Inhibition of GLI Transcriptional Activity and Prostate Cancer Cell Growth and Proliferation by DAX1.

The Hedgehog (Hh) signaling pathway plays an essential role in the initiation and progression of prostate cancer. This is mediated by transcriptional factors belonging to the GLI (glioma-associated oncogene) family, which regulate downstream targets to drive prostate cancer progression. The activity of GLI proteins is tightly controlled by a range of mechanisms, including molecular interactions and post-translational modifications. In particular, mitogenic and oncogenic signaling pathways have been shown to regulate GLI protein activity independently of upstream Hh pathway signaling. Identifying GLI protein regulators is critical for the development of targeted therapies that can improve patient outcomes. This study aimed to identify a novel protein that directly regulates the activity of GLI transcription factors in prostate cancer. We performed gene expression, cellular analyses, and reporter assays to demonstrate that DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) interacts with GLI1 and GLI2, the master regulators of Hh signaling. Interestingly, DAX1 overexpression significantly inhibited Hh signaling by reducing GLI1 and GLI2 activity, prostate cancer cell proliferation, and viability. Our results shed light on a novel regulatory mechanism of Hh signaling in prostate cancer cells. The interaction between DAX1 and GLI transcription factors provides insight into the complex regulation of Hh signaling in prostate cancer. Given the importance of Hh signaling in prostate cancer progression, targeting DAX1-GLI interactions may represent a promising therapeutic approach against prostate cancer. Overall, this study provides new insights into the regulation of the Hh pathway and its role in prostate cancer progression. The findings suggest that DAX1 could serve as a potential therapeutic target for the treatment of prostate cancer.

A modified endoscopic full thickness resection for gastric subepithelial tumors from muscularis propria layer: Novel method.

BACKGROUND AND AIM: The removal of subepithelial tumors (SETs) is challenging, particularly in tumors originating from the muscularis propria (MP) in the upper gastrointestinal (GI) tract, owing to the high risk of perforation. We developed mechanical spray lumpectomy (MSL), which is a novel method to safely and easily remove the tumor. This study aimed to evaluate the feasibility and safety of MSL as a novel endoscopic treatment for gastric subepithelial lesions. METHODS: We performed MSL in a total of 13 patients with upper GI SETs originating from the MP layer. First, mucosectomy was performed using a conventional snare. Repeated injections were performed towards the subserosal layer. After injection, the lesion was mechanically pushed to separate the MP layer using an endoscopic cap. Finally, the mucosa, submucosa, and MP layer with SETs were completely dissected using the spray coagulation mode, and the remaining defect was closed with clipping. RESULTS: All tumors were completely resected. The mean procedure time was 84.38 ± 41.73 min. There were four leiomyomas, six GI stromal tumors, one mucosa-associated lymphoid tissue lymphoma, and two ectopic pancreases. Although small perforation occurred in only one case, the defect was successfully closed using hemostatic clipping. Moreover, no serious complications related to MSL were encountered during or after the procedure. No residual lesion or recurrence was observed during the follow-up period. CONCLUSIONS: Mechanical spray lumpectomy can be a novel method that provides a safe and minimally invasive endoscopic treatment for upper GI SETs originating from the MP layer.

Utility of EUS elastography in the diagnosis of gastric subepithelial tumors: a pilot study (with video).

BACKGROUND AND AIMS: EUS elastography is a real-time imaging technique that analyzes tissue elasticity. The aim of this study was to investigate the applicability of quantitative EUS elastography in the differential diagnosis of gastric subepithelial tumors (SETs). METHODS: We prospectively registered 41 consecutive patients with gastric SETs and measured their strain ratios with EUS elastography. The strain ratios of gastric SETs were compared with the histopathologic diagnosis. RESULTS: Thirty-one patients (mean age, 51.4 ± 12.6 years) were included in the analysis. The mean size of the SETs was 2.3 ± 0.7 cm. Lipomas had the lowest strain ratio of 1.6 (1.1-2.0), followed by leiomyomas 6.0 (2.0-29.0), ectopic pancreas 11.8 (1.7-29.3), gastrointestinal stromal tumors (GISTs) 51.1 (29.0-67.0), and schwannomas 62.0. With a cut-off value of 22.7, EUS elastography could differentiate GISTs from leiomyomas with sensitivity and specificity of 100% and 94.1%, respectively (P = .001; 95% confidence interval, 0.979-1.000). CONCLUSIONS: EUS elastography could be a promising diagnostic adjunct for the assessment of gastric SETs, especially in differentiating GISTs from leiomyomas.

Anti-reflux mucosectomy using a cap-assisted endoscopic mucosal resection method for refractory gastroesophageal disease: a prospective feasibility study.

BACKGROUND AND AIMS: Endoscopic therapy of gastroesophageal reflux disease (GERD) overcomes the "treatment gap" for patients with refractory GERD, who are not willing to go into surgery. We propose an easy and efficient technique that is referred to as anti-reflux mucosectomy (ARMS) using cap-assisted endoscopic mucosal resection (EMR-C) which could be called ARMS-C. This study aimed to investigate the short-term outcomes of ARMS-C in GERD patients. METHODS: From December 2016 to February 2018, we performed ARMS-C in 33 patients with pathologic reflux disease and esophageal hypersensitivity. ARMS-C involved endoscopic mucosal resection at the circumference of the esophagogastric junction (EGJ), resulting in narrowing of the hiatal opening after healing. The GERD symptoms, 24-h pH monitoring results, manometry, endoscopy, and EGJ distensibility were compared before and after the procedure. RESULTS: Six months after ARMS-C, 63% of patients discontinued the use of pump inhibitors (PPIs), while 30% patients reduced their PPI dose. The GERD questionnaire scores significantly decreased after ARMS-C, from 11.0 to 6.0 (P < 0.001). The median DeMeester score and acid exposure time based on pH monitoring also improved after ARMS-C. Furthermore, the median flap valve grade and EGJ distensibility decreased from 3.0 to 1.0 (P < 0.001) and from 19.0 to 13.9 (P < 0.001), respectively. Two patients were treated with balloon dilation due to stricture, but no other serious adverse events were encountered. CONCLUSION: ARMS-C may be an effective and safe treatment method for GERD in terms of short-term outcomes.

Feasibility of intraperitoneal placental-derived mesenchymal stem cell injection in stomachs of diabetic mice.

BACKGROUND AND AIM: Diabetic gastropathy is associated with loss of interstitial cells of Cajal and autonomic neuropathy. Effective management for diabetic gastropathy is still unavailable. This study was aimed to confirm the pathogenetic changes in diabetic gastropathy and to examine the effect of treatment with placental-derived mesenchymal stem cells (PDMSCs) in stomachs of animal models. METHODS: Fourteen non-obese diabetic/ShiLtJ mice of 8 weeks were bled until week 30. Diabetes mellitus developed in 10 out of 14 mice, which all survived with insulin. The mice were grouped into three groups: nondiabetic group (n = 4), diabetic sham group (n = 5), and diabetic PDMSC group (n = 5) all of which were treated with intraperitoneal PDMSCs injection at week 30. All mice were killed at week 34, and the stomachs were examined by immunohistochemical stain with c-kit and neuronal nitric oxide synthase antibodies. RESULTS: The number of c-kit positive cells in stomach decreased significantly in the diabetic sham group compared with that in the nondiabetic group (21.2 ± 6.7 vs 88.0 ± 29.3, P = 0.006) but increased with PDMSC treatment (21.2 ± 6.7 vs 64.0 ± 15.1, P = 0.02). The positive rate of neuronal nitric oxide synthase in neural plexus was also significantly lower in the diabetic sham group than in the nondiabetic group (22.3% ± 18.5% vs 48.0% ± 22.7%, P = 0.003) but increased with PDMSC treatment (22.3% ± 18.5% vs 43.3% ± 20.5%, P = 0.03). CONCLUSIONS: Interstitial cells of Cajal and neural plexus decreased in stomachs of mice with diabetes mellitus but were significantly repaired with intraperitoneal injection of PDMSC.

Experimental study on the friction effect of plastic stents for biliary stone fragmentation (with video).

BACKGROUND AND AIM: In patients with irretrievable or intractable bile duct stone, temporary insertion of a plastic stent (PS) followed by further endoscopic retrograde cholangiopancreatography (ERCP) or surgery has been recommended as a 'bridge' therapy. However, the exact mechanism of stone fragmentation has not been discovered. The aim of the present study was to evaluate whether PS shape can facilitate stone fragmentation. METHODS: Using a new in vitro bile flow phantom model, we compared the friction effect among three different PS groups (straight PS group, double pigtail-shaped PS group, and screw-shaped PS group) and a control group. Each group had 10 silicon tube blocks that separately contained one stone and two PS. The control group had 10 blocks each with only a stone and no PS. We carried out analysis of the friction effect by stone weight and volume changes among the groups, excluding fragmented stones. RESULTS: After 8 weeks, complete fragmentation was noted in one out of 34 cholesterol stones (2.9%) and in four out of six pigmented stones (66.7%). Fragmentation tended to be more prominent in the screw-shaped PS group than in the straight PS group, double pigtail-shaped group, and control group (volume change: -11.33%, 7.94%, 4.43%, and 2.05%, respectively, P = 0.1390; weight change: -9.30%, 0.71%, -0.10%, and -1.23%, respectively, P = 0.3553). CONCLUSION: Stone fragmentation may be induced by PS friction effect. Also, screw-shaped plastic stents may improve friction effect. These results may help guide future PS development and clinical decisions.

A double blind, placebo-controlled, randomized clinical trial that breast milk derived-Lactobacillus gasseri BNR17 mitigated diarrhea-dominant irritable bowel syndrome.

The exact pathogenesis of diarrhea-dominant irritable bowel syndrome (IBS) is not known, but the abnormal microbiota of the gastrointestinal tract is considered to be one of the important contributing factors as in other gastrointestinal diseases such as inflammatory bowel disease, antibiotic-associated diarrhea, and colorectal cancer as well as systemic diseases. Though diverse trials of probiotics had been continued in the treatment of diarrhea-IBS, only a few proved by randomized clinical trial. To prove the efficacy of Lactobacillus gasseri BNR17 isolated from breast milk in patients with diarrhea-IBS, prospective, randomized, placebo controlled clinical trial was done including health related-quality of life analysis, colon transit time, and the changes of fecal microbiota. BNR17 significantly improved the symptoms of diarrhea compared to control group. Health related-QOL analysis showed significant improvement of abdominal pain, distension, disturbed daily life, and mean defecation frequency with BNR17. On comparative CTT before and after BNR17, 6 out of 24 subjects showed significant correction of rapid colon transit pattern, while only 2 out of 24 in placebo (p<0.01). Upon fecal microbiota analysis, BNR17 significantly increased B. fecalis, E. rectale, C. aerofaciens, F. prausnitzil and B. steroris. Conclusively, Lactobacillus gasseri BNR17 can be a potential probiotics to ameliorate diarrhea-IBS.

Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts.

BACKGROUND: Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs). METHODS: HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-ß1 and co-incubated with or without one of two synthetic PPAR-γ agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and α-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-ß1 induced expression of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs. The irreversible PPAR-γ antagonist GW9662 was used to investigate whether the effect of PPAR-γ agonists was PPAR-γ dependent. RESULTS: Both PPAR-γ agonists reduced the TGF-ß1-induced expression of α-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and α-smooth muscle actin-specific immunocytochemistry. PPAR-γ agonists also inhibited TGF-ß1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-ß1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-ß1 induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-γ agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-γ independent. CONCLUSIONS: Troglitazone and rosiglitazone suppress TGF-ß1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.

The Stent Patency and Migration Rate of Different Shaped Plastic Stents in Bile Flow Phantom Model and In Vivo Animal Bile Duct Dilation Model.

BACKGROUND/AIM: In research and development of biliary plastic stents (PS), continuous efforts have been made to overcome short patency time and high rate of migration. The aim of this study was to evaluate the patency and migration rate of different PS shapes for a given period of time. METHODS: Using an in vitro bile phantom model, we compared the patency among different shapes of PS (three straight PS, four double-pigtail PS, and a new screw-shaped PS). We performed an analysis of the degree of luminal narrowing by light microscopic examination. Using an in vivo swine model, we compared the patency and migration rate among the three different types of PS. RESULTS: Eight weeks after the bile exposure in the bile flow phantom model, 80 PS were retrieved and analyzed. The straight PS showed less biofilm formation and luminal narrowing than other types of PS (p < 0.05). Forty-nine PS were inserted into the dilated bile ducts of 10 swine models, and 39 PS were successfully retrieved 8 weeks later. The stent migration occurred less frequently in the double-pigtail PS and the screw-shaped PS than it did in the straight PS (11.1, 10, and 27.3%, respectively). However, there was no statistical difference in stent patency among the different shapes. CONCLUSIONS: Stent patency may not be significantly different depending on the shape of PS for 8 weeks. The screw-shaped PS showed similar patency and migration rate to the double-pigtail PS. These results may help guiding future PS development and clinical decisions.

Tissue diagnosis of GI subepithelial tumor only through Trucut biopsy under a forward-viewing endoscope: applicability as newer diagnostic modality.

BACKGROUND: Trucut biopsy (TCB) has been proposed to overcome the limitations of endoscopic ultrasonography (EUS)-guided fine-needle aspiration for the pathologic diagnosis of upper gastrointestinal (GI) subepithelial tumor (SET); however, it can be difficult to perform because the Trucut biopsy needle is very stiff. Although technical failures have been reported with the use of TCB, recently the forward-viewing echoendoscope showed a high diagnostic accuracy. We hypothesized that TCB under a conventional forward-viewing endoscope can be applied with higher yield of tissue diagnosis. METHODS: To evaluate the feasibility of TCB under a forward-looking endoscopy without cumbersome EUS guidance, we introduced a 19-gauge TCB needle into the working channel of a conventional upper endoscope in 27 patients with GI SET to make tissue diagnosis. Prospectively collected data were analyzed, including technical success rate, pathologic result, and adverse events. RESULTS: Twenty-seven patients with GI SET (18 esophageal tumors and nine gastric tumors) underwent TCB under a forward-looking endoscope. All procedures were performed safely without any TCB-related complications. Subsequently, histopathology examination revealed gastrointestinal stromal tumors (GISTs) in three cases and leiomyomas in 21 cases. Histologic assessment was completed in 24 out of 27 patients (88.9 %) because tissue obtained from three patients, whose tumors were located in the stomach, was not sufficient for the pathologic diagnosis. CONCLUSIONS: TCB using a conventional forward-viewing endoscope without EUS guidance provided an excellent pathologic diagnosis of upper GI SET.

Novel 3D-printing technique for caps to enable tailored therapeutic endoscopy.

BACKGROUND AND AIM: To evaluate the feasibility of a tailored endoscopic cap created using 3D-printing technology that is customized according to esophagogastric lesions of each patient. METHODS: Tailored endoscopic caps, which were designed and fabricated with a 3D printer, were inserted in 35 patients. The types of cap were side-hole cap made for cap-assisted endoscopic mucosal resection (EMRC), oblique-head cap designed for endoscopic submucosal dissection (ESD), wide-head cap used for Trucut biopsy (TCB), and narrow-tip cap to facilitate peroral endoscopic myotomy (POEM). RESULTS: EMRC in the esophagus and gastroesophageal junction was carried out using a side-hole cap in seven patients. Median total procedure time for successful removal of lesions was 14 min (range 8-50 min). Gastric ESD was carried out using with an oblique-head cap in 16 patients, for which the median total procedure time was 53 min. TCB in the esophagus was done using a wide-head cap in eight patients. While carrying out POEM for tunneling, a narrow-tip cap was used in four patients with achalasia. CONCLUSION: Based on the current proof-of-concept study, we anticipate that creating a tailored endoscopic cap is feasible for therapeutic endoscopy.

Bio-sheet graft therapy for artificial gastric ulcer after endoscopic submucosal dissection: an animal feasibility study.

BACKGROUND: Various bio-sheet grafts have been attempted either to accelerate healing of artificial ulcers or to prevent adverse events after endoscopic submucosal dissection (ESD), but neither prospective nor mechanistic studies were available. OBJECTIVE: To evaluate the substantial effect of a bio-sheet graft on artificial ulcer healing and its feasibility as an endoscopic treatment modality. DESIGN: Preclinical, in vivo animal experiment and proof-of-concept study. SETTING: Animal laboratory. SUBJECTS: Three mini-pigs, Sus scrofa, mean age 14 months. INTERVENTION: Multiple ulcers sized 2.5 cm in diameter were generated by ESD in 3 mini-pigs and were assigned randomly into the following 3 groups; control group, bio-sheet group, or combination (bio-sheet plus drug) group. Bio-sheet grafts or bio-sheet plus drug combinations were applied on the artificial ulcers immediately after the ESD. MAIN OUTCOME MEASUREMENTS: Feasibility and efficacy of endoscopic bio-sheet graft therapy for the management of artificial ulcers and the evaluation of healing conditions based on histology changes in the remaining gastric bed tissues harvested from the stomachs. RESULTS: Thirty-three ESD specimens were obtained. On an image analysis of the ratio of healed area in the remaining gastric bed tissue compared with the matched dissected gastric mucosa, the control group showed the most significant improvement in healing activity among the 3 groups (P < .05), whereas the severity of inflammation in the remaining ulcer tissue was significantly attenuated in bio-sheet and combination groups (P < .05). LIMITATIONS: Animal model. CONCLUSION: Although the bio-sheet grafts provided physical protection from gastric acid attack as reflected in the attenuated inflammation on the ulcer beds, unexpected delayed ulcer healing was noted in the bio-sheet graft group because of its physical hindrance of the healing process.

Discovery of 11ß-hydroxysteroid dehydrogenase type 1 inhibitor.

Various adamantane sulfonamides showed potent inhibitory activity against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). In continuation of our efforts to discover a more potent, selective and metabolically stable 11ß-HSD1 inhibitor in mice as well as in humans, we optimized the adamantane sulfonamide using structure-based molecular modeling. Compound 3, which has alkyl side chains on the linker, demonstrated a potent inhibitory activity against human and mouse 11ß-HSD1 (IC50 of 0.6 nM and 26 nM, respectively) and good physicochemical properties as a new anti-diabetes drug candidate.

Nrf2-mediated mucoprotective and anti-inflammatory actions of Artemisia extracts led to attenuate stress related mucosal damages.

The aim of this study was to compare biological actions between isopropanol and ethanol extracts of Artemisia including antioxidant, anti-inflammatory, and cytoprotective actions. Antioxidant activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and confocal microscopy on lipopolysaccharide-induced RGM1 cells, cytoprotection effects evaluated by detecting heme oxygenase-1 (HO-1), Nf-E2 related factor2 (Nrf2) and heat shock protein 70 (HSP70), and anti-inflammatory effects investigated by measuring inflammatory mediators. Water immersion restraint stress was imposed to provoke stress related mucosal damages (SRMD) in rats. Isopropanol extracts of Artemisia showed the higher DPPH radical scavenging activity and lesser LPS-induced reactive oxygen species productions and increased HO-1 expression through increased nuclear translocation of Nrf2 transcription factor compared to ethanol extracts. The increased expression of HSP70 and decreased expression of endothelin-1 were only increased with isopropanol extracts. A concentration-dependent inhibition of LPS-induced COX-2 and iNOS even at a rather lower concentration than ethanol extract was achieved with isopropanol extracts. Cytokine protein array revealed Artemisia extracts significantly attenuated the levels of CXCL-1, CXCL-16, and MCP-1. These orchestrated actions led to significant rescue from SRMD. Conclusively, Artemisia extracts imposed significant antioxidant and anti-inflammatory activity against SRMD and isopropanol extracts were superior to ethanol extracts in these beneficiary actions of Artemisia.

Under-through levator complex plication for correction of mild to moderate congenital ptosis.

PURPOSE: Congenital ptosis is most commonly of mild to moderate severity, with good to fair levator function. The appropriate procedures for this condition are levator resection or levator aponeurosis approaches. Among the latter, the levator plication method has received little attention because of a relatively high rate of ptosis recurrence secondary to weak adhesion. In this study, the authors described and retrospectively analyzed the results of an alternative plication technique, the "under-through levator complex plication" method. This method differs from conventional levator plication primarily by the posterior part of the levator complex being advanced to the tarsal plate to produce strong adhesion. METHODS: Five hundred and ten eyelids of 255 consecutive patients who underwent the under-through levator complex plication for congenital bilateral symmetrical ptosis were included in this study. Final outcomes were assessed at more than 5 months after surgery. RESULTS: The mean preoperative and postoperative marginal reflex distance 1 (MRD1) were 1.73 and 3.71 mm, respectively, and the mean amount of levator plication for every 1-mm increase in MRD1 was 3.31 mm. After the levator complex was plicated by the amount planned preoperatively, 65.1% of eyelids were at the target height. After subsequent intraoperative adjustments of the amount of plication, the overall surgery success rate was 94.5%. Recurrent ptosis due to relapse was not observed. CONCLUSIONS: The newly described surgical technique has overcome the limitations of conventional levator plication, by increasing the success rate and markedly reducing the relapse rate, while preserving the advantages of the conventional technique.

Global trends in incidence and prevalence of achalasia, 1925-2021: A systematic review and meta-analysis.

BACKGROUND: Achalasia poses a significant socioeconomic burden, yet global trends remain undocumented. This study aims to describe the worldwide trends in the incidence and prevalence of achalasia from 1925 to 2021 and explore their correlation with various factors through a comprehensive systematic review. METHODS: We searched the PubMed/MEDLINE, Embase, and Cochrane databases from inception to 30 June 2023, to identify studies reporting the incidence or prevalence of achalasia in the general population. This study utilized pooled estimates with 95% confidence intervals (CI) to estimate the incidence and prevalence of achalasia, and conducted various subgroup analyses. RESULTS: A total of 26 eligible studies covering approximately 269 million participants and 20,873 patients from 14 countries across five continents were included. Global pooled incidence and prevalence of achalasia were estimated to be 0.78 cases per 100,000 person-years (95% CI, 0.64-0.93; number of studies, 26; sample population, 269,315,171) and 10.82 cases per 100,000 person-years (95% CI, 8.15-13.48; number of studies, 14; sample population, 192,176,076), respectively. The incidence of achalasia was higher in Oceania (than Asia and Africa) and in adults (than children) after the introduction of the Chicago classification. Prevalence followed a similar pattern. The pooled incidence of achalasia showed an overall upward trend from 1925 to 2021 (1925-1999; 0.40 [0.32-0.49] vs. 2018-2021; 1.64 [1.33-1.95] cases per 100,000 person-years). CONCLUSIONS: The incidence and prevalence of achalasia have notably increased, particularly with advancements in diagnosis, and show significant variation worldwide, despite the large heterogeneity within the sample population. Further studies are necessary to accurately assess the global incidence and prevalence of achalasia.

Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with gastric cancer risk and survival in the Korean population.

We investigated whether four common microRNA polymorphisms (miR-146aC>G [rs2910164], miR-149T>C [rs2292832], miR-196a2T>C [rs11614913], and miR-499A>G [rs3746444]) are associated with the susceptibility and prognosis of gastric cancer in the Korean population. The four microRNA single-nucleotide polymorphisms (SNPs) were identified in a case-control study (461 patients; 447 controls) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in the Korean population. When patients were stratified into diffuse and intestinal-type gastric cancer groups, subjects with the miR-499AG and AG + GG genotypes had reduced adjusted odds ratios (AORs) for diffuse-type gastric cancer (AOR = 0.54 with 95% confidence interval [CI] = 0.31-0.97; AOR = 0.57 with 95% CI = 0.33-0.97). In the stratified analyses for gastric cancer risk, the miR-146aGG and CG + GG genotypes were associated with increased risk of gastric cancers among the non-smokers, whereas the miR-149TC and TC + CC genotypes showed lower risk of gastric cancer in males. The miR-196a2CC genotype was associated with elevated gastric cancer risk among females. For gastric cancer prognosis, intestinal-type gastric cancer patients with miR-146aCG + GG genotypes had significantly higher survival rates (log-rank P = 0.030) than patients with the CC genotype, and patients with the miR-499AA genotype had significantly increased survival rates compared to patients with the AG + GG genotypes (log-rank P = 0.013). When miR-146aCG + GG and miR-499AA genotypes were combined, the survival rate of intestinal-type gastric cancer patients was elevated (log-rank P < 0.001). No association was found between gastric or diffuse-type cancer prognosis and other miRNAs. Our data demonstrate that specific miRNA SNPs are associated with gastric cancer susceptibility (miR-499A>G) and prognosis (miR-146aC>G and miR-499A>G) in the Korean population depending on gastric cancer type.

New antireflux self-expandable metal stent for malignant lower biliary obstruction: in vitro and in vivo preliminary study.

AIM: Antireflux plastic biliary stents prevent duodenal biliary reflux and improve the stent patency rate. However, the efficacy of the antireflux valve in a self-expandable metal stent (SEMS) for a malignant biliary obstruction has not been well established. We evaluated the efficacy of a SEMS with an antireflux valve using in vitro flow studies and determined the impact of reducing duodenobiliary reflux on the stent patency rate. METHODS: In vitro testing was conducted using a bile perfusion system to evaluate the antegrade and retrograde flow resistance, and to determine the ideal shape for the valve. Then, a prospective case series in humans was conducted with an adequately designed SEMS with an antireflux valve. RESULTS: During the study period, five patients with an unresectable non-hilar malignant biliary obstruction underwent insertion of a SEMS with an antireflux valve. Placement of the SEMS with antireflux valve was successful on the first attempt in all patients, and no procedure-related complications occurred. Follow up was obtained in all cases. Serum bilirubin level did not decrease to the normal range within 1 month in four patients. Stent occlusions occurred in all four patients as a result of valve malfunctions due to sludge impaction or a clog. Therefore, the study was terminated early due to unexpected results. CONCLUSION: SEMS with an antireflux valve was ineffective in patients with non-hilar malignant biliary obstruction due to limitations on current stent technology.