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Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are regarded as useful tools for cancer detection, particularly for the early stage; however, little is known about their diagnostic impact on gastric cancer (GC). We hypothesized that GC-related lncRNAs might release into the circulation during tumor initiation and could be utilized to detect and monitor GC. 8 lncRNAs which previously found to be differently expressed in GC were selected as candidate targets for subsequent circulating lncRNA assay. After validating in 20 pairs of tissues and plasma in training set, H19 was selected for further analysis in another 70 patients and 70 controls. Plasma level of H19 was significantly higher in GC patients compared with normal controls (p < 0.0001). By receiver operating characteristic curve (ROC) analysis, the area under the ROC curve (AUC) was 0.838; p < 0.001; sensitivity, 82.9%; specificity, 72.9%). Furthermore, H19 expression enabled the differentiation of early stage GC from controls with AUC of 0.877; sensitivity, 85.5%; specificity, 80.1%. Besides, plasma levels of H19 were significantly lower in postoperative samples than preoperative samples (p = 0.001). In conclusion, plasma H19 could serve as a potential biomarker for diagnosis of GC, in particular for early tumor screening.

Background Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) and can modulate gene expression by binding to miRNAs; further, circRNAs have been shown to participate in several pathological processes. However, the expression and biological function of circCUL2 in gastric cancer (GC) remains largely unknown. Methods circRNA microarrays and quantitative real-time PCR (qRT-PCR) were used to identify differentially expressed circRNAs in GC tissues and cell lines. circCUL2 knockdown and overexpression were performed to indicate the functional role of circCUL2 in vitro and in vivo. The expression and regulation of circCUL2, miR-142-3p and ROCK2 were evaluated using fluorescence in situ hybridization (FISH), dual-luciferase assays, RNA pull-down assays, RNA immunoprecipitation (RIP) and rescue experiments. Furthermore, the regulation of cisplatin sensitivity and autophagy by circCUL2/miR-142-3p/ROCK2 was demonstrated by cellular apoptosis assays, western blot, immunofluorescence and transmission electron microscopy analyses. Results The level of circCUL2, which is stable and cytoplasmically localized, was significantly reduced in GC tissues and cells. Overexpressed circCUL2 inhibited malignant transformation in vitro and tumorigenicity in vivo. In the AGS and SGC-7901 cell lines, circCUL2 sponged miR-142-3p to regulate ROCK2, thus modulating tumor progression. Furthermore, in the AGS/DDP and SGC-7901/DDP cell lines, circCUL2 regulated cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation. Conclusion circCUL2 may function as a tumor suppressor and regulator of cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation, which could be a key mechanism and therapeutic target for GC.

Background and aimEndoscopic submucosal dissection (ESD) is used to treat early esophageal cancer and precancerous lesions. Patients undergoing ESD are prone to esophageal stenosis, which impairs therapeutic efficacy and quality of life. This retrospective study aimed to investigate the potential association between patient demographics and esophageal lesion characteristics with the risk of esophageal stenosis following ESD.MethodsFor this retrospective study 190 consecutive patients who underwent ESD between January 2013 and January 2015 were recruited. Data on patient demographics, esophageal lesion-related factors, operation details, esophageal stenosis occurrence and measures taken to prevent or treat stricture were collected, and the normality of distribution of each indicator was assessed with a Kolmogorov–Smirnov test. Stenosis risk factors were then identified using univariate and multivariate logistic regression.ResultsPost-ESD esophageal stenosis occurred in 51 cases. Multivariate logistic regression analysis was performed to identify independent risk factors. A history of EMR/ESD (OR = 4.185, 95% CI: 1.511–11.589), resection circumferential diameter (OR = 1.721, 95% CI: 1.135–2.610), non-en bloc resection (OR = 7.413, 95% CI: 2.398–22.921), submucosal infiltration (OR = 3.449, 95% CI: 1.014–11.734) and circumferential resection range (OR = 57.493, 95% CI: 17.236–191.782) were identified as independent risk factors for post-ESD esophageal stenosis. Spraying porcine fibrin adhesive on the resection bed reduced neither the incidence of postoperative stenosis nor the extent of postoperative dilation.ConclusionPost-ESD esophageal stenosis is significantly related to size and circumferential range of lesion resection. EMR/ESD history, non-en bloc resection and submucosal infiltration may be additional risk factors.

Circular RNAs (circRNAs) play a vital role in the occurrence and development of tumors, including gastric cancer (GC). However, there are still many circRNAs related to GC whose functions and molecular mechanisms remain undetermined. Herein, we discover circRNA RELL1, which has not been investigated in GC, and it is markedly downregulated in GC tissues, which is related with poor prognosis, more pronounced lymph node metastasis and poor TNM stage. After confirming the circular structure of circRELL1, we found that circRELL1 could block cell proliferation, invasion, migration, and anti-apoptosis in patients with GC by a series of in vivo and in vitro function-related studies. Further mechanism investigation demonstrated that circRELL1 could sponge miR-637 and indirectly unregulated the expression of EPHB3 via modulating autophagy activation in GC. Additionally, circRELL1 can be transmitted by exosomal communication, and exosomal circRELL1 suppressed the malignant behavior of GC in vivo and in vitro. Taken together, this study elucidates the suppressive roles of circRELL1/miR-637/EPHB3 axis through autophagy activation in GC progression, inspiring for further understanding of the underlying molecular mechanisms of GC and providing a promising novel diagnostic circulating biomarker and therapeutic target in GC.

Background Exosomes are essential for tumor growth, metastasis, and are used as novel signaling molecules in targeted therapies. Therefore, exosomal miRNAs can be used in new diagnostic and therapeutic approaches due to their involvement in the development of cancers. However, the detailed biological function, potential molecular mechanism and clinical application of exo-miR-15b-3p in gastric cancer (GC) remains unclear. Methods miR-15b-3p mRNA levels in tissues, serum, cells and exosomes were analyzed using qRT-PCR assays. qRT-PCR, immunohistochemical and western blotting analyses were utilized for the determination of DYNLT1 expression. The interrelationship connecting miR-15b-3p with DYNLT1 was verified using Dual-luciferase report, western blotting and qRT-PCR assays. Fluorescent PKH-26 or GFP-Lv-CD63 labeled exosomes, as well as Cy3-miR-15b-3p, were utilized to determine the efficacy of the transfer of exo-miR-15b-3p between BGC-823 and recipient cells. Several in vitro assays and xenograft tumor models were conducted to determine exo-miR-15b-3p impact on GC progression. Results This is the first study to confirm high miR-15b-3p expression in GC cell lines, tissues and serum. Exosomes obtained from 108 GC patient serum samples and GC cell-conditioned medium were found to show upregulation of exo-miR-15b-3p, with the area under the ROC curve (AUC) being 0.820 [0.763–0.876], which is superior to the AUC of tissues and serum miR-15b-3p (0.674 [0.600–0.748] and 0.642 [0.499–0.786], respectively). In addition, high exo-miR-15b-3p expression in serum was found to accurately predict worse overall survival. SGC-7901 and GES-1 cells are capable of internalizing BGC-823 cell-derived exosomes, allowing the transfer of miR-15b-3p. Migration, invasion, proliferation and inhibition of apoptosis in vitro and in vivo were enhanced by exo-miR-15b-3p, by restraining DYNLT1, Cleaved Caspase-9 and Caspase-3 expression. Conclusions This study identified a previously unknown regulatory pathway, exo-miR-15b-3p/DYNLT1/Caspase-3/Caspase-9, which promotes GC development and GES-1 cell malignant transformation. Therefore, serum exo-miR-15b-3p may be a potential GC diagnosis and prognosis biomarker, which can be used in precise targeted GC therapy.

Objectives: Despite significant advances in neuroscience, the mechanisms of AD are not fully understood. Single-cell RNA sequencing (scRNA-seq) techniques provide potential solutions to analyze cellular composition of complex brain tissue and explore cellular and molecular biological mechanisms of AD. Methods: We investigated cellular heterogeneity in AD via utilization of bioinformatic analysis of scRNA-seq in AD patients and healthy controls from the Gene Expression Omnibus (GEO) database. The “GOplot” package was applied to explore possible biological processes in oligodendrocytes, astrocytes, and oligodendrocyte progenitor cells (OPCs). Expression patterns and biological functions of differentially expressed genes (DEGs) from scRNA-seq data were validated in RNA sequencing data. DEGs in astrocytes interacted with ferroptosis-related genes in FerrDb. CCK-8 and EdU assays were performed to measure cell proliferation ability. ROS, Fe2+ level, mitochondrial membrane potentials, iron concentrations, and total iron binding capacity (TIBC) in serum were evaluated. Y-maze and elevated maze were used to measure anxiety-like behavior. Autonomous and exploration behaviors or learning and memory ability in mice were analyzed using open field test and novel object recognition test. Results: Multiple clusters were identified, including oligodendrocytes, astrocytes, OPCs, neurons, microglia, doublets, and endothelial cells. Astrocytes were significantly decreased in AD, while oligodendrocytes and OPCs increased. Cell-to-cell ligand–receptor interaction analysis revealed that astrocytes, neurons, and OPCs mainly established contacts with other cells via the NRG3–ERBB4 ligand–receptor pair. GO and KEGG analyses found that astrocytes were enriched in the ferroptosis pathway. FTH1 and SAT1 in astrocytes were identified as hub mRNAs associated with ferroptosis. Serum iron concentration of 5xFAD mice was higher than that of WT, and emotional and cognitive function were significantly impaired as compared to WT. Serum iron concentration was negatively correlated with number of astrocytes and percentage of time spent entering the novelty arm in the Y-maze test, while it was positively correlated with percentage of time spent in the central area. Meanwhile, number of astrocytes was negatively correlated with percentage of time spent in the central area, while it was positively correlated with percentage of time spent entering the novelty arm. Conclusions: Through scRNA-seq analysis, we found that ferroptosis was activated in astrocytes and may contribute to the pathophysiological process in the entorhinal cortex. FTH1 and SAT1 were identified to impact astrocyte ferroptosis. Emotional and cognitive impairment in AD was associated with astrocyte ferroptosis. Our findings provide clues to reveal the pathophysiological processes following AD at the cellular level and highlight potential drug targets for the treatment of AD.

Previous meta-analyses reported that probiotics improve the effectiveness of Helicobacter pylori (H. pylori) eradication during antibiotic therapy, while results regarding a possible reduction of side effects remained inconclusive. Moreover, the effectiveness of different strains of probiotics has not been studied so far. It is further conceivable that probiotics will produce additional effects only if antibiotics are relatively ineffective. This meta-analysis includes eligible randomized controlled trials examining effects of probiotics supplementation on eradication rates (ER) and side effects, published up to May 2014. Sub-group analysis was performed to compare different probiotic strains and antibiotic therapies with different effectiveness in controls (ER <80% vs.>80%). Publication bias was assessed with funnel plots and Harbord's test. The quality of the trials was assessed with the Cochrane risk of bias tool. Thirty-three RCTs involving a total of 4459 patients met the inclusion criteria in case of eradication rates of which 20 assessed total side effects in addition. Overall, the pooled eradication rate in probiotics supplementation groups was significantly higher than in controls (ITT analysis: RR 1.122, 95% CI 1.086-1.159, PP analysis: RR 1.114, 95% CI 1.070-1.159). Sub group-analysis could, however, confirm this finding only for four individual strains (Lactobacillus acidophilus, Lactobacillus casei DN-114001, Lactobacillus gasseri, and Bifidobacterium infantis 2036) and for relatively ineffective antibiotic therapies. There was a significant difference between groups in the overall incidence of side effects (RR 0.735, 95% CI 0.598-0.902). This result was, however, only confirmed for non-blinded trials. The pooled data suggest that supplementation with specific strains of probiotics compared with eradication therapy may be considered an option for increasing eradication rates, particularly when antibiotic therapies are relatively ineffective. The impact on side effects remains unclear and more high quality trials on specific probiotic strains and side effects are thus needed.

Objectives. There is mounting evidence to suggest that the pathophysiology of stroke is greatly influenced by the microbiota of the gut and its metabolites, in particular short-chain fatty acids (SCFAs). The primary purpose of the study was to evaluate whether the levels of SCFAs and the gut microbiota are altered in poststroke patients and to examine the relationship between these alterations and the physical condition, intestinal health, pain, or nutritional status of patients. Methods. Twenty stroke patients and twenty healthy controls were enrolled in the current study, and their demographics were matched. Gas chromatography was used to determine the fecal SCFAs, and 16S rRNA gene sequencing was used to evaluate their fecal microbiota. Microbial diversity and richness were examined using the diversity indices alpha and beta, and taxonomic analysis was utilized to determine group differences. The relationships between the gut microbiome and fecal SCFAs, discriminant bacteria, and poststroke clinical outcomes were analyzed. Results. Less community richness (ACE and Chao) was observed in the poststroke patients (P<0.05), but the differences between the poststroke group and the healthy control group in terms of species diversity (Shannon and Simpson) were not statistically significant. The makeup of the poststroke gut microbiota was distinct from that of the control group, as evidenced by beta diversity. Then, the relative abundances of the taxa in the poststroke and control groups were compared in order to identify the specific microbiota changes. At the level of phylum, the poststroke subjects showed a significant increase in the relative abundances of Akkermansiaceae, Fusobacteriota, Desulfobacterota, Ruminococcaceae, and Oscillospirales and a particularly noticeable decrease in the relative abundance of Acidobacteriota compared to the control subjects (P<0.05). In regard to SCFA concentrations, lower levels of fecal acetic acid (P=0.001) and propionic acid (P=0.049) were found in poststroke subjects. Agathobacter was highly correlated with acetic acid level (r=0.473, P=0.002), whereas Fusobacteria (r=−0.371, P=0.018), Flavonifractor (r=−0.334, P=0.034), Desulfovibrio (r=−0.362, P=0.018), and Akkermansia (r=−0.321, P=0.043) were negatively related to acetic acid levels. Additionally, the findings of the correlation analysis revealed that Akkermansia (r=−0.356, P=0.024), Desulfovibrio (r=−0.316, P=0.047), and Alloprevotella (r=−0.366, P=0.020) were significantly negatively correlated with high-density lipoprotein cholesterol. In addition, the Neurogenic Bowel Dysfunction score (r=0.495, P=0.026), Barthel index (r=−0.531, P=0.015), Fugl-Meyer Assessment score (r=−0.565, P=0.009), Visual Analogue Scale score (r=0.605, P=0.005), and Brief Pain Inventory score (r=0.507, P=0.023) were significantly associated with alterations of distinctive gut microbiota. Conclusions. Stroke generates extensive and substantial alterations in the gut microbiota and SCFAs, according to our findings. The differences of intestinal flora and lower fecal SCFA levels are closely related to the physical function, intestinal function, pain, or nutritional status of poststroke patients. Treatment strategies aimed at modulating the gut microbiota and SCFAs may have the potential to enhance the clinical results of patients.

Background and aimEndoscopic closure of chronic gastrointestinal fistulas (CGFs) is challenging due to their epithelialized surfaces. The aim of this study was to assess the efficacy and long-term closure rate of endosuturing for CGFs with an Apollo Overstitch device.Patients and methodsConsecutive CGF patients undergoing endosuturing for fistula closure from April 2018 to January 2020 at the First Affiliated Hospital of Nanjing Medical University were enrolled for retrospective review. Demographics, fistula characteristics, details of the suturing procedures and outcomes were collected for analysis.ResultsTwenty patients (mean age 59.8 ± 9.1 years; 85% males) with a total of 23 CGFs underwent sutured fistula closure. Esophagotracheal fistulas were the most common CGFs (12/23, 52.2%), and prior cancer surgery was the most common fistulization etiology (14/20, 70%). Twelve patients (12/20, 60%) had undergone failed endoscopic attempts at fistula closure before suturing. Additional endoscopic therapies used during suturing were 100% argon plasma coagulation, 50% clip fixation, and 10% stent placement. Although all patients undergoing suturing achieved immediate technical success of fistula closure, sustained fistula closure was observed in only 5 patients (5/20, 25.0%) on surveillance endoscopy 3 months after suturing with a mean follow-up of 19.5 months. Esophagotracheal fistula patients were predisposed to shorter dehiscence-free survival than those with other fistulas (HR 3.378; 95% CI 1.127–10.13).ConclusionsEndosuturing is safe and should be considered for use as the first-line or salvage therapy for CGF closure, primarily for patients with fistulas not involving the trachea. However, the long-term healing of CGFs by suturing is challenging, and CGF patients might not benefit from repeated suturing.

ObjectiveTo establish and validate a model to determine the progression risk of gastric low-grade intraepithelial neoplasia (LGIN).MethodsA total of 705 patients with gastric LGIN at the endoscopy center of Jiangsu Provincial People's Hospital during January 2010 and August 2017 were retrospectively reviewed. Basic clinical and pathological information were recorded. According to the time sequence of the initial examination, the first 605 patients were enrolled in the derivation group, and the remaining 100 patients were used in the validation group. SPSS 19 software was used as statistical analysis to determine independent risk factors for progression of LGIN of the stomach and to establish a risk model. The ROC was used to verify the application value of the predictive model.ResultsUnivariate and multivariate analysis suggested that sex, multiple location, congestion, ulceration and form were independent risk factors for prolonged or advanced progression in patients with LGIN. Based on this, a predictive model is constructed: P = ex/(1 + ex) X = − 10.399 + 0.922 × Sex + 1.934 × Multiple Location + 1.382 × Congestion + 0.797 × Ulceration + 0.525 × Form. The higher of the P value means the higher risk of progression. The AUC of the derivation group and validation group were 0.784 and 0.766, respectively.ConclusionSex, multi-site, hyperemia, ulcer and morphology are independent risk factors for the prolongation or progression of patients with gastric LGIN. These factors are objective and easy to obtain data. Based on this, a predictive model is constructed, which can be used in management of patients. The model can be used to identify high-risk groups in patients with LGIN that may progress to gastric cancer. Strengthening follow-up or endoscopic treatment to improve the detection rate of early cancer or reduce the incidence of gastric cancer can provide a reliable basis for the treatment of LGIN.