Search

Background/aims: Endoscopic submucosal dissection (ESD) of a superficial esophageal neoplasm (SEN) is a technically difficult procedure. We investigated the clinical outcomes of ESD to determine its feasibility and effectiveness for the treatment of SEN., Methods: Patients who underwent ESD for SEN between August 2005 and June 2014 were eligible for this study. The clinical features of patients and tumors, histopathologic characteristics, adverse events, results of endoscopic resection, and survival were investigated., Results: ESD was performed in 225 patients with 261 lesions, including 70 cases (26.8%) of dysplasias and 191 cases (73.2%) of squamous cell carcinomas. The median age was 65 years (range, 44 to 86), and the male to female ratio was 21.5:1. Median tumor size was 37 mm (range, 5 to 85) and median procedure time was 45 minutes (range, 9 to 160). En bloc resection was performed in 245 of 261 lesions (93.9%), with complete resection in 234 lesions (89.7%) and curative resection in 201 lesions (77.0%). Adverse events occurred in 33 cases (12.6%), including bleeding (1.5%), perforation (4.6%), and stricture (6.5%). During a median follow-up period of 35.0 months (interquartile range, 18 to 62), none of the patients showed local recurrence. The 5-year overall and disease-specific survival rates were 89.7% and 100%, respectively., Conclusions: ESD is a feasible and effective procedure for the treatment of SEN based on our 10-year experience, which showed favorable outcomes., Competing Interests: No potential conflict of interest relevant to this article was reported.

Recently, we reported that earlier stages of Alzheimer's disease (AD) can be categorized into 3 following anatomical subtypes using a hierarchical cluster analysis of cortical thickness across the entire brain: medial temporal-dominant (MT), parietal-dominant (P), and diffuse atrophy (D). The goal of this study was to investigate the rates of cognitive decline in these anatomical subtypes. Of the patients included in the prior study, 100 AD patients (MT, n = 36; P, n = 20; D, n = 44) who underwent follow-up neuropsychological assessments over a 3-year period were included. A linear mixed model analysis was performed to compare the longitudinal changes in neuropsychological test scores. The P subtype exhibited the most rapid cognitive decline in attention, language, visuospatial, memory, and frontal executive function, whereas MT and D subtypes did not differ in their longitudinal decline. When repeating the analyses with early-onset AD, which is known to progress faster than late-onset AD, only the P subtype showed such rapid progression. The P subtype appears to be a unique subtype of AD characterized by an aggressive rate of progression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Recent studies have shown that Helicobacter pylori (H. pylori) activates signal transducer and activator of transcription 3 (STAT3) that plays an important role in gastric carcinogenesis. However, the molecular mechanism underlying H. pylori-mediated STAT3 activation is still not fully understood. In this study, we investigated H. pylori-induced activation of STAT3 signaling in AGS human gastric cancer cells and the underlying mechanism., Materials and Methods: AGS cells were cocultured with H. pylori, and STAT3 activation was assessed by Western blot analysis, electrophoretic mobility shift assay and immunocytochemistry. To demonstrate the involvement of reactive oxygen species (ROS) in H. pylori-activated STAT3 signaling, the antioxidant N-acetylcysteine was utilized. The expression and production of interleukin-6 (IL-6) were measured by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. The interaction between IL-6 and IL-6 receptor (IL-6R) was determined by the immunoprecipitation assay., Results: H. pylori activates STAT3 as evidenced by increases in phosphorylation on Tyr(705) , nuclear localization, DNA binding and transcriptional activity of this transcription factor. The nuclear translocation of STAT3 was also observed in H. pylori-inoculated mouse stomach. In the subsequent study, we found that H. pylori-induced STAT3 phosphorylation was dependent on IL-6. Notably, the increased IL-6 expression and the IL-6 and IL-6R binding were mediated by ROS produced as a consequence of H. pylori infection., Conclusions: H. pylori-induced STAT3 activation is mediated, at least in part, through ROS-induced upregulation of IL-6 expression. These findings provide a novel molecular mechanism responsible for H. pylori-induced gastritis and gastric carcinogenesis., (© 2016 John Wiley & Sons Ltd.)

The implication of inflammatory tissue damage in pathophysiology of human cancer as well as some metabolic disorders has been under intense investigation. Numerous studies have identified a series of critical signaling molecules involved in cellular responses to inflammatory stimuli. These include nuclear factor κB, peroxisome proliferator-activated receptor γ, nuclear factor erythroid 2 p45-related factor 2 and sterol regulatory element-binding protein 1. The proper regulation of these transcription factors mediating pro- and anti-inflammatory signaling hence provides an important strategy for the chemoprevention of inflammation-associated cancer. There is compelling evidence supporting that dietary supplementation with fish oil-derived ω-3 polyunsaturated fatty acids including docosahexaenoic acid (DHA) ameliorates symptomatic inflammation associated with cancer as well as other divergent human disorders. Acute or physiologic inflammation is an essential body's first line of defence to microbial infection and tissue injuries, but it must be properly completed by a process termed 'resolution'. Failure of resolution mechanisms can result in persistence of inflammation, leading to chronic inflammatory conditions and related malignancies. The phagocytic engulfment of apoptotic neutrophils and clearance of their potentially histotoxic contents by macrophages, called efferocytosis is an essential component in resolving inflammation. Of note, DHA is a precursor of endogenous proresolving lipid mediators which regulate the leukocyte trafficking and recruitment and thereby facilitate efferocytosis. Therefore, DHA and its metabolites may have a preventive potential in the management of human cancer which arises as a consequence of impaired resolution of inflammation as well as chronic inflammation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

15-Deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), a representative J-series cyclopentenone prostaglandin, has biphasic roles in cell proliferation and apoptosis. Hypoxia inducible factor-1 (HIF-1) regulates expression of various genes involved in tumor growth and angiogenesis. In the present study, treatment of human breast cancer (MCF-7) cells with 15d-PGJ 2 resulted in the accumulation of the α-subunit of HIF-1. Pretreatment with zinc protoporphyrin IX, a pharmacological inhibitor of heme oxygenase-1 (HO-1), as well as siRNA knockdown of HO-1 gene in MCF-7 cells attenuated 15d-PGJ 2 -mediated HIF-1α accumulation. 15d-PGJ 2 treatment increased intracellular production of reactive oxygen species (ROS), which was mediated by HO-1 induction. Preincubation of MCF-7 cells with trolox, a water-soluble form of vitamin E, attenuated 15d-PGJ 2 -induced HIF-1α expression although HO-1 expression was unchanged. This finding suggests that ROS accumulated as a consequence of HO-1 up-regulation can enhance HIF-1α expression in MCF-7 cells treated with 15d-PGJ 2 . Alternatively, 15d-PGJ 2 was found to covalently bind to HIF-1α prolyl-4-hydroxylase 2 (PHD2) in MCF-7 cells, which hampers the proline hydroxylation of HIF-1α, thereby disrupting ubiquitin-dependent proteasomal degradation of this transcription factor. Pretreatment with thiol reducing agents blunted 15d-PGJ 2 -induced HIF-1α stabilization, indicative of a cysteine residue as a direct target of 15d-PGJ 2 . Molecular docking analysis suggests that 15d-PGJ 2 preferentially binds to PHD2 in the vicinity of the Cys 201 residue based on binding energies and carbon-sulfur distances. In summary, 15d-PGJ 2 stabilizes HIF-1α in MCF-7 cells through HO-1 induction with subsequent ROS generation and also through direct modification of PHD2.

Nanoparticles have shown great potential as vehicles for the delivery of drugs, nucleic acids, and therapeutic proteins; an efficient, high-throughput screening method to analyze nanoparticle interaction with the cytomembrane would substantially improve the efficiency and accuracy of the delivery. Here, we developed a capacitance sensor array that monitored the capacitance values of nanoparticle-treated cells in a real-time manner, without the need for labeling. Upon cellular uptake of the nanoparticles, a capacitance peak was observed at a low frequency (e.g., 100 Hz) as a function of time based on zeta potential changes. In the high frequency region (e.g., 15-20 kHz), the rate of decreasing capacitance slowed as a function of time compared to the cell growth control group, due to increased cytoplasm resistance and decreased membrane capacitance and resistance. The information provided by our capacitance sensor array will be a powerful tool for scientists designing nanoparticles for specific purposes.

Background/aims: We developed a new endoscopic biopsy training simulator and determined its efficacy for improving the endoscopic biopsy skills of beginners., Methods: This biopsy simulator, which presents seven biopsy sites, was constructed using readily available materials. We enrolled 40 participants: 14 residents, 11 first-year clinical fellows, 10 second-year clinical fellows, and five staff members. We recorded the simulation completion time for all participants, and then simulator performance was assessed via a questionnaire using the 7-point Likert scale., Results: The mean times for completing the five trials were 417.7±138.8, 145.2±31.5, 112.7±21.9, and 90.5±20.0 seconds for the residents, first-year clinical fellows, second-year clinical fellows, and staff members, respectively. Endoscopists with less experience reported that they found this simulator more useful for improving their biopsy technique (6.8±0.4 in the resident group and 5.7±1.0 in the first-year clinical fellow group). The realism score of the simulator for endoscopic handling was 6.4±0.5 in the staff group., Conclusions: This new, easy-to-manufacture endoscopic biopsy simulator is useful for biopsy training for beginner endoscopists and shows good efficacy and realism.

Background/aims: We investigated the effectiveness of Helicobacter pylori eradication therapy for gastric mucosaassociated lymphoid tissue (MALT) lymphoma regardless of the H. pylori infection status or disease stage., Methods: From November 1995 to September 2014, 345 subjects who were diagnosed with gastric MALT lymphoma and had received eradication therapy as their first-line treatment were eligible for inclusion in this study. A retrospective review was performed using the medical records., Results: Of the 345 patients, H. pylori infection was detected in 317 patients (91.9%). The complete remission (CR) rate after eradication therapy was 82.3%, which was higher in H. pylori -positive patients than in H. pylori-negative patients (84.5% vs 57.1%, p=0.001). CR rates after eradication did not present significant differences between stages, and the CR rate was 83.3% for stage IE1 and 74.4% for stage IE2 or above (p=0.167). The overall CR rate was 87.2% after additional treatment, and neither H. pylori infection status nor stage showed differences according to the treatment response., Conclusions: Eradication therapy led to CR in 57.1% of H. pylori-negative patients and in 74.4% of patients with stage IE2 or above. Eradication therapy is worthwhile as an initial treatment for gastric MALT lymphoma regardless of the H. pylori infection status and stage.

Background/aims: Self-expandable metal stents (SEMSs) can be used for the palliation of malignant obstruction in the upper gastrointestinal tract. This study assessed the feasibility and efficacy of endoscopically inserted SEMSs for the palliation of malignant obstruction in the stomach and duodenum., Methods: Between January 2011 and April 2014, 220 patients with gastric or duodenal obstruction due to malignancy underwent endoscopic SEMS insertion at Asan Medical Center. The associations of technical/clinical outcomes and complications with the type of stent and site of obstruction were analyzed., Results: The 220 patients included 125 men (56.8 %) and 95 women (43.2 %); median patient age was 63 years. Fully covered, partially covered, and uncovered SEMSs were inserted into 16, 77, and 120 patients, respectively. Obstructions were located in the gastric outlet, including the duodenal bulb, in 106 patients, and in the duodenal second and third portions in 114 patients. Technical success was achieved in 213 of 220 patients (96.8 %) and clinical success in 184 of 213 (86.4 %). Clinical success rates were similar to the type of stent, but were significantly greater for gastric outlet (95/104, 91.3 %) than for duodenal (89/109, 81.7 %) obstructions (p = 0.039). Stent migration was observed in 20 patients (9.1 %) and stent obstruction in 51 (23.2 %). Rates of stent migration were significantly higher for fully covered (6/16, 37.5 %) than for partially covered (7/77, 9.1 %) and uncovered (7/120, 5.8 %) SEMSs (p < 0.001) and were significantly higher for gastric outlet (16/104, 15.4 %) than for duodenal (4/109, 1.2 %) obstructions (p = 0.003). Rates of stent obstruction were similar for fully covered (2/16, 12.5 %), partially covered (17/77, 22.1 %), and uncovered (32/120, 26.7 %) SEMSs (p = 0.409) and in patients with gastric outlet (26/104, 25.0 %) and duodenal (25/109, 22.9 %) obstruction (p = 0.724)., Conclusions: SEMS selection for malignant obstruction of the upper gastrointestinal tract depends on the site of obstruction.

Photodynamic therapy (PDT) is a noninvasive strategy to treat diseases by light-triggered activation of a photosensitizer (PS). One aim of the recent researches on PDT is to overcome the limitation of conventional PDT by improving selective activation of PS on targeted region. Here, a microRNA (miRNA)-responsive drug activation system is developed which focuses on the role of endogenous miRNA as an internal cancer specific stimulus for initiating drug release in cancer treatment. The present system consists of PS chlorin e6 (Ce6) conjugated to peptide nucleic acid (PNA) having complementary sequence to cancer specific miRNA and dextran coated reduced graphene oxide nanocolloid (Dex-RGON). In the presence of oncogenic miR-21 in cancer cells, Ce6-PNA drug gets hybridized with miR-21, resulting in the release of Ce6-PNA from Dex-RGON and subsequent recovery of Ce6 fluorescence and activation of Ce6 as a photosensitizer under near IR irradiation. It is demonstrated that the Ce6-PNA/Dex-RGON complex shows sequence-specific fluorescence in response to miR-21 and selective cytotoxic effect for tumor growth inhibition. The present study will pave a new way for utilizing PDT in cancer treatment with tightly regulated activation of a photosensitizer by oncogenic miRNA as an internal stimulus to reduce potential risk associated with conventional PDT., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective Bone marrow (BM) examination is recommended as part of the initial staging work-up in patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, the clinical significance of BM involvement in gastric MALT lymphoma patients has not been evaluated. Materials and methods From November 1995 to September 2014, 496 subjects who were diagnosed with gastric MALT lymphoma and underwent BM examination were eligible to be included in this study. BM involvement was found in 33 patients (6.7%) by retrospective review, and after exclusions, the clinical outcomes of 28 patients with BM involvement and 412 patients without BM involvement were evaluated. Results When comparing the characteristics of patients, age (median 60 vs. 53 years, p = 0.007) and Helicobacter pylori infection rate (71.0% vs. 85.5%, p = 0.040) were different between patients with and without BM involvement, while the location, macroscopic findings, and depth of invasion were similar. The overall complete remission (CR) rate was 85.2% during a median follow-up period of 42 months (interquartile range, 23-66 months) and did not differ between the two groups (78.6 and 85.7%, p = 0.280). Eradication therapy was performed as the first-line treatment in 18 of the 28 patients (64.3%) with BM involvement, and CR was achieved in 13 patients (72.2%). Logistic regression analysis showed that age and location in the upper part of the stomach were factors related to remission failure. Conclusion Gastric MALT lymphoma has a favorable outcome, and eradication therapy can be justified in selected cases even with BM involvement, when these patients are closely monitored.

Background and Aim: Although follow-up endoscopy is routinely performed after endoscopic resection (ER) for early gastric cancer (EGC), it remains unclear whether resection scar biopsies should also be taken. This study sought to predict local recurrence at the ER scar on the basis of endoscopic criteria after margin-negative EGC resection and to determine the necessity of taking scar biopsies., Methods: All consecutive patients with EGC who underwent margin-negative ER in June 1995 to December 2011 and developed recurrence at the scar were identified. Each case was matched by four controls with EGC and margin-negative ER but without local recurrence for age, sex, and en-bloc resectability (en-bloc vs. piecemeal resection). Endoscopic data were reviewed by consensus of two endoscopists. Key endoscopic criteria were gross morphology (evenly elevated, unevenly elevated, and flat), hyperemic change, mucosal defect, and spontaneous bleeding., Results: Of 3037 cases, which underwent margin-negative ER, 22 developed local recurrence (mean age, 63.8 years; 72.9% male). En-bloc resection was achieved in 20 of the 22 (90.9%). Flat endoscopic morphology without hyperemic changes predicted non-recurrence at the scar with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 95.5%, 68.2%, 2.6%, 99.94%, and 73.6%, respectively. For patients who underwent en-bloc resection for differentiated EGC, these values were 100%, 71.4%, 3.0%, 100%, and 75.8%, respectively., Conclusions: Routine follow-up biopsies may be unnecessary when follow-up endoscopy reveals flat mucosa without hyperemic changes at the scar, especially for en-bloc resected and differentiated EGCs., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Selenium has been reported to induce the expression of some cytoprotective enzymes, which may account for its chemoprotective and chemopreventive effects. However, it remains largely unresolved whether these effects are exerted by selenium itself or mediated by its metabolite(s). In the present study, methylseleninic acid (MSeA), a monomethylated selenium, induced the expression of NAD(P)H:quinone oxidoreductase-1 (NQO-1) in human Chang liver cells. Expression of NQO-1 and other antioxidant/stress response genes is primarily regulated by the transcription factor NF-E2-related factor2 (Nrf2). Exposure of human Chang liver cells to MSeA (3 μM) increased nuclear translocation of Nrf2 and binding to antioxidant response elements. Silencing Nrf2 markedly reduced the MSeA-induced NQO-1 expression. In comparison with embryonic fibroblasts from Nrf2 wild-type mice, those from Nrf2 knockout mice failed to induce NQO-1 expression when treated with MSeA. Moreover, MSeA treatment enhanced ubiquitination of Keap1, but repressed Nrf2 ubiquitination. Pretreatment of cells with dithiothreitol abrogated the MSeA-induced NQO-1 expression, suggesting that MSeA causes Keap1 thiol modification. MSeA-induced NQO-1 upregulation was attenuated in cells harbouring the mutant Keap1 in which the cysteine 151 residue was replaced by serine. Oral administration of MSeA (1 mg/kg) by gavage to mice induced hepatic NQO-1 expression. Similar to MSeA, methylselenol generated from selenomethionine by methioninase activity induced NQO-1 expression. In conclusion, MSeA, the immediate precursor of methylselenol, upregulates the expression of NQO-1 via the Keap1-Nrf2 signaling. The above findings suggest that biological activities of selenium are dependent on the nature of the metabolites as well as the type of ingested selenium formulations., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Scope: The health beneficial effects of docosahexaenoic acid (DHA) have been attributed to its anti-inflammatory properties. However, the molecular mechanism underlying anti-inflammatory effects of DHA remains largely elusive., Methods and Results: In the present study, DHA was found to suppress the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) induced by Helicobacter pylori infection in human gastric cancer AGS cells. Notably, DHA induced expression of suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3. Knockdown of SOCS3 abolished the suppressive effect of DHA on STAT3(Tyr705) phosphorylation induced by H. pylori infection. DHA also induced nuclear translocation, DNA binding, and transcriptional activities of peroxisome proliferator-activated receptor gamma (PPARγ) in AGS cells. Knockdown of PPARγ inhibited the transcription of SOCS3 and attenuated the suppressive effect of DHA on phosphorylation of STAT3(Tyr705) induced by H. pylori. The PPARγ antagonist bisphenol A diglycidyl ether also mitigated the suppressive effect of DHA on H. pylori-induced phosphorylation of STAT3(Tyr705) . In addition, DHA inhibited the expression of c-Myc, which was attenuated in the AGS cells harboring SOCS3 specific siRNA. DHA also markedly decreased anchorage-independent growth of AGS cells infected by H. pylori., Conclusion: DHA inhibits H. pylori-induced STAT3 phosphorylation in a PPARγ/SOCS3-dependent manner., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene; PIC) is a naturally occurring stilbene present in diverse plant sources. PIC is a hydroxylated analog of resveratrol and produced from resveratrol by microsomal cytochrome P450 1A11/2 and 1B1 activities. Like resveratrol, PIC has a broad spectrum of health beneficial effects, many of which are attributable to its antioxidative and anti-inflammatory activities. PIC exerts anticarcinogenic effects by targeting specific proteins involved in regulating cancer cell proliferation, survival/death, invasion, metastasis, angiogenesis, etc. in tumor microenvironment. PIC also has other health promoting and disease preventing functions, such as anti-obese, antidiabetic, neuroptotective, cardioprotective, anti-allergic, anti-aging properties. This review outlines the principal biological activities of PIC and underlying mechanisms with special focus on intracellular signaling molecules/pathways involved.

Objective: EUS-guided fine needle biopsy (EUS-FNB) was introduced to obtain tissue cores. However, data on the efficacy of EUS-FNB for the diagnosis of gastric subepithelial tumors (SET) are limited. This study was aimed to determine the tissue acquisition and diagnostic yield of EUS-FNB using a novel 22-gauge FNB needle., Material and Methods: Between May 2012 and February 2014, we retrieved data on 78 consecutive patients who underwent 22-gauge EUS-FNB for tissue sampling of gastric SET larger than 2 cm. Relevant tumor and EUS-related parameters were reviewed retrospectively., Results: The median tumor diameter was 2.8 cm and tumors were punctured successfully in 77 SET (98.7%). EUS-FNB was diagnostic in 81.8% of SET (63/77), by obtaining core biopsy tissue in 96.8% (61/63) and aspirates in 27.0% (17/63). FNB specimens permitted immunostaining for the diagnosis of gastrointestinal stromal tumors (GIST) in 30 SET (47.6%), 20 leiomyomas (31.7%), and 3 schwannomas (4.8%). Diagnoses could be made without immunostaining in 10 SET (15.9%). Tissue adequacy was optimal in 85.7% of FNB specimens by endosonographers' on-site visual evaluation. Endosonographers' evaluation of tissue adequacy was the only factor significantly associated with a higher diagnostic yield in univariate analysis. No adequate high-power fields for GIST risk stratification were available in FNB specimens. There was a single case of post-procedural bleeding (1.3%)., Conclusion: EUS-FNB using 22-gauge needle obtains a high yield for the diagnosis of gastric SET ≥2 cm, mostly via core tissue acquisition. Endosonographers should pay careful attention to the adequacy of FNB specimens.

Tobacco smoking is currently on the rise among women, and can pose a greater health risk. In order to understand the nature of the increase in smoking prevalence among women, we focused on the vulnerability of women to smoking behaviors--smoking cessation or tobacco addiction--and performed a systematic review of the socioeconomic and intrinsic factors as well as tobacco ingredients that affect women's susceptibility to smoking tobacco. We observed that nicotine and other tobacco components including cocoa-relatives, licorice products, and menthol aggravate tobacco addiction in women rather than in men. Various genetic and epigenetic alterations in dopamine pathway and the pharmaco-kinetics and -dynamic factors of nicotine also showed potential evidences for high susceptibility to tobacco addiction in women. Therefore, we suggest systemic approaches to prevent tobacco smoking-related health risks, considering gene-environment-gender interaction.

Although apolipoprotein B100 (ApoB100) plays a key role in peripheral fat deposition, it is not considered a suitable therapeutic target in obesity. In the present study we describe a novel ApoB100 mimotope, peptide pB1, and the use of pB1-based vaccine-like formulations (BVFs) against high-fat diet (HFD)-induced obesity. In HFD- compared with chow-fed adolescent mice, BVFs reduced the 3-month body-weight gains attributable to increased dietary fat by 44-65%, and prevented mesenteric fat accumulation and liver steatosis. The body-weight reductions paralleled the titres of pB1-reactive immunoglobulin G (IgG) antibodies, and pB1-reactive antibodies specifically recognized native ApoB100 and a synthetic peptide from the C-terminal half of ApoB100. In cultured 3T3L1 adipocytes, anti-pB1 antibodies increased lipolysis and inhibited low-density lipoprotein (LDL) uptake. In cultured RAW 264.7 macrophages, the same antibodies enhanced LDL uptake (without causing foam cell formation). These findings make ApoB100 a promising target for an immunization strategy against HFD-induced obesity., (© 2016 The Author(s).)

The aim of this study was to investigate with endoscopic ultrasound (EUS) the features of the gastric wall that can be used to predict malignant disease in patients with large gastric folds. We retrospectively reviewed the EUS findings of 65 patients (26 with benign and 39 with malignant disease) with large gastric folds on endoscopy and EUS and analyzed the predictors of malignant disease (e.g., gastric wall thickness, preservation of five-layered structure, thickened layers). Gastric wall thickness (≥9.8 mm), thickened deep layer, thickened muscularis propria and non-preserved wall layer structures were significantly more prevalent in patients with malignant disease on EUS. Among them, gastric wall thickness (≥9.8 mm) (odds ratio = 6.72, 95% confidence interval = 1.23-36.73, p = 0.028) and thickened muscularis propria (odds ratio = 37.14, 95% confidence interval = 7.02-196.49, p < 0.001) were significantly associated with malignant disease. Our data indicate that EUS is a useful tool for assessing large gastric folds and that gastric wall thickness (≥9.8 mm) and thickened muscularis propria are significant features predictive of malignant disease on EUS., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

The paper reports a facile one-pot synthesis of core@shell nanoparticles (NPs) composed of Au core and graphene oxide nanocolloid (GON) shell. Unique properties of Au NPs and GON can be incorporated into a single nanohybrid structure to provide desirable functions for theranosis such as localized surface plasmon resonance, Raman scattering, amphiphilic surface, and photothermal conversion. Synthesis of Au@GON NPs is achieved by simple one-pot reaction in aqueous phase utilizing GON as a reducing and stabilizing agent without any additional reducing agent. The zinc phthalocyanine, a photosensitizer, loaded Au@GON NPs show excellent multifunctional properties for combinational treatment of photothermal and photodynamic therapy in addition to Raman bioimaging with low cytotoxicity., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background/aims: The efficacy of surveillance for esopha-geal squamous cell neoplasia (ESCN) in patients with head and neck squamous cell carcinoma (HNSCC) remains contro-versial. Our study aimed to provide clinical data concerning the necessity of surveillance for detecting early ESCN in pa-tients with HNSCC., Methods: We retrospectively reviewed the data from 714 patients who were pathologically confirmed as having HNSCC (n=236 oral cavity cancers, 137 oropha-ryngeal cancers, 87 hypopharyngeal cancers, and 254 la-ryngeal cancers)., Results: Of 714 patients, during a median follow-up of 31 months, 48 ESCNs (37 synchronous and 11 metachronous) were detected in 36 patients (5%). Fifteen synchronous lesions (40.3%) were early ESCN, whereas nine metachronous lesions (81.8%) were early ESCN. The 3-year survival rates of HNSCC only and HNSCC combined with ESCN were 71.2% and 48.2%, respectively (p<0.001). Among 36 patients with ESCN, the 3-year survival rates for early and advanced ESCN were 77.7% and 21.7%, respec-tively (p=0.01). In the multivariate analysis, alcohol consump-tion and hypopharyngeal cancer were significant factors associated with the development of ESCN., Conclusions: HN-SCC patients with early ESCN were similar in prognosis with patients without ESCN, in contrast to patients with advanced ESCN. Therefore, surveillance for the early detection of ESCN in patients with HNSCC, especially in alcohol drinkers and those with hypopharyngeal cancer, is warranted. (Gut Liver, 2015;9159-166).

Background/aims: To evaluate the yields and utility of 19-gauge (G) Trucut biopsy (TCB) versus 22 G fine needle aspiration (FNA) for diagnosing gastric subepithelial tumors (SETs)., Methods: We retrieved data for 152 patients with a gastric SET larger than 2 cm who had undergone endoscopic ultrasonography (EUS)-guided 19 G TCB (n=90) or 22 G FNA (n=62). Relevant clinical, tumor-specific, and EUS procedural information was reviewed retrospectively., Results: A specific diagnosis was made for 76 gastrointestinal stromal tumors (GISTs) and 51 non-GIST SETs. The diagnostic yield of TCB was greater than that of FNA (77.8% vs. 38.7%, p<0.001). The percentage of non-diagnostic specimens (suspicious and insufficient) was significantly lower in the TCB group (6.7% and 15.5%, respectively) than in the FNA group (22.6% and 38.7%, respectively; both p<0.001). TCB accurately diagnosed 90.9% of GISTs and 81.1% of non-GIST SETs, whereas FNA accurately diagnosed 68.8% of GISTs and 14.3% of non-GIST SETs. There were nine technical failures with TCB, and the rate of adverse events did not differ between the groups (TCB vs. FNA, 3.3% vs. 8.1%; p=0.27)., Conclusions: Nineteen-gauge TCB is safe and highly valuable for diagnosing gastric SETs larger than 2 cm if technical failure can be avoided.

Objective: To investigate the prevalence and associations of cortical superficial siderosis (cSS) utilizing MRI markers of cerebral small vessel disease and amyloid burden assessed through in vivo amyloid imaging in a cognitively impaired population., Methods: Gradient-recalled echo, T2*-weighted MRIs from 232 patients (Alzheimer disease-related cognitive impairment [ADCI], n = 90; subcortical vascular cognitive impairment [SVCI], n = 142) were reviewed for cSS. All subjects underwent in vivo amyloid imaging using [(11)C] Pittsburgh compound B (PiB)-PET. A multivariate logistic regression model was constructed to evaluate the predictive factors of cSS. A follow-up MRI was performed in 154 (66.4%) of 232 patients., Results: Twelve patients (5.2%) with cSS were equally distributed in ADCI (n = 6) and SVCI (n = 6) groups, but cSS was not present in any of the patients with a negative PiB scan. cSS was associated with markers of cerebral amyloid angiopathy, including higher global PiB retention ratio, APOE ε2 allele presence, and a strictly lobar distribution of cerebral microbleeds. Of those patients with baseline cSS, 33% showed progression over time; there were 2 cases of symptomatic intracranial hemorrhage., Conclusions: cSS occurred in both ADCI and SVCI groups, but not in patients with amyloid-negative SVCI, supporting the hypothesis that cSS reflects an amyloid rather than ischemic etiology. The associations with strictly lobar cerebral microbleeds and APOE ε2 suggest that cerebral amyloid angiopathy, with increased vascular fragility related to APOE genotype, contributes to cSS in this population, with a high risk of progression over time and future intracranial hemorrhage., (© 2015 American Academy of Neurology.)

Tobacco smoking is a well-known cause of various diseases, however, its toxic mechanisms for diseases are not completely understood, yet. Therefore, we performed biological monitoring to find tobacco smoking-responsive mechanisms including oxidative stress in Korean men (N=36). Whole genome microarray analyses were performed with peripheral blood from smokers and age-matched nonsmokers. We also performed qRT-PCR to confirm the microarray results and compared the gene expression of blood to those of buccal cells. To assess the effects of tobacco smoking on oxidative stress, we analyzed urinary levels of malondialdehyde (MDA), a lipid peroxidation marker, and performed PCR-based arrays on reactive oxygen species (ROS)-related genes. As results, 34 genes were differently expressed in blood between smokers and nonsmokers (ps<0.01 and >1.5-fold change). Particularly, the genes involved in immune responsive pathways, e.g., the Fcγ-receptor mediated phagocytosis and the leukocyte transendothelial migration pathways, were differentially expressed between smokers and nonsmokers. Among the above genes, the ACTG1, involved in the maintenance of actin cytoskeleton, cell migration and cancer metastasis, was highly expressed by smoking in both blood and buccal cells. Concerning oxidative stress, smokers showed high levels of urinary MDA and down-regulation of expressions of antioxidant related genes including TPO, MPO, GPX2, PTGR1, and NUDT1 as compared to nonsmokers (ps<0.05). In conclusion, these results suggest that systemically altered immune response and oxidative stress can be tobacco-responsive mechanisms for the related diseases. Based on consistent results in blood and buccal cells, expression of the ACTG1 can be a tobacco smoking-responsive biomarker., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The 26S proteasome is the primary machinery that degrades ubiquitin (Ub)-conjugated proteins, including many proteotoxic proteins implicated in neurodegeneraton. It has been suggested that the elevation of proteasomal activity is tolerable to cells and may be beneficial to prevent the accumulation of protein aggregates. Here we show that purified proteasomes can be directly transported into cells through mesoporous silica nanoparticle-mediated endocytosis. Proteasomes that are loaded onto nanoparticles through non-covalent interactions between polyhistidine tags and nickel ions fully retain their proteolytic activity. Cells treated with exogenous proteasomes are more efficient in degrading overexpressed human tau than endogenous proteasomal substrates, resulting in decreased levels of tau aggregates. Moreover, exogenous proteasome delivery significantly promotes cell survival against proteotoxic stress caused by tau and reactive oxygen species. These data demonstrate that increasing cellular proteasome activity through the direct delivery of purified proteasomes may be an effective strategy for reducing cellular levels of proteotoxic proteins.

Helicobacter pylori infection has been considered to be one of the major factors implicated in etiology of gastric cancer. Aberrant DNA methylation accounts for epigenetic modifications induced by H. pylori. H. pylori-induced hypermethylation has been linked to enhancement of the rates of metastasis and recurrence in gastric cancer patients. H. pylori-induced gene hypermethylation has been known to be associated with inflammation. However, the molecular mechanisms underlying H. pylori-induced hypermethylation remain largely unknown. This review highlights possible involvement of reactive oxygen/nitrogen species in H. pylori-induced hypermethylation and gastric carcinogenesis.

Background: Placement of self-expandable nitinol stents is useful for the treatment of esophageal and upper gastrointestinal (GI) obstruction. However, complications such as stent migration, tumor overgrowth, and bleeding occur. Although stent migration and tumor overgrowth are well documented in previous studies, the occurrence of bleeding has not been fully evaluated., Purpose: To evaluate the incidence, management strategies, and predictors of bleeding after placement of self-expandable nitinol stents in patients with esophageal and upper GI obstruction., Material and Methods: We retrospectively reviewed the medical records and results of computed tomography and endoscopy of 1485 consecutive patients with esophageal and upper GI obstructions who underwent fluoroscopically guided stent placement., Results: Bleeding occurred in 25 of 1485 (1.7%) patients 0 to 348 days after stent placement. Early stent-related bleeding occurred in 10 patients (40%) and angiographic embolization was used for 5/10. Late bleeding occurred in 15 patients (60%) and endoscopic hemostasis was used for 7/15. Twenty-two of 25 (88%) patients with bleeding had received prior radiotherapy and/or chemotherapy., Conclusion: Bleeding is a rare complication after placement of expandable nitinol stents in patients with esophageal and upper GI obstruction, but patients with early bleeding may require embolization for control. Care must be exercised on placing stents in patients who have received prior radiotherapy or chemotherapy., (© The Foundation Acta Radiologica 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Multiple lines of compelling evidence from clinical and population-based studies support that hyperinsulinemia often accompanying obesity-associated insulin insensitivity promotes colon carcinogenesis. Insulin can acetylate, thereby activating sterol regulator element-binding protein 1 (SREBP-1), a prime transcription factor responsible for expression of genes involved in lipogenesis. Moreover, SREBP-1 upregulates cyclooxygenase-2 (COX-2), a key player in inflammatory signaling. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been known to negatively regulate SREBP-1, but the underlying molecular mechanism is not fully clarified yet. This prompted us to investigate whether DHA could inhibit insulin-induced activation of SREBP-1 and COX-2 expression in the context of its potential protective effect on obesity-induced inflammation and carcinogenesis. SIRT1, a NAD(+)-dependent histone/non-histone protein deacetylase, has been reported to inhibit intracellular signaling mediated by SREBP-1 through deacetylation of this transcription factor. We found that DHA induced SIRT1 expression in CCD841CoN human colon epithelial cells. DHA abrogated insulin-induced acetylation as well as expression of SREBP-1 and COX-2 upregulation. Insulin-induced stimulation of CCD841CoN cell migration was also inhibited by DHA. These effects mediated by DHA were attenuated by pharmacologic inhibition of SIRT1. Hyperinsulinemia or insulin resistance is considered to be associated with obesity-associated inflammation. Genetically obese (ob/ob) mice showed higher colonic expression levels of both SREBP-1 and COX-2 than did normal lean mice. Likewise, expression of SREBP-1 and COX-2 was elevated in human colon tumor specimens compared with surrounding normal tissues. In conclusion, DHA may protect against obesity-associated inflammation and colon carcinogenesis by suppressing insulin-induced activation of SREBP-1 and expression of COX-2 through up-regulation of SIRT1., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Genistein, an isoflavone present in soy products, has chemopreventive effects on mammary carcinogenesis. In the present study, we have investigated the effects of genistein on phorbol ester-induced expression of cyclooxygenase-2 (COX-2) that plays an important role in the pathophysiology of inflammation-associated carcinogenesis. Pretreatment of cultured human breast epithelial (MCF10A) cells with genistein reduced COX-2 expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). There are multiple lines of evidence supporting that the induction of COX-2 is regulated by the eukaryotic transcription factor NF-κB. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-κB as well as degradation of IκB. However, genistein abrogated the TPA-induced transcriptional activity of NF-κB as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-κB and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-κB phosphorylation was abolished by pharmacological inhibition of extracellular signal-regulated kinase (ERK). Likewise, pharmacologic inhibition or dominant negative mutation of ERK suppressed phosphorylation of p65. The above findings, taken together, suggest that genistein inhibits TPA-induced COX-2 expression in MCF10A cells by blocking ERK-mediated phosphorylation of p65 and its subsequent interaction with CBP and TBP., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Overproduction of prostaglandin E2 (PGE2) has been reported to be implicated in carcinogenesis. The intracellular level of PGE2 is maintained not only by its biosynthesis, but also by inactivation/degradation. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of oncogenic PGE2 to a biologically inactive keto metabolite. In the present study, we demonstrate that 15-deoxy-Δ(12,14)-prostaglandin J2 (15 d-PGJ2), one of the terminal products of cyclooxygenase-2, updregulates the expression and the activity of 15-PGDH in human breast cancer MDA-MB-231 cells. By using deletion constructs of the 15-PGDH promoter, we have found that E-twenty six (Ets) is the most essential determinant for 15-PGDH induction. 15 d-PGJ2 induced phosphorylation of Elk-1, one of Ets transcription factor family members, in the nucleus. Knockdown of Elk-1 abolished the ability of 15 d-PGJ2 to upregulate 15-PGDH expression. Furthermore, 15 d-PGJ2-mediated activation of Elk-1 was found to be dependent on activation of extracellular-signal related kinase (ERK) 1/2. Treatment of U0126, a pharmacological inhibitor of MEK1/2-ERK, abolished phosphorylation and DNA binding of Elk-1 as well as 15-PGDH induction in 15 d-PGJ2-treated MDA-MB-231 cells. Moreover, 15 d-PGJ2 generated reactive oxygen species (ROS), which contribute to the expression of 15-PGDH as well as phosphorylation of ERK1/2 and Elk-1. 15 d-PGJ2 inhibited the migration of MDA-MB-231 cells, which was attenuated by transient transfection with 15-PGDH siRNA. Taken together, these findings suggest that 15 d-PGJ2 induces the expression of 15-PGDH through ROS-mediated activation of ERK1/2 and subsequently Elk-1 in the MDA-MB-231 cells, which may contribute to tumor suppressive activity of this cyclopentenone prostaglandin., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Exposure to ultraviolet B (UVB) radiation, a complete environmental carcinogen, induces oxidative and inflammatory skin damage, thereby increasing the risk of skin carcinogenesis. The antioxidant and anti-inflammatory activities of a wide variety of plant polyphenols have been reported. Rutin (3-rhamnosyl-glucosylquercetin), a polyphenol present in many edible plants, possesses diverse pharmacological properties including antioxidant, anti-inflammatory, antimutagenic and anticancer activities. The present study was aimed to investigate the effects of rutin on UVB-induced inflammation in mouse skin in vivo. Topical application of rutin onto the dorsal skin of female HR-1 hairless mice 30 min prior to UVB irradiation diminished epidermal hyperplasia and the levels of proteins modified by 4-hydroxynonenal, which is a biochemical hallmark of lipid peroxidation. Topical application of rutin also significantly inhibited UVB-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), two representative inflammatory enzymes, in hairless mouse skin. Rutin inhibited the DNA binding of activator protein-1 (AP-1) and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in mouse skin exposed to UVB. Moreover, rutin attenuated UVB-induced phosphorylation of p38 mitogen-activated protein (MAP) kinase and c-Jun-N-terminal kinase (JNK). Pharmacological inhibition of p38 MAP kinase and JNK decreased UVB-induced expression of COX-2 in mouse skin. Taken together, these findings suggest that rutin exerts anti-inflammatory effects in UVB-irradiated mouse skin by inhibiting expression of COX-2 and iNOS, which is attributable to its suppression of p38 MAP kinase and JNK signaling responsible for AP-1 activation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that has antioxidant and cytoprotective functions. However, HO-1 has oncogenic functions in cancerous or transformed cells. In the present work, we investigated the effects of HO-1 on the expression of p53 induced by 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) in human breast cancer (MCF-7) cells. Treatment of MCF-7 cells with 15d-PGJ2 led to time-dependent increases in the expression of p53 as well as HO-1. Upregulation of p53 expression by 15d-PGJ2 was abrogated by si-RNA knock-down of HO-1. In MCF-7 cells transfected with HO-1 si-RNA, 15d-PGJ2 failed to induce expression of p53 as well as HO-1. In addition, HO-1 inducers enhanced the p53 expression. We speculated that iron, a by-product of HO-1-catalyzed reactions, could mediate 15d-PGJ2-induced p53 expression. Upregulation of p53 expression by 15d-PGJ2 was abrogated by the iron chelator desferrioxamine in MCF-7 cells. Iron released from heme by HO-1 activity is mostly in the Fe(2+) form. When MCF-7 cells were treated with the Fe(2+)-specific chelator phenanthroline, 15d-PGJ2-induced p53 expression was attenuated. In addition, levels of the Fe-sequestering protein H-ferritin were elevated in 15d-PGJ2-treated MCF-7 cells. In conclusion, upregulation of p53 and p21 via HO-1 induction and subsequent release of iron with accumulation of H-ferritin may confer resistance to oxidative damage in cancer cells frequently challenged by redox-cycling anticancer drugs.

Sulforaphane, an isothiocyanate present in cruciferous vegetables, has been reported to possess anti-inflammatory and cancer chemopreventive properties. However, the molecular mechanisms by which sulforaphane suppresses inflammation and carcinogenesis are yet to be fully elucidated. Since the aberrant expression of cyclooxygenase-2 (COX-2) links inflammation and cancer, the present study was aimed to elucidate the mechanisms by which sulforaphane modulates COX-2 overexpression in human mammary epithelial (MCF-10A) cells stimulated with a prototypic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of MCF-10A cells with sulforaphane significantly inhibited TPA-induced expression of COX-2 protein and its mRNA transcript. Transient transfection of cells with deletion mutant constructs of COX-2 promoter revealed that the transcription factor nuclear factor-kappaB (NF-κB) plays a key role in TPA-induced COX-2 expression in MCF-10A cells. Pretreatment with sulforaphane significantly attenuated nuclear localization, DNA binding and the transcriptional activity of NF-κB through inhibition of phosphorylation and subsequent degradation of IκBα in MCF-10A cells stimulated with TPA. Sulforaphane also attenuated TPA-induced activation of IκB kinases (IKK), NF-κB-activating kinase (NAK) and extracellular signal-regulated kinase-1/2 (ERK1/2). Pharmacological inhibition of IKK or transient transfection of cells with dominant-negative mutant forms of this kinase abrogated TPA-induced NF-κB activation and COX-2 expression. In addition, the blockade of ERK1/2 activation negated the catalytic activity of IKKα, but not that of IKKβ, whereas silencing NAK by specific siRNA abrogated the IKKβ activity in TPA-treated cells. Taken together, sulforaphane inhibits TPA-induced NF-κB activation and COX-2 expression in MCF-10A cells by blocking two distinct signaling pathways mediated by ERK1/2-IKKα and NAK-IKKβ., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Endoscopic forceps biopsy (EFB) is a major diagnostic procedure for gastric epithelial neoplasia (GEN). However, discrepancy between the result of EFB and endoscopic resection (ER) is not uncommon. Thus, there is controversy over whether specimens obtained by EFB are optimal for diagnosis of GEN. We investigated the discrepancy between EFB and ER in the diagnosis of GEN., Methods: A total of 1,850 GEN cases were histologically diagnosed with EFB, including 954 low-grade dysplasias (LGDs), 315 high-grade dysplasias (HGDs), and 581 carcinomas. Following diagnosis with EFB, all patients were treated with ER. We retrospectively reviewed the pathologic findings and patient characteristics and analyzed predictors for the discrepancy between the two procedures (largest diameter, number of biopsy fragments, number of biopsy fragments/largest diameter, location, macroscopic type, color, surface unevenness, and erosion)., Results: The overall discrepancy rate between EFB and ER was 31.7 % (587/1,850). Among the discordant group, 440 (23.9 %) cases showed a higher grade of disease after ER; 229 of the 954 LGDs (24.0 %) were diagnosed as HGD or carcinoma, 166 of the 315 HGDs (52.7 %) as carcinoma, and 45 of the 581 differentiated carcinomas (7.7 %) as undifferentiated carcinoma. In the LGD group with EFB, the largest diameter (≥1.8 cm; P < 0.001), surface unevenness (P = 0.014), and depressed macroscopic type (P < 0.001) were factors associated with discrepancy. In the carcinoma group with EFB, flat macroscopic type (P = 0.043) was the only significant factor. In the HGD group with EFB, there were no significant factors for discrepancy., Conclusions: EFB can be insufficient for diagnosing GENs, and ER can be considered not only as treatment but also as a diagnostic modality in GEN. It is especially pertinent to all cases of HGD regardless of their endoscopic features and to cases of LGDs with the largest lesion diameter ≥1.8 cm, surface unevenness, or a depressed macroscopic type.

Ginsenoside Rg3, one of the major ingredients of heat-processed ginseng, has been reported to inhibit the growth of various cancer cells. We previously reported that Rg3 inhibited the proliferation and induced apoptosis of breast cancer (MDA-MB-231) cells. In the present study, we have explored the mechanism underlying the anti-proliferative and proapoptotic effects of Rg3 in MDA-MB-231 cells, which have constitutively activated NF-κB and the mutant form of p53. Rg3 inhibited DNA binding and transcriptional activity of NF-κB and these effects were attributable to its suppression of IKKβ activity, degradation of IκBα and subsequent nuclear translocation of the p65 subunit of NF-κB. Similarly, the constitutive activation of ERK and Akt through phosphorylation was gradually reduced in MDA-MB-231 cells treated with Rg3. The pharmacological inhibitors of these kinases both U0126 (MEK1/2 inhibitor) and LY294002 (PI3K inhibitor) abrogated the NF-κB DNA binding activity in MDA-MB-231 cells. In addition, Rg3 treatment lowered the levels of the mutant p53 in concentration- and time-dependent manners. Rg3 also increased the association between p53 and its negative regulator Mdm2 in MDA-MB-231 cells. These findings suggest that Rg3 induced apoptosis in MDA-MB-231 cells, which is mediated by blocking NF-κB signaling via inactivation of ERK and Akt as well as destabilization of mutant p53.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential component of cellular defense against a vast variety of endogenous and exogenous insults, including oxidative stress. Nrf2 acts as a master switch in the circuits upregulating the expression of various stress-response proteins, especially heme oxygenase-1 (HO-1). Paradoxically, however, recent studies have demonstrated oncogenic functions of Nrf2 and its major target protein HO-1. Levels of Nrf2 and HO-1 are elevated in many different types of human malignancies, which may facilitate the remodeling of the tumor microenvironment making it advantageous for the autonomic growth of cancer cells, metastasis, angiogenesis, and tolerance to chemotherapeutic agents and radiation and photodynamic therapy. In this context, the cellular stress response or cytoprotective signaling mediated via the Nrf2-HO-1 axis is hijacked by cancer cells for their growth advantage and survival of anticancer treatment. Therefore, Nrf2 and HO-1 may represent potential therapeutic targets in the management of cancer. This review highlights the roles of Nrf2 and HO-1 in proliferation of cancer cells, their tolerance/resistance to anticancer treatments, and metastasis or angiogenesis in tumor progression., (© 2013 Elsevier Inc. All rights reserved.)

Diallyl sulfide, diallyl disulfide, and daillyl trisulfide (DATS) are major volatile components of garlic oil. In this study, we assessed their relative potency in inducing antioxidant enzyme expression. Among the three organosulfur compounds, DATS was found to be most potent in inducing heme oxygenase-1 (HO-1) and, Nad(p)h: quinone oxidoreductase-1 (NQO1) in human gastric epithelial (AGS) cells. Furthermore, DATS administration by gavage increased the expression of HO-1 and NQO1 in C57BL/6 mouse stomach. Treatment with DATS increased the accumulation of nuclear factor-erythroid-2-related factor-2 (Nrf2) in the nucleus of cultured AGS cells and in mouse stomach in vivo. The DATS-induced expression of HO-1 and NQO1 was abrogated in the cells transiently transfected with Nrf2-siRNA or in the embryonic fibroblasts from Nrf2-null mice, indicating that Nrf2 is a key mediator of the cytoprotective effects of DATS. Pretreatment of AGS cells with N-acetylcysteine or dithiothreitol attenuated DATS-induced nuclear localization of Nrf2 and the expression of HO-1 and NQO1. Cysteine-151, -273 and -288 of Kelch-like ECH-associated protein-1 (Keap1), a cytosolic repressor of Nrf2, have been considered to act as a redox sensor and play a role in Nrf2 activation. To determine whether DATS could inactivate Keap1 through thiol modification, we established cell lines constitutively expressing wild type-Keap1 or three different mutant constructs in which cysteine-151, -273, or -288 of Keap1 was replaced with serine by retroviral gene transfer. DATS failed to activate Nrf2, and to induce expression of HO-1 and NQO1 only in Keap1-C288S mutant cells. LC-ESI-MS/MS analysis of recombinant Keap1 treated with DATS revealed that the peptide fragment containing Cys288 gained a molecular mass of 72.1 Da equivalent to the molecular weight of mono-allyl mono-sulfide. Taken together, these findings suggest that DATS may directly interact with the Cys288 residue of Keap1, which partly accounts for its ability to induce Nrf2 activation and upregulate defensive gene expression.

A novel Gram-stain-positive, facultatively anaerobic, non-motile and lactic-acid-producing bacterium, designated strain ORL-24(T), was isolated from the gut of the camel cricket, Diestrammena coreana. Optimal growth occurred at 37 °C, pH 8 and with 0 % (w/v) NaCl. The ratio of l-lactate to d-lactate in strain ORL-24(T) was 96 : 4. Lancefield antigen D was not detected. The strain was negative for oxidase activity and catalase activity. According to a phylogenetic analysis based on 16S rRNA gene sequences, strain ORL-24(T) was most closely related to the type strain of Enterococcus asini (96.9 % similarity). Comparative pheS and rpoA sequence analyses of strain ORL-24(T) indicated that the strain belonged to the genus Enterococcus. The major fatty acids were C16 : 0 and C18 : 1ω9c. The DNA G+C content was 41.3 mol%. Based on phenotypic, genotypic and phylogenetic analyses, strain ORL-24(T) represents a novel species of the genus Enterococcus, for which the name Enterococcus diestrammenae is proposed. The type strain is ORL-24(T) ( = KACC 16708(T) = JCM 18359(T)).

Background: Self-expandable metallic stent placement is widely used to manage malignant gastroduodenal obstructions. However, the techniques and effectiveness of additional gastroduodenal stent placement have not been evaluated until now., Purpose: To evaluate the technical feasibility, clinical effectiveness, and complications of additional gastroduodenal stent placement in patients with recurrent obstructive symptoms after primary gastroduodenal stenting., Material and Methods: We retrospectively analyzed data from 68 consecutive patients who had additional gastroduodenal stents placed for recurrent obstruction. Clinical effectiveness was assessed using technical and clinical success rates, gastric outlet obstruction score improvement after primary and additional stent placement, and complications., Results: Additional stent placement was technically successful in 66 of the 68 patients (97%) and symptomatic improvement was achieved in 58 (85%). The gastric outlet obstruction score improved after primary stent placement (0.3 to 1.4) and additional stent placement (0.2 to 1.4). Complications occurred in 12 of 68 patients (18%) and were caused by tumor overgrowth (n = 7), stent collapse (n = 2), food impaction (n = 1), jaundice (n = 1), and duodenal perforation (n = 1)., Conclusion: Additional gastroduodenal stent placement is technically feasible and clinically effective for patients with recurrent gastric outlet obstruction after stent placement.

The multifunctional DNAzyme (Dz) delivery system is developed based on nano-sized graphene oxide (nGO) for simultaneous detection and knockdown of the target gene. The Dz/nGO complex system allowed convenient monitoring of HCV mRNA in living cells and silencing of the HCV gene expression by Dz-mediated catalytic cleavage concurrently.

Epstein-Barr virus (EBV) plays an etiological role in various diseases. EBV-associated lymphoproliferative disorder (LPD) is usually observed in individuals with congenital or acquired immune deficiencies but was also recently reported in non-immunocompromised individuals. Two cases of immunocompetent patients with EBV-associated T-cell LPD of the small bowel and colon who were initially misdiagnosed as Crohn's disease (CD) are reported here. EBV-associated T-cell LPD with primary gastrointestinal tract involvement can manifest as multiple discrete ulcers of the small and/or large bowel that are similar to the lesions found in CD or intestinal tuberculosis. However, when patients have multiple intestinal ulcers that are not typical of CD or intestinal tuberculosis and the clinical course is unusual, clinicians should consider the possibility of EBV-associated LPD that involves the gastrointestinal tract because the treatment strategy and prognosis are completely different., (Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: There are insufficient reports on the outcomes and local recurrence rates for gastric neoplasms treated using argon plasma coagulation (APC). The purpose of this study was to analyze the clinical outcomes in early gastric cancer or gastric adenoma patients following APC treatment., Methods: Seventy-one patients were enrolled and all underwent APC at the Asan Medical Center between July 2007 and August 2011. Clinical and oncological outcomes were analyzed., Results: The median follow-up period was 20 months (interquartile range 13-29 months). Among the 71 patients we evaluated, nonlifting after submucosal saline injection was found in 35 patients and 15 patients (21.2%) experienced local recurrence with a median period of 10 months (IQR 5-13 months). The rate of local recurrence was higher in the nonlifting group and the 40-W group than in the lifting group and the 60- or 80-W groups (31.4 vs. 11.1%, p = 0.045 and 31.7 vs. 6.7%, p = 0.017, respectively). Multivariate analysis showed that the power setting with the 40-W and nonlifting groups after submucosal injection was associated with local recurrence., Conclusions: APC therapy after submucosal saline injection using high power (60 or 80 W) appears to be an effective alternative in the management of gastric neoplasm.

Background: The outcomes of balloon dilation for the treatment of strictures caused by endoscopic submucosal dissection (ESD) have not been evaluated previously. This study was designed to evaluate and compare the effectiveness and complications of balloon dilation for post-ESD strictures and peptic strictures., Methods: The medical records of 14 patients with post-ESD strictures and 48 patients with peptic strictures who underwent fluoroscopically or endoscopically guided balloon dilation between January 1997 and April 2011 at the Asan Medical Center in Korea were reviewed retrospectively., Results: The technical success rates (defined as successful dilation without major complications) of the post-ESD and peptic stricture groups were 92.9% (13/14) and 93.8% (45/48), respectively (p = 1.000). For the post-ESD and peptic stricture groups, the clinical success rates (defined as symptom improvement, as determined by the patient) at 1 month were 92.9% (13/14) and 83.3% (40/48), respectively (p = 0.67). Their clinical success rates at 6 months were 71.4% (10/14) and 70 % (28/40), respectively (p = 1.000). The mean weight gains of the post-ESD stricture group 1 and 6 months after balloon dilation were 1.1 and 4.8 kg, respectively, whereas the peptic group gained 1.4 and 3.4 kg, respectively (p = 0.814). All complications were perforations. The complication rates of the post-ESD and peptic stricture groups were 7.1 % (1/14) and 10.5 % (5/48), respectively (p = 1.000)., Conclusions: Balloon dilation is an effective and safe treatment for post-ESD strictures.

Diallyl trisulfide (DATS), one of the volatile constituents of garlic oil, has been reported to possess antioxidant, anti-inflammatory, and anti-carcinogenic properties. In this study, DATS (10μmol) given orally for 7days before and for another 7days after starting administration of 2.5% dextran sulfate sodium (DSS) in drinking water protected against colitis induced by DSS in male ICR mice. DATS significantly inhibited the DSS-induced DNA binding of NF-κB, phosphorylation of IκBα and the expression of pro-inflammatory proteins, such as cyclooxygenase-2 and inducible nitric oxide synthase, which are major target proteins of NF-κB. The DSS-induced DNA binding and phosphorylation at the Tyr 705 residue of signal transducer and activator of transcription 3 (STAT3), and expression of its major target protein cyclin D1 in mouse colonic mucosa were also attenuated by DATS administration. Likewise, DSS-induced phosphorylation of extracellular signal-regulated kinase 1/2 was suppressed by DATS treatment. In conclusion, DATS ameliorates the DSS-induced mouse colitis presumably by blocking inflammatory signaling mediated by NF-κB and STAT3., (Copyright © 2013 Elsevier Inc. All rights reserved.)

MicroRNA (miRNA) is an important small RNA which regulates diverse gene expression at the post-transcriptional level. miRNAs are considered as important biomarkers since abnormal expression of specific miRNAs is associated with many diseases including cancer and diabetes. Therefore, it is important to develop biosensors to quantitatively detect miRNA expression levels. Here, we develop a nanosized graphene oxide (NGO) based miRNA sensor, which allows quantitative monitoring of target miRNA expression levels in living cells. The strategy is based on tight binding of NGO with peptide nucleic acid (PNA) probes, resulting in fluorescence quenching of the dye that is conjugated to the PNA, and subsequent recovery of the fluorescence upon addition of target miRNA. PNA as a probe for miRNA sensing offers many advantages including high sequence specificity, high loading capacity on the NGO surface compared to DNA and resistance against nuclease-mediated degradation. The present miRNA sensor allowed the detection of specific target miRNAs with the detection limit as low as ~1 pM and the simultaneous monitoring of three different miRNAs in a living cell.

Aims: To evaluate the effects of oligonol administration on experimentally induced colitis and colonic adenoma formation., Results: Oral administration of oligonol protected against mouse colitis induced by dextran sulfate sodium (DSS). Under the same experimental conditions, oligonol administration significantly inhibited the activation of nuclear factor-kappa B and signal transducer and activator of transcription (STAT) 3 and expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and cyclin D1 in the mouse colon. Further, oligonol inhibited azoxymethane-initiated and DSS-promoted adenoma formation in the mouse colon. Oligonol administration also attenuated lipid peroxidation (malondialdehyde) and protein oxidation (4-hydroxy-2-nonenal), thereby preventing oxidative stress-induced apoptosis of colonic epithelial cells. In vitro studies demonstrated that oligonol treatment reduced lipopolysaccharide-induced expression of interleukin (IL)-1β, tumor necrosis factor α, il-6, cox-2, and inos in murine macrophage RAW 264.7 cells. In another study, oligonol upregulated the antioxidant gene expression in the intestinal epithelial CCD841CoN cells and in the mouse colon., Innovation: Oligonol, an innovative formulation of catechin-type oligomers derived from the lychee fruit extract, was tested in this study for the first time to evaluate its effects on experimentally induced colitis and colonic adenoma formation in mice., Conclusion: Oligonol is effective in protecting against DSS-induced mouse colitis and colon carcinogenesis, suggesting that this polyphenol formulation may have a potential for the amelioration of inflammatory bowel disease and related disorders.

Objective: The purpose of this study was to evaluate the clinical features of patients with gastric conduit strictures after esophagectomy and to report our initial experience in the management of these strictures with fluoroscopically guided balloon dilation, temporary stent placement, or both., Materials and Methods: From January 1996 to January 2012, 12 patients with gastric conduit stricture after esophagectomy underwent fluoroscopic balloon dilation, temporary stent placement, or both. Stent placement was indicated in patients who had gastro-respiratory fistulas or recurrent symptoms within 2 weeks of balloon dilation. Technical and clinical success, complications, and length of strictures were retrospectively evaluated., Results: The mean length of strictures in all patients was 49 mm (range, 21-76 mm). The strictures were accompanied by gastrorespiratory fistulas in four patients. Seven patients with gastric conduit strictures without fistulas underwent 23 balloon dilations. Five patients underwent stent placement owing to gastrorespiratory fistula formation (n = 4) and frequent recurrent symptoms after balloon dilation (n = 1). During a mean follow-up period of 8 months (range, 2-28 months), clinical success was achieved in 11 patients (91.6%) after a single balloon dilation (n = 1), multiple balloon dilations (n = 5), or stent placement (n = 5). Complications occurred in 3 of 10 patients (30%) after balloon dilation and in one of five patients (20%) after stent placement., Conclusion: Gastric conduit strictures are characterized by their substantial length and tend to be accompanied by gastrorespiratory fistulas. Despite relatively high complication and recurrence rates, this study may offer a viable treatment of gastric conduit strictures by using fluoroscopically guided balloon dilation and stent placement.

Background: Rg3, a major ginsenoside derived from heat-processed ginseng, has been reported to have anti-inflammatory and anti-proliferative activities. In our previous studies, Rg3 inhibited phorbol ester-induced cyclooxygenase-2 expression and NF-κB activation in cultured human mammary epithelial (MCF-10A) cells and in mouse skin in vivo. In this study, we investigated Rg3-induced apoptosis in human breast cancer (MDA-MB-231) cells and underlying molecular mechanisms., Methods: After Rg3 treatment, apoptotic cell death of MDA-MB-231 cell was investigated by the MTT reduction assay and measurement of the mitochondrial membrane depolarization. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells as well as measurement of reactive oxygen species. Expression of apoptotic-related proteins was determined by immunoblot analysis., Results: MDA-MB-231 cells treated with Rg3 (30μM) exhibited the increased proportion of hypodiploid or apoptotic cells. Rg3 treatment resulted in an increase in the ratio of proapoptotic Bax to antiapoptotic Bcl-2, depolarization of the mitochondria membrane potential and the release of cytochrome c from mitochondria. Rg3 also induced the proteolytic cleavage of caspase-3 and poly (ADP-ribose) polymerase, which was attenuated by a caspase-3 inhibitor, z-VAD-fmk., Conclusions: Based on these findings, it is likely that Rg3 induces apoptosis in MDA-MB-231 cells via classical mitochondria-dependent caspase activation. These data suggest that Rg3 might be a potential candidate as a breast cancer chemopreventive agent.

Turmeric (Curcuma longa L., Zingiberaceae) has a long history of use in medicine for the treatment of inflammatory conditions. One of the major constituents of turmeric is curcumin (diferuloylmethane), which is responsible for its characteristic yellow color. In the present study, we have examined the chemoprotective effects of curcuminon dextran sulfate sodium (DSS)-induced mouse colitis. For this purpose, we pre-treated male ICR mice with curcumin (0.1 or 0.25 mmol/kg in 0.05% carboxymethyl cellulose) by gavage for a week and then co-treated the animals with curcumin by gavage and 3% DSS in drinking water for another 7 days. Our study revealed that administration of curcumin significantly attenuated the severity of DSS-induced colitis and STAT3 signaling in mouse colon. The levels of the cell cycle regulators CDK4 and cylinD1 were significantly reduced by curcumin administration. Moreover, the expression of p53, which is an upstream regulator of the CDK4-cylinD1 complex, was inhibited by curcumin treatment.

Purpose: To investigate the efficacy of an IN-1233-eluting covered stent in preventing tissue hyperplasia in a rabbit esophageal model., Materials and Methods: The local animal research committee approved all experiments. Esophageal stents were placed in 40 male New Zealand rabbits (weight range, 2.8-3.2 kg). The drug group (D) received IN-1233-eluting covered stents (n = 20); the control group (C) received polyurethane-covered stents (n = 20). Drug loading of IN-1233-eluting covered stent was 10%. Four study groups were formed: C and D animals sacrificed at 4 (D4, C4) and 8 (D8, C8) weeks after stent placement (n = 10). Esophagography was used to assess the percentage of diameter stenosis. Histologic findings of the drug and control stents were compared. The Mann-Whitney U test was used to evaluate differences., Results: The mean percentage ± standard deviation of diameter stenosis was significantly lower in D groups than in C groups at both 4 (C4 = 36.15% ± 12.63, D4 = 7.83% ± 8.12 [P < .001]) and 8 (C8 = 50.21% ± 20.43, D8 = 27.78% ± 14.40 [P = .019]) weeks. Percentage of granulation tissue area (C4 = 33.07% ± 19.11, D4 = 21.59% ± 18.22 [P = .028]; C8 = 44.70% ± 21.71, D8 = 31.97% ± 22.54 [P = .131]), number of epithelial layers (C4 = 4.77 ± 1.55, D4 = 3.37 ± 1.73 [P = .002]; C8 = 5.50 ± 1.38, D8 = 4.50 ± 1.63 [P = .057]), and thickness of submucosal fibrosis (C4 = 2.42 mm ± 1.08, D4 = 1.62 mm ± 0.77 [P = .006]; C8 = 2.89 mm ± 1.00, D8 = 2.07 mm ± 0.71 [P = .007]) were lower in D than in C groups. Inflammatory cell infiltration was significantly higher in D than in C groups (C4 = 2.63 ± 0.81, D4 = 3.33 ± 1.09 [P = .032]; C8 = 2.20 ± 0.81, D8 = 3.00 ± 0.95 [P = .012])., Conclusion: The use of an IN-1233-eluting covered stents decreased tissue hyperplasia secondary to stent placement in a rabbit esophageal model., (© RSNA, 2013.)