Yuichiro Ichikawa

Association between individual response to food taste and gastroesophageal symptoms

Taste is an important element in food preferences. Gastroesophageal reflux disease (GERD) is related to lifestyles including eating habits. We aimed to investigate the relationship between responses to specific tastes and GERD.

Sa1931 Association Between Common Genetic Variants in Pre-MicroRNAs and Prognosis of Advanced Gastric Cancer Treated Chemotherapy

BACKGROUND Common single-nucleotide polymorphisms (SNPs) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) have been associated with various malignancies and their prognoses. We evaluated the associations of three selected SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) with the prognosis of advanced gastric cancers (GCs) treated by chemotherapy. MATERIALS AND METHODS The rs11614913 (T>C), rs2910164 (C>T), and rs3746444 (A>G) SNPs were genotyped in 130 advanced GCs performing chemotherapy. Survival and response evaluation was based on overall survival (OS) and progression-free survival (PFS). Response rate (RR) was also evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS 63 patients performed gastrectomy after chemotherapy (neoadjuvant chemotherapy) and the remaining cases performed chemotherapy alone as treatment (chemotherapy alone). The majority of cases performed S-1-based chemotherapy as the first line treatment (n=119, 92%). The rs3746444 (A>G) SNP was significantly associated with OS by the log-rank test (p=0.018), while other SNPs were not associated with OS. The rs3746444 (A>G) SNP was also associated with OS and PFS among cases of neoadjuvant chemotherapy (p=0.038, 0.024, respectively). Multivariate survival analysis using the Coxs regression model revealed that non-responder by the RECIST (Hazard ratio (HR): 2.14 95%CI 1.06-4.19), upper third cancer (HR: 2.48 95%CI 1.12-5.49) and more advanced stage (HR: 4.12 95%CI 1.06-16.02) were predictive factors for worse OS, while the rs3746444 A allele carrier was predictive factor for better OS (HR: 0.33 95%CI 0.18-0.75). CONCLUSION The rs3746444 A allele carrier in the hsa-mir-499 is associated with better prognosis in advanced GC performing chemotherapy.

Tu1324 Telomere Length in Non-Neoplastic Colonic Mucosa in Ulcerative Colitis and Its Relationship to the Severe Clinical Phenotypes

Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. To clarify the clinical importance of telomere shortening in colonic mucosa in ulcerative colitis (UC), we measured average telomere length using quantitative real-time PCR in non-neoplastic colonic mucosa in UC patients and assessed its relationship to various clinical subtypes. Relative telomere length in genomic DNA was measured in colonic biopsies obtained from rectal inflammatory mucosa from 86 UC patients as well as paired non-inflammatory proximal colonic mucosae from 10 patients. Data were correlated with various clinical phenotypes. In paired samples, average relative telomere length of rectal inflammatory mucosa was shortened compared to normal appearing proximal colon in eight out of ten cases (p = 0.01). Telomere length shortening was significantly associated with more severe Mayo endoscopic subscore (p < 0.0001) and cases needing surgery due to toxic megacolon or cancer occurrence (p = 0.043). When the severe clinical phenotype was defined as having at least one of following phenotypes, more than two times of hospitalization, highest Mayo endoscopic subscore, steroid dependent, refractory, or needing operation, average relative telomere length was significantly shortened in the same phenotypes than the others (p = 0.003). Telomere shortening is associated with more severe clinical phenotypes of UC, reflecting severe inflammatory state in the colonic mucosa.

Tu1325 Association Between Common Functional Genetic Polymorphisms and CpG Island Methylation Status in Colonic Mucosa in Ulcerative Colitis

Introduction/Aims: Lubiprostone enhances intestinal fluid secretion by activation of ClC-2, and likely CFTR chloride channels, and is used clinically to treat constipation. It has also been shown to stimulate recovery of mucosal barrier function in ischemic porcine intestine and modify tight junction (TJ) proteins. A defect in barrier function is thought to contribute to both the pathogenesis of inflammatory bowel disease (IBD) and to disease relapse. The aim of this study was to investigate if lubiprostone improves barrier function in colonic biopsies from IBD patients. Methods: Mucosal biopsies were obtained from the sigmoid colon of normal subjects undergoing screening colonoscopy, Crohns disease (CD) and ulcerative colitis (UC) patients in remission with approval of UCSD IRB. Biopsies were mounted in Ussing chambers, and bathed in Ringers solution at 37oC. After stabilization for 30 minutes, the tissues were treated with lubiprostone (0.01, 0.1 or 1.0 μM), or vehicle. Paracellular permeability to macromolecules was assessed with the fluorescent marker, FITCdextran (4 kD). Transepithelial electrical resistance (TER) was monitored over 120 minutes. Ion transport responses, measured as short-circuit current (Isc), were recorded for lubiprostone, the cAMP agonist forskolin, and the calcium agonist carbachol (CCh). Statistical analysis was performed using ANOVA or Students t-test. Results: Lubiprostone increased Isc across human colon in a concentration-dependent manner in all tissues (p<0.05; n=1517). Peak responses to lubiprostone were significantly lower in CD and UC vs. controls (p<0.05; n=15-17). The Isc response to forskolin was similar in controls, CD and UC tissues, while lubiprostone reduced the Isc response to forskolin in a dose-dependent manner. The Isc response to CChwas similar in all three subject groups and was unaffected by lubiprostone pre-treatment. Lubiprostone (1.0 μM) increased the diminished TER in CD biopsies vs. untreated by 8 ± 3 % (n=17, p<0.05) but had no significant effect on UC or normal biopsies. FITC-dextran permeability was not increased in CD or UC vs. controls and was unaffected by lubiprostone. Conclusion: Lubiprostone restored TER in CD biopsies indicating a possible role for lubiprostone as an enhancer of barrier function in CD vs. UC. Moreover, the Isc response to lubiprostone was lower in biopsies from IBD patients vs. normal controls whereas responses to forskolin or CCh were unchanged by disease status. This suggests that lubiprostone could be used to improve barrier function in CD without a risk of excessive fluid secretion. Support provided by Takeda Pharmaceuticals North America, Inc. & NIH DK080506.

Mo1582 Association Between Common Functional Genetic Polymorphisms Predisposed to CpG Island Methylation in Non-Neoplastic Gastric Mucosa

G A A b st ra ct s risk factors for cancer included age OR=1.04 (1.02-1.06), male sex OR=1.68 (1.03-2.74), and endoscopic evidence of gastropathy OR=4.07 (2.22-7.44). Conclusion: GIM predicts the risk of gastric cancer with age, male sex, and patients with endoscopic evidence of gastropathy, being the highest risk categories. Patients with GIM were older, more likely to be male, and more likely to have H. pylori, compared to patients without GIM. Further risk factors for gastric cancer in patients with GIM must be identified, and surveillance EGDs should be considered in groups at higher risk.

Su1864 Association Between Common Functional Genetic Polymorphisms and Survival of Gastric Cancer Patients

G A A b st ra ct s activation of DNMT3b, the majority of the differentially methylated genes (83.2%, 886/ 1,065) were CpG hypermethylated in AGS-EBV cells as compared with AGS cells (foldchanges 2.43~65.2). Gene ontology analysis indicated that hypermethylated genes were enriched in the following KEGG pathways (≥10 genes each, P≤0.05): cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, axon guidance, regulation of actin cytoskeleton, insulin signaling pathway, cell adhesion molecules (CAMs), endocytosis, calcium signaling pathway, glutamatergic synapse and focal adhesion. Seven novel hypermethylated genes (MDGA2, IL15RA, OSR1, SCARF2, EPHB6, SSTR1 and REC8) were chosen for further validation. Our results revealed that all seven genes were down-regulated in AGSEBV cells as compared with AGS cells. Demethylation treatment increased transcription levels of the seven genes in AGS-EBV cells. Dense methylation in the promoter of these candidates was further confirmed by BGS. Conclusions: EBV infection in AGS cells induced genome-wide aberrant promoter hypermethylation of 886 genes involving in several important cancer-related pathways. Induction of promoter methylation by EBV is regulated by upregulation of DNMT3b through LMP2A.