Hung-Pin Tu

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.

Genomewide Scan for Gout in Taiwanese Aborigines Reveals Linkage to Chromosome 4q25

Gout is a disorder of uric-acid metabolism. The Pacific Austronesian population, including Taiwanese aborigines, has a remarkably high prevalence of hyperuricemia and gout, which suggests a founder effect across the Pacific region. We report here a genomewide linkage study of 21 multiplex pedigrees with gout from an aboriginal tribe in Taiwan. From observations of familial clustering, early onset of gout, and clinically severe manifestations, we hypothesized that a major gene plays a role in this trait. Using 382 random polymorphic markers spread across 22 autosomes, we demonstrated a highly significant linkage for gout at marker D4S2623 on chromosome 4q25 (P=.0002 by nonparametric linkage [the NPL(all) statistic]; empirical P=.0006; LOD=4.3, P=4.4x10-6 by logistic regression). When alcohol consumption was included as a covariate in the model, the LOD score increased to 5.66 (P=1.3x10-6). Quantitative traits, including serum uric acid and creatinine, also showed a moderate linkage to this region. To our knowledge, this is the first genome-scan report to identify a genetic locus harboring a gout-susceptibility gene.

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.

Distinct SPINK5 and IL‐31 polymorphisms are associated with atopic eczema and non‐atopic hand dermatitis in Taiwanese nursing population

Abstract:  The term ‘hand dermatitis’ describes inflammatory skin condition localized to the hands. Nurses working at hospital settings are prone to develop hand dermatitis. The current study aimed to evaluate whether certain genetic polymorphisms were associated with the development of atopic eczema or non‐atopic hand dermatitis in Taiwanese population. Nurses of Kaohsiung Medical University Hospital were recruited. Atopic eczema, non‐atopic hand dermatitis and normal control groups were identified. The serine protease inhibitor Kazal type 5 (SPINK5), filaggrin and interleukin‐31 (IL‐31) gene variants were compared between the diseased and control groups. Our results showed that rs2303070 T allele of SPINK5 (assuming recessive model; OR = 3.58, 95% CI 1.63–7.84; P = 0.0014) and rs7977932 G allele of IL‐31 (assuming recessive model; OR = 18.25, 95% CI = 3.27–101.94; P = 0.0009) were associated with increased risks of developing atopic eczema, while rs6892205 G allele of SPINK5 (assuming dominant model; OR = 3.79, 95% CI 1.55–9.28; P = 0.0036) was associated with the development of non‐atopic hand dermatitis. In summary, our results showed that distinct SPINK5 and IL‐31 gene variants were associated with the development of atopic eczema and non‐atopic hand dermatitis. The barrier function, particularly those regulated by SPINK5, may play an important role in the development of both atopic eczema and non‐atopic hand dermatitis.

Hand dermatitis among university hospital nursing staff with or without atopic eczema: assessment of risk factors.

Background. Nurses are prone to develop hand dermatitis. Although an atopic constitution has been identified as a genetic risk factor, the behavioural risk factors associated with hand dermatitis in wet work conditions have not been fully explored.

Lymphocyte α-kinase is a gout-susceptible gene involved in monosodium urate monohydrate-induced inflammatory responses

The molecular functions and pathophysiologic role of the lymphocyte α-kinase gene (ALPK1) in gout are unknown. We aimed to examine ALPK1 expression in patients with gout and investigate its role in monosodium urate monohydrate (MSU)-induced inflammatory responses. Microarray data mining was performed with six datasets containing three clinical gout and three volunteer samples. Real-time quantitative polymerase chain reaction (qPCR) assay was used to profile ALPK1 mRNA expression in 62 independent samples. RNA interference for ALPK1 suppression in THP1 cells (human monocytic cell line) was used to scrutinize the functional role of ALPK1 in MSU-mediated inflammatory responses, and ALPK1 expression in MSU-treated THP1 cells was determined by qPCR and Western blot analysis. Cytokine mRNA expression in HEK293 cells after incubation with different concentrations of MSU crystals in the presence or absence of ALPK1 was also detected by qPCR, and ERK1/2, p38, and JNK expressions were investigated by Western blot analysis. ALPK1 mRNA was overexpressed in the clinical gout samples. MSU treatment promoted ALPK1 expression at the mRNA and protein levels. Furthermore, ALPK1 knockdown in THP1 cells resulted in a markedly decreased IL-1β, TNF-α, and IL-8 mRNA expression; plasmid ALPK1 transfection and MSU stimulation synergistically increased the mRNA expression of these cytokines in a concentration-dependent manner. The synergistic effect also led to ERK1/2 activation. ALPK1 is a gout-susceptible gene involved in MSU-induced inflammatory responses. It may contribute to the development of gout by enhancing the inflammatory responses via the mitogen-activated protein kinase pathway.

Persistent mechanical allodynia positively correlates with an increase in activated microglia and increased P‐p38 mitogen‐activated protein kinase activation in streptozotocin‐induced diabetic rats

In experimental early painful diabetic neuropathy, persistent hyperglycaemia induces dys‐regulated sodium channel (Navs) expression in the dorsal root ganglion (DRG) and activates microglia in the spinal dorsal horn (SDH). However, information on diabetes‐induced chronic neuropathic pain is limited. Therefore, we investigated abnormal Navs in the DRG and activated glial cells in the SDH of diabetic rats with chronic neuropathic pain.

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 …

The Relationship Between Visceral Adiposity and the Risk of Erosive Esophagitis in Severely Obese Chinese Patients

A higher prevalence of erosive esophagitis is found in obese than in nonobese patients; however, it remains unclear why some obese patients develop this disease, whereas others do not. Accordingly, we elucidated the risk factors associated with erosive esophagitis in severely obese Chinese patients. Between June 2007 and January 2009, a total of 260 Chinese patients with morbid obesity referred for bariatric surgery were enrolled in this cross‐sectional study. All patients received preoperative endoscopy for evaluation of the presence and severity of erosive esophagitis. Demographic variables, anthropometric measurements, and metabolic factors were included in a logistic regression model to identify the factors predictive of erosive esophagitis. The prevalence of erosive esophagitis was 32.3%. Multiple logistic regression showed that increased waist circumference (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 1.01–1.04), increased insulin resistance (OR = 1.57, 95% CI = 1.06–2.31), and presence of reflux symptoms (OR = 2.40, 95% CI = 1.22–4.74) were independent risk factors associated with erosive esophagitis. In conclusion, among Chinese patients with morbid obesity, increased waist circumference and insulin resistance were risk factors for erosive esophagitis, which highlights the critical role of visceral adiposity in the pathogenesis of erosive esophagitis.