35.0) had elevated urinary 1-OHP (greater than the overall median value, 0.11 micromol/mol creatinine). The results of this study suggest smoking contributes to the elevated urinary 1-OHP levels in taxi drivers in addition to taxi driving, and the excess level contributed from traffic exhaust and smoke was regulated by the CYP1A1 MspI genotype. Traffic exhaust exposure, smoking and CYP1A1 MspI genotype contributed to the variation in levels of urinary 1-OHP excretion.
Journal of Occupational Health 04/2007; 49(2):140-51. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study investigated whether urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of oxidative stress, was associated with indoor air quality for non-smokers in high-rise building offices. With informed consents, urine samples from 344 non-smoking employees in 86 offices were collected to determine 8-OHdG concentrations. The concentrations of carbon dioxide (CO(2)) and total volatile organic compounds (TVOCs) in each office and outside of the building were simultaneously measured for eight office hours. The average workday difference between indoor and outdoor CO(2) concentrations (dCO(2)) was used as a surrogate measure of the ventilation efficiency for each office unit. The CO(2) levels in the offices ranged 467-2810ppm with a mean of 1170ppm, or 2.7 times higher than that in the outside air. The average urinary 8-OHdG levels among employees increased from 3.10 micro g/g creatinine, for those at the lowest tertile levels of both dCO(2) and TVOCs, to 6.27 micro g/g creatinine, for those at the highest tertile levels. Multivariate logistic regression analysis showed that the risk of having the urinary 8-OHdG level of greater than the median, 4.53 micro g/g creatinine, for participants was increased significantly at the highest tertile dCO(2) level of >680ppm (odds ratio (OR)=3.37, 95% confidence interval (CI)=1.20-9.46). The effect was significant at the middle tertile TVOCs level of 114-360ppb (OR=2.62, 95% CI=1.43-4.79), but not at the highest tertile. Inadequate ventilation in office increases the risk of building-related oxidative stress in non-smoking employees.
Environmental Research 04/2007; 103(3):331-7. · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nitrogen oxides (NOx) and polycyclic aromatic hydrocarbons are common air pollutants generated from automobile exhaust and cigarette smoke. This study was to investigate urinary 8-hydroxydeoxyguanosine (8-OHdG) as an effective biomarker on DNA damage from traffic exhaust and/or smoking in exposed and non-exposed individuals. With subject consents, the levels of plasma NOx, urinary 1-hydroxypyrene (1-OHP) and 8-OHdG were determined for 95 male taxi drivers and 75 male community residents as the reference group. After adjusting for associate variables, there was a significant correlation between the levels of urinary 8-OHdG and 1-OHP but not NOx. The average level of urinary 8-OHdG was significantly higher in drivers than in community men (13.4+/-4.7 vs. 11.5+/-4.7 microg/g creatinine in mean+/-standard deviation). Compared with non-smoking community men, the multivariate logistic regression showed that the odds ratios (OR) of having elevated levels of urinary 8-OHdG (greater than the overall median value, 12.1 microg/g creatinine) were 6.6 (95% confidence interval (CI)=2.1-20.8) for smoking community men, 5.0 (95% CI=1.7-14.7) for non-smoking taxi drivers and 4.6 (95% CI=1.4-15.0) for smoking taxi drivers. Higher risk was also observed for areca quid chewers compared with non-chewers (OR=1.6; 95% CI=1.1-3.6). In conclusion, taxi driving and smoking may contribute independently to elevated DNA damage using urinary 8-OHdG levels as a sensitive biomarker. This effect is most potent on heavy smokers.