Background Peroral endoscopic myotomy (POEM) has shown excellent results for the treatment of achalasia in adults, but studies for children are limited. The study was aimed to analyze outcomes of peroral endoscopic myotomy (POEM) in children and compared with those in adults in a large multi-center study. Methods Records of consecutive patients with achalasia who underwent POEM at three tertiary centers were reviewed. A total of 130 children were included in this study. The primary outcomes of perioperative outcomes and clinical follow-up data were analyzed. Results One child (0.8%) experienced technical failure. Five children (3.8%) had major adverse events, including one with pneumothorax requiring drainage, two with delayed mucosa barrier failure, one with readmission, and one with vital-sign instability. Both post-POEM Eckardt score and median LES pressure were significantly lower than their pre-POEM reference values in children (0.7 vs 7.4; 7.0 vs 27.1 mmHg; both P < 0.001). During a median follow-up time of 40 months, clinical reflux rate was 27.0% and clinical failure rates at 1, 3, and 5 years were 1.8%, 3.5%, and 4.4% for children. The technical failure, major adverse events, and postoperative clinical reflux were comparable between children and adults (all P > 0.05). Kaplan-Meier analysis showed that the risk of clinical failure was lower in children than adults (log-rank test, hazard ratio = 0.37, 95% confidence interval 0.15-0.91, P = 0.023). Conclusions POEM can be safely performed in children with achalasia, and produce a better clinical response during long-term follow-up compared with that in adults.
BackgroundGenome-wide association studies have identified genes in the transforming growth factor- (TGF) signaling pathway that are responsible for regulating carcinogenesis.MethodsWe searched for single-nucleotide polymorphisms (SNPs) located within 3-untranslated regions (3-UTRs) that might affect the ability of miRNAs to bind genes in the TGF pathway for further analysis. We used TaqMan technology to genotype these SNPs in a population-based case-control study of 1147 colorectal cancer patients and 1203 matched controls in a Chinese population.ResultsThe rs1590 variant of TGFBR1 exhibited a significant association with colorectal cancer risk. Compared with individuals carrying the rs1590 TT genotype, individuals carrying the GT/GG genotypes had a decreased risk of colorectal cancer [odd ratio (OR)=0.82, 95% confidence interval (CI)=0.68-0.97], which was more evident among older individuals with a family history of cancer. Luciferase assays confirmed that the rs1590 T allele altered the capacity of miR-532-5p to bind TGFBR1.ConclusionsBased on these findings, the rs1590 variant in the 3-UTR of TGFBR1 may contribute to the susceptibility to colorectal cancer, predominantly by altering miR-532-5p binding.
The impact of different Helicobacter pylori (H. pylori) status (H. pylori negative, H. pylori eradication and H. pylori persistence) on the development of metachronous gastric lesions after endoscopic resection of early gastric cancer is not well defined. Thus, a systematic review and meta-analysis was performed to investigate this relationship. Two authors independently searched the electronic databases (Pubmed, Embase, the Cochrane Library and Web of Science) through March 2018, without language restriction. Pooled risk ratio for metachronous gastric lesions with regard to H. pylori status was calculated using fixed- or random-effects models, and heterogeneity and publication bias were also measured. 20 eligible studies were finally identified in systematic review, and 17 out of 20 studies were further included in meta-analysis. H. pylori eradication was associated with overall 50% lower odds of metachronous events (RR=0.50; 95 % CI 0.41-0.61). Pooled risk ratios for metachronous gastric neoplasm were 0.85 (95 % CI 0.43-1.68) between H. pylori-eradicated and -negative patients, and 0.63 (95 % CI 0.35-1.12) between H. pylori-negative and -persistent patients, respectively. In conclusion, based on the best available evidence, eradication of H. pylori can provide protection against secondary gastric neoplasm, and this quantitative benefit seemed greater than among asymptomatic individuals. Metachronous risk seems comparable between H. pylori-eradicated and -negative population, or between H. pylori-negative and -persistent patients.
BackgroundThe gut is implicated in the pathogenesis of acute pancreatitis (AP) and the infectious complications of AP are commonly associated with enteric bacteria, yet whether gut microbiota dysbiosis participants in AP severity remains largely unknown.MethodsWe collected clinical information and fecal samples from 165 adult participants, including 41 with mild AP (MAP), 59 with moderately severe AP (MSAP), 30 with severe AP (SAP) and 35 healthy controls (HC). The serum inflammatory cytokines and gut barrier indexes were detected. Male C57BL/6 mice with AP were established and injuries of pancreas were evaluated in antibiotic-treated mice, germ-free mice as well as those transplanted with fecal microbiota. The gut microbiota was analyzed by 16S rRNA gene sequencing.ResultsThe structure of gut microbiota was significantly different between AP and HC, and the disturbed microbiota was closely correlated with systematic inflammation and gut barrier dysfunction. Notably, the microbial composition changed further with the worsening of AP and the abundance of beneficial bacteria such as Blautia was decreased in SAP compared with MAP and MSAP. The increased capacity for the inferred pathway, bacterial invasion of epithelial cells in AP, highly correlated with the abundance of Escherichia-Shigella. Furthermore, the antibiotic-treated mice and germ-free mice exhibited alleviated pancreatic injury after AP induction and subsequent fecal microbiota transplantation in turn exacerbated the disease.ConclusionsThis study identifies the gut microbiota as an important mediator during AP and its dysbiosis is associated with AP severity, which suggests its role as potential therapeutic target.
BackgroundInositol 1,4,5-trisphosphate receptors (IP(3)Rs) are a family of intracellular Ca2+ release channels located on the membrane of endoplasmic reticulum, which have been shown to play critical roles in various cellular and physiological functions. However, their function in regulating gastrointestinal (GI) tract motility in vivo remains unknown. Here, we investigated the physiological function of IP(3)R1 in the GI tract using genetically engineered mouse models.MethodsPdgfrb-Cre mice were bred with homozygous Itpr1 floxed (Itpr1(f/f)) mice to generate conditional IP(3)R1 knockout (pcR1KO) mice. Cell lineage tracing was used to determine where Pdgfrb-Cre-mediated gene deletion occurred in the GI tract. Isometric tension recording was used to measure the effects of IP(3)R1 deletion on muscle contraction.ResultsIn the mouse GI tract, Itpr1 gene deletion by Pdgfrb-Cre occurred in smooth muscle cells, enteric neurons, and interstitial cells of Cajal. pcR1KO mice developed impaired GI motility, with prolonged whole-gut transit time and abdominal distention. pcR1KO mice also exhibited lethality as early as 8weeks of age and 50% of pcR1KO mice were dead by 40weeks after birth. The frequency of spontaneous contractions in colonic circular muscles was dramatically decreased and the amplitude of spontaneous contractions was increased in pcR1KO mice. Deletion of IP(3)R1 in the GI tract also reduced the contractile response to the muscarinic agonist, carbachol, as well as to electrical field stimulation. However, KCl-induced contraction and expression of smooth muscle-specific contractile genes were not significantly altered in pcR1KO mice.ConclusionsHere, we provided a novel mouse model for impaired GI motility and demonstrated that IP(3)R1 plays a critical role in regulating physiological function of GI tract in vivo.
Background The interaction between nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis B infection (CBI) was unclear. We aimed to investigate the association between NAFLD and CBI and the effect of NAFLD on response to antiviral therapy in pediatric population. Methods All children aged 0-18 years with liver biopsy-proven NAFLD, CBI, and co-existing NAFLD and CBI were consecutively collected. Children with co-existing CBI and NAFLD were considered as cases and n:m matched with simple NAFLD and simple CBI patients in the same cohort, respectively. In longitude study, the role of NAFLD in antiviral response was further analyzed in children with CBI who received antiviral treatment. Logistic or Cox regression models were used appropriately for analysis. Results 765 subjects were finally enrolled with 62 co-existing patients, 560 CBI patients, and 143 NAFLD patients. Multivariate analysis showed that HBV DNA level was negatively associated with NAFLD in CBI children (OR 0.376, 95% CI 0.173-0.818). Conversely, the severity of steatosis and levels of serum lipid profile were found to be inversely associated with CBI in NAFLD subjects. Then, in longitude study, we found that HBsAg loss at 96 weeks of antiviral treatment was independently associated with NAFLD (aHR 3.245, 95% CI 1.288-8.176). Conclusions An inverse association between CBI and NAFLD reciprocally existed in pediatric population. In longitude study, HBsAg loss was associated with NAFLD at week 96 of antiviral therapy.
Background Ulcerative colitis (UC) is characterized by chronic inflammation in the colon and epigenetic factors underlying the occurrence. Circular RNAs (circRNAs) have been under intensive focus due to the circular construct and gene-regulating functions. However, the changes and roles of circRNAs in UC remain unknown. Methods Microarrays were used to detect the differentially expressed genes, and quantitative real-time PCR was used to identify the changes in UC. In silico analyses were performed to predict the functions of circRNAs and mRNAs. In vitro, epithelial cell lines were stimulated by pro-inflammation effectors to test the alterations in circRNAs. CircRNAs-microRNAs-mRNAs network clarified the potential mechanisms underlying circRNAs in UC. The binding site between hsa_circ_0007919 and miR-138 or let-7a was verified using dual-luciferase assay. Results A total of 264 significantly dysregulated circRNAs and 1869 differentially expressed mRNAs in inflamed mucosa were compared with the non-inflamed mucosa in UC. Hsa_circ_0004662 and hsa_circ_0007919 were altered largely in UC tissues. Hsa_circ_0007919 was reduced persistently after inflammatory treatments, and it was relevant to Mayo endoscopic subscores and the expression of tight junction molecules. Finally, hsa_circ_0007919 could harbor miR-138, and let-7a to regulate the targeted mRNAs EPC1 and VIPR1. Conclusions Several circRNAs were differentially expressed in UC. Hsa_circ_0007919 is related to clinical characteristics and epithelial integrity by binding to hsa-let-7a, hsa-miR-138 to regulate the target genes. CircRNAs, especially hsa_circ_0007919, are associated with the pathogenesis and development of UC, with potential diagnostic and therapeutic implications.
Background Oxaliplatin (L-OHP) is a commonly used first-line chemotherapy for colorectal cancer. Genetic variants in nucleotide excision repair (NER) pathway genes may alter genomic integrity and the efficacy of oxaliplatin-based chemotherapy in colorectal cancer. Methods We investigated the association between genetic variants in 19 NER pathway genes and the disease control rate (DCR) and progression-free survival (PFS) among 166 colorectal cancer patients who received oxaliplatin-based chemotherapy. Expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression (GTEx) portal. Gene harboring significant SNP was overexpressed or knocked down to demonstrate the effect on cell phenotypes with or without oxaliplatin treatment. Results We found that rs5030740, located in the 3 '-untranslated region (3 '-UTR) of RPA1, was associated with DCR [OR = 2.99 (1.33-5.69), P = 4.00 x 10(-3)] and PFS [HR = 1.86 (1.30-2.68), P = 7.39 x 10(-4)]. The C allele was significantly associated with higher RPA1 mRNA expression levels according to eQTL analysis (P = 0.010 for sigmoid colon and P = 0.004 for transverse colon). The C allele of rs5030740 disrupted let-7e-5p binding to enhance RPA1 expression. Functionally, RPA1 knockdown inhibited cell proliferation and promoted cell apoptosis, whereas RPA1 overexpression promoted proliferation and suppressed apoptosis. Furthermore, low RPA1 expression increased sensitivity to oxaliplatin in colon cancer cells and inhibited proliferation after oxaliplatin treatment. Conclusions Our findings demonstrate an association between rs5030740 and the DCR and PFS of colorectal cancer patients. RPA1 functions as a putative oncogene in tumorigenesis by reducing sensitivity to oxaliplatin and could serve as a potential prognostic biomarker in colorectal cancer.
The ALEX is a novel member of the armadillo family and ALEX1 was reported to be reduced or even lost in multiple solid tumors. However, its expression profile and oncogenic role in gastric cancer (GC) remains largely unknown. ALEX1 expression was detected in 161 GC samples by immunohistochemistry staining. NCI-N87 cells transfected by ALEX1 lentivirus vectors and MKN28 cells transfected by ALEX1 shRNA were used for biological function investigation. Western blot was applied to explore the molecular mechanism and pull-down assays were applied to measure the activity of Rho GTPases. In vivo tumorigenicity, peritoneal and lung metastasis experiments were performed by tumor cell engraftment into nude mice. Bisulfite genomic sequencing and methylation-specific PCR were applied to check the methylation status of the ALEX1 gene. The expression rate of ALEX1 was significantly reduced in gastric tumor samples compared to non-tumor samples (43.5 vs. 90.2%), and its expression was closely related to the tumor differentiation, TNM staging, and lymph nodes metastasis. ALEX1 overexpression in NCI-N87 cells significantly inhibited cell proliferation, migration, and invasion in vitro, and disrupted the structure of the cytoskeleton. ALEX1 overexpression attenuated xenografts growth, peritoneal, and lung metastasis in nude mice. Mechanistically, the overexpression of ALEX1 inhibits thrombin-induced metastasis and Rho GTPases activation. Bisulfite genomic sequencing and methylation-specific PCR revealed that the promoter of ALEX1 is highly methylated in GC cells and tissues. ALEX1 expression is reduced in GC and is involved in diverse cellular functions. ALEX1 inhibits metastasis through the PAR-1/Rho GTPase signaling pathway.
The use of proton pump inhibitors (PPIs) may potentially predispose to the development of small intestinal bacterial overgrowth (SIBO), but this association is controversial due to conflicting results from studies conducted to date. The aim of this meta-analysis was to evaluate the association between the use of PPIs and the risk of SIBO. We systematically searched the online PubMed, Embase, and Cochrane Library databases and Web of Science for relevant articles published up to November 2016. Two researchers identified and extracted data independent of each other. The pooled analysis was performed using the generic inverse-variance random-effects model. Subgroup and sensitivity analysis were conducted to assess the stability and heterogeneity of the pooled results. The risk of publication bias was evaluated by assessing for funnel plot asymmetry and by Egger's test and Begg's test. A total of 19 articles met the eligibility criteria for the meta-analysis, reporting on 7055 subjects. The pooled odds ratio (OR) showed a statistically significant association between increased risk of SIBO and PPI use (OR 1.71, 95% confidence interval 1.20-2.43). Subgroup analyses demonstrated an association between SIBO and PPI use in studies that employed small bowel aspirates culture and glucose hydrogen breath tests (GHBT) as diagnostic tests for SIBO. Our meta-analysis suggests that the use of PPI moderately increases the risk of SIBO, thereby highlighting the need for appropriate prescribing of PPIs.
Insufficient attention is paid to the underlying tumor microenvironment (TME) evolution, that resulting in tumor heterogeneity and driving differences in cancer aggressiveness and treatment outcomes. The morphological evaluation of the proportion of the stroma at the most invasive part of primary tumor (tumor-stromal ratio, TSR) in cancer is gaining momentum as evidence strengthens for the clinical relevance. Tissue samples from the most invasive part of the primary gastric cancer (GC) of 494 patients were analyzed for their TSR, and a new TSNM (tumor-stromal node metastasis) staging system based on patho-biological behaviors was established and assessed. TSR is a new and strong independent prognostic factor for GC patients. The likelihood of tumor invasion is increased significantly for patients in the stromal-high subgroup compared to those in the stromal-low subgroup (P = 0.011). The discrimination ability of TSR was not less than the TNM staging system and was better in patients with stages I and II GC. We integrated the TSR parameter into the TNM staging system and proposed a new TSNM staging system creatively. There were three new subgroups (IC, IIC, IIID). There were four major groups and 10 subgroups in the TSNM system. The difference in overall survival (OS) was statistically significant among all TSNM system (P < 0.005 for all). Deep analyses revealed well predictive performance of the TSNM (P < 0.001). This study confirms the TSR as a TME prognostic factor for GC. TSR is a candidate TME parameter that could easily be implemented in routine pathology diagnostics, and the TSNM staging system has been established to optimize risk stratification for GC. The value of the TSNM staging system should be validated in further prospective study.
Colorectal polyps are commonly seen in colonoscopy and the management of neoplastic polyps and non-neoplastic polyps are different. It is necessary to distinguish neoplastic polyps from non-neoplastic polyps in real-time. Therefore, we conducted a meta-analysis to assess the diagnostic accuracy of magnifying endoscopy with narrow-band imaging (ME-NBI) in diagnosing neoplastic colorectal polyps from non-neoplastic colorectal polyps. PubMed and EMBASE were searched for trials that used magnifying endoscopy with ME-NBI for diagnosing neoplastic colorectal polyps. Sixteen articles and 20 fourfold tables were obtained. Sensitivity (Sen), specificity (Spe), positive likelihood ratios (+ LRs), negative likelihood ratios (-LRs) and diagnostic odds ratios (DORs) were calculated. A summary receiver-operating characteristic (SROC) curve was constructed, and the area under the ROC curve (AUC) was calculated. We performed subgroup analyses based on polyp size and assessment criteria: (1) According to data extracted from 20 fourfold tables, the pooled Sen and Spe of ME-NBI for diagnosing neoplastic colorectal polyps < 10 mm were 0.94 (95% CI 0.92-0.95) and 0.76 (95% CI 0.72-0.80), respectively. The pooled Sen and Spe of ME-NBI for diagnosing all neoplastic polyps were 0.98 (95% CI 0.98-0.99) and 0.88 (95% CI 0.85-0.90), respectively. (2) Data pertaining to the following three assessment methods were analysed from 15 fourfold tables: surface pattern (SP), vessel pattern (VP) and the combination of SP and VP. The AUCs for these assessment criteria were 0.9533, 0.9518 and 0.9954, respectively. Conclusions were made that ME- NBI has high diagnostic accuracy in diagnosing neoplastic colorectal polyps based on the combination of SP with VP and is helpful in making real- time diagnoses.
The reported prevalence of small intestinal bacterial overgrowth (SIBO) among individuals with irritable bowel syndrome (IBS) is highly variable. The aim of the study is to estimate the prevalence and identify predictors of SIBO in IBS. PubMed, Cochrane Library, and EMBASE through July 2017 were searched to identify studies evaluating the prevalence of SIBO in IBS. The pooled prevalence of SIBO among individuals with IBS and the pooled odds ratio (OR) of SIBO among those with IBS compared with healthy controls were calculated. Predictors of SIBO among IBS patients were also evaluated. Fifty studies (8398 IBS, 1432 controls) met the inclusion criteria. Overall pooled prevalence of SIBO in IBS was 38% (95% CI 32-44) and was higher among individuals with IBS (OR 4.7, 95% CI 3.1-7.2) compared with controls. The pooled prevaleared with cultures (19%, 95% CI 8-30). Among those with IBS, female gender (OR 1.5, 95% CI 1.0-2.1), older nce of SIBO in IBS was higher in studies diagnosed by breath tests (40%, 95% CI 33-46) compage (standard mean difference 3.1 years, 95% CI 0.9-5.4), and IBS-diarrhea (OR 1.7, 95% CI 1.3-2.3) compared with other IBS subtypes increased the odds of SIBO; proton pump inhibitor (PPI) use (OR 1.1, 95% CI 0.7-1.7) was not associated with SIBO. More than one-third of IBS patients tested positive for SIBO, and the odds of SIBO in IBS were increased by nearly fivefold. The prevalence of SIBO varied according to the diagnostic modality performed. Female gender, older age, and IBS-diarrhea, but not PPI use, were associated with SIBO among individuals with IBS.
Crohn's disease (CD) is a chronic, progressive, and destructive disease of the gastrointestinal tract. Although its incidence appears to be stable or decreasing in most countries in the North America and Europe, the incidence is rising rapidly in Asian countries. Immunomodulators and biologics are increasingly used to avoid long-term bowel damage and subsequent disability. Therapeutic drug monitoring facilitates optimizing thiopurines and anti-TNFs use. New biologic agents targeting various pathological pathways of CD are blooming in recent years, and the high cost of biologics and expiration of patents for several biologic agents have driven the utility of biosimilars for CD treatment. Here, the literature regarding the efficacy, safety, and withdrawal of the drugs, as well as the evolution of therapeutic targets will be reviewed.