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Although the 9-minute mean withdrawal time (m-WT) is often reported to be associated with the optimal adenoma detection rate (ADR), no randomized trials of screening colonoscopy have confirmed the impact of a 9-minute m-WT on adenoma miss rate (AMR) and ADR.A multicenter tandem trial was conducted in 11 centers. Seven hundred thirty-three asymptomatic participants were randomized to receive segmental tandem screening colonoscopy with a 9-minute withdrawal, followed by a 6-minute withdrawal (9-minute-first group, 9MF, n = 366) or vice versa (6-minute-first group, 6MF, n = 367). The primary outcome was the lesion-level AMR.The intention-to-treat analysis revealed that 9MF significantly reduced the lesion-level (14.5% vs 36.6%, P0.001) and participant-level AMR (10.9% vs 25.9%, P0.001), advanced adenoma miss rate (AAMR, 5.3% vs 46.9%, P = 0.002), multiple adenomas miss rate (20.7% vs 56.5%, P = 0.01), and high-risk adenomas miss rate (14.6% vs 39.5%, P = 0.01) of 6MF without compromising detection efficiency ( P = 0.79). In addition, a lower false-negative rate for adenomas ( P = 0.002) and high-risk adenomas ( P0.05), and a lower rate of shortening surveillance schedule ( P0.001) were also found in 9MF, accompanying with an improved ADR in the 9-minute vs 6-minute m-WT (42.3% vs 33.5%, P = 0.02). The independent inverse association between m-WT and AMR remained significant even after adjusting ADR, and meanwhile, 9-minute m-WT was identified as an independent protector for AMR and AAMR.In addition to increasing ADR, 9-minute m-WT also significantly reduces the AMR and AAMR of screening colonoscopy without compromising detection efficiency.

The sperm-associated antigen 5 (SPAG5) is an important protein in mitosis and cell cycle checkpoint regulation, with more attention as a novel oncogene in various cancers. High level of SPAG5 expression has been detected in our clinical gastric cancer (GC) samples and The Cancer Genome Atlas GC data. However, the bio-function and potential mechanism of SPAG5 in GC remain unclear. In this study, we investigated the role of SPAG5 in GC development and the correlation between SPAG5 and 5-fluorouracil (5-FU) treatment. SPAG5 expression was increased in GC samples compared with that in normal tissues (80.8% vs. 22.0%), which was apparently associated with a worse outcome. Biological experiments showed that knockdown of SPAG5 induced apoptosis and suppressed proliferation in cells and animal models. Downregulation of SPAG5 enhanced the sensitivity of 5-FU in GC cells. Gene microarray chip identified 856 upregulated and 787 downregulated genes in SPAG5 silencing cells. Furthermore, 12 significant genes, including CDKN1A, CDKN1B, EIF4E, MAPK1, and HSP90B1, belonged to the PI3K/AKT signaling pathway using ingenuity pathway analysis. Meanwhile, real-time PCR and Western blotting results showed that knockdown of SPAG5 inhibited PI3K/AKT signaling pathway. Collectively, SPAG5 promotes the growth of GC cells by regulating PI3K/AKT signaling pathway, which could be the promising target gene in GC therapy.

Background Colony-stimulating factor 3 (CSF3) is a cytokine associated with inflammation, which mainly stimulates myeloid stem cell maturation, proliferation, and migration into circulation. However, the significance of CSF3 in colorectal cancer (CRC) remains unclear. Here, we aimed to examine the expression and impacts of CSF3 in CRC. Methods CSF3 expression was examined in CRC tissues and cells by IHC staining and western blot. RNA interference was used to silence CSF3 in CRC cells. The effects of CSF3 on biological behaviors such as proliferation and migration of CRC cells were examined in vitro and in vivo. Results CSF3 was highly expressed in CRC tissues and cells. CSF3 high level was correlated to patients’ age, with a feature of a higher pathological stage, more distant lymphatic metastasis and more severe lymph node invasion. Knocking down CSF3 led to decreased proliferation and migration, increased apoptosis, arrested cell cycle in vitro as well as impaired tumor growth in vivo. Mechanistically, CSF3 regulates CRC cell proliferation and apoptosis dependent on enhances p65 phosphorylation to facilitate NF-κB-mediated transcriptional activity. Conclusion Our study demonstrated that CSF3 interacts with the NF-κB signaling pathway to promote the progression of CRC. CSF3 might be a potential therapeutic target for CRC patients.

Background: The most widely used noninvasive screening tests for colorectal cancer are fecal occult blood tests. Stool DNA test was developed in recent years. However, direct comparative analyses of these tests within the same population are still sparse. Methods: A total of 2,842 participants who visited outpatient clinics or cancer screening centers were enrolled. Stool DNA test-I (KRAS, BMP3, NDRG4, and hemoglobin immunochemical tests), stool DNA test-II (SDC2 and SFRP2 tests), and fecal immunochemical test (FIT) alone were performed and colonoscopy was used as the gold standard among 2,240 participants. Forty-two and 302 participants had colorectal cancer and advanced adenomas (AA), respectively. Results: The sensitivity for colorectal cancer of stool DNA test-I, -II, and FIT was 90.5%, 92.9%, and 81.0%, respectively. The sensitivity for advanced neoplasm (AN; colorectal cancer plus AA) of stool DNA test-I, -II, and FIT was 34.9%, 42.2%, and 25.9%, respectively. The specificity of stool DNA test-I, -II, and FIT was 91.4%, 93.3%, and 96.8%, respectively, among those with negative results on colonoscopy. When the specificity of FIT was adjusted to match that of stool DNA tests by changing the threshold, no significant difference was seen in the sensitivities among the three tests for detecting colorectal cancer. For AN, the sensitivity of FIT was higher than DNA test-I and similar to DNA test-II under the same specificities. Conclusions: There was no significant advantage of the two stool DNA tests compared with FIT in detecting colorectal cancer or AN in this study. Impact: Our findings do not support extensive use of stool DNA tests instead of FIT.

The Asia-Pacific Colorectal Screening (APCS) scoring system was developed to stratify the risk of colorectal advanced neoplasm (AN). We aimed to evaluate the performance of the APCS score combined with a stool DNA test used for colorectal cancer screening.A total of 2842 subjects who visited outpatient clinics or cancer screening centers were enrolled. Age, sex, smoking status, and family history were recorded and APCS scores were calculated in 2439 participants. A stool DNA test (SDC2 and SFRP2 tests) and fecal immunochemical test (FIT) were performed and colonoscopy was used as the gold standard among 2240 subjects who completed all study procedures. We used a threshold of 4.4 μg/g for the FIT, in addition to the manufacturer's recommended threshold of 20 μg/g to match the specificity of a stool DNA test.Based on the APCS score, 38.8% (946 of 2439) of the subjects were categorized as high risk, and they had a 1.8-fold increase in risk for AN (95% CI, 1.4-2.3) compared with low and moderate risk. The APCS combined with the stool DNA test detected 95.2% of invasive cancers (40 of 42) and 73.5% of ANs (253 of 344), while the colonoscopy workload was only 47.1% (1056 of 2240). The sensitivity for AN of APCS combined with stool DNA test was significantly higher than that of APCS combined with FIT (73.5% vs 62.8% with FIT cut-off value of 20 μg/g, and 73.5% vs 68.0% with FIT cut-off value of 4.4 μg/g; both P.01).The APCS score combined with a stool DNA test significantly improved the detection of advanced colorectal advanced neoplasms, while limiting colonoscopy resource utilization (Chictr.org.cn, ChiCTR-DDD-17011169).

Opioid prescription for inflammatory bowel disease (IBD)-related pain is on the rise. However, the use of strong opioids can result in severe complications, and even death, in IBD patients. This study aimed to define the role of fentanyl and morphine, two representative strong opioids, in the pathogenesis of dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis.DSS and TNBS models were induced in C57BL/6J and Balb/c mice, respectively. Disease activity index (DAI), histopathology, enzyme-linked immunosorbent assay (ELISA), multiplex ELISA, and flow cytometry were performed to evaluate the effects of fentanyl and morphine.Fentanyl exacerbated DSS- and TNBS-induced colitis, while morphine exhibited no significant immunomodulatory effect. Fentanyl and morphine had no obvious effects on the serum levels of adrenocorticotropic hormone (ACTH), glucocorticoid (GC), and prostaglandin E2 (PGE-2) in DSS and TNBS models. Fentanyl elevated the proportions of Th1 cells, μ-opioid receptor (MOR) + Th1 cells, and MOR + macrophages in the colonic mucosa of DSS-treated mice, and enhanced the proportions of Th1 cells, macrophages, MOR + Th1 cells, and MOR + macrophages in the colonic mucosa of TNBS-treated mice. We found that fentanyl upregulated the levels of inflammatory cytokines/chemokines in MOR + macrophages of the colonic lamina propria mononuclear cells (LPMCs) from DSS-treated mice, whereas it had no effect on the expression of most inflammatory cytokines/chemokines in MOR + macrophages in the colonic LPMCs from TNBS-treated mice.Our findings suggest that fentanyl exacerbates murine colitis

Introduction Glioma is the primary malignant brain tumor with poor prognosis. Berberine (BBR) was the potential drug for anti-tumor in glioma cells. Based on its limitation of poor aqueous solubility and instability, little information of BBR nanoparticles is reported in glioma. Methods Different solutions including 5% glucose, 1*PBS, ddH2O, 0.9% NaCl, cell culture medium were selected, and only 5% glucose and ddH2O exhibited BBR-related nanoparticles. After heating for a longer time or adding a higher concentration of glucose solution, BBR nanoparticles were detected by TEM analysis. The uptake of BBR-Glu or BBR-Water nanoparticles were detected by immunofluorescence analysis for BBR autofluorescence. Cell viability was measured by MTT assay and Western blotting analysis. Apoptosis was performed with flow cytometric analysis and was detected by cleaved caspase-3 immuno-fluorescent staining. Cell cycle was used by flow cytometric analysis. Cytoskeleton was observed by confocal analysis using the neuron specific Class III s-tubulin and s-tubulin antibodies. Mitochondrial-related proteins were detected by Western blotting analyses and mito-tracker staining in live cells. Mitochondrion structures were observed by TEM analysis. ROS generation and ATP production were detected by related commercial kits. The tracking of BBR-Glu or BBR-Water nanoparticles into blood-brain barrier was observed in primary tumor-bearing models. The fluorescence of BBR was detected by confocal analyses in brains and gliomas. Results BBR-Glu nanoparticles became more homogenized and smaller with dose- and time-dependent manners. BBR-Glu nanoparticles were easily absorbed in glioma cells. The IC50 of BBR-Glu in U87 and U251 was far lower than that of BBR-Water. BBR-Glu performed better cytotoxicity, with higher G2/M phase arrest, decreased cell viability by targeting mitochondrion. In primary U87 glioma-bearing mice, BBR-Glu exhibited better imaging in brains and gliomas, indicating that more BBR moved across the blood-brain tumor barrier. Discussion BBR-Glu nanoparticles have better solubility and stability, providing a promising strategy in glioma precision treatment.

Background Gastrin (GAST) is a well-known hormone regulating gastric biofunctions in the secretion of acid and maintaining its structural integrity. Furthermore, the dysregulation of GAST is also involved in the development of various forms of cancer. However, there are some limitations for illustrating the cellular regulation of GAST and its regulatory mechanisms in gastric malignant transformation and the potential epigenetic regulators systematically. Methods We explored the role of GAST expression in gastric cancer (GC) and normal tissues with the clinical features and investigated the potential relationship between GAST and STAT3/MMP11 pathway by gain or loss of function analyses. Besides, based on our microRNA/mRNA expression profiles, miR-30a-3p was the potential epigenetic regulator and additional experiments were performed to identify the hypothesis. Results Elevated GAST expression was frequently detected in GC and was associated with worse outcomes (p

Summary Background Chemoprevention of colorectal adenoma and colorectal cancer remains an important public health goal. The present study aimed to investigate the clinical potential and safety of berberine for prevention of colorectal adenoma recurrence. Methods This double-blind, randomised, placebo-controlled trial was done in seven hospital centres across six provinces in China. Individuals aged 18–75 years who had at least one but no more than six histologically confirmed colorectal adenomas that had undergone complete polypectomy within the 6 months before recruitment were recruited and randomly assigned (1:1) to receive berberine (0·3 g twice daily) or placebo tablets via block randomisation (block size of six). Participants were to undergo a first follow-up colonoscopy 1 year after enrolment, and if no colorectal adenomas were detected, a second follow-up colonoscopy at 2 years was planned. The study continued until the last enrolled participant reached the 2-year follow-up point. All participants, investigators, endoscopists, and pathologists were blinded to treatment assignment. The primary efficacy endpoint was the recurrence of adenomas at any follow-up colonoscopy. Analysis was based on modified intention-to-treat, with the full analysis set including all randomised participants who received at least one dose of study medication and who had available efficacy data. The study is registered with ClinicalTrials.gov , number NCT02226185 ; the trial has ended and this report represents the final analysis. Findings Between Nov 14, 2014, and Dec 30, 2016, 553 participants were randomly assigned to the berberine group and 555 to the placebo group. The full analysis set consisted of 429 participants in the berberine group and 462 in the placebo group. 155 (36%) participants in the berberine group and 216 (47%) in the placebo group were found to have recurrent adenoma during follow-up (unadjusted relative risk ratio for recurrence 0·77, 95% CI 0·66–0·91; p=0·001). No colorectal cancers were detected during follow-up. The most common adverse event was constipation (six [1%] of 446 patients in the berberine group vs one [ Interpretation Berberine 0·3 g twice daily was safe and effective in reducing the risk of recurrence of colorectal adenoma and could be an option for chemoprevention after polypectomy. Funding National Natural Science Foundation of China.

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenoma to adenocarcinoma, which provides a long screening window for clinical detection. However, early diagnosis of sporadic colorectal adenoma (CRA) and CRC using serum metabolic screening remains unclear. The purpose of this study was to identify some promising signatures for distinguishing the different pathological metabolites of colorectal mucosal malignant transformation. A total of 238 endogenous metabolites were elected. We found that CRA and CRC patients had 72 and 73 different metabolites compared with healthy controls, respectively. There were 20 different metabolites between CRA and CRC patients. The potential metabolites of tumor growth (including patients with CRA and CRC) were found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, Sarcosine, TXB 2, 12-Hete, and chenodeoxycholic acid. Compared with CRA, 3,4,5-trimethoxybenzoic acid was significantly higher in CRC patients. There results prompt us to use the potential serum signatures to screen CRC as the novel strategy. Serum metabolite screening is useful for early detection of mucosal intestinal malignancy. We will further investigate the roles of these promising biomarkers during intestinal tumorigenesis in future. SIGNIFICANCE: CRC is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenomas to adenocarcinoma, which provides a long screening window for about 5-10 years. We adopt the metabolic analysis of extensive targeted metabolic technology. The main purpose of the metabolic group analysis is to detect and screen the different metabolites, thereby performing related functional prediction and analysis of the differential metabolites. In our study, 30 samples are selected, divided into 3 groups for metabolic analysis, and 238 metabolites are elected. In 238 metabolites, we find that CRA patients have 72 different metabolites compared with health control. Compared with health control, CRC have 73 different metabolites. Compared with CRA and CRC patients, there are 20 different metabolites. The annotation results of the significantly different metabolites are classified according to the KEGG pathway type. The potential metabolites of tumor growth stage (including patients with CRA and CRC) are found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, sarcosine, TXB 2, 12-Hete and chenodeoxycholic acid. Compared with CRA patients, CRC patients had significantly higher 3,4,5-trimethoxybenzoic acid level. It is prompted to use serum different metabolites to screen CRC to provide new possibilities.

A high salt diet (HSD) is often associated with a high risk for a variety of diseases, such as obesity and cardiovascular disease. Previous studies have demonstrated that an HSD enhances Th17 responses and increases the severity of autoimmune diseases. In this study, we investigated the effects of HSD (4% NaCl w/w) on colitis in IL-10

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited intestinal polyposis syndrome accounting for about 1% of colorectal cancers (CRC). Despite increasing researches on the molecular pathogenesis of CRC, we are still unclear about metabolic pathways and alterations probably involved in the development of CRC. To obtain new insights into the mechanisms underlying APC mutation and to elucidate the mechanisms of CRC development, we performed to identify the potential metabolites in FAP based on metabolomic strategy. Serum metabolites from FAP patients (n = 30) and healthy individuals (n = 34) were detected and qualified using Ultra Performance Liquid Chromatography and Tandem Mass Spectrometry (UPLC− MS/MS). 118 metabolites were identified with statistical tests of orthogonal partial least-squares-discriminant analysis (OPLS−DA), with the conditions of variable importance in projection (VIP) >1, p < 0.05 using the Mann−Whitney U test, and fold change (FC) ≥2 or ≤0.5. OPLS-DA model was useful for distinguishing FAP patients from healthy controls. Unique metabolic signatures were pooled in FAP patients covering tricarboxylic acid (TCA) cycle, amino acids metabolism, vitamin D, fatty acids metabolism, and bile acids (BAs) metabolism. Our results demonstrated that metabolites alterations in FAP can be helpful for further analysis of metabonomics induced by APC mutation, and these alterations might be involved in the progress of intestinal carcinogenesis.

There are limited data regarding the safety and efficacy of cold snare polypectomy (CSP) for large colorectal polyps. We evaluated factors affecting the clinical outcomes of CSP for polyps between 5 and 15 mm in size.This was a prospective single-center observational study involving 1000 patients undergoing colonoscopy. Polyps (5-15 mm) were removed using CSP, and biopsies were taken from the resection margin. The primary outcome was the incomplete resection rate (IRR), and was determined by the presence of residual neoplasia on biopsy. Correlations between IRR and polyp size, morphology, histology, and resection time were assessed by generalized estimating equation model.A total of 440 neoplastic polyps were removed from 261 patients. The overall IRR was 2.27%, 1.98% for small (5-9 mm) vs 3.45% for large (10-15 mm) polyps (P = .411). In univariate analysis, the IRR was more likely to be related to sessile serrated lesions (odds ratio [OR], 6.93; 95% confidence interval [CI], 1.88-25.45; P = .004), piecemeal resection (OR, 11.83; 95% CI, 1.20-116.49; P = .034), and prolonged resection time60 seconds (OR, 7.56; 95% CI, 1.75-32.69; P = .007). In multivariable regression analysis, sessile serrated lesions (OR, 6.45; 95% CI, 1.48-28.03; P = .013) and resection time (OR, 7.39; 95% CI, 1.48-36.96; P = .015, respectively) were independent risk factors for IRR. Immediate bleeding was more frequent with resection of large polyps (6.90% vs 1.42%; P = .003). No recurrence was seen on follow-up colonoscopy in 37 cases with large polyps.CSP is safe and effective for removal of colorectal polyps up to 15 mm in size, with a low IRR. (ClinicalTrials.gov; Number: NCT03647176).

Background Endoscopic resection has been used for high-grade intraepithelial neoplasia (HGIN) and superficial esophageal squamous cell carcinoma (ESCC) with limited risk of lymph node metastasis. However, some of these lesions cannot be accurately diagnosed based on forceps biopsy prior to treatment. In this study we aimed to investigate how to solve this histological discrepancy and avoid over- and under-treatment. Methods The medical records of patients with superficial esophageal squamous cell neoplasia who underwent endoscopic resection at our hospital from January 2012 to December 2019 were reviewed retrospectively. The histological discrepancy between the biopsy and resected specimens was calculated and its association with clinicopathological parameters was analyzed. Results A total of 137 lesions from 129 patients were included. The discrepancy rate between forceps biopsy and resected specimens was 45.3% (62/137). Histological discrepancy was associated with the histological category of the biopsy (p p = 0.002) and type B intrapapillary capillary loops (p p = 0.001), location (p = 0.018), and pink color sign (p = 0.002). Conclusions Histological discrepancy between forceps biopsy and resected specimens is common in clinical practice. Recognizing the risk factors for each histological category of biopsy may reduce these discrepancies and improve clinical management.

Background: Gastric cancer (GC) is one of the major malignancies of gastrointestinal tract. Hydrogen-potassium ATPase beta (ATP4B) gene is aberrantly downexpressed in gastric cancer that is associated with worse disease outcome. The objective of this study was to investigate the biological significance of ATP4B in GC carcinogenesis and development. Methods: The expression level of ATP4B was analyzed via clinical tissues and TCGA database. Then, we overexpressed ATP4B in SGC7901 and utilized isobaric Tags for Relative and Absolute Quantitation (iTRAQ) technique validate the ATP4B-regulated proteomics profile alterations. Bioinformatics analysis was performed to evaluate the biological processes of ATP4B in GC. Western blot was used for the verification of significant downstream proteins of ATP4B based on bioinformatics analysis data.Results: We identified 293 differentially expressed proteins between the ATP4B overexpressing and control groups in SGC7901, including 145 upregulated proteins and 148 downregulated proteins. GO enrichment analysis indicated that ATP4B-modulating downstream proteins were primarily related to mitochondria function and metabolism. ATP4B-induced enrichments of biological functions were partly associated with suppressing tumor advancement, illustrating an inhibitory role for ATP4B in the progression of GC. Co-expression interaction network analysis exhibited the significant alterations in p53 and STAT3/NF-κB signaling pathway. Consistently, KEGG pathway analysis showed that DEPs are enriched in cell metabolism and cancer-related signaling pathway. Western blot validated the activation of p53 pathway and the inhibition of NF-κB /CD44 pathway after ATP4B overexpressing in GC cells.Conclusion: ATP4B plays a critical anticancer effect by regulating p53/NF-κΒ/mitochondrial pathway. Our data suggested a novel role and mechanism for ATP4B in GC progression.

Background Cytomegalovirus (CMV) infection can significantly complicate and worsen the condition of acute severe ulcerative colitis (UC) patients. We aimed to explore the predictive risk factors to prevent and identify CMV infection at an early stage in acute UC patients. Methods A total of 115 moderate-to-severe active UC patients from 17 hospitals throughout China were enrolled. Active CMV infection was diagnosed by one of the following: CMV pp65 antigens, CMV IgM antibodies or CMV DNA. We identified the independent risk factors by multivariate analyses. Results A total of 64 of 115 active UC patients had active CMV infection. Compared to the non-CMV-infected patients, the CMV-infected patients had a tendency to be male and to exhibit abdominal pain; fever; oral ulcers; eosinopenia; low albumin, immunoglobulin (Ig) A, IgM, and IgG levels; increased high-sensitivity C-reactive protein (hsCRP) levels; hyponatremia; pancolonic lesions; initial onset type; severe activity; and glucocorticoid (high-dose) and immunosuppressive agent use (P P P = 0.04) were independent risk factors for CMV infection. A decrease eosinophil and albumin levels were risk factors for CMV infection. With every 0.1*10^9/L decrease in the peripheral blood eosinophil level or 1 g/L decrease in the serum albumin level, the risk for CMV infection in UC patients increased by 5.21-fold (1/0.192) or 1.19-fold (1/0.839), respectively. Conclusions High-dose glucocorticoid and immunosuppressive agent treatment significantly increase the risk of CMV infection, and correcting eosinopenia and low albumin levels may help prevent CMV infection in UC patients.

Although current quality indicators of colonoscopy recommend 6 minutes as the minimum standard for withdrawal time (WT), the impact of a WT longer than 6 minutes on neoplasia detection is unclear.A multicenter randomized controlled trial involving 1027 patients was conducted from January 2018 to July 2019. Participants were randomly divided into a 9-minute (n = 514) and 6-minute (n = 513) WT group, and a timer was used to adjust the withdrawal speed. The primary outcome was the adenoma detection rate (ADR).Intention-to-treat analysis showed a significantly higher ADR in the 9-minute versus 6-minute WT group (36.6% vs. 27.1%, P = .001). Prolonging WT from 6 to 9 minutes significantly increased ADR of the proximal colon (21.4% vs. 11.9%, P.001) as well as of the less experienced colonoscopists (36.8% vs. 23.5%, P = .001). Improvements were also observed in the polyp detection rate (58.0% vs. 47.8%, P.001), and mean number of polyps and adenomas detected per colonoscopy (1.1 vs. 0.9, P = .002; 0.5 vs. 0.4, P = .008, respectively). The higher ADRs in 9-minute WT were also confirmed by the per-protocol (PP) analysis and subgroup analyses, with an increased rate of sessile serrated lesion detection in the 9-minute WT by PP analysis (4.0% vs. 1.3%, P = .04). Multivariate logistic regression demonstrated that the 9-minute WT was independently associated with increased ADR (P = .005).Prolonging WT from 6 to 9 minutes significantly improved ADR, especially in the proximal colon and for less experienced colonoscopists. A 9-minute WT benchmark should be considered as one of the quality indicators of colonoscopy. ClinicalTrials.gov (identifier, NCT03399045).

Hydrogen/potassium ATPase β (ATP4B) is a proton pump acting an essential role in gastric acid secretion. This study aimed to investigate the diagnostic performance of ATP4B and its biological role in tumor progression in gastric cancer.The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in gastric cancer were verified by gain- and loss-of-function cell models and tumor xenograft models. The possible downstream effects of ATP4B were analyzed by iTRAQ-based quantitative proteomics analysis.A dramatic decrease in ATP4B was associated with malignant transformation in gastric mucosa lesions and correlated with poor differentiation. Restoration of ATP4B expression in gastric cancer cells significantly suppressed cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a quality control on mitochondrial metabolism and functions in ATP4B-overexpression GC cells.Our data suggest that decreasing ATP4B is an indicator for gastric mucosa malignant transformation and GC aggressive phenotype and it plays an inhibitory role in gastric cancer as a tumor suppressor via regulating mitochondrial metabolism and apoptosis pathway.

Background Cytomegalovirus (CMV) infection can significantly complicate and worsen the condition of acute severe ulcerative colitis (UC) patients. We aimed to explore the predictive risk factors to prevent and identify CMV infection at an early stage in acute UC patients. Methods A total of 115 moderate-to-severe active UC patients from 17 hospitals throughout China were enrolled. Active CMV infection was diagnosed by one of the following: CMV pp65 antigens, CMV IgM antibodies or CMV DNA. We identified the independent risk factors by multivariate analyses. Results A total of 64 of 115 active UC patients had active CMV infection. Compared to the non-CMV-infected patients, the CMV-infected patients had a tendency to be male and to exhibit abdominal pain; fever; oral ulcers; eosinopenia; low albumin, immunoglobulin (Ig)A, IgM, and IgG levels; increased high-sensitivity C-reactive protein (hsCRP) levels; hyponatremia; pancolonic lesions; initial onset type; severe activity; and glucocorticoid (high-dose) and immunosuppressive agent use (P

Background: Hydrogen/Potassium ATPase β (ATP4B) is a key protein in gastric mucosa barrier acting an essential role in gastric acid secretion. However, the exact role and precise mechanism of ATP4B in gastric cancer (GC) remain obscure. This study aimed to investigate the clinical significance of ATP4B in GC and its biological role in tumor progression.Methods: We evaluated ATP4B expression in GC cell lines and patient specimens via qPCR and Immunofluorescence. The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in GC were verified by gain- and loss-of-function cell models and xenograft tumor model. The possible downstream effects of ATP4B were analyzed by iTRAQ‑based quantitative proteomics analysis.Results: A dramatic decrease of ATP4B expression in GC cells and tissues compared with the adjacent normal tissues was observed; Downexpression of ATP4B was associated with the malignant transformation in gastric mucosa lesions and correlated with poor prognosis, high grade of TNM stage, and vessel carcinoma embolus in GC patients. Restoration of ATP4B expression in GC cells significantly inhibited cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a constitutive activation of p53 and inactivation of NF-κB signaling correlated with the mitochondrial pathway in ATP4B-overexpressing GC cells.Conclusion: Our data suggest that ATP4B perform the promising tumor suppressor gene by regulating p53/NF-κB/mitochondrial pathway in GC.

Additional file 1 Supplementary Table 1 Clinical Manifestations of Patients Satisfying Different Diagnostic Criteria.

Background and Aim Multiple colorectal polyps are relevant in hereditary colorectal cancer (CRC) syndromes, which are thought to be caused by multiple events including germline mutations. This study was aimed to characterize germline mutations in Chinese patients with multiple colorectal polyps. Methods Patients with > 10 colorectal polyps at the Department of Gastroenterology of the PLA Army General Hospital were enrolled from January 2014 to December 2015. These patients were divided into the high-risk, moderate-risk, and mild-risk groups. White blood cell samples were collected, and DNA was extracted to sequence a panel of 19 genes previously associated with CRC by next-generation sequencing. Results A total of 96 patients were enrolled in the study. Pathogenic germline mutations were found in 24 (24/33, 72.73%), nine (9/24, 37.5%), and three patients (3/39, 7.7%) in the high-risk, moderate-risk, and mild-risk groups, respectively. Based on the results given, we suggested a strategy about gene sequencing test for the patients with multiple polyps, and the sensitivity and specificity of the screening strategy were 97% and 57%, respectively. Four of eight patients with MUTYH pathogenic germline mutations had the c.A934-2G monoallelic germline mutation, whereas three of eight patients had the C55T MUTYH germline mutation. Concurrent pathogenic germline mutations in APC and MUTYH were also observed. Conclusions A genetic screening strategy comprising 19 genes was effective to screen for hereditary CRC syndromes in patients with multiple colorectal polyps. The MUTYH germline mutation hotspots in Chinese patients may be different from those in Caucasian patients.

// Jun-Yu Lu 1, 2 , Peng Jin 2 , Wei Gao 3 , De-Zhi Wang 2 and Jian-Qiu Sheng 2 1 Third Military Medical University, Chongqing, China, 400038 2 Department of Gastroenterology, PLA Army General Hospital, Beijing, China, 100700 3 Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, China, 116044 Correspondence to: Jian-qiu Sheng, email: jianqiu@263.net Keywords: colorectal cancer, estrogen, estrogen receptor beta, mismatch repair, MLH1 Received: July 22, 2016 Accepted: January 03, 2017 Published: March 18, 2017 ABSTRACT Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo . We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo , combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo , via induction of MLH1 expression mediated by ERβ.

Background This study aimed to understand the disease characteristics and treatment outcomes of Crohn’s disease (CD) in a real-world setting in China. Methods In this prospective, non-interventional, multicenter disease registry, adults (≥18 years) with existing and newly diagnosed CD were recruited from 14 medical centers across China from January 2015 to January 2017. The study consisted of the enrollment and follow-up periods, of 12 months each. Demographic, clinical characteristics, diagnostic duration and management of CD at enrollment were evaluated. Logistic regression analysis and stepwise multivariate logistic regression analysis used to assess the relationship between the risk factors and CD. Results Of 504 enrolled patients, 499 (99.0%) were eligible for analysis. The mean (SD) age at study enrollment was 32.3 (11.43) years and the majority (69.7%) of participants were male. In the past 15 years, a sustained decrease of the period of time in the diagnosis of CD was observed, at about 39.4 (24.11) months in 2010, which decreased to 3.1 (2.13) months in 2015. The most common presenting symptoms of CD included abdominal pain (78.0%), diarrhea (58.1%), weight loss (52.9%) and fever (30.1%). Oral ulcer (19.4%) and arthritis (9.8%) were the most common extra-intestinal manifestations. Non-stricturing non-penetrating (B1) (49.9%) behavior and ileocolonic involvement (L3) (56.2%) location were more frequent. Perianal disease was observed in 29.1% of the patients. Around 23.8% (119/499) patients had CD-related surgery other than perianal disease surgery. Older age at enrollment, longer disease course, complicated disease behavior and absence of perianal disease were all surgery risk factors (p

Background The population characteristics of Inflammatory Bowel Disease (IBD) in China are different from those of western countries, and this population lacks large sample clinical data. This study aimed to analyze the clinical characteristics of inpatients with severe complications of IBD in our center. Methods In this study, medical records of 510 hospitalized IBD patients (excluding pediatrics) were included, digestive tract perforation, massive digestive tract hemorrhage, thrombosis, toxic megacolon, digestive tract fistula, digestive tract stenosis, severe malnutrition, severe infection, and carcinogenesis were defined as severe complications. The clinical process and follow-up were retrospectively analyzed. Results The incidence of severe complications in patients with IBD was 39.02%, 71.31%, 23.81% and 50.68% for CD, UC and IBDU, respectively, and the incidence of severe complications in CD was significantly higher than that in UC (P10 years (χ2=4.054, P=0.044). The incidence of carcinogenesis in UC patients with the course of 0-10 years was 1.56%, which was significantly lower than 8.47% of UC patients with the course of >10 years (P for 10 years is an independent risk factor for carcinogenesis of UC patients.

BACKGROUND AND AIM Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype-phenotype correlation in mutated patients. METHODS Mutation screening of 46 unrelated probands was performed using multigene panels by next-generation sequencing. Clinical data of the index were used to assess genotype-phenotype correlations. RESULTS Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. CONCLUSION In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.

To explore the clinical features, pathological features, gene test results, diagnosis, treatment and prognosis of Peutz-Jeghers syndrome(PJS). Methods: We retrospectively analyzed clinical data of 46 hospitalized cases of PJS during 2007 and 2017. Results: All 46 patients had mucocutaneous melanin pigmentation and multiple gastrointestinal polyposis. The pigmentation was first noticed often within 5 years old, and 14 cases had family history. The clinical manifestations mainly included black spots, abdominal pain, hematochezia, and anemia. Histological examinations showed that 20 patients were classified as hamartomatous polyps,18 as adenomatous polyps, 14 as inflammatory polyps, and 10 as zigzag polyps. Eleven patients sequenced a panel of 20 genes previously associated with colorectal cancer (CRC) by next-generation sequencing, and the results showed 5 patients with gene mutations, and 3 of them with intussusception and surgical histories were found to have pathogenic germline mutations in the STK11 gene. Endoscopic treatment was the main therapy, but endoscopy combined with laparoscopy or surgical treatment was performed when complications occurred or the polyp was too large. Malignant tumors were found in 3 patients during follow-up. Conclusion: PJS is a hereditary disease which is characterized by spots of the skin or mucosa and gastrointestinal multiple polyps. The main pathological features are hamartoma and adenoma. The risks for intussusception and surgical operation are found to be high in the patients with pathogenic germline mutations in the STK11 gene. Endoscopic treatment is the main therapy. PJS patients should be followed up regularly due to the increasing risk for cancer and being easily to relapse.目的：探讨黑斑息肉综合征(Peutz-Jeghers syndrome，PJS)的临床特点、病理特征、基因检测结果、诊断治疗及预后。方法：对2007—2017年收治的46例PJS患者的临床资料进行回顾性分析。 结果：46例患者均存在口唇黏膜黑斑及消化道多发息肉，黑斑多于5岁以内出现，14例有家族史。临床上表现为黑斑、腹痛、便血、贫血等。病理学检查可表现为错构瘤(20例)、腺瘤(18例)、炎性息肉(14例)及锯齿状息肉(10例)等。11例患者行遗传性结直肠癌易感基因(20个)检测，结果提示5例有丝/苏氨酸蛋白激酶(serine/threonine kinase 11，STK11)基因突变，其中3例STK11基因致病证据明确者均有肠套叠及外科手术史。治疗以内镜下微创为主，出现并发症及息肉过大时行内镜和腹腔镜联合或外科手术治疗。随访发现3例患者发生恶性肿瘤。结论：PJS以特殊部位的皮肤、黏膜黑斑和消化道多发息肉为特征。病理学表现以错构瘤及腺瘤多见。STK11基因致病证据明确者发生肠套叠及外科手术风险较大。PJS早期治疗以内镜下微创为主，因增加恶性肿瘤风险，容易复发，应密切随访。.

Table S1. List of participating centers; Full analysis set. Table S2. Subject dispositions; Screened analysis set. Table S3. Logistic model for each correlation factor to Crohn’s disease behavior (B1 vs. B2 + B3); Full analysis set. Table S4. Logistic model for each correlation factors to Crohn’s disease localization (L1 vs. L2 vs. L3 vs. L4); Full analysis set. (DOC 111 kb)

ObjectiveThe pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study aims to characterise the mucosal virome and their functions in health and UC.DesignDeep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2.ResultsIn UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC.ConclusionWe demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.

LAMP2A is the key protein of chaperone-mediated autophagy (CMA), downregulation of LAMP2A leads to CMA blockade. CMA activation has been implicated in cancer growth, but the exact mechanisms are unclear. Elevated expression of LAMP2A was found in 8 kinds of tumors (n=747), suggesting that LAMP2A may have an important role in cancer progression. Unsurprisingly, LAMP2A knockdown in gastric cancer (GC) cells hindered proliferation, accompanied with altered expression of cell cycle-related proteins and accumulation of RND3/RhoE. Interactomic and KEGG analysis revealed that RND3 was a putative CMA substrate. Further study demonstrated that RND3 silencing could partly rescue the proliferation arrest induced by LAMP2A knockdown; RND3 was increased upon lysosome inhibition via both chemicals and LAMP2A-shRNA; Furthermore, RND3 could interact with CMA components HSPA8 and LAMP2A, and be engulfed by isolated lysosomes. Thus, constant degradation of RND3 by CMA is required to sustain rapid proliferation of GC cells. At last, the clinical significance of LAMP2A was explored in 593 gastric noncancerous lesions and 173 GC tissues, the results revealed that LAMP2A is a promising biomarker for GC early warning and prognosis of female GC patients.

Background To compare the clinical characteristics of Crohn’s disease (CD) and primary intestinal lymphoma (PIL), to find out valuable, relevant indicators for differential diagnosis. Methods The clinical, endoscopic and pathological data of 67 cases (54 cases of Crohn’s disease and 13 cases of primary intestinal lymphoma) admitted by the PLA Army General Hospital in the last seven years were analysed retrospectively. Results The average age of CD was lower than that of PIL, but the course of CD was longer than that of PIL (p Abdominal pain, oral ulcers, perianal lesions, history of surgery (appendectomy or intestinal resection), and multi-site lesions were more common in CD than in PIL (p The biopsy diagnosis rate of PIL was 92.3%, while 85.1% of CD’s pathological manifestations were non-specific inflammation. So the biopsy diagnosis rate of PIL was significantly higher than that of CD (p Two patients were initially diagnosed with CD based on the clinical comprehensive analysis. The clinical symptoms disappeared, and the colonoscopy achieved mucosal healing after treatment. But the patients‘ symptoms repeated, and they were eventually diagnosed as PIL. Conclusions The clinical and endoscopic characteristics of Crohn’s disease (CD) and primary intestinal lymphoma (PIL) are similar, but they have their own characteristics. Therefore, the differential diagnosis is difficult. The diagnosis of CD is more supported by young, long course of the disease, abdominal pain, oral ulcers, perianal lesions, history of surgery (appendectomy, resection), and multi-site lesions. Short disease duration, abdominal mass and single-site lesion are more common in PIL. Biopsy diagnosis rate of PIL is higher than that of CD. In the case of the diagnosis of PIL after CD treatment, misdiagnosis, a combination of the two and drug induction should be considered.

Background To evaluate the efficacy and safety of Infliximab (IFX) in the management of refractory ulcerative colitis (UC) and UC with extra-intestinal manifestations. Methods The clinical data for 36 cases including refractory UC patients and UC patients with special extra-intestinal manifestations, who all accepted treatment with IFX, were analysed retrospectively. Results Among all the 36 cases, 33 were refractory UC (5 with extra-intestinal manifestations) and another 3 with special extra-intestinal manifestations (2 with perianal abscess and 1 with ankylosing spondylitis). After treatment with IFX, 13 patients achieved clinical remission, of whom 3 achieved mucosal healing, 15 achieved clinical response and 8 failed to respond. The total effective rate of IFX treatment was 77.78%, remission rate 36.11%; Among 8 cases with extra-intestinal manifestations, 5 patients‘ extra-intestinal manifestations improved and the efficacy rate was 62.5%. No serious adverse events occurred during observation. Conclusions IFX is effective and safe in the management of refractory UC and extra-intestinal manifestations.

Background To explore the clinical features, endoscope expression, pathology features, gene test results, diagnosis, treatment and prognosis of Peutz-Jeghers’syndrome (PJS). Methods Retrospective analyses were performed on the clinical data of 46 cases of PJS patients in Department of Gastroenterology, PLA Army General Hospital from 2007 to 2017. Results All 46 patients had mucocutaneous melanin pigmentation and multiple gastrointestinal polyposis. The pigmentation was first noticed often within 5 y, and 14 cases had a family history. The clinical manifestations were mainly black spots, abdominal pain, hematochezia and anaemia. Histological examinations showed that 20 patients were classified as hamartomatous polyps, 18 as adenomatous polyps, 14 as inflammatory polyps and 10 as zigzag polyps. The results of 11 patients sequenced a panel of 20 genes previously associated with CRC by next-generation sequencing showed 5 cases with gene mutations, and three of which with intussusception and surgical histories were found to have pathogenic germline mutations in the STK11 gene. Endoscopic treatment is the main therapy, but endoscopy combined with laparoscopy or surgical treatment should be available when complications occur, or the polyp is too large. A few patients found malignant tumours during follow-up. Conclusions PJS is a hereditary disease which is characterised by spots of the skin or mucosa and gastrointestinal multiple polyps. The main pathological features were hamartoma and adenoma. The risk of intussusception and surgical operation is found to be high in the patients with pathogenic germline mutations in the STK11 gene, but the sample size was too small and needs to be further expanded. Endoscopic treatment is the main therapy. PJS patients should follow-up regularly due to the increased risk of cancer and being easy to relapse.

Endoscopic submucosal dissection (ESD) is a prolonged procedure with serious adverse events. The clip with line traction method was reported to improve ESD. However, there was no comparison with conventional ESD especially for trainees. We report here on the feasibility and efficacy of traction using dental floss with endoscopic clip to facilitate ESD versus conventional method for ESD trainees. Twenty simulated gastric lesions, paired with location and size, were created in porcine stomachs using a standard template. After a circular incision was made, submucosal dissection (control, n = 10) was performed with standard ESD, while the study (clip, n = 10) was performed with traction using dental floss and endoclip. Primary outcome was speed of submucosal dissection. Secondary outcome included frequency of submucosal injection and adverse event. Compared with controls, median procedure time was significantly shorter in the clip group (5.6 ± 1.1 vs. 13.6 ± 2.5 min, P = 0.003), with a significantly faster submucosal dissection time (1.8 ± 0.3 vs. 0.6 ± 0.1 cm2/min, P = 0.001) and less frequent submucosal injection (5.7 ± 0.6 vs. 8.5 ± 1.0 times, P = 0.024). There were no perforations in either group, but less adverse events (bleeding and injury to muscularis propria) in the clip group (1 vs. 7, P = 0.068, α = 0.1). Traction provided by dental floss and endoclip improves visualization of the submucosal layer during ESD. It allows a faster and safer gastric ESD especially among trainees in the early learning phase.