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Several reports indicate crosstalk between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and estrogen, which has a protective effect in colorectal cancer (CRC). The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrogen using Nrf2 knockout (Nrf2 KO) mouse embryonic fibroblasts (MEFs), a powerful system to test the function of target genes due to their easy accessibility, and rapid growth rates. After inducing inflammation by tumor necrosis factor alpha (TNF-α), the effects of 17β-estradiol (E2) on the expression of proinflammatory mediators [i.e., NF-κB and inducible nitric oxide synthase (iNOS)] and estrogen receptors were evaluated by Western blot. In wild type (WT) MEFs, E2 treatment ameliorated TNF-α-induced nuclear translocation of NF-κB and expression of its target protein iNOS. Estrogen receptor beta (ERβ) expression was decreased by TNF-α-induced inflammation and restored by E2 treatment. When treated to WT MEFs, E2 induced nuclear translocation of Nrf2. The inhibitory effect of E2 on TNF-α-induced enhancement of iNOS was markedly dampened in Nrf2 KO MEFs. Notably, ERβ expression was significantly diminished in Nrf2 KO MEFs compared to that in WT cells. Promoter Database (EPD) revealed two putative anti-oxidant response elements (AREs) within the mouse ERβ promoter. Furthermore, in WT MEFs, E2 treatment repressed TNF-α-induced expression of iNOS protein and recovered by 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), a selective ERβ antagonist, treatment, but not in Nrf2 KO MEFs. In conclusion, Nrf2 plays a pivotal role in the anti-inflammatory of estrogen by direct regulating the expression of ERβ. [ABSTRACT FROM AUTHOR]

Alternative polyadenylation (APA) in 3’ untranslated regions (3’ UTR) plays an important role in regulating transcript abundance, localization, and interaction with microRNAs. Length-variation of 3’UTRs by APA contributes to efficient proliferation of cancer cells. In this study, we investigated APA in single cancer cells and tumor microenvironment cells to understand the physiological implication of APA in different cell types. We analyzed APA patterns and the expression level of genes from the 515 single-cell RNA sequencing (scRNA-seq) dataset from 11 breast cancer patients. Although the overall 3’UTR length of individual genes was distributed equally in tumor and non-tumor cells, we found a differential pattern of polyadenylation in gene sets between tumor and non-tumor cells. In addition, we found a differential pattern of APA across tumor types using scRNA-seq data from 3 glioblastoma patients and 1 renal cell carcinoma patients. In detail, 1,176 gene sets and 53 genes showed the distinct pattern of 3’UTR shortening and over-expression as signatures for five cell types including B lymphocytes, T lymphocytes, myeloid cells, stromal cells, and breast cancer cells. Functional categories of gene sets for cellular proliferation demonstrated concordant regulation of APA and gene expression specific to cell types. The expression of APA genes in breast cancer was significantly correlated with the clinical outcome of earlier stage breast cancer patients. We identified cell type-specific APA in single cells, which allows the identification of cell types based on 3’UTR length variation in combination with gene expression. Specifically, an immune-specific APA signature in breast cancer could be utilized as a prognostic marker of early stage breast cancer. [ABSTRACT FROM AUTHOR]

The role of macrophage migration inhibitory factor (MIF) and autophagy in gastric cancer is not clear. We determined H. pylori infection status of the subjects and investigated the expression of MIF and autophagy markers (Atg5, LC3A and LC3B) in human gastric tissue at baseline. Then H. pylori eradication was done for H. pylori positive patients and MIF and Atg5 levels were investigated on each follow-up for both H. pylori-eradicated and H. pylori negative patients. Baseline tissue mRNA expression of MIF, Atg5, LC3A and LC3B was measured by real-time PCR in 453 patients (control 165, gastric dysplasia 82, and gastric cancer 206). Three hundred three patients (66.9%) had H. pylori infection at the time of enrollment. Only within H. pylori-positive group, MIF level was significantly elevated in patients with cancer than in control or dysplasia groups (P<0.05). LC3A and LC3B levels also showed significant differences within H. pylori-positive subgroups. H. pylori-positive dysplasia subgroup showed significantly lower (LC3A) (P<0.05) and higher (LC3B) mRNA levels (P<0.05) than in other subgroups. On follow-up, within H. pylori-eradicated group, Atg5 expression increased sequentially from control to dysplasia and cancer subgroups. Multiple linear regression showed autophagy markers (LC3A, LC3B, and Atg5) directly predicted MIF level (adjusted R2 = 0.492, P<0.001). Serial follow-up showed longitudinal increase in Atg5 level in general, with constantly higher levels in H. pylori-eradicated group than in -negative group. Intestinal metaplasia (IM) group initially showed higher Atg5 expression than the IM-negative group. However, it was reversed between the groups eventually because of the lower rate of increase in IM group. These results suggest a role of MIF and autophagy markers and their interaction in H. pylori-associated gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

The aims of this study were to demonstrate the trends in seropositivity and the eradication therapy rate for Helicobacter pylori (H. pylori) over an 18-year period in an asymptomatic Korean population and to explore the factors associated with H. pylori seropositivity and its eradication therapy. In total, 23,770 subjects (aged 17–97 years) from a health examination center participated in this cross-sectional study from January 2016 to June 2017. Questionnaires that included questions about the participants’ H. pylori eradication therapy history were collected, and anti-H. pylori IgG antibodies were measured. Among the eligible subjects, the seroprevalence of H. pylori infection was 41.5%. The H. pylori eradication therapy rate increased continuously from 2005 (13.9%) to 2011 (19.3%) and then increased again until the first half of 2017 (23.5%) (P < 0.001). After exclusion of subjects with a history of gastric surgery, gastric cancer, H. pylori eradication therapy, or gastric symptoms, H. pylori seropositivity was 43.9% in 16,885 subjects, which was significantly lower than the seropositivities in 1998 (66.9%), 2005 (59.6%), and 2011 (54.4%). The risk factors associated with H. pylori seropositivity according to multivariable analysis were male sex (odds ratio (OR) 1.34, 95% confidence interval (CI): 1.23–1.46), medium educational level (OR 1.17, 95% CI: 1.05–1.31), medium household income level (OR 1.10, 95% CI: 1.03–1.19), and age of 60–69 years (OR 8.78, 95% CI: 6.41–11.85). The observed downward trend in H. pylori seroprevalence and increase in H. pylori eradication over the 18-year period will affect upper gastrointestinal disorders in South Korea. [ABSTRACT FROM AUTHOR]

The colonic response to stress is greater in female rats than in male rats. The aim of this study was to evaluate the effect of probiotics in the repeated water avoidance stress (rWAS)-induced colonic microinflammation model of Wistar rats in a sex-specific manner. The three groups (no-stress, WAS, and WAS with probiotics) were exposed to r-WAS for 1 h daily for 10 days, and Lactobacillus farciminis was administered by oral gavage for 10 days to animals in the probiotics group. The visceromotor response (VMR) to colorectal distension (CRD) was assessed using a barostat and noninvasive manometry before and after WAS exposure. Immunohistochemistry for mast cells and real-time polymerase chain reaction (RT-PCR) for detection of mucosal cytokines were performed using distal colon tissue after the animals were sacrificed. Significant reduction of VMR to CRD (visceral analgesia) was observed at 60 mmHg in the female WAS group (P = 0.045), but not in males. In addition, the female WAS with probiotics group showed a significantly lower colonic mucosal mast cell count in comparison to the female WAS group (P = 0.013), but this phenomenon was not observed in the male group. The colonic mucosal mRNA levels of interferon-γ (IFNR), tumor necrosis factor-α (TNFA), interleukin (IL) 6, and IL17 were higher in the female WAS group than in the male WAS group. The mRNA levels of IFNR, TNFA, and IL6 were significantly decreased in WAS females who received probiotics (all P < 0.050). In conclusion, rWAS is induced in a sex-specific manner. A 10-day-long treatment with L. farciminis is an effective therapy for rWAS-induced colonic microinflammation in female rates, but not in male rats. [ABSTRACT FROM AUTHOR]

The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs), neuronal nitric oxide synthase (nNOS)-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years). The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP) 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF), nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005) and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, P<0.001), while endomysial area of circular muscle did not significantly decrease. The proportions of NOS-immunoreactive cells and c-Kit-immunoreactive areas declined with aging (6 week vs 2 year; P<0.001 and P = 0.004, respectively), but there was no significant change of PGP 9.5-immunopositiviy. The expressions of nNOS, c-Kit and SCF mRNA also reduced with aging (6 week vs 2 year; P = 0.006, P = 0.001 and P = 0.006, respectively), while the change of PGP 9.5 mRNA expression was not significant. Western blot showed the significant decreases of nNOS and c-Kit protein expression with aging (6 week vs 2 year; P = 0.008 and P = 0.012, respectively). The EFS-induced esophageal contractions significantly decreased in 2-yr-old rat compared with 6-wk-old rats, however, L-NG-Nitroarginine methylester did not significantly increase the spontaneous and EFS-induced contractions in the 6-wk- and 2-yr-old rat esophagus. In conclusion, an increase of lamina propria thickness, a decrease of endomysial area, c-Kit, SCF and NOS expression with preserved total enteric neurons, and contractility in aged rat esophagus may explain the aging-associated esophageal dysmotility. [ABSTRACT FROM AUTHOR]

The gastric accommodation reflex is an important mechanism in gastric physiology. However, the aging-associated structural and functional changes in gastric relaxation have not yet been established. Thus, we evaluated the molecular changes of interstitial cell of Cajal (ICC) and neuronal nitric oxide synthase (nNOS) and the function changes in the corpus of F344 rats at different ages (6-, 31-, 74-wk and 2-yr). The proportion of the c-Kit-positive area in the submucosal border (SMB) and myenteric plexus (MP) layer was significantly lower in the older rats, as indicated by immunohistochemistry. The density of the nNOS-positive immunoreactive area also decreased with age in the SMB, circular muscle (CM), and MP. Similarly, the percent of nNOS-positive neuronal cells per total neuronal cells and the proportion of nNOS immunoreactive area of MP also decreased in aged rats. In addition, the mRNA and protein expression of c-Kit and nNOS significantly decreased with age. Expression of stem cell factor (SCF) and the pan-neuronal marker PGP 9.5 mRNA was significantly lower in the older rats than in the younger rats. Barostat studies showed no difference depending on age. Instead, the change of volume was significantly decreased by L-NG63-nitroarginine methyl ester in the 2-yr-old rats compared with the 6-wk-old rats (P = 0.003). Taken together, the quantitative and molecular nNOS changes in the stomach might play a role in the decrease of gastric accommodation with age. [ABSTRACT FROM AUTHOR]

Humanized pigs have been developed to reduce the incidence of immune rejection in xenotransplantation, but significant concerns remain, such as transmission of viral zoonosis. Porcine endogenous retroviruses (PERV), which exist in the genome of pigs, are produced as infectious virions from all porcine cells and cause zoonosis. Here, we examined the possibility of zoonosis of hosts under conditions of immune suppression or xenotransplantation of cells producing host-adapted viruses. Upon transplantation of PERV-producing porcine cells into mice, no transmission of PERV was detected, whereas, transmission of PERV from mice transplanted with mouse-adapted PERV-producing cells was detected. In addition, the frequency of PERV transmission was increased in CsA treated mice transplanted with PERV-producing murine cells, compared with PERV-producing porcine cells. Transmission of PERV to host animals did not affect weight but immune responses, in particular, the number of T cells from PERV-transmitted mice, were notably reduced. The observed risk of PERV zoonosis highlights the requirement for thorough evaluation of viral zoonosis under particular host conditions, such as immunosuppressive treatment and transplantation with host-adapted virus-producing cells. [ABSTRACT FROM AUTHOR]

The immunoglobulin (Ig)-like domain containing receptor 1 (ILDR1) gene encodes angulin-2/ILDR1, a recently discovered tight junction protein, which forms tricellular tight junction (tTJ) structures with tricellulin and lipolysis-stimulated lipoprotein receptor (LSR) at tricellular contacts (TCs) in the inner ear. Previously reported recessive mutations within ILDR1 have been shown to cause severe to profound nonsyndromic sensorineural hearing loss (SNHL), DFNB42. Whole-exome sequencing of a Korean multiplex family segregating partial deafness identified a novel homozygous ILDR1 variant (p.P69H) within the Ig-like domain. To address the pathogenicity of p.P69H, the angulin-2/ILDR1 p.P69H variant protein, along with the previously reported pathogenic ILDR1 mutations, was expressed in angulin-1/LSR knockdown epithelial cells. Interestingly, partial mislocalization of the p.P69H variant protein and tricellulin at TCs was observed, in contrast to a severe mislocalization and complete failure of tricellulin recruitment of the other reported ILDR1 mutations. Additionally, three-dimensional protein modeling revealed that angulin-2/ILDR1 contributed to tTJ by forming a homo-trimer structure through its Ig-like domain, and the p.P69H variant was predicted to disturb homo-trimer formation. In this study, we propose a possible role of angulin-2/ILDR1 in tTJ formation in the inner ear and a wider audiologic phenotypic spectrum of DFNB42 caused by mutations within ILDR1. [ABSTRACT FROM AUTHOR]

Background: The use of biologics in inflammatory bowel disease (IBD) has increased recently. However, studies on whether the proportion of IBD patient visits to the emergency department (ED) has decreased are scarce. We investigated the trends in IBD-related ED visits and hospitalization rates. Methods: Medical records of IBD-related visits to the ambulatory department (AD) and the ED of the Seoul National University Bundang Hospital in 2007, 2009, 2012, and 2014 were reviewed. Multiple-variable logistic regression analysis was used to identify significant risk factors for hospitalization. Results: The proportion of IBD patients who visited ED was 12.3% in 2007, 9.7% in 2009, 8.3% in 2012, and 6.4% in 2014 (P = 0.002). The most common chief complaints were abdominal pain (66.9%) in Crohn’s disease (CD) patients and hematochezia (36.5%) in ulcerative colitis (UC) patients. The hospitalization rate following ED visits was 47.2% in CD patients and 55.6% in UC patients (P = 0.100). Multiple-variable analysis showed that significant risk factors associated with hospitalization in CD were aggressive disease behavior (odds ratio[OR] 3.54, P = 0.017) and presence of steroid exposure (OR 2.35, P = 0.047). Elevated C-reactive protein (CRP) (>0.5 mg/dL) (OR 5.40, P = 0.016) was the only risk factor associated with hospitalization in UC. Conclusions: The proportion of ED visits decreased from 2007 to 2014; there was no significant change in hospitalization rates. Disease behavior/presence of steroid exposure and elevated CRP were associated with hospitalization among CD and UC patients who visited the ED, respectively. [ABSTRACT FROM AUTHOR]

Background: Growing evidence supports that prostate cancer (PCa) is a metabolic syndrome-related cancer, but the evidence is lacking regarding the association between nonalcoholic fatty liver disease (NAFLD) and PCa. We aimed to investigate whether PCa is related with NAFLD in Korean adults. Methods: Data from the National Health Insurance Corporation between 2009 and 2012 were analyzed using multivariate logistic regression method. NALFD was defined based on the fatty liver index (FLI) and hepatic steatosis index (HSI). Newly diagnosed PCa was identified using the claims data. Results: NAFLD based on FLI and HSI was identified in 2,002,375 (19%) and 2,629,858 (25%) of 10,516,985 subjects, respectively. Each FLI ≥ 60 and HSI ≥ 36 was independently associated with the development of PCa after adjusting for other confounders (hazard ratio (HR) 1.09, 95% CI: 1.06–1.12 and HR 1.19, 95% CI: 1.16–1.23). The association was more prominent among those who were older (FLI, ≥ 65 years old and HSI, ≥ 40 years old), were not currently smoking, were presently consuming alcohol (< 30g/day) and had null components of metabolic syndrome than each counterpart. Non-obese persons with NAFLD defined by HSI had a higher risk of developing PCa than those with body mass index > 25 Kg/m2. Conclusions: NAFLD defined by FLI or HSI may help identify high-risk individuals for developing PCa particular in the elderly, even in the absence of obesity or metabolic syndrome. Future studies on this topic should necessarily be repeated based on ultrasonographic findings. [ABSTRACT FROM AUTHOR]

There have been only a few reports investigating the clinical efficacy of follow-up endoscopy for detection of recurrent gastric cancer after total gastrectomy (TG). We reviewed the records of 747 patients undergoing TG from 2003 to 2012 and enrolled 267 patients (70 with early gastric cancer (EGC) and 197 with advanced gastric cancer (AGC)), who received one or more follow-up endoscopy and contrast abdominal computed tomography (CT) scan. We found no tumor recurrence in the 70 EGC patients during the mean follow-up periods of 42.1 ± 18 and 43.2 ± 19 months by endoscopy and contrast abdominal CT scan. In 197 AGC patients, 59 patients (29.8%) had confirmed tumor recurrence during mean follow-up periods of 40.5 ± 21 and 45.3 ± 22 months. The most common pattern of tumor recurrence was distant metastasis (n = 35) followed by peritoneal metastasis (n = 11). Among the other 13 cases with loco-regional recurrence, seven cases were regional lymph node metastases, four were anastomosis site recurrences, and two were duodenal stump and jejunal loop site recurrences. Three of the four cases of anastomosis site recurrence were found by both endoscopy and contrast abdominal CT scan; one case was missed by contrast abdominal CT scan. However, the two cases with duodenal stump and jejunal loop recurrences were detected by contrast abdominal CT scan only. An annual follow-up endoscopy for gastric cancer after TG might have a limited role in the detection of tumor recurrence, especially in patients with EGC. Contrast abdominal CT scan may be sufficient as a follow-up method for recurrent gastric cancer after TG. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic findings of low-volume alcohol consumption in relation to gastrointestinal cancers including gastric cancer are inconsistent. Methods: The association between alcohol intake and esophageal, gastric and colorectal cancer risk was examined in a population-based prospective cohort of 23,323,730 adults in Korea who had undergone a biennial evaluation provided by the National Health Insurance Corporation between the years 2009 and 2012. After median 5.4 years of follow-up, 9,171 esophageal, 135,382 gastric and 154,970 colorectal cancer cases were identified. Cox regression models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Results: Light drinking as well as moderate to heavy alcohol consumption significantly increased the risks of the three gastrointestinal cancers (HR 1.51; 95% CI, 1.43–1.60; HR 1.08; 95% CI, 1.06–1.09; HR 1.12; 95% CI, 1.11–1.14) compared with non-drinkers after adjusting for age, sex, smoking, exercise, income, body mass index, and diabetes. The synergistically increased cancer risk between excessive amount of alcohol consumption and currently smoking or underweight individuals was observed only in the esophageal cancers. Conclusions: Light drinking including even one alcoholic drink a day is associated with increased risks of esophageal, gastric and colorectal cancer. [ABSTRACT FROM AUTHOR]

Gamma-glutamyltransferase (GGT) is a marker for hepatic injury and alcohol consumption. However, the association of GGT with the risk of oesophageal carcinoma (OC) has not been fully recognized to date. Therefore, this study aimed to determine the association between elevated GGT and OC, by also considering the body mass index (BMI) of the subjects. Clinical data from 8,388,256 Korean individuals, who were aged 40 years and over and who received healthcare check-ups arranged by the national insurance program in 2007 and 2008, were analysed. Newly diagnosed OC was identified using claims data during a median follow-up duration of 8.72 years. During the study period, 6,863 individuals (0.08%) developed OC. We found that there was an increased risk of OC in subjects with serum GGT values >18 IU/L. Furthermore, a BMI <18.5 kg/m2 (underweight) was associated with increased OC risk, while a BMI ≥23.0 kg/m2 was associated with a reduced OC risk. Individuals who were both underweight and in the highest GGT quartile (≥40 IU/L) had a far greater risk of OC compared to other individuals (hazard ratio: 3.65, 95% confidence interval: 3.10–4.30). In conclusion, increased serum GGT was associated with an increased risk of developing OC in the general Korean population, regardless of age, sex, smoker status, or alcohol consumption. [ABSTRACT FROM AUTHOR]

Although alpha-fetoprotein (AFP) is the most widely used biomarker in hepatocellular carcinoma (HCC) surveillance, disease activity may also increase AFP levels in chronic hepatitis B (CHB). Since nucleos(t)ide analog (NA) therapy may reduce not only HBV viral loads and transaminase levels but also the falsely elevated AFP levels in CHB, we tried to determine whether exposure to NA therapy influences AFP performance and whether selective application can optimize the performance of AFP testing in CHB during HCC surveillance. A retrospective cohort of 6,453 CHB patients who received HCC surveillance was constructed from the electronic clinical data warehouse. Covariates of AFP elevation were determined from 53,137 AFP measurements, and covariate-specific receiver operating characteristics regression analysis revealed that albumin levels and exposure to NA therapy were independent determinants of AFP performance. C statistics were largest in patients with albumin levels ≥ 3.7 g/dL who were followed without NA therapy during study period, whereas AFP performance was poorest when tested in patients with NA therapy during study and albumin levels were < 3.7 g/dL (difference in C statics = 0.35, p < 0.0001). Contrary to expectation, CHB patients with current or recent exposure to NA therapy showed poorer performance of AFP during HCC surveillance. Combination of concomitant albumin levels and status of NA therapy can identify subgroup of CHB patients who will show optimized AFP performance. [ABSTRACT FROM AUTHOR]

Epidemiological data indicate that type 2 diabetes is associated with increased risk of hepatocellular carcinoma (HCC). However, risk stratification for HCC has not been fully elucidated in diabetic population. The aim of this study was to identify potential predictors of HCC in diabetic patients without chronic viral hepatitis. A cohort of 3,544 diabetic patients without chronic viral hepatitis or alcoholic cirrhosis was established and subjects were randomly allocated into a derivation and a validation set. A scoring system was developed by using potential predictors of increased risk of HCC from the Cox proportional hazards model. The performance of the scoring system was tested for validation by using receiver operating characteristics analysis. During median follow-up of 55 months, 36 cases of HCC developed (190 per 100,000 person-years). The 5- and 10-year cumulative incidences of HCC were 1.0%, and 2.2%, respectively. Multivariate Cox regression analysis showed that age > 65 years, low triglyceride levels and high gamma-glutamyl transferase levels were independently associated with an increased risk of HCC. DM-HCC risk score, a weighted sum of scores from these 3 parameters, predicted 10-year development of HCC with area under the receiver operating characteristics curve of 0.86, and discriminated different risk categories for HCC in the derivation and validation cohort. In conclusion, old age, low triglyceride level and high gamma-glutamyl transferase level may help to identify individuals at high risk of developing HCC in diabetic patients without chronic viral hepatitis or alcoholic cirrhosis. [ABSTRACT FROM AUTHOR]