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// Tomomitsu Tahara 1 , Ichiro Hirata 2 , Naoko Nakano 1 , Sayumi Tahara 3 , Noriyuki Horiguchi 1 , Tomohiko Kawamura 1 , Masaaki Okubo 1 , Takamitsu Ishizuka 1 , Hyuga Yamada 1 , Dai Yoshida 1 , Takafumi Ohmori 1 , Kohei Maeda 1 , Naruomi Komura 1 , Hirokazu Ikuno 1 , Yasutaka Jodai 1 , Toshiaki Kamano 1 , Mitsuo Nagasaka 1 , Yoshihito Nakagawa 1 , Tetsuya Tuskamoto 3 , Makoto Urano 3 , Tomoyuki Shibata 1 , Makoto Kuroda 3 and Naoki Ohmiya 1 1 Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan 2 Department of Gastroenterology, Kenporen Osaka Central Hospital Japan, Osaka, Japan 3 Department of Diagnostic Pathology I, School of Medicine, Fujita Health University, Toyoake, Japan Correspondence to: Tomomitsu Tahara, email: tomomiccyu@yahoo.co.jp Keywords: DNA methylation, colonic mucosa, ulcerative colitis, Fusobacterium , genome-wide methylation Received: February 08, 2017 Accepted: May 23, 2017 Published: June 27, 2017 ABSTRACT BACKGROUND AND AIM: Fusobacterium enrichment has been associated with colorectal cancer development. Ulcerative colitis (UC) associated tumorigenesis is characterized as high degree of methylation accumulation through continuous colonic inflammation. The aim of this study was to investigate a potential link between Fusobacterium enrichment and DNA methylation accumulation in the inflammatory colonic mucosa in UC. METHODS: In the candidate analysis, inflamed colonic mucosa from 86 UC patients were characterized the methylation status of colorectal a panel of cancer related 24 genes. In the genome-wide analysis, an Infinium HumanMethylation450 BeadChip array was utilized to characterize the methylation status of >450,000 CpG sites for fourteen UC patients. Results were correlated with Fusobacterium status. RESULTS: UC with Fusobacterium enrichment (FB-high) was characterized as high degree of type C (for cancer-specific) methylation compared to other (FB-low/neg) samples ( P

DNA methylation is associated with “field defect” in the gastric mucosa. To characterize “field defect” morphologically, we examined DNA methylation of non-neoplastic gastric mucosa in relation to their morphology seen by narrow-band imaging (NBI) with magnifying endoscopy. Magnifying NBI of non-neoplastic gastric body was classified as follows: normal—small and round pits with uniform subepithelial capillary networks; type 1—a little enlarged round pits with indistinct subepithelial capillary networks; type 2—remarkably enlarged pits with irregular vessels; and type 3—clearly demarcated oval or tubulovillous pits with bulky coiled or wavy vessels. Methylation of nine candidate genes (MYOD1, SLC16A12, GDNF, IGF2, MIR 124A1, CDH1, PRDM5, RORA and MLF1) were determined by bisulfite pyrosequencing. Infinium HumanMethylation450 array was used to characterize the methylation of >450,000 CpG sites. Mean Z score methylation of nine genes positively correlated with the changes of mucosal patterns from normal to types 1, 2, and 3 (P

Neoadjuvant chemotherapy may improve outcomes for patients with locally advanced gastric cancer (GC). To explore useful predictive factors for the response of advanced GC to neoadjuvant chemotherapy, tumor responses were assessed using computed tomography (CT) with histological based criteria. A total of 78 patients with advanced GC undergoing neoadjuvant chemotherapy were included. CT-based response assessment was performed following 2 courses of treatment. Histological evaluation of resected specimens was also performed according to the Japanese classification of gastric carcinoma. Grade 1b, 2 and 3 (viable tumor cells remaining in

The molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication remain unclear. We examined the telomere length of gastric mucosa samples after successful H. pylori eradication in patients without and those with gastric cancer. Telomere length was measured by the real-time PCR among four different groups of biopsies: gastric body from subjects without history of H. pylori infection (Hp-: n = 23), gastric body from cancer-free subjects after H. pylori eradication (cancer-free body: n = 24), gastric body from early gastric cancer patients diagnosed after H. pylori eradication (EGC body: n = 35) and its paired samples from adjacent mucosa of cancerous area (EGC ADJ: n = 35). The Hp-group presented the longest telomeres among the all groups (Hp- vs. all others, all P

// Tomomitsu Tahara 1 , Tomoyuki Shibata 1 , Masaaki Okubo 1 , Tomohiko Kawamura 1 , Noriyuki Horiguchi 1 , Takamitsu Ishizuka 1 , Naoko Nakano 1 , Mitsuo Nagasaka 1 , Yoshihito Nakagawa 1 , Naoki Ohmiya 1 1 Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan Correspondence to: Tomomitsu Tahara, email: tomomiccyu@yahoo.co.jp Keywords: DNA methylation, telomere length, gastric mucosa, H. pylori, gastritis Received: October 24, 2015 Accepted: May 02, 2016 Published: June 01, 2016 ABSTRACT Background: Telomere length shortening in Helicobacter pylori ( H. pylori ) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa. Methods: Telomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive element Results: We identified five PCGIs ( IGF2 , SLC16A12 , SOX11 , P2RX7 and MYOD1 ), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis ( P

// Tomomitsu Tahara 1 , Tomoyuki Shibata 1 , Yasuyuki Okamoto 2 , Jumpei Yamazaki 3 , Tomohiko Kawamura 1 , Noriyuki Horiguchi 1 , Masaaki Okubo 1 , Naoko Nakano 1 , Takamitsu Ishizuka 1 , Mitsuo Nagasaka 1 , Yoshihito Nakagawa 1 , Naoki Ohmiya 1 1 Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan 2 Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 3 Laboratory of Molecular Medicine, Hokkaido University Graduate School of Veterinary Medicine, Sapporo, Japan Correspondence to: Tomomitsu Tahara, e-mail: tomomiccyu@yahoo.co.jp Keywords: TP53 mutation, gastric cancer, spectrum, survival, hotspot mutations Received: October 24, 2015 Accepted: April 18, 2016 Published: June 01, 2016 ABSTRACT Background and aim: TP53 gene is frequently mutated in gastric cancer (GC), but the relationship with clinicopathological features and prognosis is conflicting. Here, we screened TP53 mutation spectrum of 214 GC patients in relation to their clinicopathological features and prognosis. Results: TP53 nonsilent mutations were detected in 80 cases (37.4%), being frequently occurred as C:G to T:A single nucleotide transitions at 5’-CpG-3’ sites. TP53 mutations occurred more frequently in differentiated histologic type than in undifferentiated type in the early stage (48.6% vs. 7%, P =0.0006), while the mutations correlated with venous invasion among advanced stage (47.7% vs. 20.7%, P =0.04). Subset of GC with TP53 hot spot mutations (R175, G245, R248, R273, R282) presented significantly worse overall survival and recurrence free survival compared to others (both P =0.001). Methods: Matched biopsies from GC and adjacent tissues from 214 patients were used for the experiment. All coding regions of TP53 gene (exon2 to exon11) were examined using Sanger sequencing. Conclusion: Our data suggest that GC with TP53 mutations seems to develop as differentiated histologic type and show aggressive biological behavior such as venous invasion. Moreover, our data emphasizes the importance of discriminating TP53 hot spot mutations (R175, G245, R248, R273, R282) to predict worse overall survival and recurrence free survival of GC patients.

Telomere shortening occurs in many organs and tissues and is accelerated by oxidative injury and rapid cell turnover. Short telomeres initiate chromosomal instability and may eventually contribute to tumorigenesis. To evaluate telomere length as potential biomarker for gastric cancer (GC) risk, we measured average telomere length using quantitative real-time PCR in GC tissues and in non-neoplastic mucosa from patients with GC and without GC. We obtained of 217 GC patients matched biopsies from the GC and adjacent tissues as well as gastric biopsies of 102 subjects without GC. Relative telomere length was measured in genomic DNA by real-time PCR. Relative telomere length decreased gradually in Helicobacter pylori (H. pylori) negative and positive gastric mucosa of GC free subjects compared with adjacent mucosa and cancer tissue from GC patients (4.03 ± 0.3 vs. 2.82 ± 0.19 vs. 0.82 ± 0.07 vs. 0.29 ± 0.09, P

The aim of this study was to investigate the effect of consuming small amounts of beer or a nonalcoholic beer taste beverage (non-beer) on gastric emptying and the polymorphisms in alcohol metabolism-related enzyme-encoding genes. Twenty male healthy volunteers were questioned regarding their alcohol consumption status, and body measurement was performed. The genetic polymorphisms in ADH1B (rs1229984, Arg47His) and ALDH2 (rs671 Glu487Lys) were analyzed. The subjects consumed 150 mL of beer or non-beer once per week, followed by the ingestion of 200 kcal of the test nutrient containing 13C-acetate 15 min later, after which the subjects' exhalations were collected up to 120 min. The concentration peak of 13C was measured as Tmax. Diamine oxidase (DAO) activity for the marker of small intestinal function activity was also measured the day after the test. Gastric emptying was significantly slower in the group that consumed a small amount of beer, and in daily beer consumption group, and also in the ADH1B *2/*2, ALDH2 *1/*2 genotypes compared to non-beer drinking group. DAO values were not significantly changed between beer and non-beer group. The consumption of even a small amount of beer and the polymorphisms in ADH1B / ALDH2 affects gastric motility.

Background. Gastric cancer is discovered even after successful eradication ofH. pylori. We investigated clinic pathological features of early gastric cancers afterH. pylorieradication.Methods. 51 early gastric cancers (EGCs) from 44 patients diagnosed after successfulH. pylorieradication were included as eradication group. The clinic-pathological features were compared with that of 131 EGCs from 120 patients who did not have a history ofH. pylorieradication (control group).Results. Compared with control group, clinic-pathological features of eradication group were characterized as depressed (p<0.0001), reddish (p=0.0001), and smaller (p=0.0095) lesions, which was also confirmed in the comparison of six metachronous lesions diagnosed after initial ESD and subsequent successfulH. pylorieradication. Prevalence of both SM2 (submucosal invasion greater than 500 μm) and unexpected SM2 cases tended to be higher in eradication group (p=0.077, 0.0867, resp.). Prevalence of inconclusive diagnosis of gastric cancer during pretreatment biopsy was also higher in the same group (26.0% versus 1.6%,p<0.0001).Conclusions. Informative clinic pathological features of EGC afterH. pylorieradication are depressed, reddish appearances, which should be treated as a caution because histological diagnosis of cancerous tissue is sometimes difficult by endoscopic biopsy.

Objective 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. Methods Altogether 280 patients including 170 men with a mean age of 58.6 years were included in the study to determine the relationship between their liking for specific tastes and GERD using a new self-administered questionnaire (responses to various tastes and participants' sensitivity to taste and hot food and on the frequency of stomatitis). Another self-administrated questionnaire was administrated for a diagnosis of GERD (the frequency scale for the symptoms of GERD cut-off score of 10). Furthermore, 142 of 280 patients who had received esophagogastroduodenoscopy (EGD) were investigated on the association between endoscopic esophagitis and their favorite tastes. Results In the association analyses between responses to specific tastes and GERD, the group liking salty food and the group with a high frequency of stomatitis had a significantly higher incidence of GERD (salty food: odds ratio [OR] 2.059, 95% confidence interval [CI] 1.215–3.488, P = 0.0073; stomatitis: OR 2.861, 95% CI 1.558–5.253, P = 0.0007, respectively). In association analyses with endoscopic esophagitis, the groups liking salty and sour food had a significantly higher incidence rate of endoscopic esophagitis (salty: OR 2.718, 95% CI 1.330–5.555, P = 0.0061; sour: OR 3.267, 95% CI 1.491–7.160, P = 0.0031, respectively). Conclusions Sensitivity and response to specific food taste were associated with GERD. The results of a preference to hot or salty food and endoscopic esophagitis suggest that physical stimuli are important for esophageal injuries.

Background/aim Telomere shortening in leukocytes has been thought to be associated with reduced immune response capacity and increased chromosome instability. Several studies indicate that telomere length in the peripheral blood leukocyte DNA can predict clinical outcome of several cancers. We evaluated the potential association between telomere shortening in the leukocyte DNA and clinicopathological features and prognosis of gastric cancer (GC) in Japanese patients. Materials and methods Telomere length in leukocyte DNA was measured using quantitative real-time polymerase chain reaction (PCR) in 207 GC patients. The association between telomere length and clinicopathological features and prognosis was evaluated. Results These short-telomere group was significantly associated with advanced stage (p=0.015), worse overall survival (OS) and progression-free survival (PFS) (p=0.046 and 0.026, respectively). The same group was also weakly associated with overall and peritoneal recurrences (p=0.052 and 0.059, respectively). Conclusion Telomere shortening in leukocyte DNA is associated with advanced stage and poor prognosis of GC, which may reflect their reduced immune response capacity or increased chromosome instability.

Background Chemotherapy may improve outcomes in gastric cancer (GC), especially for the patients with advanced stage. To explore useful predictive factor for GC performing chemotherapy, we compared the tumor responses assessed using computed tomography (CT) with endoscopy based criteria. Methods 192 GC patients performing chemotherapy were retrospectively studied. CT based response assessment was performed after 2 courses of treatment. Endoscopic evaluation according to The Japanese classification of gastric carcinoma was also performed at same period. Data were correlated with overall survival (OS) and progression-free survival (PFS). Results Majority of the cases (n = 178, 93%) received S-1 based chemotherapy as the first line treatment. 55 (29%) and 91 (47%) cases were considered to be CT and endoscopic responders. Endoscopic responder was more clearly associated with better OS and PFS compared to CT based responder by the log-rank test (P

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.

Plummer-Vinson syndrome (PVS) is a rare entity characterized by upper esophageal webs and iron deficiency anemia. We report a case of PVS whose esophageal web was rapidly improved by iron therapy. A 77-year-old woman was admitted to our hospital with complaints of dysphagia, vomiting, shortness of breath and weight loss for 1 month. Physical examination revealed conjunctival pallor, koilonychia, angular cheilitis and smooth tongue, and laboratory findings were consistent with microcytic hypochromic anemia with iron deficiency. Gastrointestinal endoscopy and barium-swallow esophagography detected a web that prevented passage of the endoscope into the upper portion of the esophagus. The patient received oral iron therapy daily; the hemoglobin concentration rose to 8.9 g/dl and the complaints of dysphagia were dramatically improved after 2 weeks, with improvement of luminal stenosis confirmed by gastrointestinal endoscopy and barium-swallow esophagography. The PVS described in this report had a distinct clinical course, showing very rapid improvement of dysphagia and esophageal web after 2 weeks of oral iron therapy.

Previous studies have demonstrated the protective role of inducible heat-shock protein (HSP) 70 in intestinal cells. The HSP70-2 gene has a PstI site due to an A–G transition at the 1,267 position and different genotypes are associated with various levels of mRNA expression. The present study aimed to clarify the effect of the HSP70-2 polymorphism on the risk of ulcerative colitis (UC), including its clinical phenotypes. A total of 121 patients with UC and 500 healthy control (HC) subjects participated in the study. To assess the polymorphisms at the 1,267 position of the HSP70-2 gene, restriction fragment length polymorphism analysis was performed. The subjects in the study were classified by disease behavior, severity and extent of disease. Although no significant difference of the HSP70-2 genotype distribution was identified between the HC and UC groups, the BB genotype exhibited a lower risk of the steroid-dependent phenotype [odds ratio (OR), 0.12; 95% confidence interval (CI), 0.02–0.95; P=0.02]. The same genotype was also associated with a lower risk of the refractory phenotype (OR, 0.16; 95% CI, 0.04–0.73; P=0.01). There was no direct correlation between the polymorphism of the HSP70-2 gene and UC susceptibility. However, there was an association between a reduced risk of the steroid-dependent and refractory phenotypes of UC and the BB genotype.

The aim of this study was to investigate the effect of consuming small amounts of beer or a nonalcoholic beer taste beverage (non-beer) on gastric emptying and the polymorphisms in alcohol metabolism-related enzyme-encoding genes. Twenty male healthy volunteers were questioned regarding their alcohol consumption status, and body measurement was performed. The genetic polymorphisms in ADH1B (rs1229984, Arg47His) and ALDH2 (rs671 Glu487Lys) were analyzed. The subjects consumed 150 mL of beer or non-beer once per week, followed by the ingestion of 200 kcal of the test nutrient containing

Background The effect of H. pylori eradication in gastric cancer prevention can be attributed to the improvement of atrophic gastritis, which is a known risk of gastric cancer. However, gastric cancer has also been diagnosed after long-term H. pylori eradication. This study aimed to clarify the association between gastric atrophy and gastric cancer after H. pylori eradication, including its clinicopathological features. Methods A total of 55 consecutive patients with 64 early gastric cancers (EGCs) diagnosed after H. pylori eradication were enrolled. The degree of endoscopic atrophy and the histological degrees of mononuclear cell infiltration, atrophy, and metaplasia in the corpus and adjacent mucosa of the EGCs were determined and scored. Results The majority of EGCs (63/64) were located within the endoscopically assessed atrophic mucosa or along the atrophic border. The adjacent mucosa of the EGCs presented significantly higher degrees of all histological parameters than in the corpus (mononuclear cell infiltration, 0.86+/-0.09 vs. 0.51+/-0.11, P = 0.016; atrophy, 1.77+/-0.13 vs. 0.65+/-0.14, P

BACKGROUND: Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non-neoplastic gastric mucosa. METHODS: XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP-kinase and CDH1) loci, assessed by Methylation-Specific-Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated. RESULTS: Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.30, 95%CI = 0.13-0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19-0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (>50 and

Combining the narrow-band imaging (NBI) system and magnifying endoscopy allows simple and clear visualization of microscopic structures of the superficial mucosa and its capillary patterns, which may be useful for precise endoscopic diagnosis in the gastrointestinal tract, being more closely to histopathological diagnosis. In the non-neoplastic gastric mucosa, there have been reports showing a potential usefulness of magnifying NBI for the diagnosis of Helicobacter pylori infection, degree of histological gastritis, and intestinal metaplasia. We have shown that magnifying NBI appearances in the non-neoplastic gastric mucosa also predicts pepsinogen levels, which indicates extension of gastric atrophy in the entire stomach, and gastric cancer occurrence. Furthermore, we have shown that magnifying NBI appearances predicts the result of H. pylori treatment. Clear visualization of fine mucosal and capillary patterns, obtained by magnifying NBI, allows prediction of the histological condition, more in detail without biopsy, and it may also be useful for less invasive, and cost-effective endoscopic gastric cancer surveillance, and prediction of H. pylori eradication.

Background: Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human cancers. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of gastric cancer (GC) and peptic ulcer diseases, and with the severity of Helicobacter pylori-induced gastritis in Japanese population. Methods: The rs11614913 (C>T), rs2910164 (G>C), and rs3746444 (A>G) SNPs were genotyped in 552 GC, and 697 non-cancer subjects, including 141 gastric and 73 duodenal ulcer, and 483 non-ulcer subjects. The degree of histologic gastritis was classified according to the updated Sydney System, and the serum pepsinogen levels were measured in selected 579 and 204 cases. Results: The rs2910164 CC genotype held a significantly higher risk of GC when compared to non-cancer subjects (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.02–1.66, p =.03). Similarly, the rs2910164 C carrier was associated with higher risk of GC when compared to both non-cancer and non-ulcer subjects (OR = 1.39, 95%CI = 1.00–1.93, p =.05, adjusted OR = 1.57, 95%CI = 1.09–2.27, p =.016, respectively). The rs2910164 CC genotype was associated with non-cardia and upper third, diffuse type and advanced stage GC. The rs11614913 TT genotype was associated with higher degree of mononuclear cell infiltration (score 0–1 vs 2∼, adjusted OR = 1.62, 95%CI = 1.05–2.49, p =.03). Conclusions: The rs2910164 (G>C) SNP in the miR-146a is associated with susceptibility to GC. In addition, the rs11614913 (C>T) SNP in the miR-196a2 is associated with the degree of H. pylori-induced mononuclear cell infiltration.

Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human diseases. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of ulcerative colitis (UC) in a Japanese population. The rs11614913 (T > C), rs2910164 (C > G), and rs3746444 (A > G) SNPs were genotyped in 170 UC and 403 control subjects. The rs3746444 AG genotype was significantly higher among the UC group (odds ratio (OR) = 1.51, 95% CI = 1.03–2.21, p = 0.037). The rs3746444 AG genotype was associated with onset at an older age (OR = 1.70, 95% CI = 1.04–2.78, p = 0.035), left-sided colitis and pancolitis (left-sided colitis, OR = 2.10, 95% CI = 1.12–3.94, p = 0.024; pancolitis, OR = 1.81, 95% CI = 1.09–3.01, p = 0.028, left-sided colitis + pancolitis, OR = 1.91, 95% CI = 1.26–2.92, p = 0.003), higher number of times hospitalized (OR = 2.63, 95% CI = 1.22–5.69, p = 0.017), steroid dependence (OR = 2.63, 95% CI = 1.27–5.44, p = 0.014), and refractory phenotypes (OR = 2.76, 95% CI = 1.46–5.21, p = 0.002) while the rs3746444 AA genotype was inversely associated with the number of times hospitalized (2∼, OR = 0.36, 95% CI = 0.17–0.79, p = 0.012), steroid dependence (OR = 0.42, 95% CI = 0.21–0.88, p = 0.021), and refractory phenotypes (OR = 0.38, 95% CI = 0.20–0.72, p = 0.003). The rs1161913 TT genotype also held a significantly higher risk of refractory phenotype (T/T vs. T/C + C/C, OR = 2.21, 95% CI = 1.17–4.18, p = 0.016). Our results provided the first evidence that rs3746444 SNP may influence the susceptibility to UC, and both rs3746444 and rs11614913 SNPs may influence the pathophysiological features of UC.

Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) have been shown to be associated with susceptibility to several types of human cancer. We evaluated the association between three SNPs (rs11614913, rs2910164 and rs3746444) in pre-miRNAs (miR-196a2, miR-146a and miR-499) and various clinicopathological characteristics, including CpG island hypermethylation (CIHM) status and overall survival in gastric cancer (GC) patients. rs11614913 (T>C), rs2910164 (C>G) and rs3746444 (A>G) SNPs were genotyped in 127 GC patients. CIHM of p14, p16, DAP-kinase and CDH1 genes was determined by methylation-specific polymerase chain reaction in the cancer tissues. A significant marginal association was found between the rs11614913 CC genotype and polypoid or elevated type morphology in early-stage GC (OR=6.29, 95% CI 1.18–33.47, p=0.03). The rs2910164 CC and CG genotypes were associated with increased susceptibility to CIHM of DAP-kinase (CC+CG, OR=5.48, 95% CI 1.30–23.10, p=0.02; CC, OR=6.93, 95% CI 1.37–35.02, p=0.02; CG, OR=4.24, 95% CI 0.87–20.78, p=0.07). The 11614913 TT and TC genotypes were associated with a higher number of CIHM (no. of CIHM 0–1 vs. 2–4; TT+TC, OR=3.67, 95% CI 0.98–13.72, p=0.05; TC, OR=4.08, 95% CI 1.04–15.97, p=0.04). When the subjects were divided according to age group, the combined rs11614913 TT+TC genotype tended to be associated with worse overall survival than the CC genotype in patients younger than 65 years of age (p=0.05). The combined rs2910164 CG+GG genotype also tended to be associated with worse overall survival than the CC genotype in the same age group (p=0.09). It appears that rs11614913 and rs2910164 SNPs in pre-miRNAs (miR-196a2 and miR-146a) affect the clinicopathological characteristics of GC, including its morphological appearance, CIHM status and overall survival.

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.Altogether 280 patients including 170 men with a mean age of 58.6 years were included in the study to determine the relationship between their liking for specific tastes and GERD using a new self-administered questionnaire (responses to various tastes and participants' sensitivity to taste and hot food and on the frequency of stomatitis). Another self-administrated questionnaire was administrated for a diagnosis of GERD (the frequency scale for the symptoms of GERD cut-off score of 10). Furthermore, 142 of 280 patients who had received esophagogastroduodenoscopy (EGD) were investigated on the association between endoscopic esophagitis and their favorite tastes.In the association analyses between responses to specific tastes and GERD, the group liking salty food and the group with a high frequency of stomatitis had a significantly higher incidence of GERD (salty food: odds ratio [OR] 2.059, 95% confidence interval [CI] 1.215-3.488, P = 0.0073; stomatitis: OR 2.861, 95% CI 1.558-5.253, P = 0.0007, respectively). In association analyses with endoscopic esophagitis, the groups liking salty and sour food had a significantly higher incidence rate of endoscopic esophagitis (salty: OR 2.718, 95% CI 1.330-5.555, P = 0.0061; sour: OR 3.267, 95% CI 1.491-7.160, P = 0.0031, respectively).Sensitivity and response to specific food taste were associated with GERD. The results of a preference to hot or salty food and endoscopic esophagitis suggest that physical stimuli are important for esophageal injuries.

Residual DNA methylation in the gastric mucosa after Helicobacter pylori (H. pylori) eradication may have a role in gastric carcinogenesis. We examined the association between morphologic features and promoter methylation status of non‐neoplastic gastric mucosa especially after H. pylori eradication. A total of 140 gastric specimens from 99 participants who had at least 6 months of post‐eradication period were examined. The magnifying narrow‐band imaging (NBI) endoscopic feature of gastric mucosa was divided into two types: restored‐small, round pits, accompanied with honeycomb‐like subepithelial capillary networks; atrophic‐well‐demarcated oval or tubulovillous pits with clearly visible coiled or wavy vessels. Methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA, and PRDM5) were examined by bisulfite pyrosequencing. The atrophic type, informative endoscopic features of intestinal metaplasia, demonstrated higher methylation levels in all five genes compared to the restored type (all P 0.1). Multivariate analysis demonstrated that atrophic type or presence of intestinal held an independent factor for hyper methylation (odds ratio: 24.69, 95% confidence interval: 6.95–87.76, P

Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. We measured average telomere length using quantitative real-time PCR in non-neoplastic gastric mucosa and assessed its relationship to H. pylori-related gastritis, DNA methylation, ulcer disease, and nonsteroidal anti-inflammatory drug (NSAID) usage. Gastric biopsies were obtained from 151 cancer-free subjects including 49 chronic NSAID users and 102 nonusers. Relative telomere length in genomic DNA was measured by real-time PCR. H. pylori infection status, histological severity of gastritis, and serum pepsinogens (PGs) were also investigated. E-cadherin (CDH1) methylation status was determined by methylation-specific PCR (MSP). Average relative telomere length of H. pylori-infected subjects was significantly shortened when compared to H. pylori-negative subjects (p = 0.002) and was closely associated with all histological parameter of gastritis (all p values

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.The rs11614913 (TC), rs2910164 (CT), and rs3746444 (AG) 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).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 (AG) SNP was significantly associated with OS by the log-rank test (p=0.018), while other SNPs were not associated with OS. The rs3746444 (AG) SNP was also associated with OS and PFS among cases of neoadjuvant chemotherapy (p=0.038, 0.024, respectively). Multivariate survival analysis using the Cox's 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).The rs3746444 A allele carrier in the hsa-mir-499 is associated with better prognosis in advanced GC performing chemotherapy.

A complex interaction of genetic and environmental factors is closely associated with the development of inflammatory bowel disease. Previous studies reported that the expression of the regulated upon activation, normal T-cell expressed and secreted (RANTES) gene is enhanced in the colonic mucosa of ulcerative colitis (UC). Quantitative differences in RANTES gene expression among numerous promoter genotypes have also been reported. The aim of the present study was to clarify the effect of RANTES promoter polymorphism on the risk of UC, including its clinical phenotypes. A total of 150 UC patients and 372 healthy control (HC) subjects participated in the study. The UC patients were classified by disease behavior, severity and extent of disease. Restriction fragment length polymorphism analysis was performed for polymorphisms at -28 C/G in the RANTES gene promoter region. Although no significant difference of the RANTES promoter genotype distribution was observed between the HC and UC groups, the G/G genotype was significantly higher among female (OR=3.95, 95% CI=1.22-12.82, P=0.03), non-steroid dependent (OR=3.37, 95% CI=1.16-9.85, P=0.03) and non-refractory (OR=3.76, 95% CI=1.29-10.98, P=0.02) UC patients. The G carrier was also found to be associated with an increased risk of rectal colitis (OR=2.21, 95% CI=1.12-4.39, P=0.03). The data indicate that the polymorphism of the RANTES promoter is not directly associated with the susceptibility to UC, but the -28 G allele is associated with female UC patients and mild clinical phenotypes of UC, including non-steroid dependency, non-refractory and rectal colitis.

Interleukin (IL)‑1β, and tumor necrosis factor (TNF)‑α have significant roles in the mediation of inflammatory immune responses and are also potent inhibitors of gastric acid secretion in the stomach. The present study aimed to investigate the associations between polymorphisms at position ‑31 (T>C) of the IL‑1β gene and ‑857 (C>T) of the TNF‑α gene with dyspeptic symptoms. Polymorphisms at position ‑31 (T>C) of the IL‑1β gene and ‑857 (C>T) of the TNF‑α gene were genotyped in 261 subjects, including 126 subjects without symptoms and 135 subjects exhibiting symptoms of dyspepsia. The IL‑1β ‑31 CC genotype was inversely associated with dyspeptic symptoms in all subjects, as determined by the Fisher's exact test [odds ratio (OR), 0.57; 95% confidence interval (CI), 0.34‑0.96; P=0.046]; however, this association was not detected following logistic regression analysis. Within the subgroups of symptoms, the CC genotype was also inversely associated with upper abdominal pain (OR, 0.28; 95% CI, 0.12‑0.67; P=0.003) and epigastric pain syndrome (EPS)‑like symptoms (OR, 0.14; 95% CI, 0.07‑0.28; P=0.003), according to the Rome III classifications. These associations were also found following logistic regression analysis (upper abdominal pain: OR, 0.34; 95% CI, 0.14‑0.80; P=0.014; and EPS‑like symptoms: OR, 0.41; 95% CI, 0.20‑0.84; P=0.015). No significant associations were identified between the TNF‑α ‑857 polymorphism and dyspeptic symptoms, including amongst the various subtypes analyzed. In conclusion, the IL‑1β ‑31 CC genotype was inversely associated with susceptibility to dyspeptic symptoms, in particular, upper abdominal pain and EPS‑like symptoms.

BACKGROUND: The neurochemical serotonin (5-HT) is an important signaling molecule in the gastrointestinal motor and sensory functions. A key regulator of 5-HT levels is the transmembrane serotonin transporter (5-HTT; SLC6A4) that governs the reuptake of 5-HT. Recent studies have indicated 5-HTT expression may be regulated by epigenetic mechanisms. We investigated DNA methylation status of SLC6A4 gene in the gastric mucosa from functional dyspepsia (FD) because of their potential role in dyspeptic symptoms. METHODS: Endoscopic gastric biopsies were obtained from 78 subjects with no upper abdominal symptoms and 79 patients with FD. Bisulfite Pyrosequencing was carried out to determine the methylation status of promoter CpG islands (PCGIs), promoter non-CpG islands (PNCGIs) and gene body non-CpG islands (NPNCGIs) in the SLC6A4 gene. Gene expression was examined by real-time PCR. RESULTS: In overall, methylation level of PCGIs was significantly lower in FD compared to control subjects (p = 0.04). On the other hand, methylation level of NPNCGIs was significantly higher in FD compared to control subjects (p = 0.03). Lower methylation level in PNCGIs was highlighted in the patients with PDS (p = 0.01), while higher methylation level in NPNCGIs was more prominent in the patients with EPS (p = 0.017). Methylation levels of PCGIs and PNCGIs were inversely correlated, while methylation levels of NPNCGIs was positively correlated with SLC6A4 mRNA levels in FD patients. CONCLUSIONS: Our data suggest that change in DNA methylation pattern of SLC6A4 in the gastric mucosa may have a role for developing FD. A role of epigenetics for developing FD needs to be further evaluated.

The patient was a 35-year-old man who felt persistent hunger pain for five months. Upper gastrointestinal scope studies revealed a 20-mm polypoid lesion located in the middle body of the stomach. The pathological diagnosis revealed a granuloma in the biopsy specimens. The eradication of Helicobacter pylori had no effect on the patient's abdominal symptoms. Ultimately, the polypoid lesion was resected using endoscopy, and the patient was relieved of his hunger pain. The final diagnosis was a pyogenic granuloma in the stomach. This study is the first report of a pyogenic granuloma in the stomach in which the patient's abdominal pain disappeared after tumor resection performed via endoscopy.

Fusobacterium species are part of the gut microbiome in humans, but some species have been recognized as opportunistic pathogens implicated in inflammatory diseases including inflammatory bowel diseases. Here, we performed prevalence screening of Fusobacterium in ulcerative colitis (UC) in Japanese patients. We examined Fusobacterium nucleatum (F. nucleatum) and whole Fusobacterium species (Pan-fusobacterium) by quantitative real-time PCR in 163 inflamed mucosae from 152 UC patients. Data were correlated with clinical subtypes of UC. In an initial prevalence screen, F. nucleatum and Pan-fusobacterium were detected in 6.3 % (4/64) and 53.1 % (34/64). For all 163 mucosae, the prevalence of Pan-fusobacterium was 54.6 % (89/163). Pan-fusobacterium status was concordant in inflamed and normal adjacent samples, and the matched cases during 1-year follow-up colonoscopy. The higher amount of Pan-fusobacterium was observed in chronic continuous type compared to one attack and relapse/remitting type (p = 0.039). The higher amount of Pan-fusobacterium was also associated with rather mild clinical course of disease, such as non-steroid dependency (p = 0.015), non-refractory phenotype (p = 0.013), and non-severe phenotype (p = 0.04). Based on the distribution of Pan-fusobacterium measurable cases, we identified 10 cases as having a high amount of Pan-fusobacterium (FB-high). The clinicopathological features of FB-high UC cases were also highlighted by chronic continuous type and mild phenotypes of disease. Whole Fusobacterium species, but not F. nucleatum, are common in UC patients and have a role in persistence of colonic inflammation in UC. However, Fusobacterium infection is associated with rather mild clinical phenotypes of UC.

We investigated the effect of IL-1β and TNF-α polymorphisms, and its synergistic effect with age, gender and H. pylori status on the gastric pre-malignant condition.IL-1β-31(TC) and -511(CT) and TNF-α-857 (CT) polymorphisms were genotyped in 123 cancer free subjects. Degree of histological gastritis in both antrum and corpus, and extension of endoscopic gastric atrophy were also evaluated.Significant associations were found between degrees of mononuclear cell infiltration (p=0.007) and atrophy (p=0.01) in the antrum with IL-1β-31(TC) polymorphism, and degree of endoscopic gastric atrophy with both IL-1β-31(TC), -511(CT) polymorphisms (p=0.03, 0.04, respectively). When subjects were divided into the 3 groups according to the histological severity of gastric mucosal atrophy: the non-atrophic gastritis (NA) group (atrophy score=0 and metaplasia score=0), the severe atrophic gastritis (SA) group (atrophy score=2 or metaplasia score=2), and the mild atrophic gastritis (MA) group (all others), synergistic effect was found between numbers of IL-1β-31C, IL-1β-511T variant alleles with co-factors on the development of gastric atrophy in the antrum (gender + H. pylori + number of IL-1β-31C allele: p=0.001, age + gender + H. pylori + number of IL-1β-31C allele: p=0.0008, gender + H. pylori + number of IL-1β-511T allele: p=0.016, age + gender + H. pylori + number of IL-1β-511T allele: p=0.013), while such association was found for TNF-α-857 T allele in the antrum and all genotypes in the corpus.IL-1β-31C, IL-1β-511T variant alleles may accelerate gastric mucosal inflammation and atrophy, not only by themselves, but also through the interaction with co-factors.

Background Several study showed usefulness of microscopic capillaries, seen by magnifying narrow band imaging (NBI) endoscopy for predicting histopathology among superficial depressed or flat elevated gastric neoplasia (GN). Here we assessed the diagnostic efficacy of magnifying NBI for predicting histopathology among gastric protruding/or polypoid lesions. Methods Using endoscopic pictures of magnifying NBI from 95 protruding/or polypoid lesions (19 fundic gland polyps: FGP, 47 hyperplastic polyps: HP, and 29 GN), fine mucosal patterns were classified into four categories: small round, prolonged, villous or ridge, and unclear patterns, and micro vascular patterns were classified into five categories: honey comb, dense vascular, fine net work, core vascular, and unclear patterns. Results Most suggestive micro vascular patterns for predicting FGP, and HP were honeycomb (sensitivity 94.7%, specificity 97.4%), and dense vascular patterns (sensitivity 93.6%, specificity 91.6%), respectively. Fine net work, core vascular, and unclear patterns presented higher specificity (97%, 100%, and 100%) for predicting GN, and diagnostic efficacy of combined of those patterns was favorable (sensitivity 86.2%, specificity 97.0%). Conclusion Micro vascular patterns by using magnifying NBI provides meaningful information for predicting the histopathology of gastric protruding/or polypoid lesions.

Genetic factors related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to Helicobacter pylori (H. pylori)-related gastric carcinogenesis. The association between XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms with gastric intestinal metaplasia, severity of histological gastritis, and peptic ulcer diseases were evaluated in a Japanese population.XRCC1 Arg399Gln and Arg194Trp, GSTP1 Ile104Val and GSTT1, GSTM1 null polymorphisms were genotyped in 280 cancer-free individuals, including 52 gastric and 31 duodenal ulcer patients.Among the five polymorphisms, a significant association between the GSTT1 and GSTM1 null genotypes and increased risk of intestinal metaplasia was found (GSTT1 null: OR=2.42, 95% CI=1.28-4.60, p=0.007, GSTM1 null: OR=2.18, 95% CI=1.15-4.13, p=0.019). When the severity of gastric atrophy was classified into the following three groups: non-atrophy (NA) (atrophy score=0 and metaplasia score=0); severe atrophy (SA) (atrophy score≥2 or metaplasia score≥2) and mild atrophy (MA) (all others), both the GSTT1 and GSTM1 null genotypes held significantly higher risk for developing more severe gastric atrophy (GSTT1 null, SA vs. others: OR=1.95, 95% CI=1.07-3.52, p=0.028, GSTM1 null, NA vs. others: OR=2.57, 95% CI=1.16-5.67, p=0.019, SA vs. others: OR=1.90, 95% CI=1.06-3.42, p=0.032). A significant association was also found between GSTM1 null genotype and increased risk of ulcer diseases (all ulcers: OR=2.42, 95% CI=1.37-4.26, p=0.002, gastric ulcer: OR=2.18, 95% CI=1.11-4.29, p=0.025, duodenal ulcer: OR=2.62, 95% CI=1.15-6.00, p=0.023).Both the GSTT1 and GSTM1 null genotypes are associated with gastric pre-malignant conditions.

CpG island hypermethylation (CIHM) in gene promoter is frequently observed in the colonic mucosa in ulcerative colitis (UC), and is strongly involved in UC-associated colorectal carcinogenesis (CRC). The influence of common single nucleotide polymorphisms (SNPs) related to inflammatory immune response on the individual susceptibility to CIHM status in the non-neoplastic rectal mucosa in UC patients was evaluated.Ten candidate SNPs, multidrug resistance 1 (MDR1) 3435 (CT), regulated upon activation, normal T-cell expressed and secreted (RANTES)-28 (CG), heat-shock protein (HSP)70-2 1267 (BA), NADPH oxidase p22PHOX 242 (CT), Toll-like receptor (TLR)2-196 to -174 (insdel), CD14-159 (CT), Mannan-binding lectin (MBL)2 codon 54 (GA), tumor necrosis factor-α(TNF-α) -857 (CT), interleukin-1β(IL-1β)-511 (CT), and IL-1β -31 (TC) were genotyped in 58 UC patients without neoplastic lesions, in relation to CIHM in the rectal mucosa of three candidate CpG (p14, p16 and E-cadherin: CDH1) loci, assessed by methylation-specific-polymerase chain reaction (MSP). High CIHM was defined as two or more CpG islands methylated.The CD14-159TT genotype held a significantly higher susceptibility to CIHM of the p16 promoter (OR=3.82, 95%CI=1.06-13.79, p=0.04) A significant association was also found between the IL-1β-31TC genotype and reduced susceptibility to high CIHM (OR=0.14, 95%CI=0.22-0.94, p=0.04). The p22PHOX 242CT genotype and MBL2 codon 54 A carrier (GA+AA) were significantly associated with a lower mean number of CIHM (p=0.029, 0.046, respectively).CD14 -159, IL-1β-31, p22PHOX 242 and MBL2 codon 54 SNPs may influence the CIHM status in the rectal mucosa of UC patients and may therefore be substantially involved in UC-associated carcinogenesis.

Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non-neoplastic gastric mucosa.XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP-kinase and CDH1) loci, assessed by Methylation-Specific-Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated. Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.30, 95%CI = 0.13-0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19-0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (50 and50), an association was found between GSTM1 null genotype and increased susceptibility to CIHM high in the 50 years and older generations (OR = 1.63, 95%CI = 1.01-2.62, p = .045).XRCC1 codon 399 Gln/Gln genotype is associated with reduced susceptibility to CIHM especially DAP-kinase. GSTM1 null genotype may increase the susceptibility to CIHM especially in older patients. Genetic factors, related to DNA repair or xenobiotic pathways may have a role in CIHM-related gastric carcinogenesis.