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Proton pump inhibitors (PPIs) may be associated with gastric cancer, but studies in recent years have proven still inconsistent results. We conducted a systematic review and meta-analysis to investigate the association between PPI use and gastric cancer.Pubmed, EMBASE, and Cochrane library were searched for studies published up to 15th February 2022. Studies on the association between PPI and the risk of gastric cancer, pooled the odds ratios (ORs) using a random-effects model. The subgroup analysis for study design, site of gastric cancer, and the duration of PPI use was performed. Heterogeneity was assessed using the ISixteen cohorts and case-control studies were included. PPI use was significantly associated with gastric cancer (OR: 1.75, 95% CI: 1.28-2.40). The subgroup analysis found a significant risk increase in non-cardia gastric cancer (OR: 2.14, 95%CI: 1.50-3.07). There was no duration-dependent effect of PPI use and gastric cancer risk ( 1 year: OR: 2.56, 95% CI: 1.41-4.64, IPPIs were significantly associated with an increased risk of gastric cancer. However, this association does not confirm causation. Several well-design studies are needed to confirm the findings in the future.

(1) Background: Open, laparoscopic, and endoscopic choledocholithotomy (OC, LC, and EC, respectively) are accepted choledocholithiasis treatment modalities. However, an assessment of the nationwide trends in their outcomes is lacking. This nationwide population-based analysis evaluated treatment outcomes of choledocholithiasis in Taiwan; (2) Methods: A total of 13,139,306 individuals were randomly enrolled from the Longitudinal Health Insurance Database (LHID) between 2000 to 2013 for cohort analysis. All patients with newly diagnosed choledocholithiasis aged 18 years or older who were treated during the study period were enrolled and allocated to the OC, LC, EC, or combined endoscopy and open choledocholithotomy (CEOC) groups. Age, readmission, retained stone, comorbidities, hospital stay, medical cost, complications, mortality were analyzed; (3) Results: A total of 58,064 individuals met the inclusion criteria, including 46.54%, 1.10%, 47.52%, and 4.85% who underwent OC, LC, EC, and CEOC, respectively. The endpoint characteristics showed that the LC group had higher readmission, longer hospital stay, and higher medical cost. Cox regression analysis showed that the adjusted hazard ratio (HR) of complications for EC was 1.259 times higher than that for OC. The adjusted HRs of readmission within 90 days for LC, EC, and CEOC were higher than that of OC. The adjusted HR of retreatment with surgery was higher in LC. The adjusted HR of retreatment with endoscopy was higher in CEOC. The adjusted HR of mortality in EC was 1.603 times that of OC; (4) Conclusions: Different choledocholithiasis treatments lead to different outcomes. However, further studies on other large or national data sets are required to support these findings.

The pathogenesis of hepatocellular carcinoma (HCC) involves many molecular pathways. Glycine N-methyltransferase (GNMT) is downregulated in almost all HCC and its gene knockout mice developed HCC with high penetrance. We identified PREX2, a novel PTEN inhibitor, as a GNMT-interacting protein. Such interaction enhanced degradation of PREX2 through an E3 ligase HectH9-mediated proteasomal ubiquitination pathway. Depletion of GNMT or HectH9 resulted in AKT activation in a PREX2 dependent manner and enhanced cell proliferation. An elevated PREX2 protein expression accompanied by activation of AKT was observed in the liver of Gnmt knockout mice. PREX2 protein expression was upregulated in 54.9% of human HCC samples, while its mRNA level was comparable in tumor and tumor-adjacent tissue, suggesting a post-translational alteration of PREX2 expression. Higher level of PREX2 in the tumor tissues was associated with poorer survival. These results reveal a novel mechanism in which GNMT participates in AKT signaling and HCC tumorigenesis by promoting HectH9-mediated PREX2 degradation.

Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC). The overexpression of Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is observed in various tumors, including HCC; and the frequent PREX2 mutations in melanoma are associated with invasiveness. We sought to identify somatic mutations and the functional changes in mutational signatures of PREX2. Genomic DNA sequencing was performed in 68 HCC samples with three types of hepatitis viral infection status: HBs Ag-positive, anti-HCV Ab-positive, and negative for any hepatitis B or C markers. Stabilities and interactions of proteins as well as cell proliferation and migration were evaluated. Fourteen non-silent point mutations in PREX2 were detected, with 16 of 68 HCC patients harboring at least one non-silent mutation. All mutant forms of PREX2, except for K400f, had an extended half-life compared with wild-type PREX2. Moreover, only the half-life of S1113R was twice that of the wild-type. PREX2 mutant-S1113R also promoted migration and activated the AKT pathway as well as impaired HectH9-mediated ubiquitination. Our study identified a gain-of-function mutation of PREX2 – S1113R in HCC. Such mutation enhanced PREX2 protein stability, promoted cell proliferation, and was associated with aggressiveness of HCC.

Glycine N-methyltransferase (GNMT) is a tumor suppressor for HCC. It is down-regulated in HCC, but the mechanism is not fully understood. MicroRNA-224 (miR-224) acts as an onco-miR in HCC. This study is the first to investigate miR-224 targeting the coding region of GNMT transcript. The GNMT-MT plasmid containing a miR-224 binding site silent mutation of the GNMT coding sequence can escape the suppression of miR-224 in HEK293T cells. Expression of both exogenous and endogenous GNMT was suppressed by miR-224, while miR-224 inhibitor enhanced GNMT expression. miR-224 counteracts the effects of GNMT on the reduction of cell proliferation and tumor growth. The levels of miR-224 and GNMT mRNA showed a significant inverse relationship in tumor specimens from HCC patients. Utilizing CCl4-treated hepatoma cells and mice as a cell damage of inflammatory or liver injury model, we observed that the decreased expression levels of GNMT were accompanied with the elevated expression levels of miR-224 in hepatoma cells and mouse liver. Finally, hepatic AAV-mediated GNMT also reduced CCl4-induced miR-224 expression and liver fibrosis. These results indicated that AAV-mediated GNMT has potential liver protection activity. miR-224 can target the GNMT mRNA coding sequence and plays an important role in GNMT suppression during liver tumorigenesis.

Gastroesophageal reflux disease (GERD) is diagnosed based on typical symptoms in clinical practice. It can be divided into two groups using endoscopy: erosive and nonerosive reflux disease (NERD). This study aims to determine the risk factors of reflux symptoms and mucosal injury. This was a two-step case-control study derived from a cohort of 998 individuals having the data of reflux disease questionnaire (RDQ) and endoscopic findings. Those with minor reflux symptoms were excluded. The first step compared symptomatic GERD patients with healthy controls. The 2 nd step compared patients with erosive esophagitis with healthy controls. In this study, the prevalence of symptomatic GERD and erosive esophagitis were 163 (16.3%) and 166 (16.6%), respectively. A total of 507 asymptomatic individuals without mucosal injury of the esophagus on endoscopy were selected as healthy controls. Compared with healthy controls, multivariate analyses showed that symptomatic GERD patients had a higher prevalence of hypertriglyceridemia [odds ratio (OR), 1.83; 95% confidence interval (CI) 1.13–2.96] and obesity (OR, 1.85; 95% CI 1.08–3.02). By contrast, male sex (OR, 2.24; 95% CI 1.42–3.52), positive Campylo-like organism (CLO) test (OR, 0.56; 95% CI 0.37–0.84), and hiatus hernia (OR, 14.36; 95% CI 3.05–67.6) were associated with erosive esophagitis. In conclusion, obesity and hypertriglyceridemia were associated with reflux symptoms. By contrast, male sex, negative infection of Helicobacter pylori , and hiatus hernia were associated with mucosal injury. Our results suggested that risk factors of reflux symptoms or mucosal injury might be different in GERD patients. The underlying mechanism awaits further studies to clarify.

Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt(-/-) mice developed hepatocellular carcinoma, we hypothesized that Gnmt(-/-) mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt(-/-) mice. Pathological examination of the spinal cords revealed that Gnmt(-/-) mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-γ and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt(-/-) than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG(35-55)-induced Gnmt(-/-) mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T-cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt(-/-) CD4(+) T cells via an IL-2- and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4(+) T cells was much milder than in those with wild-type CD4(+) T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4(+) T-cell functions.

The pathogenesis of hepatocellular carcinoma (HCC) involves many molecular pathways. Glycine N-methyltransferase (GNMT) is downregulated in almost all HCC and its gene knockout mice developed HCC with high penetrance. We identified PREX2, a novel PTEN inhibitor, as a GNMT-interacting protein. Such interaction enhanced degradation of PREX2 through an E3 ligase HectH9-mediated proteasomal ubiquitination pathway. Depletion of GNMT or HectH9 resulted in AKT activation in a PREX2 dependent manner and enhanced cell proliferation. An elevated PREX2 protein expression accompanied by activation of AKT was observed in the liver of Gnmt knockout mice. PREX2 protein expression was upregulated in 54.9% of human HCC samples, while its mRNA level was comparable in tumor and tumor-adjacent tissue, suggesting a post-translational alteration of PREX2 expression. Higher level of PREX2 in the tumor tissues was associated with poorer survival. These results reveal a novel mechanism in which GNMT participates in AKT signaling and HCC tumorigenesis by promoting HectH9-mediated PREX2 degradation.

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Phosphatidylinositol 3,4,5-trisphosphate Rac exchange factor 2 (PREX2), a highly distributed GEF, is abundant in human cancer cells. Also, PREX2 is frequently mutated in melanoma, stomach, colorectal, and lung cancers. Recently, we identified HectH9 (homologous to E6AP carboxyl terminus homologous protein 9) is the E3 ligase of PREX2 and mediates its degradation. We found that PREX2 was overexpressed in HCC and associated with the following clinical characteristics: viral infection (P = 0.004), tumor size (P = 0.03) and AFP levels (P = 0.04). Results from multivariate logistic regression analysis indicated that PREX2 expression profoundly correlated with hepatitis B virus infection (odds ratio = 14.07, P = 0.01). Moreover, high-expression level of PREX2 in the tumor tissues was associated with poor survival (P = 0.02). In addition, we performed HaloPlex sequencing to analyze the PREX2 genome among tumorous, tumor-adjacent tissues and peripheral blood mononuclear cells from 68 HCC patients. Thirteen non-silent point mutations were detected in PREX2. Compared to wild-type PREX2, the S113R mutant displayed a weaker interaction with HectH9, a reduced ubiquitination level and prolonged half-life. Moreover, the S1113R mutant further enhanced AKT activation and cell proliferation. These results reveal a novel mechanism through which GNMT restrains AKT signaling and HCC tumorigenesis. Citation Format: Yen-Fu A. Chen, Kuo-Jui Lee, Yi-Hsiung Lin, Chung-Hsien Li, Chia-Hung Yen, Hui-Kuan Lin, Yi-Ming Chen. Identification and characterization of patient-derived PREX2 mutation in HCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4418.

Background CO 2 is rapidly absorbed from the colon and eliminated via the lung. Insufflation of CO 2 instead of air during colonoscopy can reduce distention-induced pain. Objective This study aimed to evaluate the effects of CO 2 insufflation on pain during intubation and extubation and to identify predictors of pain and discomfort during colonoscope insertion. Design Prospective, randomized, controlled trial. Setting Single tertiary medical center in Taiwan. Patients A total of 193 patients enrolled from September 2010 through June 2011. Interventions Colonoscope insertion with either air or CO 2 insufflation. CO 2 was used for extubation in both groups. Main Outcome Measurements The main outcome measurement was pain, recorded on a 10-point visual analog scale (VAS) for left-sided colonoscope insertion and right-sided colonoscope insertion and at 1, 3, 6, and 24 hours post-procedure. Colonoscope cecal intubation time and extubation time, completeness of intubation, and loop formation were also assessed. Results CO 2 insufflation during colonoscope intubation was used in 98 patients and air in 97 patients. The mean pain scores during intubation were low (2-3) for patients undergoing air insufflation and were not reduced further in patients receiving CO 2 . A mean pain score of 0 was reported by both groups for all postprocedure time points. Multivariate analysis identified sex, loop formation of the sigmoid colon, time to reach the transverse colon, and requested sedation as factors that significantly affect VAS pain scores. Limitations This study was limited in scope to a single medical center with experienced endoscopists. Conclusions We detected no significant benefit to the use of CO 2 insufflation compared with air insufflation during intubation for colonoscopy performed by experienced colonoscopists. The absence of postprocedure pain in both groups supports previous observations that CO 2 insufflation during extubation is effective in reducing postprocedure pain. Female sex and loop formation were identified as key factors influencing pain scores on colonoscope insertion. (Clinical trial registration number: TSGHIRB-099-05-081.)

Glycine N-methyltransferase (GNMT) is a tumor suppressor for hepatocellular carcinoma (HCC). High rates of Gnmt knockout mice developed HCC. Epigenetic alteration and dysregulation of several pathways including wingless-type MMTV integration site (Wnt), mitogen-activated protein kinase (MAPK) and Janus kinase and signal transducer and activator of transcription (JAK-STAT) are associated with HCC development in Gnmt knockout mice. We hypothesized that GNMT may regulate signal transduction through interacting with other proteins directly. In this report, we identified a mammalian target of rapamycin (mTOR) inhibitor (DEP domain containing MTOR-interacting protein [DEPDC6/DEPTOR]) as a GNMT-binding protein by using yeast two-hybrid screening. Fluorescence resonance energy transfer assay demonstrated that the C-terminal half of GNMT interact with the PSD-95/Dlg1/ZO-1 (PDZ) domain of DEPDC6/DEPTOR. Immunohistochemical staining showed that 27.5% (14/51) of HCC patients had higher expression levels of DEPDC6/DEPTOR in the tumorous tissues than in tumor-adjacent tissues, especially among HCC patients with hepatitis B viral infection (odds ratio 10.3, 95% confidence interval [CI] 1.05–11.3) or patients with poor prognosis (death hazard ratio 4.51, 95% CI 1.60–12.7). In terms of molecular mechanism, knockdown of DEPDC6/DEPTOR expression in HuH-7 cells caused S6K and 4E-BP activation, but suppressed Akt. Overexpression of DEPDC6/DEPTOR activated Akt and increased survival of HCC cells. Overexpression of GNMT caused activation of mTOR/raptor downstream signaling and delayed G2/M cell cycle progression, which altogether resulted in cellular senescence. Furthermore, GNMT reduced proliferation of HuH-7 cells and sensitized them to rapamycin treatment both in vitro and in vivo. In conclusion, GNMT regulates HCC growth in part through interacting with DEPDC6/DEPTOR and modulating mTOR/raptor signaling pathway. Both GNMT and DEPDC6/DEPTOR are potential targets for developing therapeutics for HCC.

Background: Using EMR techniques, physicians frequently remove tumors 15 mm by piecemeal resection, which is associated with an increased rate of disease recurrence and difficulty in histologically evaluating the specimen. Endoscopic submucosal dissection (ESD) of early-stage gastric cancer improves the rate of successful en bloc resection, but it is associated with more complications, such as bleeding and perforation, than conventional EMR. Objective: To describe a simple technique that uses the pulley method to facilitate ESD procedures in the excision of large early-stage gastric cancers. Design: Case series. Setting: Tertiary medical center in Taiwan. Patients and Methods: Eleven patients with early-stage gastric cancers or adenomas 20 mm underwent ESD. Interventions: The pulley method with standard clips and dental floss was used to provide traction to improve visualization of the dissection plane during ESD. Main Outcome Measurement: Proportion with complete en bloc resection. Results: En bloc resection of the lesion was achieved in 11 patients. No perforation or emergent surgery was noted. Limitations: One endoscopist performed all procedures, and only 11 patients were studied in an uncontrolled manner. Conclusions: The pulley method seems to facilitate en bloc ESD of early-stage gastric cancers 20 mm.

Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt−/− mice developed hepatocellular carcinoma, we hypothesized that Gnmt−/− mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was significantly reduced in Gnmt−/− mice. Pathological examination of the spinal cords revealed that Gnmt−/- mice had significantly lower level of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of pro-inflammatory cytokines, including IFN-gamma and IL-17A, were much lower in the spinal cord of Gnmt−/- than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T cell proliferation and induction of T helper (Th) 1 and Th17 cells were markedly suppressed in MOG35-55 induced Gnmt−/- mice. Moreover, the amount of regulatory T cells was significantly increased in these mice. When the T cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were significantly decreased in GNMT−/- CD4+ T cells via an IL-2 and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of regulatory T cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4+ T cells was much milder than in those with wild-type CD4+ T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4+ T cell functions. Citation Format: Chung-Hsien Li, Ming-Hong Lin, Yen-Fu Chen, Shih-Han Chu, Pang-Hsien Tu, Cheng-Chieh Fang, Chia-Hung Yen, Peir-In Liang, Jason C. Huang, Yu-Chia Su, Huey-Kang Sytwu, Yi-Ming A. Chen. Role of glycine N-methyltransferase in the regulation of T cell responses in experimental autoimmune encephalomyelitis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1295. doi:10.1158/1538-7445.AM2015-1295

Nonfunctional endocrine carcinoma of the pancreas is uncommon. Without excess hormone secretion, it is clinically silent until the enlarging or metastatic tumor causes compressive symptoms. Epigastric pain, dyspepsia, jaundice, and abdominal mass are the usual symptoms, whereas upper gastrointestinal (GI) bleeding is rare. Here, we describe the case of a 24-year-old man with the chief complaint of hematemesis. Upper GI panendoscopy revealed isolated gastric varices at the fundus and upper body. Ultrasonography and computed tomography showed a tumor mass at the pancreatic tail causing a splenic vein obstruction, engorged vessels near the fundus of the stomach, and splenomegaly. After distal pancreatectomy and splenectomy, the bleeding did not recur. The final pathologic diagnosis was endocrine carcinoma of the pancreas. Gastric variceal bleeding is a possible manifestation of nonfunctional endocrine carcinoma of the pancreas if the splenic vein is affected by a tumor. In non-cirrhotic patients with isolated gastric variceal bleeding, the differential diagnosis should include pancreatic disorders.

Glycine N-methyltransferase (GNMT) is a tumor suppressor for hepatocellular carcinoma (HCC). Previously, we reported that GNMT regulates mTOR signaling pathway through interacting with an mTOR binding protein-DEPTOR. Sequence blasting and phylogenetic analysis demonstrated that the first DEP domain of DEPTOR clustered with P-Rex2, a regulator of the small guanosine triphosphatase Rac. Since P-Rex2 has been showed to be able to antagonize PTEN in PI3K pathway, the aims of this study was to analyze the interaction between GNMT and P-Rex2 and their association in PI3K-Akt signaling pathway. Gel filtration assay demonstrated that GNMT and P-Rex2 were eluted in the same fractions. Reciprocal co-immunoprecipitation experiments demonstrated that GNMT interacts with different domains of P-Rex2 including DH, PH, PDZ and InsPx4-Phosphatase. Overexpression of P-Rex2 enhanced Akt activation in HCC cell line as well as in breast cancer cell lines and such effect was blocked by over-expression of GNMT. Pulse-chase experiments showed that overexpression of GNMT caused significant reduction of the half-life of P-Rex2 from 15 hr to 9.5 hr. Finally, overexpression of GNMT in HuH-7 cells resulted in a proteasome-dependent degradation of P-Rex2. Therefore, GNMT affects PI3K-Akt pathway via direct binding with P-Rex2 and enhance its degradation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2234. doi:1538-7445.AM2012-2234

GNMT is a tumor suppressor for hepatocellular carcinoma (HCC). We found that DEPTOR, a novel mTOR binding protein, interacts with GNMT through its PDZ domain. DEPTOR expression is significantly increased in HCC, especially among patients with HCV infection. Loss of DEPTOR in HuH-7 cells activates S6K but reduces Akt activation and cell growth. DEPTOR overexpression activates Akt and extends survival of HCC cells. Overexpression of GNMT counteracts DEPTOR induced Akt activation and activates mTORC1 downstream signaling via disruption of the DEPTOR-mTOR interaction. Moreover, GNMT overexpression delays G2/M progression, which causes senescence and slows proliferation of HuH-7 cells, sensitizing them to rapamycin. We suggest that GNMT by interacting with DEPTOR regulates the cellular homeostasis of hepatocytes through modulation of Akt/mTORC1 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1990. doi:10.1158/1538-7445.AM2011-1990