Risk Analysis of Breast Cancer by Using Bilateral Mammographic Density Differences: A Case-Control Study.

The identification of risk factors helps radiologists assess the risk of breast cancer. Quantitative factors such as age and mammographic density are established risk factors for breast cancer. Asymmetric breast findings are frequently encountered during diagnostic mammography. The asymmetric area may indicate a developing mass in the early stage, causing a difference in mammographic density between the left and right sides. Therefore, this paper aims to propose a quantitative parameter named bilateral mammographic density difference (BMDD) for the quantification of breast asymmetry and to verify BMDD as a risk factor for breast cancer. To quantitatively evaluate breast asymmetry, we developed a semi-automatic method to estimate mammographic densities and calculate BMDD as the absolute difference between the left and right mammographic densities. And then, a retrospective case-control study, covering the period from July 2006 to October 2014, was conducted to analyse breast cancer risk in association with BMDD. The study included 364 women diagnosed with breast cancer and 364 matched control patients. As a result, a significant difference in BMDD was found between cases and controls (P < 0.001) and the case-control study demonstrated that women with BMDD > 10% had a 2.4-fold higher risk of breast cancer (odds ratio, 2.4; 95% confidence interval, 1.3-4.5) than women with BMDD ≤ 10%. In addition, we also demonstrated the positive association between BMDD and breast cancer risk among the subgroups with different ages and the Breast Imaging Reporting and Data System (BI-RADS) mammographic density categories. This study demonstrated that BMDD could be a potential risk factor for breast cancer.

Endoscopic screening for gastric cancer in Japan: Current status and future perspectives.

The revised 2014 Japanese Guidelines for Gastric Cancer Screening approved gastric endoscopy for use in population-based screening. Thus, it is expected that gastric cancer will be detected earlier, and gastric cancer mortality further decreased, with the widespread use of endoscopy and Helicobacter pylori eradication therapy. However, due to an increasingly aging population and relatively low gastric cancer screening rates, gastric cancer remains the leading cause of cancer death in Japan. While the era of endoscopic gastric cancer screening has begun, it does present challenges, such as limited/varying regional availability of endoscopists. This review describes the history of gastric cancer screening in Japan, achievements in endoscopic gastric cancer screening in Japan and Korea, efforts underway to improve screening by stratifying individuals according to gastric cancer risk, and initiatives by the Japan Gastroenterological Endoscopy Society aimed at improving screening, including the implementation of a board certification program for screening endoscopists.

Long-term endoscopic surveillance for Barrett's esophagus in Japan: Multicenter prospective cohort study.

OBJECTS: Although a recent study showed the cancer incidence of Barrett's esophagus (BE) to be 1.2%/year in 251 patient-years in Japan, the long-term outcomes remain unclear. The present study estimated the cancer risk of BE in Japan using our original prospective multicenter cohort. METHODS: A total of 98 patients with BE of maximum length of ≥2 cm were enrolled during the period of 2010-2012 and received at least one follow-up endoscopy over 5 years thereafter. Cancer incidence rates with 95% confidence interval for occurrence of esophageal adenocarcinoma (EAC) were calculated as the number of events divided by patient-years of follow-up and were expressed as %/year. RESULTS: Overall, the median endoscopic follow-up period was 59.9 (first and third quartiles, 48.5-60.8) months, constituting a total of 427 patient-years of observation. Since two EAC cases developed, the cancer incidence was 0.47% (0.01%-1.81%)/year. The cancer incidence was 0.39% (-0.16% to 2.44%) in 232 patient-years and 0.31% (-0.13% to 1.95%)/year in 318 patient-years for 55 cases with specialized intestinal metaplasia and 70 with BE ≥3 cm (maximum), respectively. At the end of follow-up, 12 of 92 patients (13.0%) died, but none died from EAC. CONCLUSION: This is the largest prospective follow-up study with endoscopy to investigate the incidence of EAC in unequivocal BE with the maximum length of ≥2 cm in Japan. Although a further large-scale study will be required to validate our results, the cancer risk of BE in Japan would be lower than previously reported (0.47% vs 1.2%/year).

Characteristics of gastric cancer in negative test of serum anti-Helicobacter pylori antibody and pepsinogen test: a multicenter study.

BACKGROUND AND AIM: The serological risk prediction system combines the pepsinogen test and anti-Helicobacter pylori (H. pylori) antibody determination. In this system, chronic atrophic gastritis (CAG) is diagnosed using the pepsinogen test. Patients who are H. pylori negative and pepsinogen negative are classified into group A, are assumed to be H. pylori uninfected, and are at an extremely low risk for gastric cancer. However, gastric cancers are detected in this group. The aim of this study is to clarify the clinicopathological status of group A patients with gastric cancer. METHODS: A total of 109 gastric cancer patients classified as group A were enrolled in a multicenter study. Group A patients were divided into two subgroups: group AN (H. pylori uninfected) and group AP (H. pylori infected). They were compared to 183 H. pylori-infected gastric cancer patients who were not in group A. RESULTS: Of the 109 patients, only 7 were classified as group AN; the other 102 were classified as group AP. The clinicopathological features of group AP included older age, predominantly differentiated type cancer, endoscopically visualized CAG, and pepsinogen (PG) I/II ratio lower than that of group AN. In group AN, the depressed type was dominant, and the PG I/II ratio was higher than in those gastric cancer patients who were infected with H. pylori. CONCLUSION: Patients in group AP had CAG, and their gastric cancers were similar to those of H. pylori-eradicated patients. Concerning the recent ABC classification system, advanced decision criteria should be proposed to decrease the false-negative evaluation of gastric cancer risk.

Clinicopathological features of gastric adenocarcinoma of the fundic gland (chief cell predominant type) by retrospective and prospective analyses of endoscopic findings.

BACKGROUND AND AIM: Gastric adenocarcinoma of the fundic gland type (chief cell predominant type) (GA-FG-CCP) is a variant of gastric adenocarcinoma with chief cell differentiation. GA-FG-CCP is rare and not well understood. The present study aimed to investigate the clinicopathological features of GA-FG-CCP using retrospective and prospective analyses of endoscopic findings. METHODS: A total of 20 patients including nine cases treated with endoscopic submucosal dissection (ESD) were diagnosed with GA-FG-CCP. Morphological changes were analyzed by retrospectively retracing past endoscopic records and following up after definitive diagnoses, including the status of Helicobacter pylori (H. pylori) infection. RESULTS: GA-FG-CCP were small and whitish lesions accompanied by atypical vascular growth and their macroscopic types were classified as 0-IIa (60%), 0-IIb (25%), and 0-IIc (15%), respectively. The lesions were found in the non-atrophic gastric mucosa of the upper (70%) or middle portion (30%), although gastric mucosal atrophy associated with current or past H. pylori infection was identified in 75% of cases. In the nine cases treated with ESD, submucosal invasion was identified in 80% of the resected lesions, but no lymphovenous infiltration was detected. Ki-67 labeling index of GA-FG-CCP was low at 3.2% and visible morphological changes were rarely detected during long-term endoscopic observation for 58.9 ± 13.1 months. CONCLUSIONS: These data indicate that GA-FG-CCP, even when submucosal invasion occurs easily, might be of low-grade malignancy as long as it is the chief cell predominant type without other epithelial abnormalities. In addition, GA-FG-CCP might develop despite H. pylori infection or gastric mucosal atrophy.

Association between the body mass index and the risk of Barrett's esophagus in Japan.

BACKGROUND: We investigated the association between long-segment Barrett's esophagus and obesity in the Japanese population in a multicenter case-control trial. METHODS: One hundred thirteen patients with endoscopically detected Barrett's esophagus with a length of more than 2 cm and the same number of sex- and age-matched controls were prospectively enrolled. Barrett's esophagus was diagnosed based on the Prague C and M criteria. The body mass index (BMI) of the subjects was categorized into the following groups: normal, BMI <22.9; overweight, BMI 23.0-24.9, and obese, BMI >25.0. To determine the association between BMI and the risk of Barrett's esophagus, multivariate logistic regression analyses were performed. RESULTS: The basically adjusted regression model adjusted for smoking and alcohol consumption revealed that overweight and obesity were significantly associated with an elevated risk of Barrett's esophagus (OR 2.4, 95% CI 1.2-4.7, and OR 2.5, 95% CI 1.3-4.6, respectively). The intensity of the association was not attenuated even after adjustment for gastroesophageal reflux disease-related parameters. CONCLUSIONS: An increased BMI was associated with an increased risk for Barrett's esophagus through a gastroesophageal reflux-independent mechanism in the Japanese population. Further, unlike in Caucasian populations, being even slightly overweight with a BMI of 23.0-24.9 was an independent risk factor in the Japanese population.

Localized esophageal eosinophilia: Is it an early manifestation of eosinophilic esophagitis or a subtype of gastroesophageal reflux disease?

BACKGROUND AND AIM: We recently encountered patients with localized esophageal eosinophilia in a small area of the esophagus. However, this condition remains to be described in detail, and its clinical significance has not been established. We investigated the clinical, endoscopic and histological features of localized esophageal eosinophilia in comparison with diffuse esophageal eosinophilia. METHODS: We investigated 10 patients with localized esophageal eosinophilia, and compared them with 23 who had diffuse esophageal eosinophilia. Whether esophageal eosinophilia was localized or diffuse was determined on the basis of endoscopic findings. Localized esophageal eosinophilia was defined endoscopically as a focal area of esophageal eosinophilia, whereas diffuse esophageal eosinophilia was defined as a widespread area of esophageal eosinophilia involving more than one of three locations: the upper, middle and lower esophagus. Histological esophageal eosinophilia in the mucosa showing endoscopic abnormality was confirmed by biopsy with a peak of ≥ 15 eosinophils/high-power field. RESULTS: There were no significant differences in age, gender distribution, allergic conditions or peripheral eosinophilia between the two groups. In all cases but one, localized esophageal eosinophilia was observed in a small area above the esophagogastric junction. Esophageal symptoms such as dysphagia, heartburn or chest pain were present in 20% of the localized group and in 65% of the diffuse group, the difference being statistically significant (P<0.05). The maximum amounts of eosinophils infiltrating the esophageal mucosa did not differ between the groups. CONCLUSIONS: Esophageal eosinophilia can be localized in a small area, especially above the esophagogastric junction. Gastric acid reflux or contact may influence this condition in addition to its allergic pathogenesis.

Genetic Polymorphism in Alcohol Metabolism and Drinking Behavior are Associated with Gastric Cancer Risk in Men.

Objective In recent years, there has been a growing focus on health risks associated with alcohol consumption. The present study investigated whether or not the genetic variant of aldehyde dehydrogenase 2 (ALDH2) influences the risk of gastric cancer among individuals identified as hazardous drinkers using the Alcohol Use Disorders Identification Test (AUDIT), which provides a comprehensive assessment of hazardous drinking behavior. Patients We enrolled men with hazardous drinking behavior (AUDIT score ≥ 8) who had undergone gastric cancer screening (either endoscopy or a barium X-ray examination of the upper gastrointestinal tract) between April 2013 and March 2020 within 1 year from entry and who had subsequently undergone at least one more gastric cancer screening up to March 2021. Functional single-nucleotide polymorphisms of ALDH2 (rs671) were measured using a direct TaqMan PCR method with unprocessed saliva. Results A total of 246 men were enrolled, comprising 193 individuals with active ALDH2 (ALDH2*1/*1) and 53 with less-active ALDH2 (ALDH2*1/*2). The cumulative incidence of gastric cancer in the less-active group was higher than in the active ALDH2 group (p=0.01, hazard ratio: 4.6, 95% confidence interval: 1.2-16.7). Alcohol consumption was lower in the less-active ALDH2 group than in the active ALDH2 group, although no marked difference was observed in the AUDIT score. Conclusion In individuals with hazardous drinking behavior, a heightened risk of gastric cancer was observed among those with less-active ALDH2 variants, even when their alcohol consumption was comparatively lower than in those with active ALDH2 variants.

Novel Algorithm for the Estimation of Cancer Incidence Using Claims Data in Japan: A Feasibility Study.

PURPOSE: We developed algorithms to identify patients with newly diagnosed cancer from a Japanese claims database to identify the patients with newly diagnosed cancer of the sample population, which were compared with the nationwide cancer incidence in Japan to assess the validity of the novel algorithms. METHODS: We developed two algorithms to identify patients with stomach, lung, colorectal, breast, and cervical cancers: diagnosis only (algorithm 1), and combining diagnosis, treatments, and medicines (algorithm 2). Patients with newly diagnosed cancer were identified from an anonymized commercial claims database (JMDC Claims Database) in 2017 with two inclusions/exclusion criteria: selecting all patients with cancer (extract 1) and excluding patients who had received cancer treatments in 2015 or 2016 (extract 2). We estimated the cancer incidence of the five cancer sites and compared it with the Japan National Cancer Registry incidence (calculated standardized incidence ratio with 95% CIs). RESULTS: The number of patients with newly diagnosed cancer ranged from 219 to 17,840 by the sites, algorithms, and exclusion criteria. Standardized incidence ratios were significantly higher in the JMDC Claims Database than in the national registry data for extract 1 and algorithm 1, extract 1 and algorithm 2, and extract 2 and algorithm 1. In extract 2 and algorithm 2, colorectal cancer in male and stomach, lung, and cervical cancers in females showed similar cancer incidence in the JMDC and national registry data. CONCLUSION: The novel algorithms are effective for extracting information about patients with cancer from claims data by using the combined information on diagnosis, procedures, and medicines (algorithm 2), with 2-year cancer-treatment history as an exclusion criterion (extract 2).

The balance between 4-hydroxynonenal and intrinsic glutathione/glutathione S-transferase A4 system may be critical for the epidermal growth factor receptor phosphorylation of human esophageal squamous cell carcinomas.

Oxidative stress might participate in the carcinogenesis of human esophageal squamous cell carcinomas (hESCC). 4-Hydroxynonenal (HNE) is a major product of membrane lipid peroxidation with short life. It might act as an important mediator through the generation of adducts and activate epidermal growth factor receptor (EGFR) signaling. It is mainly trapped with glutathione (GSH) and catalyzed by glutathione S-transferases (GSTs). This study aimed to elucidate the possible participation of HNE, GSH/GST system, and EGFR signaling in hESCC development. Immunohistochemistry of HNE adducts, EGFR, and phosphorylated EGFR (pEGFR) was performed with hESCC specimens. The effect of HNE on the phosphorylation of EGFR and its downstream PhospholipaseCγ1 (PLCγ1) was investigated with KYSE30 cell-line. Pretreatment with GSH inducer N-acetylcysteine (NAC) or GSH inhibitor Buthionine sulfoximine (BSO) and mandatory transfection of hGSTA4 gene in KYSE30 were conducted to investigate the relationship between HNE and GSH/GST system. Immunoreactants of HNE adducts, EGFR, and pEGFR were increased in hESCC compared to non-cancerous epithelium with positive correlations. The treatment of HNE ligand-independently induced the phosphorylation of EGFR and PLCγ1 accompanying the diminishment of intracellular GSH level. NAC increased GSH contents but BSO decreased in dose-dependent manners. Reflecting changes in GSH, HNE-induced EGFR phosphorylation was suppressed by NAC, whereas it was promoted by BSO. Mandatory expression of hGSTA4 suppressed HNE-induced events. We first demonstrated that the ligand-independent activation of EGFR by the balance between the stimulation of HNE and the prevention of intrinsic GSH/GST system might participate in the development of hESCC.

Topographic differences in gastric micromucosal patterns observed by magnifying endoscopy with narrow band imaging.

BACKGROUND AND AIM: The distributions and grades of Helicobacter pylori induced gastritis are known to vary among H. pylori-associated diseases. The aim of this study was to investigate the differences in distributions of gastric micromucosal structures observed by magnifying narrow band imaging (NBI) endoscopy among patients with different H. pylori-associated diseases. METHODS: Ninety-five patients with active duodenal ulcers (n = 24) and diffuse-type (n = 24) and intestinal-type (n = 47) early gastric cancers were enrolled. The magnified NBI findings were evaluated at the lesser and greater curvatures in the upper gastric corpus and were classified according to the modified A-B classification system. Biopsy specimens were also evaluated. RESULTS: In a total of 190 areas observed with magnifying NBI, histological grading (inflammation, activity, atrophy and intestinal metaplasia) showed significant differences among the classified micromucosal patterns (P < 0.001). Types B-1 and B-2, with mild atrophic changes and few areas of intestinal metaplasia, were seen mostly in the duodenal ulcers group. Types B-3 and A-1, with moderate atrophic changes, were seen in the diffuse-type early gastric cancers at the lesser curvature. Types A-1 and A-2, with severe atrophic change and a high frequency of intestinal metaplasia, were seen in the intestinal-type early gastric cancers at the lesser curvature. The prevalence of micromucosal structures differed significantly among the three groups both at the lesser and greater curvatures (P < 0.001). CONCLUSIONS: Magnifying NBI endoscopy clearly revealed detailed micromorphological differences corresponding to the histology and endoscopic findings among patients with different H. pylori-associated diseases.

Magnifying endoscopic findings of the surface structure of non-cancerous mucosa surrounding differentiated and undifferentiated gastric carcinoma.

BACKGROUND: Several reports have described the usefulness of magnifying endoscopy in observing the surface structure in gastric neoplasia. The aim of the present study was to evaluate the characteristics of the surface structure of non-cancerous mucosa surrounding gastric cancer. METHODS: Sixty Japanese patients with early gastric cancer were enrolled in this study. We observed the non-cancerous gastric mucosa surrounding gastric carcinoma by magnifying endoscopy and classified the magnified view into four patterns: (A) dotted; (B) short-linear; (C) striped; and (D) granular, according to Sakaki's classification. RESULTS: All patients were diagnosed as having Helicobacter pylori infection, and histological evaluation revealed 46 types of differentiated and 14 types of undifferentiated-type gastric carcinomas. There were significant differences in the gender, age and endoscopic-atrophic-border scale between patients with these two types. In all, the surface structure at 240 points (4 points each in 60 patients) of non-cancerous mucosa was observed by magnifying endoscopy. The prevalences of the surface patterns of the mucosa surrounding differentiated carcinoma were: A, 1.1%; B, 8.1%; C, 28.3%; D, 62.5%, and those of the mucosa surrounding undifferentiated carcinoma were: A, 8.9%; B, 73.2%; C, 14.3%; D, 3.6%. There were significant differences in the surface structure of the non-cancerous mucosa surrounding differentiated and undifferentiated gastric carcinoma. CONCLUSION: The microsurface structure of the gastric mucosa surrounding gastric cancer lesions differed between patients with differentiated and undifferentiated gastric cancer. These findings are expected to be useful for the early detection of gastric carcinoma lesions or for the determination of extensions of carcinoma lesions.

Clinical characteristics of gastroesophageal reflux disease in Japan.

BACKGROUND/AIMS: Little is known about the correlation between clinical symptoms in daily life and the endoscopic features of gastroesophageal reflux disease (GERD). The study aim is to evaluate the correlation between clinical symptoms in daily life and endoscopic findings in reflux esophagitis (RE), and endoscopically suspected esophageal metaplasia (ESEM) in a large number of Japanese non-clinical cases. METHODOLOGY: A total of 6504 subjects who underwent an endoscopy for their annual medical check-up at Miyagi cancer society were enrolled in this study. If esophagitis was present, it was graded according to the Los Angeles classification. ESEM describes endoscopic findings consistent with BE that await histological evaluation. It was also investigated the symptom of heartburn as a "typical symptom" of GERD, and dysphagia as an "atypical symptom" of GERD. RESULTS: The prevalence of heartburn and dysphagia significantly increased concomitantly with endoscopic the esophagitis grading. The prevalence of heartburn was significantly higher in subjects with long segment ESEM than those without it. CONCLUSION: The prevalence of heartburn and dysphagia were closely associated with RE grading. Long segment ESEM is strongly associated with the reflux symptom and RE. The more frequent the GERD symptoms, the greater the risk for the development of severe RE, and ESEM.

Helicobacterpylori eradication treatment for gastric carcinoma prevention in asymptomatic or dyspeptic adults: systematic review and Bayesian meta-analysis of randomised controlled trials.

OBJECTIVES: Recent meta-analyses of eradication therapy in Helicobacter pylori-infected adults reported significant reductions in gastric carcinoma risk. However, concerns about supporting unfocused screening and eradication programme in healthy, asymptomatic populations have arisen. We performed a systematic review and Bayesian meta-analysis to provide an accurate interpretation of randomised evidence on the preventive effectiveness of eradication therapy on gastric carcinoma risk. METHODS: We searched databases including PubMed, Cochrane Central and Embase for reference and citation tracking without language restrictions, from inception through 31 July 2018. Paired investigators independently selected randomised controlled trials (RCTs) comparing eradication therapy with placebo or no treatment for asymptomatic or dyspeptic H. pylori-infected adults with no previous gastric carcinoma. The main outcome was gastric carcinoma incidence; secondary outcomes included gastric carcinoma-specific, non-gastric carcinoma and all-cause mortality. RESULTS: A total of 5 population-based and 2 outpatient care-based RCTs involving 7303 adults were eligible. Eradication algorithms were heterogeneous, and unsuccessful eradication and reinfection were frequently observed. A Bayesian meta-analysis with competing risk outcomes found low-certainty evidence that eradication therapy might be more likely than control to reduce gastric carcinoma risk (HR=0.65; 95% credible interval (CrI) 0.41 to 1.0; I2 =11%). The CrIs included the null effects across the subgroup and sensitivity analyses, apart from those based on particular models that excluded two RCTs that enrolled subjects with specific histological findings only (HR=0.55; CrI 0.30 to 0.89; I2 =14%). The uncertainty of the average 41% risk reduction in gastric carcinoma-specific mortality included a clinically important mortality risk increase (HR=0.59 favouring eradication therapy; CrI 0.25 to 1.20; I2 =13%; low certainty). CONCLUSIONS: There is insufficient evidence to support or refute the effectiveness of eradication therapy in preventing gastric carcinoma in H. pylori-infected, high-risk populations. Rigorously conducted large RCTs of healthy infected adults only would provide evidence of the true efficacy of successful eradication. PROSPERO registration number: CRD42014009245.

Endoscopic Findings of Esophageal Adenosquamous Carcinoma Diagnosed by Endoscopic Mucosal Resection.

Adenosquamous carcinoma (ASC) is a rare histological type of esophageal carcinoma. Esophagogastroduodenoscopy for the health checkup of a 71-year-old male revealed the presence of a slightly elevated lesion like a submucosal tumor at the lower part of the esophagus. The center of it was slightly depressed, and the depressed area was not stained by iodine. Magnifying endoscopy with narrow-band imaging revealed reticular pattern vessels in the depressed area, whereas no irregularity of the microvascular pattern of the surrounding area was evident. One of the biopsied specimens taken from the depressed area was diagnosed as squamous intraepithelial neoplasia, but a malignant tumor with submucosal invasion was suspected based on the findings of endoscopic ultrasonography. Endoscopic mucosal resection using a cap-fitted endoscope was performed, and the lesion was diagnosed as esophageal ASC histologically. Carcinomas that formed nested and ductal structures existed in the lamina propria and invaded to the submucosa. Almost all of them were covered by non-invasive intraepithelial neoplasia, whereas small erosion was seen in the central depressed area. The growing pattern of ASC was quite different from that of typical differentiated squamous cell carcinomas. When we do endoscopic examination for an esophageal lesion like submucosal tumor, we have to consider the possibility of an esophageal carcinoma that has a similar growing pattern. If reticular pattern vessels are seen with magnifying endoscopy, the existence of an invasive carcinoma is suspected, and additional endoscopic ultrasonography is recommended. Possible efforts to gain histological findings have to be made using bowling biopsy, endoscopic resection, and so on.

Suppression of NO production and 8-nitroguanosine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: involvement of estrogen receptor-dependent or -independent pathways.

Since the endocrine and immune systems share portions of some intracellular signaling pathways, endocrine-disrupting chemicals (EDCs) are considered potential agents for influencing inflammatory responses. Here, we investigated the effect of EDCs on lipopolysaccharide (LPS)-induced NO production and NF-kappaB activation in the RAW264.7 mouse macrophage cell line. Five phenol-containing EDCs were investigated, namely bisphenol A (BPA), the alkyl phenols p-n-nonylphenol (NP) and p-n-octylphenol (OP), and the chlorinated phenols 2,4-dichlorophenol (DCP) and pentachlorophenol (PCP). Our results revealed that these chemicals dose-dependently suppressed LPS-induced NO production, as reflected by decreased NO(x) content. The suppressive effects of BPA, NP and OP, but not PCP or DCP, were blocked by the estrogen receptor (ER) inhibitor, ICI182780. ELISA-based quantification of the DNA-binding activity of free p65 NF-kappaB showed that LPS-induced NF-kappaB activation was significantly diminished by EDC treatment. Furthermore, immunocytochemical analysis of 8-nitroguanosine, a unique index of NO-mediated signaling, showed that 8-nitroguanosine formation increased in LPS-stimulated cells, but this increase was inhibited by the tested EDCs. These results demonstrate that EDCs suppress NO production and NF-kappaB activation in LPS-stimulated macrophages through ER-dependent (BPA, NP, OP) and -independent (PCP, DCP) pathways. The EDCs further inhibited 8-nitroguanosine formation, suggesting that they interfere with NO-mediated signaling. Thus, EDCs might play important roles in the inflammatory response and host defense system against foreign pathogens.

Prevalence of gastroesophageal reflux symptoms in a large unselected general population in Japan.

AIM: To examine the prevalence of gastroesophageal reflux disease (GERD) symptoms in a large unselected general population in Japan. METHODS: In Japan, mature adults are offered regular check-ups for the prevention of gastric cancer. A notice was sent by mail to all inhabitants aged>40 years. A total of 160983 Japanese (60774 male, 100209 female; mean age 61.9 years) who underwent a stomach check up were enrolled in this study. In addition, from these 160983 subjects, we randomly selected a total of 82894 (34275 male, 48619 female; mean age 62.4 years) to evaluate the prevalence of abdominal pain. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a 1 mo period. RESULTS: The respective prevalences of the symptoms in males and females were: heartburn, 15.8% vs 20.7%; dysphagia, 5.4% vs 7.8%; and abdominal pain, 6.6% vs 9.6%. Among these symptoms, heartburn was significantly high compared with the other symptoms, and the prevalence of heartburn was significantly more frequent in females than in males in the 60-89-year age group. Dysphagia was also significantly more frequent in female patients. CONCLUSION: The prevalence of typical GERD symptoms (heartburn) was high, at about 20% of the Japan population, and the frequency was especially high in females in the 60-89 year age group.

Tongue-like Barrett's esophagus is associated with gastroesophageal reflux disease.

AIM: To test this hypothesis of barrett esophagus (BE) classified into two types and to further determine if there was any correlation between the shape of endoscopically suspected esophageal metaplasia (ESEM), prevalence of reflux esophagitis (RE) and heartburn. METHODS: A total of 6504 Japanese who underwent endoscopy for their annual stomach check-up were enrolled in this study. BE was detected without histological confirmation that is ESEM. We originally classified cases of ESEM into 3 types based on its shape: Tongue-like (T type), Dome-like (D type) and Wave-like (W type) ESEM. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a one-month period. RESULTS: ESEM was observed in 10.3% of 6504 subjects (ESEM < 1 cm, 9.4%; 1 cm < or = ESEM < 3 cm, 1.7%; ESEM > or = 3 cm, 0.5%). The frequency of ESEM was significantly higher in males compared with female subjects. Statistical analysis showed that the prevalence of heartburn and RE were significantly higher in the T type ESEM than in the W type ESEM (P < 0.05). CONCLUSION: The T type ESEM was strongly asso-ciated with reflux symptoms and RE whereas the W type ESEM was not associated with GERD.

Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling.

We present evidence that Notch4ICD attenuates TGF-beta signaling. Cells expressing the activated form of the Notch4 receptor (ICD4) were resistant to the growth-inhibitory effects of TGF-beta. Notch4ICD was found to bind to Smad2, Smad3 and Smad4 but with higher affinity to Smad3. Deletion analysis showed that binding of Smad3 to ICD4 was mediated by its MH2 domain and was not dependent on the presence of the RAM23 region in ICD4. Using two TGF-beta/Activin reporter luciferase assays, RT-PCR and Western blot analysis, we demonstrate that ICD4 and ICD4 deltaRAM23 inhibit Smad-binding element and 3TP luciferase reporter activity and PAI-1 gene expression. MCF-7 human breast cancer cells express Notch4ICD (ICD4) and are resistant to the growth-inhibitory effects of TGF-beta. Blockage of Notch4 processing to ICD4 by gamma-secretase inhibitor renders MCF-7 cells sensitive to growth inhibition by TGF-beta. The interplay between these two signaling pathways may be a significant determinant during mammary tumorigenesis.

Systemic distribution of estrogen-responsive finger protein (Efp) in human tissues.

Estrogen-responsive finger protein (Efp), a target gene product of estrogen receptor (ER), is considered essential for estrogen-dependent cell proliferation. The biological significance of Efp remains unclear in human tissues, and therefore, we examined systemic distribution of Efp in human adult and fetal tissues using RT-PCR and immunohistochemistry. Efp mRNA expression was marked in the placenta and uterus, high in the thyroid gland, aorta, and spleen in adult, and relatively low in other human adult and fetal tissues examined in this study. Efp immunoreactivity was detected in epithelium of various adult tissues, and was also detected in cytotrophoblasts of the placenta and splenic macrophages. Efp immunolocalization in human fetus was generally similar as that in adult. These Efp-positive cells were previously reported to be associated with ERalpha and/or ERbeta expression. Therefore, these results indicate that Efp is widely expressed and may play important roles in various human tissues possibly through ERs.