Ping-Ho Chen

Predictors of betel quid chewing behavior and cessation patterns in Taiwan aborigines

BackgroundBetel quid, chewed by about 600 million people worldwide, is one of the most widely used addictive substances. Cessation factors in betel quid chewers are unknown. The present study explores prevalence and the quit rate of betel quid chewing in Taiwan aborigines. Our goal was to delineate potential predictors of chewing cessation.MethodsA stratified random community-based survey was designed for the entire aborigines communities in Taiwan. A total of 7144 participants were included between June 2003 and May 2004 in this study. Information on sociodemographic characteristics, such as gender, age, obesity, education years, marital status, ethnicity, and habits of betel quid chewing, smoking and drinking was collected by trained interviewers.ResultsThe prevalence of betel quid chewers was 46.1%. Betel quid chewing was closely associated with obesity (OR = 1.61; 95% CI: 1.40–1.85). Betel quid chewers were most likely to use alcohol and cigarettes together. Quit rate of betel quid chewers was 7.6%. Betel quid chewers who did not drink alcohol were more likely to quit (OR = 1.89; 95% CI: 1.43–2.50). Alcohol use is a significant factor related to cessation of betel quid chewing, but smoking is not.ConclusionTaiwan aborigines have a high prevalence of betel quid chewers and a low quit rate. Alcohol use is strongly association with betel quid chewing. Efforts to reduce habitual alcohol consumption might be of benefit in cessation of betel quid chewing.

Up-regulation of Inflammatory Signalings by Areca Nut Extract and Role of Cyclooxygenase-2 −1195G>A Polymorphism Reveal Risk of Oral Cancer

Because the mRNA expression of cyclooxygenase-2 (COX-2) is up-regulated by arecoline in human gingival fibroblasts, as shown in our previous study, we further investigated the mRNA expression level of COX-2 and its upstream effectors in three oral epithelial carcinoma cell lines (KB, SAS, and Ca9-22) by using areca nut extract (ANE) and saliva-reacted ANE (sANE). A case-control study of 377 oral squamous cell carcinoma (OSCC) patients and 442 controls was conducted to evaluate the gene-environment interaction between COX-2 promoter polymorphisms and substance use of alcohol, betel quid, and cigarettes (ABC) in risk of OSCC. The heterogeneous characteristics of the oral site and the COX-2 -1195G>A polymorphism in these cell lines showed diverse inflammatory response (KB>>Ca9-22>SAS) after 24-hour ANE/sANE treatments, and the COX-2 up-regulation might be mostly elicited from alternative nuclear factor-kappaB activation. In the case-control study, betel chewing [adjusted odds ratios (aOR), 42.2] posed a much higher risk of OSCC than alcohol drinking and cigarette smoking (aORs, 2.4 and 1.8, respectively), whereas the COX-2 -1195A/A homozygote presented a potential genetic risk (OR, 1.55). The strongest joint effect for OSCC was seen in betel chewers with -1195A/A homozygote (aOR, 79.44). In the non-betel chewing group, the -1195A/G and A/A genotypes together with the combined use of alcohol and cigarettes increased risk to 15.1-fold and 32.1-fold, respectively, compared with the G/G genotype without substance use. Taken together, these findings illustrate a valuable insight into the potential role of the COX-2 promoter region in contributing to the development of betel-related OSCC, including ANE/sANE-induced transcriptional effects and enhanced joint effects of COX-2 -1195A allele with substance use of ABC.

Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders

Objective To study the associations of gout, tophi and uric acid levels with the gout-related SLC2A9 (solute carrier family 2, member 9) single nucleotide polymorphisms (SNPs) between two different racial groups. Methods Eight SLC2A9 SNPs were genotyped in 109 subjects with gout and 191 control subjects from Han Chinese men in Taiwan and 69 subjects with gout and 168 control subjects from the Solomon Islands. Results Non-synonymous SLC2A9 rs3733591 Arg265His was associated with risk for gout and tophaceous gout in Han Chinese subjects (p=0.0012 and p=0.0044). The genetic effect of this SNP on tophaceous gout was replicated in Solomon Islanders (p=0.0184). Patients with SLC2A9 Arg265His risk C-allele consistently had a higher risk for tophi (OR 2.05–2.15) than non-tophi (OR 0.91–1.62). SNP rs3733591 described 3.68% and 5.98% of the total variability in uric acid levels for Chinese and Solomon Island subjects, respectively. Conclusion Non-synonymous SNP rs3733591 variant within the SLC2A9 gene from two geographically diverse populations served as an important genetic checkpoint for tophaceous gout and increased uric acid levels.

Prognostic factors associated with the survival of oral and pharyngeal carcinoma in Taiwan

BackgroundIn Taiwan, a distinct ethnic group variation in incidence and mortality rates has been suggested for most carcinomas. Our aim is to identify the role of prognostic factors associated with the survival of oral and pharyngeal carcinoma in Taiwan.MethodsTaiwan Cancer Registry records of 9039 subjects diagnosed with oral and pharyngeal carcinoma were analyzed. The population was divided into three ethnic groups by residence, which were Taiwanese aborigines, Hakka and Hokkien communities. Five-year survival rates were estimated by Kaplan-Meier methods. Ethnic curves differed significantly by log-rank test; therefore separate models for Taiwanese aborigines, Hakka and Hokkien were carried out. The Cox multivariate proportional hazards model was used to examine the role of prognostic factors on ethnic survival.ResultsThe five-year survival rates of oral and pharyngeal carcinoma were significantly poorer for Hokkien community (53.9%) and Taiwanese aborigines community (58.1%) compared with Hakka community (60.5%). The adjusted hazard ratio of Taiwanese aborigines versus Hakka was 1.07 (95%CI, 0.86–1.33) for oral and pharyngeal carcinoma mortality, and 1.16 (95%CI, 1.01–1.33) for Hokkien versus Hakka. Males had significantly poor prognosis than females. Subjects with tongue and/or mouth carcinoma presented the worst prognosis, whereas lip carcinoma had the best prognosis. Subjects with verrucous carcinoma had better survival than squamous cell carcinoma. Prognosis was the worst in elderly subjects, and subjects who underwent surgery had the highest survival rate.ConclusionOur study presented that predictive variables in oral and pharyngeal carcinoma survival have been: ethnic groups, period of diagnosis, gender, diagnostic age, anatomic site, morphologic type, and therapy.

The neoplastic impact of tobacco-free betel-quid on the histological type and the anatomical site of aerodigestive tract cancers

Little is known about any consequences of swallowing tobacco‐free betel‐quid (TF‐BQ) juice/remnants following chewing and its carcinogenic impact on the upper aerodigestive tract (UADT) to gastrointestinal tract (GIT). We investigated the neoplastic impact of TF‐BQ on different anatomical locations along UADT and GIT, and differences according to their histological categories. We conducted a multicenter case–control study examining patients with 2,163 pathology‐proven UADT and GIT cancers, comparing them with 2,250 control subjects. Generalized additive models, piecewise regression and polytomous logistic models were applied to identify possible dose‐dependent structures and cancer risks. Contrary to nonsignificant GIT‐adenocarcinoma risk (aOR = 0.9), TF‐BQ users experienced a 1.7‐ to 16.2‐fold higher risk of UADT‐squamous cell carcinomas than nonusers, with the peak risk discovered in oral neoplasms. We separately observed a curvilinear and linear TF‐BQ dose‐risk relationship in oral/pharyngeal/esophageal and laryngeal cancers. Chewers of betel inflorescence were generally at a greater UADT cancer risk. A higher first‐piecewise increased risk of esophageal cancer was recognized among areca‐fluid swallowers than among nonswallowers (continuous aOR = 1.12 vs. 1.03). TF‐BQ use accounted for 66.1–78.7% and 17.8–33.2% of the cases of oral/pharyngeal and esophageal/laryngeal cancers, respectively. However, a reduction from heavy TF‐BQ consumption to low‐to‐moderate consumption only reduced 11.3–34.6% of etiologic fraction of oral/pharyngeal cancers. Alcohol supra‐additively modified the risk of TF‐BQ in determining the development of oral, pharyngeal and esophageal cancers. In conclusion, the interplay of TF‐BQ and alcohol/tobacco use, combined with how chewing habit is practiced, influences carcinogenic consequences on anatomically diverse sites of UADT and GIT cancers, and histologically different types.

The SLC22A12 gene is associated with gout in Han Chinese and Solomon Islanders

Gout is characterised by monosodium urate crystals in hyperuricaemic individuals.1 2 Impaired excretion of urate exacerbates this condition.1 Urate transporter 1 (encoded by SLC22A12 ) is an urate–anion exchanger in the kidneys mediating urate transportation across the apical membrane of the proximal tubules.3 4 SLC22A12 has been reported to influence urate homeostasis in Caucasian and Japanese populations5,–,8 but single nucleotide polymorphism (SNP) genotype effects on gout are unclear. We studied four SLC22A12 SNP associations with gout and urate levels in male Han Chinese from Taiwan and Solomon Islanders. Clinical rheumatologists confirmed gout/tophi cases using American College of Rheumatology (ACR) criteria.9 Our controls had no diagnosis of gout and were not medicated with hypouricaemic agents during outpatient visits. We enrolled 115 …

Ingredients Contribute to Variation in Production of Reactive Oxygen Species by Areca Quid

Areca quid (AQ) chewing has been implicated an independent risk factor for the development of oral cancer. Taiwanese areca quid (AQ) refers to a combination of areca nut (AN), lime, and inflorescence of Piper betle Linn. (IPB) or Piper betle leaf (PBL). Studies of AQ in other countries reported that AN extract combined with lime generates reactive oxygen species (ROS), such as hydroxyl radical (HO·), known to be a contributing factor in oral mucosa damage. To determine whether HO· is formed in the oral cavity during AQ chewing, the formation of meta-tyrosine (m-Tyr) and ortho-tyrosine (o-Tyr) from l-phenylalanine (Phe) was confirmed. It was demonstrated that combined aqueous extracts of AN, lime, metal ions (such as Cu2+ and Fe2+), and IPB or PBL produced HO·. Thus, the yield of HO· significantly increases when higher amounts of IPB or lime are added and also when Cu2+ and Fe2+ are increased. Further, the omission of any one of these ingredients significantly reduces the formation of HO·. Our results found that chewing AQ with IPB generated significantly higher HO· than chewing AQ with PBL, and may result in greater oxidative damage to the surrounding oral mucosa. This study was supported by a grant from the Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Kaohsiung 807, Taiwan (NHRI-CN-IN-9006P).

Hydrogen Sulfide Increases Nitric Oxide Production and Subsequent S-Nitrosylation in Endothelial Cells

Hydrogen sulfide (H2S) and nitric oxide (NO), two endogenous gaseous molecules in endothelial cells, got increased attention with respect to their protective roles in the cardiovascular system. However, the details of the signaling pathways between H2S and NO in endothelia cells remain unclear. In this study, a treatment with NaHS profoundly increased the expression and the activity of endothelial nitric oxide synthase. Elevated gaseous NO levels were observed by a novel and specific fluorescent probe, 5-amino-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid methyl ester (FA-OMe), and quantified by flow cytometry. Further study indicated an increase of upstream regulator for eNOS activation, AMP-activated protein kinase (AMPK), and protein kinase B (Akt). By using a biotin switch, the level of NO-mediated protein S-nitrosylation was also enhanced. However, with the addition of the NO donor, NOC-18, the expressions of cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase were not changed. The level of H2S was also monitored by a new designed fluorescent probe, 4-nitro-7-thiocyanatobenz-2-oxa-1,3-diazole (NBD-SCN) with high specificity. Therefore, NO did not reciprocally increase the expression of H2S-generating enzymes and the H2S level. The present study provides an integrated insight of cellular responses to H2S and NO from protein expression to gaseous molecule generation, which indicates the upstream role of H2S in modulating NO production and protein S-nitrosylation.

The use of tobacco-free betel-quid in conjunction with alcohol/tobacco impacts early-onset age and carcinoma distribution for upper aerodigestive tract cancer

BACKGROUND  Recognition of how risk factors affect the age when cancers are first diagnosed may help to establish more appropriate cancer screening and preventive strategies. METHODS  To investigate the independent and synergistic effects of alcohol, tobacco-free betel-quid (TF-BQ), and cigarette use on diagnosis age and dissemination of upper aerodigestive tract squamous cell carcinoma (UADT-SCC), we recruited pathology-proven 1522 patients with UADT-SCC for study. RESULTS  A 49-, 53-, 57-, and 62-year-old stepwise older median age at carcinoma diagnosis was, respectively, found among patients with oral, pharyngeal, esophageal, and laryngeal cancer. Oral cavity (53.2%) and larynx (11.6%) were separately the dominant and recessive sites where the UADT-SCC occurred. Although alcohol and tobacco bestowed increased risks of earlier tumor occurrence only for oral/pharyngeal and oral cancers, respectively, TF-BQ was consistently observed to confer elevated age-associated risks for each UADT-SCC [adjusted hazard ratio (aHR) = 1.6-2.3]. Alcohol and TF-BQ joint consumers experienced a stepwise increased cumulative risk (CR) of contracting carcinomas of the larynx (46.2%), esophagus (47.5%), pharynx (53.5%), and oral cavity (60.5-71.0%), with >68% of CRs found among drinkers who started chewing before age 20. Alcohol + Betel + Cigarette and Alcohol + Betel users exhibited earlier diagnosis ages than non-users: 10 years ahead for oral cancer, 7, 17, and 12 years earlier for pharyngeal, esophageal, and laryngeal cancers. Noticeably, higher cumulative cancer risks regarding earlier tumor occurrence were correspondingly identified for these users aged 43, 49, 43, and 44 upward. CONCLUSIONS  Tobacco-free betel-quid, in conjunction with alcohol and/or tobacco consumption, impacts early cancer occurrence for specific UADT-SCC and influences tumor site incidence pattern of these neoplasms.

CYP26B1 is a novel candidate gene for betel quid-related oral squamous cell carcinoma

Substantial epidemiological data suggest a role for environmental factors (for example, the use of alcohol, betel quid (BQ), and cigarettes) in the occurrence of oral squamous cell carcinoma (OSCC), but the evidence for the genes involved has been inconsistent. This study was to investigate the role of CYP26B1, together with the use of alcohol, BQ, and cigarettes, on BQ-related OSCC. The association study (247 OSCC cases and 338 controls) was conducted to examine the possible interplay between CYP26B1 polymorphisms and alcohol, BQ, and cigarettes use. Additional gene expression was evaluated between OSCC tissue and adjacent normal tissue. The genetic polymorphism AA of CYP26B1 appeared to correlate with the risk of OSCC (OR=2.26; 95% CI, 1.35-3.80). Chewing BQ multiplicatively interacted with CYP26B1 AA to increase the OSCC risk (aOR=70.04; 95% CI, 13.62-360.11). The independent risk of OSCC was observed among BQ chewers with CYP26B1 AA, and compared with chewers with the CYP26B1 CC genotype (stratified aOR=2.88; 95% CI, 1.07-7.74). Increased expression of CYP26B1 was observed in tumor tissue compared with adjacent normal tissue. The CYP26B1 gene plays a novel role in the BQ dependent pathogenesis of OSCC.