YTHDF1 promotes gallbladder cancer progression via post-transcriptional regulation of the m6A/UHRF1 axis.

Gallbladder cancer is a rare but fatal malignancy. However, the mechanisms underlying gallbladder carcinogenesis and its progression are poorly understood. The function of m6A modification and its regulators was still unclear for gallbladder cancer. The current study seeks to investigate the function of YTH m6A RNA-binding protein 1 (YTHDF1) in gallbladder cancer. Transcriptomic analysis and immunochemical staining of YTHDF1 in gallbladder cancer tissues revealed its upregulation compared to paracancerous tissues. Moreover, YTHDF1 promotes the proliferation assays, Transwell migration assays, and Transwell invasion assays of gallbladder cancer cells in vitro. And it also increased tumour growth in xenograft mouse model and metastases in tail vein injection model in vivo. In vitro, UHRF1 knockdown partly reversed the effects of YTHDF1 overexpression. Mechanistically, dual-luciferase assays proved that YTHDF1 promotes UHRF1 expression via direct binding to the mRNA 3'-UTR in a m6A-dependent manner. Overexpression of YTHDF1 enhanced UHRF1 mRNA stability, as demonstrated by mRNA stability assays, and Co-IP studies confirmed a direct interaction between YTHDF1 and PABPC1. Collectively, these findings provide new insights into the progression of gallbladder cancer as well as a novel post-transcriptional mechanism of YTHDF1 via stabilizing target mRNA.

Cuproptosis in stroke: focusing on pathogenesis and treatment.

Annually, more than 15 million people worldwide suffer from stroke, a condition linked to high mortality and disability rates. This disease significantly affects daily life, impairing everyday functioning, executive function, and cognition. Moreover, stroke severely restricts patients' ability to perform daily activities, diminishing their overall quality of life. Recent scientific studies have identified cuproptosis, a newly discovered form of cell death, as a key factor in stroke development. However, the role of cuproptosis in stroke remains unclear to researchers. Therefore, it is crucial to investigate the mechanisms of cuproptosis in stroke's pathogenesis. This review examines the physiological role of copper, the characteristics and mechanisms of cuproptosis, the differences and similarities between cuproptosis and other cell death types, and the pathophysiology of cuproptosis in stroke, focusing on mitochondrial dysfunction and immune infiltration. Further research is necessary to understand the relationship between previous strokes and cuproptosis and to clarify the mechanisms behind these associations.

Consensus statements on endoscopic ultrasound-guided tissue acquisition. Guidelines from the Asian Endoscopic Ultrasound Group.

OBJECTIVES: This consensus was developed by the Asian EUS Group (AEG), who aimed to formulate a set of practice guidelines addressing various aspects of endoscopic ultrasound-guided tissue acquisition (EUS-TA). METHODS: The AEG initiated the development of consensus statements and formed an expert panel comprising surgeons, gastroenterologists, and pathologists. Three online consensus meetings were conducted to consolidate the statements and votes. The statements were presented and discussed in the first two consensus meetings and revised according to comments. Final voting was conducted at a third consensus meeting. The Grading of Recommendations, Assessment, Development, and Evaluation system was adopted to define the strength of the recommendations and quality of evidence. RESULTS: A total of 20 clinical questions and statements regarding EUS-TA were formulated. The committee recommended that fine-needle biopsy (FNB) needles be preferred over conventional fine-needle aspiration (FNA) needles for EUS-TA of subepithelial lesions. For solid pancreatic masses, rapid on-site evaluation is not routinely recommended when FNB needles are used. For dedicated FNB needles, fork-tip and Franseen-tip needles have essentially equivalent performance. CONCLUSION: This consensus provides guidance for EUS-TA, thereby enhancing the quality of EUS-TA.

Association between cardiometabolic index and controlled attenuation parameter in U.S. adults with NAFLD: findings from NHANES (2017-2020).

BACKGROUND: Cardiometabolic index (CMI), a novel indicator that combines abdominal obesity and lipid levels, has been confirmed to correlate with non-alcoholic fatty liver disease (NAFLD). However, limited research has been conducted on the relationship between CMI and controlled attenuation parameter (CAP), a parameter measured by transient elastography and reflecting the extent of fat accumulation in the liver. The objective of our study was to investigate the relationship between the two variables. METHODS: This was a cross-sectional study with a sample size of 1,759 U.S. adults with NAFLD sourced from the NHANES 2017-2020. Participants with a median CAP ≥ 248 dB/m were considered to have hepatic steatosis. CMI was calculated as [waist circumference (cm)/height(cm)]×[TG (mmol/L)/HDL-C (mmol/L)]. Multivariate linear regression, generalized additive model and subgroup analysis were employed to examine the association of CMI and CAP. RESULTS: The average age of the 1,759 participants was 50.2 years, with males accounting for 50.76% and females 49.24%. The average BMI was 32.23 kg/m². The multivariate linear regression model indicated that with every 1-unit increase in CMI, there was an associated rise of 10.40 dB/m in CAP (95% CI, 7.14-13.67) after adjusting for covariates and a p for trend < 0.05 suggested the existence of a linear association between the two variables. Similarly, generalized additive model also found it a roughly linear relationship between the two. Subgroup analysis revealed a positive correlation in the majority of subgroups. CONCLUSIONS: CMI was positively associated with CAP in U.S. adults with NAFLD. Our findings indicated that CMI may serve as an ideal indicator for monitoring the degree of hepatic steatosis among patients with NAFLD.

Plasma campesterol and ABCG5/ABCG8 gene loci on the risk of cholelithiasis and cholecystitis: evidence from Mendelian randomization and colocalization analyses.

The causal relationships between plasma metabolites and cholelithiasis/cholecystitis risks remain elusive. Using two-sample Mendelian randomization, we found that genetic proxied plasma campesterol level showed negative correlation with the risk of both cholelithiasis and cholecystitis. Furthermore, the increased risk of cholelithiasis is correlating with the increased level of plasma campesterol. Lastly, genetic colocalization study showed that the leading SNP, rs4299376, which residing at the ABCG5/ABCG8 gene loci, was shared by plasma campesterol level and cholelithiasis, indicating that the aberrant transportation of plant sterol/cholesterol from the blood stream to the bile duct/gut lumen might be the key in preventing cholesterol gallstone formation.

SI-ViT: Shuffle instance-based Vision Transformer for pancreatic cancer ROSE image classification.

BACKGROUND AND OBJECTIVE: The rapid on-site evaluation (ROSE) technique improves pancreatic cancer diagnosis by enabling immediate analysis of fast-stained cytopathological images. Automating ROSE classification could not only reduce the burden on pathologists but also broaden the application of this increasingly popular technique. However, this approach faces substantial challenges due to complex perturbations in color distribution, brightness, and contrast, which are influenced by various staining environments and devices. Additionally, the pronounced variability in cancerous patterns across samples further complicates classification, underscoring the difficulty in precisely identifying local cells and establishing their global relationships. METHODS: To address these challenges, we propose an instance-aware approach that enhances the Vision Transformer with a novel shuffle instance strategy (SI-ViT). Our approach presents a shuffle step to generate bags of shuffled instances and corresponding bag-level soft-labels, allowing the model to understand relationships and distributions beyond the limited original distributions. Simultaneously, combined with an un-shuffle step, the traditional ViT can model the relationships corresponding to the sample labels. This dual-step approach helps the model to focus on inner-sample and cross-sample instance relationships, making it potent in extracting diverse image patterns and reducing complicated perturbations. RESULTS: Compared to state-of-the-art methods, significant improvements in ROSE classification have been achieved. Aiming for interpretability, equipped with instance shuffling, SI-ViT yields precise attention regions that identifying cancer and normal cells in various scenarios. Additionally, the approach shows excellent potential in pathological image analysis through generalization validation on other datasets. CONCLUSIONS: By proposing instance relationship modeling through shuffling, we introduce a new insight in pathological image analysis. The significant improvements in ROSE classification leads to protential AI-on-site applications in pancreatic cancer diagnosis. The code and results are publicly available at https://github.com/sagizty/MIL-SI.

Preoperative H. pylori Eradication Therapy Facilitates Precise Delineation in Early Gastric Cancer with Current H. pylori Infection.

INTRODUCTION: Early gastric cancer with current Helicobacter pylori infection (HpC-EGC) is common, but it is still unclear whether H. pylori eradication therapy (Hp-ET) or endoscopic submucosal dissection (ESD) should be performed first. We evaluated Hp-ETs short-term effects on horizontal boundary delineations of HpC-EGC in ESD. METHODS: Prospectively enrolled HpC-EGC patients were randomly assigned to eradication or control groups. Operation scopes of HpC-EGC lesions were delineated with marking dots at 5 mm out of the endoscopic demarcation line by an independent endoscopist, unaware of eradication status, before formal circumferential incision. As representatives, precise delineation rate, the shortest distance of all marking dots to the pathological demarcation line in all slices of one intact resected specimen (Dmin), and negative marking dot specimen rate were examined. RESULTS: Twenty-three HpC-EGC patients (25 lesions) were allocated to eradication group and 26 patients (27 lesions) were allocated to the control group with similar eradication success rates and all were differentiated type. With improving background mucosa inflammation after Hp-ET and similar gastritis-like epithelium rates, 10 lesions (40.0%) in the eradication group were of precise delineation compared to control group with 2 lesions (7.4%) (relative risk = 5.40, 95% CI 1.31-22.28). Dmin of eradication and control groups were 4.17 ± 2.52 mm and 2.67 ± 2.30 mm (p = 0.029), accompanied by 4 (14.8%) and none (0.0%) specimens that exhibited positive marking dots (p = 0.11), respectively. CONCLUSION: For HpC-EGC patients, administrating eradication medication before ESD is beneficial for the precise delineation of lesions and reducing the risk of positive horizontal resection margins.

Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia.

BACKGROUND: Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to investigate the efficacy and safety of thalidomide for the treatment of recurrent bleeding due to SIA. Eligible patients with recurrent bleeding (at least four episodes of bleeding during the previous year) due to SIA were randomly assigned to receive thalidomide at an oral daily dose of 100 mg or 50 mg or placebo for 4 months. Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. Key secondary end points were cessation of bleeding without rebleeding, blood transfusion, hospitalization because of bleeding, duration of bleeding, and hemoglobin levels. RESULTS: Overall, 150 patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively (P<0.001 for simultaneous comparison across the three groups). The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels. CONCLUSIONS: In this placebo-controlled trial, treatment with thalidomide resulted in a reduction in bleeding in patients with recurrent bleeding due to SIA. (Funded by the National Natural Science Foundation of China and the Shanghai Municipal Education Commission, Gaofeng Clinical Medicine; ClinicalTrials.gov number, NCT02707484.).

Endoscopic and histopathological hints on infections in patients of common variable immunodeficiency disorder with gastrointestinal symptoms.

BACKGROUND AND AIMS: Common variable immunodeficiency disorder (CVID) patients may have gastrointestinal (GI) involvement and suffer from infections, which are poorly understood. This study aimed to evaluate the clinical, endoscopic, and histopathological features of CVID patients with GI symptoms and determine their correlation with infections. METHODS: We performed a retrospective study on 21 CVID patients with GI symptoms who underwent endoscopic examination in Peking Union Medical College Hospital from 2000 to 2020. The clinical, infectious, endoscopic, and histopathological features were reassessed. RESULTS: Chronic diarrhea was the most prevalent GI symptom, observed in 95.2% of our CVID cohort. Over 85% of patients had low body weight and malabsorption. Small bowel villous atrophy was found in 90.5% of patients under endoscopy and mostly confirmed by histopathology. GI infections were identified in 9 (42.9%) patients. Of these, 7 patients with diffuse and obvious nodular lymphoid hyperplasia (NLH) of small bowel under endoscopy had significantly higher infection rate (85.7% vs 21.4%, p < 0.05), predominantly with Giardia and bacteria. Small bowel biopsies showed 95% of patients lacked plasma cells and 60% had increased intraepithelial lymphocytes (IELs), but not significantly different between GI infection and non-infection group. Most patients improved after intravenous immunoglobulin and anti-infection therapy. CONCLUSIONS: CVID could involve GI tract, particularly small bowel. Obvious NLH under endoscopy could be a hint for GI infection in CVID patients. Comprehensive endoscopic and histopathological evaluation may be helpful in CVID diagnosis and identification of potential co-infection, leading to proper treatment.

Ultra-durable cell-free bioactive hydrogel with fast shape memory and on-demand drug release for cartilage regeneration.

Osteoarthritis is a worldwide prevalent disease that imposes a significant socioeconomic burden on individuals and healthcare systems. Achieving cartilage regeneration in patients with osteoarthritis remains challenging clinically. In this work, we construct a multiple hydrogen-bond crosslinked hydrogel loaded with tannic acid and Kartogenin by polyaddition reaction as a cell-free scaffold for in vivo cartilage regeneration, which features ultra-durable mechanical properties and stage-dependent drug release behavior. We demonstrate that the hydrogel can withstand 28000 loading-unloading mechanical cycles and exhibits fast shape memory at body temperature (30 s) with the potential for minimally invasive surgery. We find that the hydrogel can also alleviate the inflammatory reaction and regulate oxidative stress in situ to establish a microenvironment conducive to healing. We show that the sequential release of tannic acid and Kartogenin can promote the migration of bone marrow mesenchymal stem cells into the hydrogel scaffold, followed by the induction of chondrocyte differentiation, thus leading to full-thickness cartilage regeneration in vivo. This work may provide a promising solution to address the problem of cartilage regeneration.

Lightweight deep learning model incorporating an attention mechanism and feature fusion for automatic classification of gastric lesions in gastroscopic images.

Accurate diagnosis of various lesions in the formation stage of gastric cancer is an important problem for doctors. Automatic diagnosis tools based on deep learning can help doctors improve the accuracy of gastric lesion diagnosis. Most of the existing deep learning-based methods have been used to detect a limited number of lesions in the formation stage of gastric cancer, and the classification accuracy needs to be improved. To this end, this study proposed an attention mechanism feature fusion deep learning model with only 14 million (M) parameters. Based on that model, the automatic classification of a wide range of lesions covering the stage of gastric cancer formation was investigated, including non-neoplasm(including gastritis and intestinal metaplasia), low-grade intraepithelial neoplasia, and early gastric cancer (including high-grade intraepithelial neoplasia and early gastric cancer). 4455 magnification endoscopy with narrow-band imaging(ME-NBI) images from 1188 patients were collected to train and test the proposed method. The results of the test dataset showed that compared with the advanced gastric lesions classification method with the best performance (overall accuracy = 94.3%, parameters = 23.9 M), the proposed method achieved both higher overall accuracy and a relatively lightweight model (overall accuracy =95.6%, parameter = 14 M). The accuracy, sensitivity, and specificity of low-grade intraepithelial neoplasia were 94.5%, 93.0%, and 96.5%, respectively, achieving state-of-the-art classification performance. In conclusion, our method has demonstrated its potential in diagnosing various lesions at the stage of gastric cancer formation.

Cognition of abdominal pain and abdominal discomfort in Chinese patients with irritable bowel syndrome with diarrhea.

BACKGROUND: In Asia, the proportion of patients with irritable bowel syndrome (IBS) with abdominal discomfort alone is significantly higher than that in western countries. The purposes of this study are to understand the cognition of abdominal pain and abdominal discomfort in Chinese patients with IBS and to compare the clinical characteristics of patients with abdominal pain alone and with abdominal discomfort alone. METHODS: Patients with IBS with diarrhea (IBS-D) who met the Rome III diagnostic criteria and had episodes of at least one day/week were consecutively enrolled. The cognition of abdominal pain and abdominal discomfort were investigated through face-to-face unstructured interview. Patients were divided into a pain group and a discomfort group according to the cognition interviews, then the characteristics and severity of symptoms (IBS symptom severity scale, IBS-SSS), IBS quality of life (IBS-QOL) and psychological state were compared between groups. RESULTS: A total of 88 patients with IBS-D were enrolled. Most of the patients with self-reported abdominal pain described their pain as spasm/cramping; patients with self-reported abdominal discomfort had as many as 24 different descriptions of discomfort. Most patients having abdominal pain and discomfort could accurately distinguish the two symptoms. The degree of abdominal pain in the pain group was higher than abdominal discomfort in the discomfort group (P = 0.002). There was no significant difference in IBS-SSS, extra-intestinal pain, IBS-QOL, and psychological state between the two groups. CONCLUSIONS: For Chinese patients with IBS-D, abdominal pain and abdominal discomfort are two different symptoms, but they have similar clinical features. TRIAL REGISTRATION: ChiCTR, ChiCTR1900028082. Registered 11 December 2019 - Retrospectively registered, http://www.chictr.org.cn .

Transcutaneous electrical acupoint stimulation in adult patients receiving gastrectomy/colorectal resection: A randomized controlled trial.

BACKGROUND: Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery. The effects of transcutaneous electrical acupoint stimulation (TEAS) remain unclear. AIM: To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection. METHODS: Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive: (1) TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery, plus two 30-min daily sessions for 3 consecutive days after surgery (perioperative TEAS group); (2) Preoperative and intraoperative TEAS only; (3) Preoperative and postoperative TEAS only; or (4) Sham stimulation. The primary outcome was the time from the end of surgery to the first bowel sound. RESULTS: In total, 441 patients were randomized; 405 patients (58.4 ± 10.2 years of age; 247 males) received the planned surgery. The time to the first bowel sounds did not differ among the four groups (P = 0.90; log-rank test). On postoperative day 1, the rest pain scores differed significantly among the four groups (P = 0.04; Kruskal-Wallis test). Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group (1.4 ± 1.2) than in the sham stimulation group (1.7 ± 1.1; P = 0.04). Surgical complications did not differ among the four groups. CONCLUSION: TEAS provided analgesic effects in adult patients undergoing major abdominal surgery, and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients.

Insights into the Oncogenic, Prognostic, and Immunological Role of BRIP1 in Pan-Cancer: A Comprehensive Data-Mining-Based Study.

Background: BRCA1 interacting helicase 1 (BRIP1), an ATP-dependent DNA helicase which belongs to an Iron-Sulfur (Fe-S) helicase cluster family with a DEAH domain, plays a key role in DNA damage and repair, Fanconi anemia, and development of several cancers including breast and ovarian cancer. However, its role in pan-cancer remains largely unknown. Methods: BRIP1 expression data of tumor and normal tissues were downloaded from the Cancer Genome Atlas, Genotype-Tissue Expression, and Human Protein Atlas databases. Correlation between BRIP1 and prognosis, genomic alterations, and copy number variation (CNV) as well as methylation in pan-cancer were further analyzed. Protein-protein interaction (PPI) and gene set enrichment and variation analysis (GSEA and GSVA) were performed to identify the potential pathways and functions of BRIP1. Besides, BRIP1 correlations with tumor microenvironment (TME), immune infiltration, immune-related genes, tumor mutation burden (TMB), microsatellite instability (MSI), and immunotherapy as well as antitumor drugs were explored in pan-cancer. Results: Differential analyses showed an increased expression of BRIP1 in 28 cancer types and its aberrant expression could be an indicator for prognosis in most cancers. Among the various mutation types of BRIP1 in pan-cancer, amplification was the most common type. BRIP1 expression had a significant correlation with CNV and DNA methylation in 23 tumor types and 16 tumor types, respectively. PPI, GSEA, and GSVA results validated the association between BRIP1 and DNA damage and repair, cell cycle, and metabolism. In addition, the expression of BRIP1 and its correlation with TME, immune-infiltrating cells, immune-related genes, TMB, and MSI as well as a variety of antitumor drugs and immunotherapy were confirmed. Conclusions: Our study indicates that BRIP1 plays an imperative role in the tumorigenesis and immunity of various tumors. It may not only serve as a diagnostic and prognostic biomarker but also can be a predictor for drug sensitivity and immunoreaction during antitumor treatment in pan-cancer.

A Chinese prospective multicenter cohort study evaluating EUS-guided drainage of pancreatic fluid collections using the Hot AXIOS system.

Background and Objectives: The Hot AXIOS system, which features a cautery-enhanced lumen-apposing metal stent, facilitates EUS-guided transmural drainage of pancreatic fluid collection (PFC). We aimed to evaluate the safety and efficacy of stents in a multicenter Chinese cohort. Patients and Methods: Thirty patients from nine centers with a single pancreatic pseudocyst (PP) or walled-off necrosis (WON) who underwent EUS-guided transgastric or transduodenal drainage with the novel stent were prospectively enrolled. Results: We included 15 (50%) patients with PPs and 15 (50%) with WONs. The mean diameter of the PFCs was 11.06 ± 3.56 cm. Stent placement was technically successful in all patients (100%), whereas clinical success was achieved in 93.3% of patients (28/30). Clinical success was defined as the alleviation of clinical symptoms combined with at least a 50% reduction in PFC diameter within 60 days after surgery. 73.3% (22/30) of AXIOS stents were removed after reaching clinical success in the 1st month of follow-up. A total of 14 (46.7%) PFC-associated infections occurred (4 pre- and 10 postoperation), which recovered within 1 week after treatment. Other complications included three (10%) partially or fully blocked stents and two (6.7%) stent migrations. Regarding the fully opened stent without blocking, complete remission of PFCs within 1 month was independently predicted by a previous pancreatitis attack > 6 months prior (adjusted odds ratio: 11.143; 95% confidence interval: 1.108-112.012; P = 0.041). Conclusion: EUS-guided drainage of PFCs using the Hot AXIOS system is safe and efficient. Regarding completely patent stents, a previous pancreatitis attack > 6 months prior predicts a greater chance of achieving 100% remission of PFCs within 1 month of AXIOS treatment.