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Summary Background The use of magnetically controlled capsules for gastroscopy is in the early stages of clinical adoption. We aimed to evaluate the safety and efficacy of a fully automated magnetically controlled capsule endoscopy (FAMCE) system in clinical practice for gastroscopy and small bowel examination. Methods We did a prospective, comparative study to evaluate the safety and efficacy of FAMCE. Patients from two hospitals in Chongqing, China were consecutively enrolled. Eligible participants were aged 18–80 years with suspected gastric pathology and no previous surgery. Participants underwent FAMCE for screening of gastric lesions, then conventional transoral gastroscopy 2 h later, and stomach examination results were compared. The primary outcome was the rate of complete detection of gastric anatomy landmarks (cardia, fundus, body, angulus, antrum, and pylorus) by FAMCE. Secondary outcomes were the time required for gastric completion by FAMCE, the rate of detection of gastric lesions by FAMCE compared with conventional transoral gastroscopy, and the rate of complete small bowel examination. Adverse events were also evaluated. The study was registered in the Chinese Clinical Trial Registry, ChiCTR2000040507. Findings Between May 12 and Aug 17, 2020, 114 patients (mean age 44·0 years [IQR 34·0–55·0]; 63 [55%] female) were enrolled. The rate of complete detection of gastric anatomical structures by FAMCE was 100% (95% CI 99·3–100·0). The concordance between FAMCE and conventional transoral gastroscopy was 99·61% (99·45–99·78). The mean completion time of a gastroscopy with FAMCE was 19·17 min (SD 1·43; median 19·00, IQR 19·00–20·00), compared with 5·21 min (2·00; 5·18, 3·68–6·45) for conventional transoral gastroscopy. In 114 enrolled patients, 214 lesions were detected by FAMCE and conventional transoral gastroscopy. Of those, 193 were detected by both modalities. FAMCE missed five pathologies (four cases of gastritis and one polyp), whereas conventional transoral gastroscopy missed 16 pathologies (12 cases of gastritis, one polyp, one fundal xanthoma, and two antral erosions). FAMCE was able to provide a complete small bowel examination for all 114 patients and detected intestinal lesions in 50 (44%) patients. During the study, two (2%) patients experienced adverse events. No serious adverse events were recorded, and there was no evidence of capsule retention. Interpretation The performance of FAMCE is similar to conventional transoral gastroscopy in completion of gastric examination and lesion detection. Furthermore, it can provide a complete small bowel examination. Therefore, FAMCE could be effective method for examination of the gastrointestinal tract. Funding Chinese National Key Research and Development Program.

GOAL: The purpose of this study was to evaluate the effectiveness of vitamin C solution (VCS) in reducing adverse reactions caused by painless Lugol chromoendoscopy. BACKGROUND: Lugol chromoendoscopy is an effective method for screening superficial esophageal squamous cell carcinoma, although Lugol iodine solution (LIS) causes mucosal irritation. STUDY: In 4 hospitals in China, patients were randomized and divided into a distilled water (DW) group, an sodium thiosulfate solution (STS) group and a VCS group. Patients' esophageal mucosal surfaces were stained with either 1.2% or 0.5% LIS and then sprayed with DW, STS, or VCS at various concentrations. For the current randomized study, 1610 patients were enrolled in the 1.2% LIS group and 1355 patients were enrolled in the 0.5% LIS group. In addition, 150 patients were enrolled to assess the discoloration effect. The primary outcome for evaluation was the incidence of acute or late adverse reactions after Lugol iodine staining. The secondary outcome for evaluation was the discoloration effect on esophageal iodine-stained mucosa. RESULTS: VCS significantly reduced the occurrence of acute adverse reactions due to staining from 1.2% LIS. The effect of VCS was similar to that of STS but better than that of DW (P

Esophagogastric variceal bleeding (EVB) is a catastrophic complication of decompensated liver cirrhosis. We aimed to establish a nomogram based on noninvasive clinical and imaging variables to predict the risk of EVB.The cut-off value of each variable was determined through univariate regression analysis. The least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analyses were used to determine the risk factors and establish predictive models. The nomogram was established and validated using the calibration discrimination across different groups.Six indicators, including platelet count, hemoglobin, albumin to globulin ratio, fasting blood glucose, serum chloride, and computed tomography portal vein diameter (CTPD), were found to be related to the risk of EVB. Two models, with or without CTPD, were established and compared. Model 1 with CTPD had better discrimination than model 2 with C-index of 0.893 (95% confidence interval [CI] 0.872-0.915) and 0.862 (95% CI 0.837-0.887) in the primary cohort, respectively (Z = 2.027, P = 0.043). While the C-index of the two models in the validation cohort was 0.878 (95% CI 0.838-0.919) and 0.810 (95% CI 0.757-0.863). Moreover, the clinical decision analysis curve and clinical impact curve showed that these models might confer a significant net benefit on patients and provide a reference threshold for clinicians.A nomogram using routine clinical indicators was established to predict the risk of EVB in patients with liver cirrhosis, which was verified in an independent cohort and demonstrated a great consistency.

Despite tremendous progress made in the diagnosis and managements, head and neck squamous cell carcinoma (HNSC) remains a global medical dilemma with dismal clinical prognosis and high mortality. Gene NT5E encodes the ecto-5’-nucleotidase (CD73), which facilitates the formation of immunosuppressive tumor microenvironment (TME) permissive for tumor progression in various malignancies. Nevertheless, the cell subsets NT5E expressed on and the potential function of NT5E in the TME of HNSC remain virgin lands in HNSC. In this study, we comprehensively performed integrated prognostic analysis and elucidated that NT5E was an independent prognostic indicator for HNSC, for which a high NT5E level predicted poor overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in HNSC patients (ppppIn-situ multicolor immunofluorescence staining was later conducted and the results further verified our findings. Taken together, NT5E could be a novel biomarker in HNSC. Predominantly expressed on CAFs, the upregulation of NT5E might predict an immunosuppressive TME for HNSC patients who may benefit little from immunotherapy. Targeting CAFs with high NT5E expression might be a novel therapeutic strategy for HNSC patients.

Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell–cell and cell–extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an “activator” of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate–heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.

Background & Aims Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown. Methods Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα–/– and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ–/– and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. Results Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response. Conclusions Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori., Graphical abstract

ObjectiveMindfulness-based interventions have been widely demonstrated to be effective in reducing stress, alleviating mood disorders, and improving quality of life; however, the underlying mechanisms remained to be fully understood. Along with the advanced research in the microbiota-gut-brain axis, this study aimed to explore the impact of gut microbiota on the effectiveness and responsiveness to mindfulness-based cognitive therapy (MBCT) among high trait anxiety populations.DesignA standard MBCT was performed among 21 young adults with high trait anxiety. A total of 29 healthy controls were matched for age and sex. The differences in gut microbiota between the two groups were compared. The changes in fecal microbiota and psychological indicators were also investigated before and after the intervention.ResultsCompared with healthy controls, we found markedly decreased bacterial diversity and distinctive clusters among high trait anxiety populations, with significant overgrowth of bacteria such as Streptococcus, Blautia, and Romboutsia, and a decrease in genera such as Faecalibacterium, Coprococcus_3, and Lachnoclostridium. Moreover, MBCT attenuated trait anxiety and depression, improved mindfulness and resilience, and increased the similarity of gut microbiota to that of healthy controls. Notably, a high presence of intestinal Subdoligranulum pre-MBCT was associated with increased responsiveness to MBCT. Decreases in Subdoligranulum post-MBCT were indicative of ameliorated trait anxiety. The tryptophan metabolism pathways were significantly over-represented among high responders compared to low responders.ConclusionThe significantly increased diversity post-MBCT added evidence to gut-brain communication and highlighted the utility of mycobiota-focused strategies for promoting the effectiveness and responsiveness of the MBCT to improve trait anxiety.Clinical Trial Registrationchictr.org.cn, ChiCTR1900028389.

Background Aberrant expression of circular RNAs contributes to the initiation and progression of cancers, but the underlying mechanism remains elusive. Methods RNA-seq and qRT-PCR were performed to screen differential expressed circRNAs between gastric cancer tissues and adjacent normal tissues. Candidate circRNA (circMRPS35) was screened out and validated by qRT-PCR. Cell proliferation and invasion ability were determined by CCK-8 and cell invasion assays. RNA-seq, GO-pathway, RNA pull-down and ChIRP were further applied to search for detailed mechanism. Results Here, a novel circRNA named circMRPS35, was screened out by RNA-seq in gastric cancer tissues, whose expression is related to clinicopathological characteristics and prognosis in gastric cancer patients. Biologically, circMRPS35 suppresses the proliferation and invasion of gastric cancer cells in vitro and in vivo. Mechanistically, circMRPS35 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of FOXO1 and FOXO3a genes, which elicits acetylation of H4K5 in their promoters. Particularly, circMRPS35 specifically binds to FOXO1/3a promoter regions directly. Thus, it dramatically activates the transcription of FOXO1/3a and triggers subsequent response of their downstream target genes expression, including p21, p27, Twist1 and E-cadherin, resulting in the inhibition of cell proliferation and invasion. Moreover, circMRPS35 expression positively correlates with that of FOXO1/3a in gastric cancer tissues. Conclusions Our findings not only reveal the pivotal roles of circMRPS35 in governing histone modification in anticancer treatment, but also advocate for triggering circMRPS35/KAT7/FOXO1/3a pathway to combat gastric cancer.

Although long noncoding RNAs (lncRNAs) do not have protein coding capacities, they are involved in the pathogenesis of many types of cancers, including hepatocellular carcinoma, cervical cancer, and gastric cancer. Notably, the roles of lncRNAs are vital in nearly every aspect of tumor biology. Long non‐coding small nucleolar RNA host genes (lnc‐SNHGs) are abnormally expressed in multiple cancers, including urologic neoplasms, respiratory tumors, and digestive cancers, and play vital roles in these cancers. These host genes could participate in tumorigenesis by regulating proliferation, migration, invasion and apoptosis of tumor cells. This review focuses on the overview of the roles that lnc‐SNHGs play in the formation and progression of digestive cancers., This review provides an overview of the roles of lncSNHGs (long non‐coding small nucleolar RNA host genes) in digestive cancers.

BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori-infected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4+ T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.

Gastric carcinoma (GC) is one of the most deadly diseases due to tumour metastasis and resistance to therapy. Understanding the molecular mechanism of tumour progression and drug resistance will improve therapeutic efficacy and develop novel intervention strategies.Differentially expressed long non-coding RNAs (lncRNAs) in clinical specimens were identified by LncRNA microarrays and validated in different clinical cohorts by quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridisation and bioinformatics analysis. Biological functions of lncRNA were investigated by using cell proliferation assays, migration assays, xenograft tumour models and bioinformatics analysis. Effects of lncSLCO1C1 on GC cell survival were assessed by comet assays and immunofluorescence assays. Underlying molecular mechanisms were further explored by using a number of technologies including RNA pull-down, mass spectrometry analysis, RNA immunoprecipitation, co-immunoprecipitation, miRNA sequencing, luciferase reporter assays and molecular modelling.LncSLCO1C1 was highly upregulated in GC tissue samples and associated with GC patients' poor overall survival. Overexpression of lncSLCO1C1 promoted proliferation and migration, whereas decreased lncSLCO1C1 expression produced the opposite effects. lncSLCO1C1 also mediated tumour resistance to chemotherapy with oxaliplatin by reducing DNA damage and increasing cell proliferation. Despite sequence overlapping between lncSLCO1C1 and PDE3A, alternations of PDE3A expression had no effect on the GC cell progression, indicating that lncSLCO1C1, not PDE3A, related with the progression of GC cells. Mechanistically, lncSLCO1C1 serves as a scaffold for the structure-specific recognition protein 1 (SSRP1)/H2A/H2B complex and regulates the function of SSRP1 in reducing DNA damage. Meanwhile, lncSLCO1C1 functions as a sponge to adsorb miR-204-5p and miR-211-5p that target SSRP1 mRNA, and thus increases SSRP1 expression. Patients with high expressions of both lncSLCO1C1 and SSRP1 have poor overall survival, highlighting the role of lncSLCO1C1 in GC progression.LncSLCO1C1 promotes GC progression by enhancing cell growth and preventing DNA damage via interacting and scaffolding the SSRP1/H2A/H2b complex and absorbing both miR-211-5p and miR-204-5p to increase SSRP1 expression.

This study aimed to explore the underlying mechanism of protocadherin 17 (PCDH17) downregulated in nasopharyngeal cancer (NPC). NPC tumor and adjacent tissue samples were collected from NPC patients who received therapy in the Chinese PLA General Hospital. Meanwhile, a normal epithelial cell lines NP96 and 6 NPC and cell lines C666-1, CEN1, CEN2, HNE1, HEN2, and HONE1 were prepared. Then, the expression level of PCDH17 and the methylation level of PCDH17 promoter in both tissues samples and cell lines were determined using the PCR method. Moreover, PCDH17 was overexpressed in CNE2 and HONE1 using Lipo2000. Following this, the proliferation and apoptosis of CNE2 and HONE1 were assessed using MTT and flow cytometry. The expression of PCDH17 was significantly downregulated in NPC tissues compared with the adjacent tissues as well as in the NPC cell lines compared with the normal NP96 cells. Overexpressed PCDH17 could significantly inhibit the proliferation of CNE2 and HONE1 cells but obviously promote the apoptosis of these two cell lines. Aberrant hypermethylation in the promoter might be the explanation of PCDH17 downregulated in PCDH17 and promoted the development of NPC.

Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca2+ entry, and eventually promoted gastric cancer progression in a Ca2+ signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca2+ signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca2+ signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.

Reading small bowel capsule endoscopy (SBCE) videos is a tedious task for clinicians, and a new method should be applied to solve the situation.To develop and evaluate the performance of a convolutional neural network algorithm for SBCE video review in real-life clinical care.In this multicenter, retrospective diagnostic study, a deep learning neural network (SmartScan) was trained and validated for the SBCE video review. A total of 2927 SBCE examinations from 29 medical centers were used to train SmartScan to detect 17 types of CE structured terminology (CEST) findings from January 1, 2019, to June 30, 2020. SmartScan was later validated with conventional reading (CR) and SmartScan-assisted reading (SSAR) in 2898 SBCE examinations collected from 22 medical centers. Data analysis was performed from January 25 to December 31, 2021.An artificial intelligence-based tool for interpreting clinical images of SBCE.The detection rate and efficiency of CEST findings detected by SSAR and CR were compared.A total of 5825 SBCE examinations were retrospectively collected; 2898 examinations (1765 male participants [60.9%]; mean [SD] age, 49.8 [15.5] years) were included in the validation phase. From a total of 6084 CEST-classified SB findings, SSAR detected 5834 findings (95.9%; 95% CI, 95.4%-96.4%), significantly higher than CR, which detected 4630 findings (76.1%; 95% CI, 75.0%-77.2%). SmartScan-assisted reading achieved a higher per-patient detection rate (79.3% [2298 of 2898]) for CEST findings compared with CR (70.7% [2048 of 2298]; 95% CI, 69.0%-72.3%). With SSAR, the mean (SD) number of images (per SBCE video) requiring review was reduced to 779.2 (337.2) compared with 27 910.8 (12 882.9) with CR, for a mean (SD) reduction rate of 96.1% (4.3%). The mean (SD) reading time with SSAR was shortened to 5.4 (1.5) minutes compared with CR (51.4 [11.6] minutes), for a mean (SD) reduction rate of 89.3% (3.1%).This study suggests that a convolutional neural network-based algorithm is associated with an increased detection rate of SBCE findings and reduced SBCE video reading time.

Highlight We report that gastric cancer patients exhibiting high levels of heparanase 2 (Hpa2) survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to overexpress Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. These beneficial effects were found to associate with increased phosphorylation of AMP-activated protein kinase (AMPK) that play an instrumental role in cell metabolism and is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, possibly leading to attenuation of gastric tumorigenesis., Heparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate and, consequently, remodel the extracellular matrix underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks heparan sulfate-degrading activity typical of heparanase. We subjected sections of gastric carcinoma to immunostaining and correlated Hpa2 immunoreactivity with clinical records, including tumor grade, stage and patients' status. We over-expressed Hpa2 in gastric carcinoma cell lines and examined their tumorigenic properties in vitro and in vivo. We also evaluated the expression of Hpa2 by gastric carcinoma cells following inhibition of the proteasome, leading to proteotoxic stress, and the resulting signaling responsible for Hpa2 gene regulation. Here, we report that gastric cancer patients exhibiting high levels of Hpa2 survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to over-express Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. This was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), a kinase that is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, and AMPK was found to induce the expression of Hpa2, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, leading to attenuation of gastric tumorigenesis. These results indicate that high levels of Hpa2 in some tumors are due to stress conditions that tumors often experience due to their high rates of cell proliferation and high metabolic demands. This increase in Hpa2 levels by the stressed tumors appears critically important for patient outcomes.

The gut microbiota plays a crucial role in the development of the immune system and confers benefits or disease susceptibility to the host. Emerging studies have indicated the gut microbiota could affect pulmonary health and disease through cross talk between the gut microbiota and the lungs. Gut microbiota dysbiosis could lead to acute or chronic lung disease, such as asthma, tuberculosis, and lung cancer. In addition, the composition of the gut microbiota may be associated with different lung diseases, the prevalence of which also varies by age. Modulation of the gut microbiota through short-chain fatty acids, probiotics, and micronutrients may present potential therapeutic strategies to protect against lung diseases. In this review, we will provide an overview of the cross-talk between the gut microbiota and the lungs, as well as elucidate the underlying pathogenesis and/or potential therapeutic strategies of some lung diseases from the point of view of the gut microbiota.

Objective It is unclear how primary colorectal cancer (CRC) cells select to metastasize to the liver or lungs, the most frequent distant metastasis of CRC. We aimed to identify the key genes and pathways that may predict the distant metastasis of CRC to these sites. Methods Three gene expression array datasets from the Gene Expression Omnibus were analyzed. Protein-protein network analyses, best subsets regressions and backward stepwise regression analyses were used to screen the key genes and their expressions were used to construct a predictive logistic regression model. Expression data from local clinical samples were used as a validation dataset. The receiver operating characteristic (ROC) curve was used to test the performance of the predictive model. Results In total, 59 differentially expressed genes (DEG) related to liver-metastasis, 90 related to lung metastasis and 45 related to both liver and lung metastasis were identified. The KEGG pathways and gene oncology (GO) terms that were enriched in liver and lung metastasis were identified. A predictive logistic regression model consisted of SPARC, COL1A2, MMP9, COL11A1, COL3A1, CXCL12 and THBS2 was established. The area under the ROC curve reached 0.839 in predicting liver and lung metastasis, using our clinical samples as the validation dataset. Conclusions Seven key genes capable of predicting liver and lung metastasis of colorectal cancer were identified, which provides clues for exploring the mechanism of selecting target organs during the metastatic process in CRC and inspires the researches for new potential targets for therapy to inhibit metastasis.

M6A is the most prevalent modification among epigenetics. M6A occurs on different sites of RNA and exerts important functions in specific circumstances, such as mRNA splicing, stability, nuclear export, translation or damage response. Different aspects of the concrete machinery of m6A modification have been studied, including its writing, erasing and reading capabilities. The molecular and biological functions of the m6A modification and enzymes, as well as their functions in different cancers have been substantially published. The present review summarizes these findings and provides clear description of the problems involved. The probable roles of m6A modification may acts on other cancers, suggesting that it may be a treatment target for these cancers.

Gastric cancer is one of the most common cancer and is the second leading cause of cancer-related mortality in the world. PIN1, belonging to peptidyl-prolyl cis-trans isomerase family, uniquely catalyzes the structural transformation of phosphorylated Ser/Thr-Pro motif. It’s high expressed in most cancers and promotes their progression. However, the mechanism of PIN1 high expression and its function in gastric cancer progression are still unclear. In this research, we revealed that PIN1 not only promotes the proliferation and colony formation of gastric cancer, but also increases its migration and invasion. The PIN1 expression in metastasis lesion is usually higher than the corresponding primary site. Inhibiting PIN1 by shRNA suppresses the progression of gastric cancer significantly. Besides, we demonstrated that miR-628-5p is a novel PIN1-targeted microRNA, and the expression of miR-628-5p is negatively correlated with PIN1 in gastric cancer. Exogenous expression of miR-628-5p inhibits the progression of gastric cancer that revered by restoring PIN1 expression. However, miR-628-5p is downregulated in majority of gastric cancer tissue especially in metastasis lesion. The lower miR-628-5p level indicates poorer prognosis. In summary, our study demonstrated that deficient miR-628-5p expression facilitates the expression of PIN1, and consequently promotes the progression of gastric cancer.

Background Recent evidence suggests that neuropsychiatric stabilizers have a place in resolving gastrointestinal disorders. Lithium carbonate (LC) is one of the most commonly used drugs for bipolar disorder clinically. Here, we estimate the therapeutic function of LC against colitis and investigate the mechanism of intestinal flora and metabolism modulation. Methods A colitis model was constructed by continuously administering 2.5% dextran sodium sulfate (DSS) solution daily for 7 days. Analysis of gut microbiota was carried out by 16 S rRNA gene high-throughput sequencing. Spectrum antibiotic cocktail (ABX) and faecal microbiota transplantation (FMT) were employed to evaluate the protective effect of intestinal flora. Colonic Treg cells and related immune responses were detected by flow cytometry. Results LC treatment significantly alleviated colon inflammation by regulating gut microbial diversity and altering flora composition. Notably, LC treatment upregulated short-chain fatty acid (SCFA)-producing bacteria, especially Akkermansia muciniphila (A. muciniphila), and transformed metabolite SCFA profiles. LC activated anti-inflammatory Treg cell responses in colonic LP in a G-protein coupled receptor 43 (GPR43)-dependent mechanism. ABX, FMT and single bacteria gavage experiments were conducted to confirm the above mechanism. Conclusions As an intestinal microbiome and metabolite modulator, LC alleviates colon inflammation in a GPR43-dependent manner through activating Treg cell responses. Therefore, the therapeutic strategy of the microbiome-metabolite-immune axis, as observed in the A. muciniphila-SCFA-Treg cell axis in our study, might provide a new direction for the treatment of IBD.

Background and Aims Esophageal stricture is a common adverse event after endoscopic submucosal dissection (ESD) when it involves the entire circumference of the esophagus. We aimed to assess the effectiveness and safety of endoscopic transplantation of autologous esophageal mucosa in preventing stricture formation after circumferential ESD. Methods Nine patients who underwent circumferential ESD for early esophageal cancer were enrolled. After the patients underwent ESD, autologous esophageal mucosal patches were attached to the ulcer surface by using hemoclips and were then fixed with a covered metal mesh stent. The stent was removed 7 days after the procedure. The patients were followed up with endoscopy at scheduled times. Results Epithelialization occurred within a median of 7.1 days, with a graft survival rate of 96.5%. Strictures occurred at a mean of 24.7 days (range 18-34 days) after the procedure. The median number of endoscopic balloon dilatation sessions was 2.7 (range 0-6). Conclusions Transplantation of autologous esophageal mucosa could be a safe way of relieving the severity of esophageal stricture after circumferential ESD.

Pin1 is the only known peptidyl-prolyl cis–trans isomerase (PPIase) that specifically recognizes and isomerizes the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif. The Pin1-mediated structural transformation posttranslationally regulates the biofunctions of multiple proteins. Pin1 is involved in many cellular processes, the aberrance of which lead to both degenerative and neoplastic diseases. Pin1 is highly expressed in the majority of cancers and its deficiency significantly suppresses cancer progression. According to the ground-breaking summaries by Hanahan D and Weinberg RA, the hallmarks of cancer comprise ten biological capabilities. Multiple researches illuminated that Pin1 contributes to these aberrant behaviors of cancer via promoting various cancer-driving pathways. This review summarized the detailed mechanisms of Pin1 in different cancer capabilities and certain Pin1-targeted small-molecule compounds that exhibit anticancer activities, expecting to facilitate anticancer therapies by targeting Pin1.

The gut microbiota forms a symbiotic relationship with the host and benefits the body in many critical aspects of life. However, immune system defects, alterations in the gut microbiota and environmental changes can destroy this symbiotic relationship and may lead to diseases, including cancer. Due to the anatomic and functional connection of the gut and liver, increasing studies show the important role of the gut microbiota in the carcinogenesis of hepatocellular carcinoma (HCC). In this manuscript, we review the available evidence and analyze some potential mechanisms of the gut microbiota, including bacterial dysbiosis, lipopolysaccharide (LPS), and genotoxins, in the progression and promotion of HCC. Furthermore, we discuss the possible therapeutic applications of probiotics, chemotherapy modulation, immunotherapy, targeted drugs and fecal microbiota transplantation (FMT) in targeting the gut microbiota.

Long noncoding RNAs (lncRNAs) play a crucial role in cancer development, but few lncRNAs have been functionally characterized in gastric cancer (GC). Here, we reported an lncRNA LINC00675 whose expression was significantly decreased in GC tissues compared with the adjacent non-tumor tissues, and its low expression was associated with the poor survival of GC patients. Gain-and loss-of-function studies indicated that LINC00675 was a tumor suppressor because it repressed the proliferation, migration and invasion of GC cells in vitro and also inhibited the distal pulmonary and hepatic metastases of GC cells in vivo. Mechanistic investigations revealed that LINC00675 interacted with vimentin, a protein involved in cell metastasis, and enhanced its phosphorylation level on Ser83 to result in the collapse of vimentin filament in GC cells, thereby reducing cell metastasis. Taken together, our findings indicate that LINC00675 expression signature may serve as a novel biomarker for the diagnosis and prognosis of GC, and also highlight that LINC00675/vimentin complex may be a potentially therapeutic target of GC.

Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here, we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer development. CaSR expression was enhanced in gastric cancer specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in gastric cancer patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were colocalized in gastric cancer cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of gastric cancer cells through a Ca2+/AKT/β-catenin relay, which occurred only in gastric cancer cells or normal cells overexpressing CaSR. Tumor growth and metastasis of gastric cancer depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote gastric cancer, and that targeting the novel CaSR/TRPV4/Ca2+ pathway might serve as preventive or therapeutic strategies for gastric cancer. Cancer Res; 77(23); 6499–512. ©2017 AACR.

Aberrant expression of microRNAs (miRNAs) plays an important role in gastric cancer (GC) development. miR-93-5p has shown opposing functions in different types of cancers, but the exact expression pattern and molecular mechanism of miR-93-5p in GC development remain to be elucidated. Here, we reported that miR-93-5p expression was increased in GC tissues compared with the adjacent normal tissues and that its overexpression was correlated with distant metastasis and poor survival in GC patients. miR-93-5p knockdown inhibited the migration, invasion and proliferation of GC cells in vitro and in vivo, while its overexpression displayed an opposite result. Using an mRNA microarray, we found that miR-93-5p significantly downregulated IFNAR1 expression in GC cells, which was further identified as a direct target of miR-93-5p. IFNAR1 knockdown promoted GC cell migration and invasion, but its restoration could rescue GC cell migration and invasion induced by miR-93-5p overexpression. Moreover, miR-93-5p-IFNAR1 axis increased MMP9 expression via STAT3 pathway in GC cells. Taken together, we reveal that miR-93-5p overexpression is associated with the poor survival of GC patients and miR-93-5p-IFNAR1 axis promotes GC metastasis through activation of STAT3 pathway.

MicroRNA (miRNAs) is post-transcriptional regulator of mRNA. However, the prevalence and activity of miRNA are regulated by other regulators. miRNA inhibitors are natural or artificial RNA transcripts that sequestrate miRNAs and decrease or even eliminate miRNA activity. Competing endogenous RNAs (ceRNAs) are natural and intracellular miRNA inhibitors that compete to bind to shared miRNA recognition elements (MREs) to decrease microRNA availability and relieve the repression of target RNAs. In recent years, studies have revealed that ceRNA crosstalk is involved in many pathophysiological processes and adds a new dimension to miRNA regulation. Artificial miRNA inhibitors are RNA transcripts that are synthesized via chemical and genetic methods. Artificial miRNA inhibitors can be used in miRNA loss-of-function research and gene therapies for certain diseases. In this review, we summarize the recent advances in the two different types of miRNA inhibitors.

Hookworm infections are widely prevalent in tropical and subtropical areas, especially in low income regions. In the body, hookworms parasitize the proximal small intestine, leading to chronic intestinal hemorrhage and iron deficiency anemia. Occasionally, hookworms can cause overt gastrointestinal bleeding, but this is often ignored in heavily burdened individuals from endemic infectious areas. A total of 424 patients with overt obscure gastrointestinal bleeding were diagnosed by numerous blood tests or stool examinations as well as esophagogastroduodenoscopy, colonoscopy, capsule endoscopy or double-balloon enteroscopy. All of the patients lived in hookworm endemic areas and were not screened for hookworm infection using sensitive tests before the final diagnosis. The patients recovered after albendazole treatment, blood transfusion, and iron replacement, and none of the patients experienced recurrent bleeding in the follow-up. All the 31 patients were diagnosed with hookworm infections without other concomitant bleeding lesions, a rate of 7.3% (31/424). Seventeen out of 227 patients were diagnosed with hookworm infections in the capsule endoscopy (CE), and 14 out of 197 patients were diagnosed with hookworm infections in the double balloon enteroscopy (DBE). Hookworm infections can cause overt gastrointestinal bleeding and should be screened in patients with overt obscure gastrointestinal bleeding (OGIB) in endemic infectious areas with sensitive methods. Specifically, the examination of stool specimens is clinically warranted for most patients, and the proper examination for stool eggs relies on staff’s communication.

Cancer stem cells (CSCs), which comprise a small proportion of total cancer cells, have special capacities for self-renewal, differentiation and tumor formation. Currently, CSCs are regarded as the major cause of the failure in anticancer therapy, such as chemoresistance and/or radioresistance, tumor recurrence and metastasis. Autophagy, a process of cellular self-digestion and response to stress, has a role in tumor formation and progression, and it may play a dual role in CSCs-related resistance to anticancer therapy. Most researchers believe that autophagy contributes to stemness maintenance of CSCs and is responsible for the failure of anticancer therapy. Unexpectedly, several studies have also suggested that loss of stemness in CSCs could be mediated by autophagy. Here, we review the recent advances in CSCs and autophagy, especially analyze the complex relationship between them, and hope to apply this new knowledge to the strategies for anticancer therapy.

Tumors are one of the most serious human diseases and cause numerous global deaths per year. In spite of many strategies applied in tumor therapy, such as radiation therapy, chemotherapy, surgery, and a combination of these treatments, tumors are still the foremost killer worldwide among human diseases, due to their specific limitations, such as multidrug resistance and side effects. Therefore, it is urgent and necessary to develop new strategies for tumor therapy. Recently, the fast development of nanoscience has paved the way for designing new strategies to treat tumors. Nanomaterials have shown great potential in tumor therapy, due to their unique properties, including passive targeting, hyperthermia effects, and tumor-specific inhibition. This review summarizes the recent progress using the innate antitumor properties of metallic and nonmetallic nanomaterials to treat tumors, and related challenges and prospects are discussed.

// Chao Du 1,2 , Shiming Yang 1 , Xiaoyan Zhao 1 and Hui Dong 1,3 1 Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China 2 Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan Province, China 3 Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, California, USA Correspondence to: Xiaoyan Zhao, email: // Hui Dong, email: // Keywords : vitamin D, vitamin D receptor, gastric cancer, tumorigenesis Received : December 10, 2016 Accepted : January 20, 2017 Published : February 11, 2017 Abstract Gastric cancer is currently the second leading cause of cancer-related death worldwide, especially in Japan, Korea and China, and the 5-year survival rate of gastric cancer is less than 30%. Thus, it is important to shed more lights on novel agents to prevent gastric cancer or to improve survival rate of the patients. Vitamin D not only maintains calcium and bone homeostasis, but also mostly inhibits tumor genesis, invasion, and metastasis through activation of vitamin D receptor. Although epidemiological results are not consistent, accumulating evidence from gastric cancer cells, animal models, and clinical trials suggest that vitamin D deficiency may increase the risk and mortality of gastric cancer, but vitamin D supplement might be a safe and economical way to prevent or treat gastric cancer. Here, we reviewed the current studies on vitamin D and its receptor and focused on the pathogenic roles of their alterations in gastric tumorigenesis.

Human telomerase reverse transcriptase (hTERT) is the core subunit of human telomerase and plays important roles in human cancers. Aberrant expression of hTERT is closely associated with tumorigenesis, cancer cell stemness maintaining, cell proliferation, apoptosis inhibition, senescence evasion and metastasis. The molecular basis of hTERT regulation is highly complicated and consists of various layers. A deep and full-scale comprehension of the regulatory mechanisms of hTERT is pivotal in understanding the pathogenesis and searching for therapeutic approaches. In this review, we summarize the recent advances regarding the diverse regulatory mechanisms of hTERT, including the transcriptional (promoter mutation, promoter region methylation and histone acetylation), post-transcriptional (mRNA alternative splicing and non-coding RNAs) and post-translational levels (phosphorylation and ubiquitination), which may provide novel perspectives for further translational diagnosis or therapeutic strategies targeting hTERT.

HACE1 belongs to the family of HECT domain-containing E3 ligases, which plays an important role in the occurrence, invasion and metastatic process in many human malignancies. HACE1 is a tumor suppressor gene that is reduced in most cancer tissues compared to adjacent normal tissue. The loss or knocking out of HACE1 leads to enhanced tumor growth, invasion, and metastasis; in contrast, the overexpression of HACE1 can inhibit the development of tumors. Hypermethylation reduces the expression of HACE1, thereby promoting tumor development. HACE1 can inhibit the development of inflammation or tumors via the ubiquitination pathway. Therefore, HACE1 may be a potential therapeutic target, providing new strategies for disease prevention and treatment.

Background Although proton pump inhibitors (PPIs) are widely used in the prevention of gastric bleeding caused by endoscopic submucosal dissection (ESD), there is no consensus on the optimal regimen for these patients. Therefore, we aim to investigate whether intermittent use of low-dose PPI is sufficient to prevent post-ESD bleeding. Methods This multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose or continuous high-dose PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%. Results 526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to low-dose (n = 209) or high-dose (n = 205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 13 (6.2 %, 95 % CI 3.3–9.6) of 209 within 7 days in the intermittent low-dose group, and 12 (5.9 %, 95 % CI 2.9–9.3) of 205 in the continuous high-dose group. The absolute risk reduction (ARR) was 0.4 % (−4.2, 4.9). One month after ESD, There are 44 patients (21.1 %, 95 % CI 15.8, 26.8) and 39 patients (19.0 % 95 % CI 13.7, 24.4) in scar stage respectively in low-dose group and high-dose group (P = 0.875).The hospital costs in the low-dose PPI group was lower than high -dose group (P = 0.005). Conclusion The intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs.

In mice, antigen-specific CD4+ T cell response is indispensible for the protective immunity against Helicobacter pylori (H. pylori). It has been demonstrated that neuraminyllactose-binding hemagglutinin (HpaA) immunization protected mice from H. pylori infection in a CD4+ T cell dependent manner. However, much remains unclear concerning the human CD4+ T cell responses to HpaA. We conducted a systematic study here to explore the immunodominant, HpaA-specific CD4+ T cell responses in H. pylori infected individuals. We found that HpaA-specific CD4+ T cell responses varied remarkably in their magnitude and had broad epitope-specificity. Importantly, the main responses focused on two regions: HpaA76-105 and HpaA130-159. The HLA-DRB1*0901 restricted HpaA142-159 specific CD4+ T cell response was the most immunodominant response at a population level. The immunodominant epitope HpaA142-159 was naturally presented and highly conserved. We also demonstrated that it was not the broad peptide specificity, but the strength of HpaA specific CD4+ T cell responses associated with gastric diseases potentially caused by H. pylori infection. Such investigation will aid development of novel vaccines against H. pylori infection.

The calcium sensing receptor (CaSR) is functionally expressed in normal human pancreases, but its pathological role in pancreatic tumorigenesis is currently unknown. We sought to investigate the role of CaSR in pancreatic cancer (PC) and the underlying molecular mechanisms. We revealed that the expression of CaSR was consistently downregulated in the primary cancer tissues from PC patients, which was correlated with tumor size, differentiation and poor survival of the patients. CaSR activation markedly suppressed pancreatic tumorigenesis in vitro and in vivo likely through the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger 1 (NCX1) to induce Ca(2+) entry into PC cells. Moreover, NCX1-mediated Ca(2+) entry resulted in Ca(2+)-dependent inhibition of β-catenin signaling in PC cells, eventually leading to the inhibition of pancreatic tumorigenesis. Collectively, we demonstrate for the first time that CaSR exerts a suppressive function in pancreatic tumorigenesis through a novel NCX1/Ca(2+)/β-catenin signaling pathway. Targeting this specific signaling pathway could be a potential therapeutic strategy for PC.

// Xia Xie 1 , Bo Tang 1 , Yu-Feng Xiao 1 , Rui Xie 1 , Bo-Sheng Li 1 , Hui Dong 1,2 , Jian-Yun Zhou 1 and Shi-Ming Yang 1 1 Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China 2 Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA Correspondence to: Shi-Ming Yang, email: // Jian-Yun Zhou, email: // Keywords : colorectal cancer, long non-coding RNAs, epigenetic modifications, pseudogenes, X-inactive-specific transcript Received : August 15, 2015 Accepted : November 21, 2015 Published : December 02, 2015 Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Despite substantial progress in understanding the molecular mechanisms and treatment of CRC in recent years, the overall survival rate of CRC patients has not improved dramatically. The development of CRC is multifactor and multistep processes, in which abnormal gene expression may play an important role. With the advance of human tumor molecular biology, a series of studies have highlighted the role of long non-coding RNAs (lncRNAs) in the development of CRC. CRC-related lncRNAs have been demonstrated to regulate the genes by various mechanisms, including epigenetic modifications, lncRNA-miRNA and lncRNA-protein interactions, and by their actions as miRNA precursors or pseudogenes. Since some lncRNAs can be detected in human body fluid and have good specificity and accessibility, they have been suggested to be used as novel potential biomarkers for CRC diagnosis and prognosis as well as in the prediction of the response to therapy. Therefore, in this review, we will focus on lncRNAs in CRC development, the mechanisms and biomarkers of lncRNAs in CRC.

BACKGROUND AND PURPOSE: As little is known about the effect of caffeine, one of the most widely consumed substances worldwide, on intestinal function, we aimed to study its action on intestinal anion secretion and the underlying molecular mechanisms. EXPERIMENTAL APPROACH: Anion secretion and channel expression were examined in mouse duodenal epithelium by Ussing chambers and immunocytochemistry. Ca(2+) imaging was also performed in intestinal epithelial cells (IECs). KEY RESULTS: Caffeine (10 mM) markedly increased mouse duodenal short‐circuit current (I (sc)), which was attenuated by a removal of either Cl(−) or HCO(3) (−), Ca(2+)‐free serosal solutions and selective blockers of store‐operated Ca(2+) channels (SOC/Ca(2+) release‐activated Ca(2+) channels), and knockdown of Orai1 channels on the serosal side of duodenal tissues. Caffeine induced SOC entry in IEC, which was inhibited by ruthenium red and selective blockers of SOC. Caffeine‐stimulated duodenal I (sc) was inhibited by the endoplasmic reticulum Ca(2+) chelator (N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethylenediamine), selective blockers (ruthenium red and dantrolene) of ryanodine receptors (RyR), and of Ca(2+)‐activated Cl(−) channels (niflumic acid and T16A). There was synergism between cAMP and Ca(2+) signalling, in which cAMP/PKA promoted caffeine/Ca(2+)‐mediated anion secretion. Expression of STIM1 and Orai1 was detected in mouse duodenal mucosa and human IECs. The Orai1 proteins were primarily co‐located with the basolateral marker Na(+), K(+)‐ATPase. CONCLUSIONS AND IMPLICATIONS: Caffeine stimulated intestinal anion secretion mainly through the RyR/Orai1/Ca(2+) signalling pathway. There is synergism between cAMP/PKA and caffeine/Ca(2+)‐mediated anion secretion. Our findings suggest that a caffeine‐mediated RyR/Orai1/Ca(2+) pathway could provide novel potential drug targets to control intestinal anion secretion.

Objective Endoscopic balloon dilation (EBD) is still considered the standard treatment for patients with anastomotic strictures after esophagectomy. However, repeated dilation sessions are often required to maintain the lumen patency. We therefore developed a novel method called circular incision and cutting (CIC) and compared the efficacy of CIC and EBD among patients with anastomotic strictures after esophagectomy or gastrectomy. Methods In this retrospective study, 71 consecutive patients with esophageal cancer with anastomotic strictures after esophagectomy or gastrectomy between January 2011 and December 2016 were included. Among them, 22 patients received CIC therapy and 49 were treated with EBD. Results The dysphagia in all patients immediately ameliorated and no serious adverse events requiring further intervention were observed after CIC therapy. Compared with EBD, CIC exhibited a greater score in the difference of dysphagia before and after treatment (1.73 vs 1.16, P = 0.03). Moreover, the interval of restenosis and 6-month lumen patency in CIC had a better effect than that in EBD (88.07 days vs 62.76 days, P = 0.001; dysphagia score 0.63 vs 1.44, P = 0.007). Conclusion The CIC method may be an effective and safe option for patients with esophageal cancer with anastomotic strictures after esophagectomy.

Interleukin-17 receptor B (IL-17RB), a member of the IL-17 receptor family activated by IL-17B/IL-17E, has been shown to be involved in inflammatory diseases. However, the regulation and function of IL-17RB in Helicobacter pylori (H. pylori) infection, especially in the early-phase is still unknown. Here, we found that gastric IL-17RB mRNA and protein were decreased in gastric mucosa of both patients and mice infected with H. pylori. In vitro experiments show that IL-17RB expression was down regulated via PI3K/AKT pathway on gastric epithelial cells (GECs) stimulated with H. pylori in a cagA-involved manner, while in vivo studies showed that the effect was partially dependent on cagA expression. IL-17E was also decreased during the early-phase of H. pylori infection, and provision of exogenous IL-17E resulted in increased CD11b+CD11c− myeloid cells accumulation and decreased bacteria colonization within the gastric mucosa. In the early-phase of H. pylori infection, IL-17E-IL-17RB promoted gastric epithelial cell-derived CXCL1/2/5/6 to attract CD11b+CD11c− myeloid cells, and also contributed to host defense by promoting the production of antibacterial protein Reg3a. This study defines a negative regulatory network involving IL-17E, GECs, IL-17RB, CD11b+CD11c− myeloid cells, and Reg3a in the early-phase of H. pylori infection, which results in an impaired host defense within the gastric microenvironment, suggesting IL-17RB as a potential early intervening target in H. pylori infection.

The MiT/TFE transcription factors play a pivotal role in the regulation of autophagy and lysosomal biogenesis. The subcellular localization and activity of MiT/TFE proteins are primarily regulated through phosphorylation. And the phosphorylated protein is retained in the cytoplasm and subsequently translocates to the nucleus upon dephosphorylation, where it stimulates the expression of hundreds of genes, leading to lysosomal biogenesis and autophagy induction. The transcription factor-mediated lysosome-to-nucleus signaling can be directly controlled by several signaling molecules involved in the mTORC1, PKC, and AKT pathways. MiT/TFE family members have attracted much attention owing to their intracellular clearance of pathogenic factors in numerous diseases. Recently, multiple studies have also revealed the MiT/TFE proteins as master regulators of cellular metabolic reprogramming, converging on autophagic and lysosomal function and playing a critical role in cancer, suggesting that novel therapeutic strategies could be based on the modulation of MiT/TFE family member activity. Here, we present an overview of the latest research on MiT/TFE transcriptional factors and their potential mechanisms in cancer.

Interleukin (IL)-induced inflammatory responses are critical for the pathogenesis of Helicobacter pylori (H. pylori)-induced gastritis. IL-33 represents a recently discovered proinflammatory cytokine involved in inflammatory diseases, but its relevance to H. pylori-induced gastritis is unknown. Here, we found that gastric IL-33 mRNA and protein expression were elevated in gastric mucosa of both patients and mice infected with H. pylori, which is positively correlated with bacterial load and the degree of gastritis. IL-33 production was promoted via extracellular regulated protein kinases (ERK) signaling pathway activation by gastric epithelial cells in a cagA-dependent manner during H. pylori infection, and resulted in increased inflammation and bacteria burden within the gastric mucosa. Gastric epithelial cell-derived IL-33 promoted TNF-α production from mast cells in vitro, and IL-33 increased TNF-α production in vivo. Increased TNF-α inhibited gastric epithelial cell proliferation, conducing to the progress of H. pylori-associated gastritis and bacteria colonization. This study defined a patent regulatory networks involving H. pylori, gastric epithelial cell, IL-33, mast cell, and TNF-α, which jointly play a pathological effect within the gastric circumstances. It may be a valuable strategy to restrain this IL-33-dependent pathway in the treatment of H. pylori-associated gastritis.