RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells.

BACKGROUND & AIMS: Clinical evidence substantiates a link between inflammatory bowel disease, particularly Crohn's disease (CD), and metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to explore the underlying molecular mechanisms responsible for this association. METHODS: MASLD was induced by administering high-fat and western diets, while inflammatory bowel disease was induced using DSS (dextran sulfate sodium) and the Il10 knockout (KO) mouse model. The investigation into the role of secondary bile acids (SBAs) in ileitis involved employing metagenomic sequencing, conducting metabolomics detection, performing fecal microbiota transplantation, and constructing CD8+ T cell-specific gene knockout mice. RESULTS: In MASLD+DSS and Il10 KO MASLD mice, we observed ileitis characterized by T-cell infiltration and activation in the terminal ileum. This condition resulted in decreased bile acid levels in the portal vein and liver, inhibited hepatic farnesoid X receptor (FXR) activation, and exacerbated MASLD. Metagenomic and metabolomic analysis of ileal contents revealed increased Clostridium proliferation and elevated SBA levels in MASLD-associated ileitis. Experiments using germ-free mice and fecal microbiota transplantation suggested an association between SBA and MASLD-related ileitis. In vitro, SBAs promoted CD8+ T-cell activation via the TGR5, mTOR, and oxidative phosphorylation pathways. In vivo, TGR5 KO in CD8+ T cells effectively alleviated ileitis and reversed the MASLD phenotype. Clinical data further supported these findings, demonstrating a positive correlation between ileitis and MASLD. CONCLUSION: MASLD-induced changes in intestinal flora result in elevated levels of SBAs in the ileum. In the presence of a compromised intestinal barrier, this leads to severe CD8+ T cell-mediated ileitis through the TGR5/mTOR/oxidative phosphorylation signaling pathway. Ileitis-induced tissue damage impairs enterohepatic circulation, inhibits hepatic FXR activation, and exacerbates the MASLD phenotype. IMPACT AND IMPLICATIONS: Our study provides a comprehensive investigation of the interplay and underlying mechanisms connecting ileitis and metabolic dysfunction-associated steatotic liver disease (MASLD). Secondary bile acids produced by intestinal bacteria act as the critical link between MASLD and ileitis. Secondary bile acids exert their influence by disrupting liver lipid metabolism through the promotion of CD8+ T cell-mediated ileitis. In future endeavors to prevent and treat MASLD, it is essential to thoroughly account for the impact of the intestinal tract, especially the ileum, on liver function via the enterohepatic circulation.

Risk factors of missed early gastric cancer in endoscopic resected population: a retrospective, case-control study.

BACKGROUND: Missed early gastric cancer (MEGC) is prevalent during esophagogastroduodenoscopy (EGD), which is the first-line recommended strategy for detecting early gastric cancer (EGC). Hence, we explored the risk factors for MEGC and different types of MEGC, based on the endoscopic resected population. METHODS: This retrospective, case-control study was conducted at Nanjing Drum Tower Hospital (NJDTH). We included patients who were diagnosed with EGC during screening EGD, underwent endoscopic resection, and were confirmed by postoperative pathology at the NJDTH from January 2014 to December 2021, and classified them into different types according to the different root causes of misses. Univariable, multivariable, subgroup and propensity score analyses were used to explore the risk factors for MEGC and different types of MEGC. RESULTS: A total of 447 patients, comprising 345 with initially detected early gastric cancer (IDEGC) and 102 with MEGC, were included in this study. Larger size (≥ 1 cm) (OR 0.45, 95% CI 0.27-0.74, P = 0.002) and invasion depth of submucosa (OR 0.26, 95% CI 0.10-0.69, P = 0.007) were negatively associated with MEGC. Use of sedation (OR 0.32, 95% CI 0.20-0.52, P < 0.001) and longer observation time (OR 0.60, 95% CI 0.37-0.96, P = 0.034) exhibited protective effect on MEGC. CONCLUSIONS: Smaller and more superficial EGC lesions are more susceptible to misdiagnosis. The use of sedation and prolonged observation time during EGD could help reduce the occurrence of MEGC.

Acetyltransferase from Akkermansia muciniphila blunts colorectal tumourigenesis by reprogramming tumour microenvironment.

OBJECTIVE: The protein post-translational modification (PTM) in host cells can be rewritten by bacterial enzymes and represents an unprecedented mechanism in the communication between intestinal flora and the host. Although Akkermansia muciniphila has been widely investigated as a probiotic and blunts colitis-associated tumourigenesis in mice, there is little understanding regarding whether A. muciniphila is involved in the PTM of colorectal cancer (CRC). This study investigates whether and how A. muciniphila engages in the PTM of host CRC. DESIGN: The secreting extracellular vesicles from A. muciniphila and purified Amuc_2172 were used for different tumourigenesis mice models. Amuc_2172-induced immune activity of CD8+ cytotoxic T lymphocytes (CTLs) were evaluated in vitro and in vivo. The acetyltransferase activity and downstream target genes of Amuc_2172 were investigated. RESULTS: Amuc_2172, a general control non-derepressible 5-related acetyltransferase of A. muciniphila, was accessible to colorectal cells by macropinocytosis and functioned as an acetyltransferase of Lys14 on histone H3 (H3K14ac). Elevated H3K14ac on Hspa1a loci promoted the transcription and secretion of heat-shock protein 70 (HSP70) in cancer cells. High level of HSP70 promoted the immune activity of CTLs in vitro and in vivo. Moreover, bioengineered nanoparticles provided a safe and reliable drug delivery strategy of Amuc_2172 for CRC treatment in an allograft mice model. CONCLUSION: Amuc_2172 reprogrammed tumour microenvironment by inducing HSP70 secretion and promoting CTL-related immune response in the process of tumourigenesis.

NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma.

OBJECTIVE: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq). DESIGN: scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. RESULTS: Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression. CONCLUSION: Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

Protein tyrosine phosphatase nonreceptor type 2 exerts antimetastatic functions in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive tumor with a dismal prognosis. Recent studies have demonstrated PTPN2 (protein tyrosine phosphatase nonreceptor type 2) as a potential target for cancer therapy. However, the functions of PTPN2 in PDAC progression remain poorly understood. In this study, we found PTPN2 expression was downregulated in PDAC tissues, and decreased PTPN2 expression was associated with unfavorable prognosis. Functional studies indicated that PTPN2 knockdown promoted the migration and invasion abilities of PDAC cells in vitro, and the liver metastasis in vivo through epithelial-mesenchymal transition process. Mechanistically, MMP-1 was identified as a downstream target of PTPN2 via RNA-seq data and was responsible for the enhanced metastasis of PDAC cells upon PTPN2 knockdown. Moreover, according to chromatin immunoprecipitation and electrophoretic mobility shift assay, PTPN2 depletion transcriptionally activated MMP-1 via regulating the interaction of p-STAT3 with its distal promoter. This study, for the first time, demonstrated that PTPN2 inhibited PDAC metastasis, and presented a novel PTPN2/p-STAT3/MMP-1 axis in PDAC progression.

Cinchonine-induced cell death in pancreatic cancer cells by downregulating RRP15.

Pancreatic cancer is characterized by poor prognosis and high mortality, while its treatment remains unsatisfactory. Cinchonine, a natural compound present in cinchona bark, is a potential anticancer drug. Whether cinchonine is of relevance to pancreatic cancer therapeutics is unclear. This research showed that the ribosomal RNA-processing 15 homolog (RRP15) expression is decreased in the pancreatic cancer, and RRP15 knockdown inhibited autophagy, and caused apoptosis in pancreatic cancer cells. Cinchonine treatment inhibits the expression of RRP15 and autophagy, and caused apoptosis by leading to the activation of Nrf2 axis in pancreatic cancer cells. Taken together, the above results indicate that cinchonine treatment inhibited autophagy and induced apoptosis through activating Nrf2 axis by downregulating RRP15 in pancreatic cancer cells.

The Characteristics and Treatment Outcomes of 71 Duodenal Brunner's Gland Adenomas with Endoscopic Submucosal Dissection.

INTRODUCTION: The aim of this study was to investigate outcomes of patients with duodenal Brunner's gland adenomas (BGAs) that were treated endoscopically. METHODS: We identified 71 consecutive patients treated at our center with endoscopic submucosal dissection (ESD) for their duodenal tumors diagnosed pathologically as BGAs over the period between January 1, 2011 and December 31, 2021. We retrospectively analyzed our experience and short- and long-term outcomes of ESD therapy on patients with BGAs. RESULTS: Among 71 BGA patients with an average age of 57 ± 11.7 years (range: 30-82), 48 (67.6%) were male and 23 (32.4%) were female. The accuracy of preoperative diagnosis with endoscopic ultrasonography was 44.0% (22/50). The H. pylori infection was found in 29 patients (29/71, 40.8%). The median size of BGAs was 1.5 cm (interquartile range [IQR] 0.8-2.7 cm). The most common location was the duodenum bulb (50/71, 64.8%). For the ESD procedure, the median operation time was 15.0 min (IQR 9.5-25.5 min). The en bloc and the complete resection rates were 97.2% and 92.3%, respectively. ESD-related mild acute obstructive pancreatitis was present in 2 patients (2/4, 50%) with BGAs located in the ampulla region. During the follow-up period, 1 patient with a positive peripheral margin experienced tumor recurrence 2 years after the initial ESD. There was no disease-related death for the cohort. CONCLUSION: ESD was an effective and safe therapeutic option for BGA patients with excellent outcomes. Long-term follow-up is needed.

Comparison of Safety and Outcomes between Endoscopic and Surgical Resections of Intermediate-Risk Primary Gastric Gastrointestinal Stromal Tumors.

BACKGROUND AND AIMS: The objective of this study was to compare the safety and efficacy of endoscopic resection with surgical resection in the treatment of intermediate-risk gastric gastrointestinal stromal tumors (GISTs) and to further evaluate whether imatinib adjuvant treatment is necessary for resected intermediate-risk gastric GIST by ER. METHODS: We retrospectively studied 128 cases for intermediate-risk gastric GISTs that were distributed in endoscopic (n = 33) and surgical groups (n = 95) at our center between December 2009 to July 2020. We statistically compared the clinical features, pathological reports, perioperative data, and long-term follow-up outcomes. RESULTS: Compared with the surgery group, the endoscopy group was associated with smaller tumor size (2.4 ± 1.0 vs. 6.0 ± 1.7 cm, p < 0.001), shorter operating time (67.3 ± 36.5 vs. 145.9 ± 74.8 min, p < 0.001), fewer incidence of short-term postoperative complications (3% vs. 32.6%, p = 0.002). Shorter postoperative hospital days (4.5 ± 1.4 vs. 8.5 ± 2.4 days, p < 0.001), shorter gastric functional recovery time (p < 0.001), and a lower overall medical cost of hospitalization (p < 0.001) was detected in the endoscopy group. During the median 44.5 months follow-up period, there were no cases of recurrence, metastasis, and death in the endoscopy group. Among 128 patients, 68 accepted adjuvant therapy with imatinib after resection. It was observed that the OS of the adjuvant treatment group with imatinib was lower than that of the group without imatinib (p = 0.033). CONCLUSION: Endoscopic resection for intermediate-risk gastric GIST is a feasible and safe method, and there is no significant benefit for patients with intermediate-risk gastric GIST to accept imatinib adjuvant treatment after ER.

Risk factors of perforation in gastric stromal tumors during endoscopic resection: a retrospective case-control study.

BACKGROUND AND AIMS: Perforation is a common complication during endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) associated with secondary infections, sepsis, hospitalization time and cost. However, the risk factors of perforation remain controversial. This study aimed to investigate the risk factors for perforation during ER of gGISTs. METHODS: This retrospective case-control study included consecutive patients with gGISTs who underwent ER between June 2009 and November 2021 at the Nanjing Drum Tower Hospital. Univariate and multivariate analyses were performed to investigate the risk factors for perforation. Sensitivity analyses with propensity scoring (PS) were performed to evaluate the stability of the independent effects. RESULTS: In total, 422 patients with gGISTs were included. The following factors were associated with perforation during ER: in the non-intraluminal growth patterns (all confounders adjusted odds ratio [aOR]: 5.39, 95% CI 2.99-9.72, P < 0.001), in the gastric fundus (aOR 2.25, 95% CI 1.40-3.60, P = 0.007), sized ≥ 2 cm (aOR 1.70, 95% CI 1.04-2.77, P = 0.035), in the lesser curvature (aOR 0.12, 95% CI 0.05-0.27, P < 0.001), and in the gastric cardia (aOR 0.13, 95% CI 0.04-0.50, P = 0.003). The PS analysis confirmed the stable independent effects of these identified risk factors. CONCLUSIONS: ERs of gGISTs in non-intraluminal growth patterns, in the gastric fundus, and with larger tumor size were independent risk factors for perforation. While tumors in the lesser curvature or gastric cardia were independent protective factor for perforation.

Bacillus subtilis and Bifidobacteria bifidum Fermentation Effects on Various Active Ingredient Contents in Cornus officinalis Fruit.

Microbial fermentation has been widely used to improve the quality and functional composition of food and edibles; however, the approach has rarely been applied to traditional Chinese medicines. In this study, to understand the effect of microbial fermentation on the active ingredients of traditional Chinese medicines, we used Bifidobacterium bifidum and Bacillus subtilis to ferment the traditional Chinese medicine, Cornus officinalis fruit (COF), and determined the levels of active ingredients using HPLC (high-performance liquid chromatography). According to the results, both B. subtilis and B. bifidum substantially increased the amount of gallic acid in the COF culture broth after fermentation; however, the two species of bacteria had no effect on the loganin content. Moreover, the B. subtilis fermentation reduced the contents of ursolic acid and oleanolic acid in the COF broth, whereas the B. bifidum fermentation did not. This study contributes to a better understanding of the mechanism by which microbial fermentation alters the active ingredient levels of traditional Chinese medicines, and suggests that fermentation may potentially improve their functional ingredients.

Development and initial validation of the psychological capital scale for nurses in Chinese local context.

BACKGROUND: Psychological capital is affected by different cultures and professional characteristics and its constituent dimensions and evaluation tools are heterogeneous. There is a lack of measurements for assessing nurses' psychological capital considering nursing professional characteristics and Chinese cultural impacts. AIMS: To develop a psychological capital scale that conforms to the Chinese cultural background and the characteristics of nursing profession, and evaluate the preliminary validation of the Nurses Psychological Capital Scale. METHODS: Nurses were conveniently recruited from two tertiary hospitals, Hebei, China. The research process included three steps: item development (Delphi survey and pilot survey), scale development (item analysis and exploratory factor analysis), scale validation (reliability and validity test). RESULTS: Exploratory factor analysis and confirmatory factor analysis showed that the 43-item scale comprised three factors (work task-oriented psychological capital, interpersonal relationship-oriented psychological capital and learning development-oriented psychological capital). Exploratory factor analysis showed the factor loadings ranging from 0.460 to 1.029. Three factors explained 68.71% of the variance. Confirmatory factor analysis showed an adequate model fit (x2/df =2.839, RMR = 0.041, RMSEA = 0.078, IFI = 0.872, TLI = 0.863, CFI = 0.871, PNFI = 0.768). The Cronbach's α for the scale was 0.975. The item-level content validity index (I-CVI) was 0.83 ~ 1.00, scale-level average content validity index (S-CVI/Ave) was 0.988. CONCLUSION: The Nurse Psychological Capital Scale had good reliability and validity, which is a reliable evaluation measure for assessing psychological capital among nurses.

Comparison of endoscopic full-thickness resection and cap-assisted endoscopic full-thickness resection in the treatment of small (≤1.5 cm) gastric GI stromal tumors.

BACKGROUND AND AIMS: With the increasing incidence of small GI stromal tumors (GISTs), endoscopic full-thickness resection (EFTR) and cap-assisted EFTR (EFTR-C) have been suggested as 2 effective resection methods. We aimed to compare the outcomes of EFTR and EFTR-C for the treatment of small (≤1.5 cm) gastric GISTs. METHODS: This retrospective study included 67 patients who underwent EFTR and 46 patients who underwent EFTR-C at Nanjing Drum Tower Hospital. Clinicopathologic features, adverse events (AEs), and outcomes were compared between the 2 groups. Univariate and multivariate linear and logistic regressions were used to analyze the effects of the procedure on the therapeutic outcomes of patients and adjusted for covariates in the multivariate analysis. RESULTS: The tumor size in the EFTR group tended to be larger (P = .005). The resection time in the EFTR-C group was shorter than that in the EFTR group (38.3 ± 20.7 minutes vs 15.0 ± 11.8 minutes, P < .001), which retained statistical significance with adjustment for the covariates (adjusted mean difference, 22.2; 95% confidence interval, 15.0-29.4; P < .001). The R0 resection rate of the EFTR group was 94.0% and of the EFTR-C group 97.8% (P = .355). The EFTR-C group was superior to the EFTR group in terms of perioperative therapeutic outcomes, AEs, and postoperative recovery. No recurrence occurred in the EFTR and EFTR-C groups. CONCLUSIONS: EFTR-C was found to be the preferable technique for small (≤1.5 cm) gastric GISTs with shorter operation times, lower AEs, faster postoperative recovery, and shorter hospitalization times as compared with EFTR.

Diagnostic value of endoscopic ultrasound-guided fine needle aspiration with rapid on-site evaluation performed by endoscopists in solid pancreatic lesions: A prospective, randomized controlled trial.

BACKGROUND AND AIM: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the most established diagnostic method for pancreatic tissue. Rapid on-site evaluation by a trained endoscopist (self-ROSE) can improve the diagnostic accuracy. This research is aimed to analyze the application value of self-ROSE for EUS-FNA in solid pancreatic lesions. METHODS: A total of 194 consecutive patients with solid pancreatic lesions in Nanjing Drum Tower Hospital were randomized in a 1:1 ratio to EUS-FNA with or without self-ROSE in this single-center randomized controlled trial. Before initiating self-ROSE, the endoscopist underwent training for pancreatic cytologic sample adequacy assessment and cytopathological diagnosis of EUS-FNA in pathology department for 1 month. Some parts of the slides of EUS-FNA were air dried, stained on-site with BASO Liu's reagent, and on-site evaluated in self-ROSE group. Between the two groups, the diagnostic performance of EUS-FNA was analyzed, including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, with a comparison of the number of needle passes and the complication rates. RESULTS: The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 94.8%, 94.4%, 100%, 100%, and 58.3% in the self-ROSE group, respectively, and 70.1%, 65.1%, 100%, 100%, and 32.6% in the non-self-ROSE group. The diagnostic accuracy (P < 0.001) and sensitivity (P < 0.001) were both significantly increased during EUS-FNA in the self-ROSE group compared to the non-self-ROSE group. The rate of cytologic sample adequacy was 100% in self-ROSE group and 80.4% in non-self-ROSE group. The number of passes were 3.38 ± 1.00 in self-ROSE group and 3.22 ± 0.89 in non-self-ROSE group (P = 0.228). No complications were found in both. There was acceptable consistency between endoscopist and pathologist in the cytopathological diagnosis (kappa = 0.666, P < 0.05) and in the sample adequacy rate (kappa = 1.000, P < 0.001). CONCLUSION: Our results demonstrated that self-ROSE is valuable for EUS-FNA in the diagnosis of solid pancreatic lesions and is an important choice to routinely increase the accuracy of EUS-FNA in centers without ROSE assessment.

Associations between nutrition risk scores and sarcopenia in gastrointestinal cancer patients: a cross-sectional study.

PURPOSE: Sarcopenia is an independent risk factor for poor prognosis of cancers. The nutritional risk screening 2002 (NRS2002) and patient-generated subjective global assessment (PG-SGA) tools are widely used tools for nutrition risk screening and assessing. The purpose of this study was to investigate whether NRS2002 and PG-SGA scores are associated with sarcopenia in gastrointestinal cancers. METHODS: A consecutive cohort comprised of 432 gastrointestinal cancer patients was conducted. We used NRS2002 and PG-SGA to assess their nutrition status. Sarcopenia was diagnosed with CT scan at the third lumber vertebra level. The correlations of nutritional scores with SMI, nutritional categories with sarcopenia were assessed by Spearman's correlation test and point biserial correlation. The cut-off value of nutritional scores for identifying sarcopenia was obtained by maximum Youden index. Logistic regression was used to confirm the associations. RESULTS: Sarcopenia patients had higher NRS2002 (2.63 ± 1.16 vs. 2.15 ± 1.20, p < 0.001) and PG-SGA (8.69 ± 1.16 vs. 5.56 ± 3.28, p < 0.001) scores. The NRS2002 (r = -0.198, p < 0.001) and PG-SGA (r = -0.409, p < 0.001) scores were significantly and negatively correlated with skeletal muscle mass index. The cut-off value of PG-SGA score for predicting sarcopenia was 7. In multivariate logistic regression, the PG-SGA exceeded 7 score (OR = 7.489, 95% CI: 4.122-13.608, p < 0.001) was significantly associated with increased risk of sarcopenia, while NRS2002 score showed no significant association with sarcopenia. CONCLUSIONS: PG-SGA ≥ 7 was associated with increased risk of sarcopenia and could serve as a useful criterion for capturing sarcopenia in gastrointestinal cancers. Routine PG-SGA evaluation for patient with gastrointestinal cancers is important.

A deep learning-based model improves diagnosis of early gastric cancer under narrow band imaging endoscopy.

BACKGROUND: Diagnosis of early gastric cancer (EGC) under narrow band imaging endoscopy (NBI) is dependent on expertise and skills. We aimed to elucidate whether artificial intelligence (AI) could diagnose EGC under NBI and evaluate the diagnostic assistance of the AI system. METHODS: In this retrospective diagnostic study, 21,785 NBI images and 20 videos from five centers were divided into a training dataset (13,151 images, 810 patients), an internal validation dataset (7057 images, 283 patients), four external validation datasets (1577 images, 147 patients), and a video validation dataset (20 videos, 20 patients). All the images were labeled manually and used to train an AI system using You look only once v3 (YOLOv3). Next, the diagnostic performance of the AI system and endoscopists were compared and the diagnostic assistance of the AI system was assessed. The accuracy, sensitivity, specificity, and AUC were primary outcomes. RESULTS: The AI system diagnosed EGCs on validation datasets with AUCs of 0.888-0.951 and diagnosed all the EGCs (100.0%) in video dataset. The AI system achieved better diagnostic performance (accuracy, 93.2%, 95% CI, 90.0-94.9%) than senior (85.9%, 95% CI, 84.2-87.4%) and junior (79.5%, 95% CI, 77.8-81.0%) endoscopists. The AI system significantly enhanced the performance of endoscopists in senior (89.4%, 95% CI, 87.9-90.7%) and junior (84.9%, 95% CI, 83.4-86.3%) endoscopists. CONCLUSION: The NBI AI system outperformed the endoscopists and exerted potential assistant impact in EGC identification. Prospective validations are needed to evaluate the clinical reinforce of the system in real clinical practice.

Injured liver-released miRNA-122 elicits acute pulmonary inflammation via activating alveolar macrophage TLR7 signaling pathway.

Hepatic injury is often accompanied by pulmonary inflammation and tissue damage, but the underlying mechanism is not fully elucidated. Here we identify hepatic miR-122 as a mediator of pulmonary inflammation induced by various liver injuries. Analyses of acute and chronic liver injury mouse models confirm that liver dysfunction can cause pulmonary inflammation and tissue damage. Injured livers release large amounts of miR-122 in an exosome-independent manner into the circulation compared with normal livers. Circulating miR-122 is then preferentially transported to mouse lungs and taken up by alveolar macrophages, in which it binds Toll-like receptor 7 (TLR7) and activates inflammatory responses. Depleting miR-122 in mouse liver or plasma largely abolishes liver injury-induced pulmonary inflammation and tissue damage. Furthermore, alveolar macrophage activation by miR-122 is blocked by mutating the TLR7-binding GU-rich sequence on miR-122 or knocking out macrophage TLR7. Our findings reveal a causative role of hepatic miR-122 in liver injury-induced pulmonary dysfunction.

Analysis of T-cell receptor repertoire in peripheral blood of patients with pancreatic cancer and other pancreatic diseases.

Pancreatic cancer (PC) has been the fourth cancer-related death worldwide, diagnosed at an unresectable stage due to its rapid progression and few symptoms of this disease at early stages. The aim of this study was to determine the association between the diversity of T-cell receptor (TCR) repertoire and clinicopathological characteristics of patients with PC and other benign pancreatic diseases. In order to make a comprehensive analysis the TCR repertoire, high-throughput sequencing was used to differentiate complementarity determining region 3 (CDR3) of the TCR ß chain in peripheral blood samples from 3 PC, 3 chronic pancreatitis, 3 pancreatic cystic lesions and 3 pancreatic neuroendocrine tumour patients. We found that there were significant differences related to TCR repertoire between PC and other pancreatic diseases, and PC is a relatively immunosuppressive tumour. Changes of peripheral TCR repertoire may be used to predict the progression of PC and the response to immunotherapy. And there may exist novel-specific antigens in PC patients which could be used to design targeting immunotherapy in the nearly future.

TRIM11 suppresses ferritinophagy and gemcitabine sensitivity through UBE2N/TAX1BP1 signaling in pancreatic ductal adenocarcinoma.

Gemcitabine is first-line chemotherapy for pancreatic cancer, however, the development of resistance limits its effectiveness. The tripartite motif-containing 11 (TRIM11) protein plays crucial roles in tumor development and undergoes auto-polyubiquitination to promote interactions in selective autophagy. Therefore, Understanding whether TRIM11 is involved in ferritinophagy and gemcitabine resistance in pancreatic cancer is critical in developing pancreatic cancer therapeutics. TRIM11 expression was validated by Western blot analysis, real-time polymease chain reaction, and immunohistochemical staining. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Colony formation assays were performed to investigate pancreatic ductal adenocarcinomas (PDAC) cell viability. Mouse xenograft model of PDAC cells was established to verify the role of TRIM11 in vivo. Coimmunoprecipitation was used to identify the reciprocal regulation between TRIM11 and UBE2N. In this study, we found that TRIM11 expression were higher in PDAC cells and tissues. TRIM11 overexpression promotes PDAC cell proliferation in vitro and tumor growth in vivo. Decreased expression of TRIM11 in PDAC patients is associated with decreased UBE2N and increased TAX1BP1 expression. Coimmunoprecipitation established that TRIM11 interacts and colocalizes with UBE2N. Mechanistically, TRIM11 promoted gemcitabine resistance and suppressed ferritinophagy through UBE2N-TAX1BP1 signaling. Our findings identify TRIM11 as a key regulator of TAX1BP1 signaling with a crucial role in ferritinophagy and gemcitabine resistance in PDAC.

EUS-guided portal pressure gradient measurement in patients with acute or subacute portal hypertension.

BACKGROUND AND AIMS: EUS-guided portal pressure gradient (EUS-PPG) measurement is a novel method to evaluate portal hypertension severity. In this study, we determined the consistency between EUS-PPG and hepatic venous pressure gradient (HVPG) measurements in patients with acute or subacute portal hypertension. METHODS: Twelve patients were prospectively enrolled. EUS-PPG measurements were performed using a 22-gauge FNA needle and a central venous pressure measurement monitor. The HVPG measurements were performed using the transjugular approach. If an HVPG measurement was not attainable and the patient underwent transjugular intrahepatic portosystemic shunt (TIPS) treatment, a PPG was recorded as a reference standard during the procedure. We assessed the feasibility and safety of EUS-PPG and calculated the correlation between the 2 measurements. RESULTS: EUS-PPG measurements were successful in 11 patients (91.7%). Subsequent HVPG measurements failed in 2 patients with Budd-Chiari syndrome (hepatic vein occlusion subtype), 1 of whom underwent TIPS treatment to obtain transjugular PPG data. A small shunt was found during 1 HVPG measurement that introduced inaccuracy. Nine patients were included in the statistical analysis. Mean EUS-PPG and HVPG/PPG (transjugular) were 18.07 ± 4.32 mm Hg and 18.82 ± 3.43 mm Hg, respectively. Pearson's correlation coefficient between the 2 methods was .923 (P < .001). CONCLUSIONS: EUS-PPG measurement using a 22-gauge FNA needle was a safe and accurate method to evaluate portal hypertension and has the potential to supplement the measurement of HVPG in liver diseases. (Clinical trial registration number: ChiCTR1800017317.).