Ying-Chin Ko

Mortality for Certain Diseases in Areas with High Levels of Arsenic in Drinking Water

Blackfoot disease was prevalent in a limited area on the southwest coast of Taiwan, where artesian well water containing arsenic (median = 0.78 ppm arsenic) had been used for many years. Previous studies of arsenic exposure in the blackfoot disease endemic area have been focused on malignant tumors. We, therefore, conducted this study to analyze mortality of all death causes in blackfoot disease endemic areas and to determine other neglected cancers or noncancer diseases related to artesian well water containing high levels of arsenic. We calculated standardized mortality ratios for cancer and noncancer diseases, by sex, during the period from 1971 to 1994 and compared them to the local reference group (i.e, Chiayi-Tainan County) and the national reference group (i.e., Taiwan population). The results revealed marked standardized mortality ratio differences for the 2 reference groups. Greater mortality was found for males and females with bladder, kidney, skin, lung, nasal-cavity, bone, liver, larynx, colon, and stomach cancers, as well as lymphoma than in the local reference population. With respect to noncancer diseases, we found greater mortality for males and females who had vascular disease, ischemic heart disease, diabetes mellitus, and bronchitis than in the local reference group. Mortalities for other diseases--including rectal cancer, cerebrovascular disease, and other diseases--were higher among cases than the local reference group. Our results indicated that the hazardous effect of arsenic is systemic. Diseases related to arsenic exposure included those reported previously by other investigators, as well as diseases reported in the present study.

Climate, traffic-related air pollutants and allergic rhinitis prevalence in middle-school children in Taiwan

The prevalence of allergic rhinitis, a common respiratory disorder, may be rapidly increasing. Epidemiological studies, however, indicate little about its association with climatic factors and air pollution. The relationship between traffic-related air pollutants and allergic rhinitis in middle-school students was therefore investigated. In a nationwide survey of middle-school students in Taiwan conducted in 1995/1996, the lifetime prevalence of physician-diagnosed allergic rhinitis and typical symptoms of allergic rhinitis were compared with air-monitoring station data on temperature, relative humidity, sulphur dioxide (SO2), nitrogen oxides (NOx), ozone (O3), carbon monoxide (CO) and particulate matter with a 50% cut-off aerodynamic diameter of 10 µm (PM10). A total of 331,686 nonsmoking children attended schools located within 2 km of 55 stations. Mean (range) annual exposures were: CO 853 (381–1,610) parts per billion (ppb), NOx 35.1 (10.2–72.4) ppb, SO2 7.57 (0.88–21.2) ppb, PM10 69.2 (40.1–116.2) µg·m−3, O3 21.3 (12.4–34.1) ppb, temperature 22.9 (19.6–25.1)°C, and relative humidity 76.2 (64.8–86.2)%. The prevalence of physician-diagnosed allergic rhinitis was 28.6 and 19.5% in males and females, respectively, with prevalence of questionnaire-determined allergic rhinitis 42.4 and 34.0%. After adjustment for age, parental education and history of atopic eczema, physician-diagnosed allergic rhinitis was found to be associated with higher nonsummer (September–May) warmth and traffic-related air pollutants, including CO, NOx and O3. Questionnaire-determined allergic rhinitis correlated only with traffic-related air pollutants. Nonsummer warmth and traffic-related air pollution, probably mediated through exposure to common allergens such as dust mites, are possible risk factors for allergic rhinitis in middle-school-aged children.

Different impact from betel quid, alcohol and cigarette: risk factors for pharyngeal and laryngeal cancer.

The risks of betel quid chewing with or without tobacco, alcohol drinking and cigarette smoking have been well explored in the oral cavity but not in the pharynx and larynx. We conducted a case‐control study to investigate the association of these three risk factors to cancers of the pharynx and larynx in Taiwan. A total cases of 148 pharyngeal cancer, 128 laryngeal cancer and 255 hospital controls, all men, were recruited. Betel quid chewing was a significant independent risk factor (adjusted odds ratio [aOR] = 7.7; 95% confidence interval [CI] = 4.1–15.0) similar to that of alcohol drinking (aOR = 6.6; 95% CI = 3.5–13.0) for pharyngeal cancer, but not for laryngeal cancer (aOR = 1.3; 95% CI = 0.7–2.5) on which cigarette smoking (aOR = 7.1) exerts a stronger significant independent risk than alcohol drinking (aOR = 3.8). For pharyngeal cancers, chewers who consumed >20 quid/day, chewed with inflorescence in the quid or swallowed the betel quid juice were at higher risks; significant dose‐response effects were found in daily quantity of drinking and chewing, and cumulative quantity of drinking. Synergistic effects from the 3 risk factors existed both on the pharynx (aOR = 96.9) and the larynx (aOR = 40.3), and attributed for 93.1% and 92.9% respectively. Our study is the first evidence to show that betel quid chewing without tobacco has different impact on the pharynx (digestive tract) and the larynx (airway), and supports the concept that exposure quantity and direct mucosal contact with the betel quid juice may contribute to carcinogenesis. Our results show an important insight into the impact of betel quid chewing on other sites of the digestive tract other than the oral cavity.

G-2548A Polymorphism of the Leptin Gene Is Correlated with Extreme Obesity in Taiwanese Aborigines

We examined the genetic associations of the G‐2548A polymorphism in the promoter of the leptin (LEP) gene and the Gln223Arg (Q223R) polymorphism of the leptin receptor (LEPR) gene with obesity. Two hundred twenty‐six obese aboriginal subjects (BMI ≥ 27 kg/m2) and 182 aboriginal subjects with normal weight (BMI < 25 kg/m2) participated in this study. The polymorphisms of LEP G‐2548A and LEPR Q223R were genotyped by polymerase chain reaction/restriction fragment length polymorphism, and their anthropometric characteristics were measured. Levels of leptin, triglycerides, and cholesterol were measured after overnight fasting. We found that the frequencies of the LEP G/G homozygote (22.6%) with Mendelian recessive (χ2 = 7.89, p = 0.005) and codominant (χ2 = 7.93, p = 0.02) models to be higher in the extremely obese subjects (BMI ≥ 35 kg/m2) than in normal weight subjects (6.9%) but not in moderately obese subjects (35 > BMI ≥ 27 kg/m2). There was no difference in genotypic frequency of the LEPR Q223R polymorphism between the extreme obese and control groups. We suggest that the LEP −2548 G/G homozygote plays a genetic recessive role in the development of extreme obesity in Taiwanese aborigines.

6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells.

This study is the first study to investigate the anticancer effect of 6-shogaol in human non-small cell lung cancer A549 cells. 6-Shogaol inhibited cell proliferation by inducing autophagic cell death, but not, predominantly, apoptosis. Pretreatment of cells with 3-methyladenine (3-MA), an autophagy inhibitor, suppressed 6-shogaol mediated antiproliferation activity, suggesting that induction of autophagy by 6-shogaol is conducive to cell death. We also found that 6-shogaol inhibited survival signaling through the AKT/mTOR signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin (mTOR), forkhead transcription factors (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). Phosphorylation of both of mTORs downstream targets, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased 6-shogaol mediated autophagic cell death, supporting inhibition of AKT beneficial to autophagy. Moreover, reduction of AKT expression by siRNA potentiated 6-shogaols effect, also supporting inhibition of AKT beneficial to autophagy. Taken together, these findings suggest that 6-shogaol may be a promising chemopreventive agent against human non-small cell lung cancer.

Interaction between cigarette, alcohol and betel nut use on esophageal cancer risk in Taiwan

Objective  In 2003 esophageal cancer was the sixth leading cause of death among men in Taiwan, but it is the fastest increasing (70%) alimentary tract cancer. The aim of this study was to investigate the impact of different habits of betel nut chewing on esophageal squamous cell carcinoma (SCC) and its interaction with cigarette use and alcohol consumption.

Effects of occupational dust exposure on the respiratory health of Portland cement workers.

The object of this study was to assess the relationship between occupational Portland cement dust exposure and respiratory health. Respiratory symptoms and ventilatory function were studied in a group of 591 male Portland cement workers employed in four cement plants. The prevalence of chronic respiratory symptoms was higher in exposed than in control workers. The exposed group had a significantly lower mean forced vital capacity (FVC), forced expiratory volume at 1 s (FEV1), and forced expiratory flows after exhalation of 50% and 75% of the vital capacity (FEF50, FEF75) than the control group. The data suggest that occupational exposure to Portland cement dust may lead to higher prevalence of chronic respiratory symptoms and the reduction of ventilatory capacity.

Intercountry prevalences and practices of betel-quid use in south, southeast and eastern asia regions and associated oral preneoplastic disorders: An international collaborative study by asian betel-quid consortium of south and east Asia

Health risks stemming from betel‐quid (BQ) chewing are frequently overlooked by people. Updated epidemiological data on the increased BQ use among Asian populations using comparable data collection methods have not been widely available. To investigate the prevalence, patterns of practice and associated types of oral preneoplastic disorders, an intercountry Asian Betel‐quid Consortium study (the ABC study) was conducted for Taiwan, Mainland China, Malaysia, Indonesia, Nepal and Sri Lanka. A random sample of 8,922 subjects was recruited, and the data were analyzed using survey‐data modules adjusted for the complex survey design. Chewing rates among men (10.7–43.6%) were significantly higher than women (1.8–34.9%) in Taiwan, Mainland China, Nepal and Sri Lanka, while womens rates (29.5–46.8%) were higher than that for men (9.8–12.0%) in Malaysia and Indonesia. An emerging, higher proportion of new‐users were identified for Hunan in Mainland China (11.1–24.7%), where Hunan chewers have the unique practice of using the dried husk of areca fruit rather than the solid nut universally used by others. Men in the Eastern and South Asian study communities were deemed likely to combine chewing with smoking and drinking (5.6–13.6%). Indonesian women who chewed BQ exhibited the highest prevalence of oral lichen planus, oral submucous fibrosis and oral leukoplakia (9.1–17.3%). Lower schooling, alcohol drinking and tobacco smoking were identified as being associated with BQ chewing. In conclusion, the ABC study reveals the significant cultural and demographic differences contributing to practice patterns of BQ usage and the great health risks that such practices pose in the Asian region.

Cancer mortality trends in a blackfoot disease endemic community of Taiwan following water source replacement.

Blackfoot disease is an endemic peripheral vascular disease found among people in a limited area on the southwest coast of Taiwan, where artesian well water has a high concentration of arsenic and was used since the turn of this century. This is an important public health problem and was noted by the authorities, who began improving the water supply in such communities in 1956. This enabled us to test the relationship between arsenic and malignant tumors using a specific exposed community. Study subjects were divided into four groups according to age (under or over 40 yr) and gender. Two methods were used for the estimation of the age-adjusted mortality rate ratios. First using the first time interval (1971-1973) as the standard, the mortality rate ratio for all malignant tumors was estimated from this interval through to the last interval (1992-1994) using Poisson regression. Cancers that were found to be related to arsenic in previous reports, such as liver, lung, bladder, kidney, and skin cancers, were examined and other malignant tumors except these cancers were also assessed. The same calculations were performed for all of Chiayi and Tainan counties, excluding the study areas, which were used as the local reference, and for the general population of Taiwan, which was used as a national reference group. Second, mortality rate ratios for the study area were compared to the local and national reference for the same time intervals for each disease category. From our results, significantly declining trends for mortality rate ratios of all malignant tumors with 1971-1973 as the standard were found for the study areas, especially in females. A decrease of mortality rate ratios from malignant cancers, compared to the local or national references, was found in those aged over 40 yr for both sexes. The decreases are mainly due to a fall in internal and skin cancer mortality rates. In conclusion, our results suggest that the improvement of drinking water supply to eliminate arsenic exposure from artesian well water decreased the mortality incidence of arsenic-related cancers in blackfoot disease endemic communities.

miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis

MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-protein-coupled receptor kinase-interacting protein 1 (GIT1)-as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p-mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal-regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clinical specimens of OSCCs, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer.