HDAC6 inhibitor ACY-1215 protects from nonalcoholic fatty liver disease via inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway.

Background & aims: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic steatosis, for which there is currently no effective treatment. ACY-1215 is a selective inhibitor of histone deacetylation 6, which has shown therapeutic potential in many tumors, as well as acute liver injury. However, no research about ACY-1215 on NAFLD has been published. Therefore, our study aims to explore the role and mechanism of ACY-1215 in the experimental model of NAFLD, to propose a new treatment strategy for NAFLD. Methods: We established cell and animal models of NAFLD and verified the effect of ACY-1215 on NAFLD. The mechanism of ACY-1215 on NAFLD was preliminarily explored through TMT relative quantitative proteomics, and then we verify the mechanism discovered in the experimental model of NAFLD. Results: ACY-1215 can reduce lipid aggregation, IL-1ß, and TNF α mRNA levels in liver cells in vitro. ACY-1215 can reduce the weight gain and steatosis in the liver of the NAFLD mouse model, alleviate the deterioration of liver function, and reduce IL-1ßs and TNF α mRNA levels in hepatocytes. TMT relative quantitative proteomics found that ACY-1215 decreased the expression of CD14 in hepatocytes. It was found that ACY-1215 can inhibit the activation level of CD14/TLR4/MyD88/MAPK/NFκB pathway in the NAFLD experimental model. Conclusions: ACY-1215 has a protective effect on the cellular model of NAFLD induced by fatty acids and lipopolysaccharide, as well as the C57BL/6J mouse model induced by a high-fat diet. ACY-1215 may play a protective role by inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway.

Endoscopic ultrasound-guided bite-on-bite biopsy and endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of gastric tumors with negative malignant endoscopy biopsies: a retrospective cohort study.

BACKGROUND: Specific types of gastric tumors, including gastric linitis plastica and lymphoma, may cause extensive deep-layer infiltration, impeding an accurate diagnosis with endoscopic biopsy. This study aims to evaluate the efficacy of endoscopic ultrasound (EUS)-guided bite-on-bite biopsy and EUS-guided fine-needle aspiration (EUS-FNA) in diagnosing gastric malignancies with negative endoscopic biopsies. METHODS: We retrospectively analyzed suspicious malignant gastric lesion cases in our hospital from October 2017 to August 2023. Clinical manifestations, radiographical examinations, endoscopic examinations, histopathological results, and therapeutic strategies were recorded and analyzed. RESULTS: Forty malignant gastric tumor cases with negative endoscopic biopsies were incorporated into our study. EUS-guided bite-on-bite biopsy was performed in 16 cases exclusively, whereas 17 patients received EUS-FNA exclusively, and seven patients underwent both simultaneously. Among the 23 patients who received the EUS-guided bite-on-bite biopsy, 22 (95.7%) were diagnosed with malignancies. Among the 24 patients who received EUS-FNA, a total of 19 cases with malignancies (79.2%) were confirmed by EUS-FNA (p = 0.11): 13 gastric adenocarcinomas, five metastatic malignancies, and one malignant stromal tumor. No adverse events were observed in any of the cases. CONCLUSIONS: EUS-guided bite-on-bite biopsy and EUS-FNA possess their advantages and disadvantages. EUS-guided bite-on-bite biopsy could serve as a reliable diagnostic method for shallow lesions with negative malignant endoscopic biopsies.

Safety and efficacy of ESD for laterally spreading tumors with hemorrhoids close to the dentate line.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a curative treatment for laterally spreading tumors (LSTs). However, the outcomes of ESD for LSTs with hemorrhoids remain largely unknown. Our study aimed to evaluate the usefulness of ESD in managing LSTs with hemorrhoids. MATERIAL AND METHODS: We retrospectively collected 418 consecutive LST patients treated with ESD between 2011 and 2023. A retrospective comparative analysis was conducted. RESULTS: There were 85 patients included in the hemorrhoids group and 333 patients included in the other group. The en-bloc resection rate, R0 resection rate, and curative resection rate were comparable in these two groups (p > 0.05). The LSTs with hemorrhoids have a significantly higher intraoperative bleeding rate during ESD when compared to the other group (12.9% vs. 5.4%, p = 0.028). Rates of intraoperative perforation and anal pain in the hemorrhoid group were significantly higher than those in the no-hemorrhoid group (2.4% vs. 0%, p = 0.041; 9.4% vs.0.6%, p < 0.001; respectively). Moreover, most of the related manifestations caused by hemorrhoids were relieved to various degrees after ESD. CONCLUSIONS: ESD is a safe and effective treatment strategy for LSTs with hemorrhoids. A multi-center and prospective study should be conducted in the future to validate our results.

Risk factors for positive resection margins after endoscopic resection for gastrointestinal neuroendocrine tumors.

BACKGROUND: In recent years, the incidence of gastrointestinal neuroendocrine tumors (GI-NETs) has remarkably increased due to the widespread use of screening gastrointestinal endoscopy. Currently, the most common treatments are surgery and endoscopic resection. Compared to surgery, endoscopic resection possesses a higher risk of resection margin residues for the treatment of GI-NETs. METHODS: A total of 315 patients who underwent surgery or endoscopic resection for GI-NETs were included. We analyzed their resection modality (surgery, ESD, EMR), margin status, Preoperative marking and Prognosis. RESULTS: Among 315 patients included, 175 cases underwent endoscopic resection and 140 cases underwent surgical treatment. A total of 43 (43/175, 24.57%) and 10 (10/140, 7.14%) patients exhibited positive resection margins after endoscopic resection and surgery, respectively. Multivariate regression analysis suggested that no preoperative marking and endoscopic treatment methods were risk factors for resection margin residues. Among the patients with positive margin residues after endoscopic resection, 5 patients underwent the radical surgical resection and 1 patient underwent additional ESD resection. The remaining 37 patients had no recurrence during a median follow-up of 36 months. CONCLUSIONS: Compared with surgery, endoscopic therapy has a higher margin residual rate. During endoscopic resection, preoperative marking may reduce the rate of lateral margin residues, and endoscopic submucosal dissection may be preferred than endoscopic mucosal resection. Periodical follow-up may be an alternative method for patients with positive margin residues after endoscopic resection.

A Mendelian randomization study on the effects of plasma lipids on irritable bowel syndrome and functional dyspepsia.

Although functional gastrointestinal disorder (FGID) is a common clinical condition, its risk factors remain unclear. We performed a Mendelian randomization study to explore the association between plasma lipids and the risk of FGID. Instrumental variables closely related to six plasma lipids were obtained from the corresponding genome-wide association studies, and summary-level data on FGID, including irritable bowel syndrome (IBS) and functional dyspepsia (FD), were extracted from the FinnGen study. The primary inverse variance weighted method and other supplementary analyses were used to evaluate the causal relationship between diverse plasma lipids and FGID. For each increase in the standard deviation of triglyceride levels, there was a 12.0% increase in the risk of IBS rather than that of FD. Low- and high-density lipoprotein cholesterol, total cholesterol, apolipoprotein A, and apolipoprotein B levels were not associated with the risk of IBS or FD. Through this study, we identified the causal role of triglycerides in the pathogenesis of IBS, which could benefit further basic and clinical research.

Lesion size affects the risk of technical difficulty in gastric endoscopic submucosal dissection.

Current evidence shows an inter-country inconsistency in the effect of lesion size on the technical difficulty of gastric endoscopic submucosal dissection (ESD). We aimed to evaluate the specific correlation and quantify the ensuing risks. This retrospective study consisted of 405 ESD cases with gastric single lesion from April 2015 to April 2023. The correlation and risk prediction of lesion size with technical difficulty was explored to provide further clinical evidence. An additive generalized model and recursive algorithm were used to describe the non-linear association, and a linear two-piece regression was constructed to analyze the inflection point. Subgroup analysis and interaction were used to explore intergroup characteristics. Overall, difficult cases had larger lesion sizes, and the more significant the increase, the higher the risk of technical difficulty. In the full model, after adjusting for all covariates, each 1 mm, 3 mm, 5 mm, 7 mm, and one standard increase in lesion size increased the risk of technical difficulty by 8%, 26%, 42%, 72%, and 125%, respectively. There is a nonlinear positive correlation between lesion size and risk of technical difficulty, and the premeditated inflection point was 40 (mm) via two-piecewise linear regression and recursive algorithm. Subgroup analysis showed a stronger correlation between lesion size and difficult ESD in the upper site and submucosal fibrosis groups. Available evidence suggests that lesion size as a risk signal nonlinearly increases the technical difficulty of gastric ESD procedure, especially in cases of upper site and submucosal fibrosis, which deserves further investigation.

Research progress in cuproptosis in liver cancer. / é“œæ­»äº¡åœ¨è‚ç™Œä¸­çš„ç ”ç©¶è¿›å±•.

Copper, like iron, is an essential trace metal element for human cells. The role of iron overload and ferroptosis has been gradually clarified in tumors, but the role of copper overload and cuproptosis is still being explored. Cuproptosis is a novel mode of cell death, secondary to impaired mitochondrial function induced by copper overload, and characterized by copper-dependent and programmed. The excessive copper leads to protein toxicity stress by binding to sulfhydryl proteins in the tricarboxylic acid (TCA) cycle of mitochondria, disrupting cellular homeostasis and triggering cuproptosis. Copper accumulation has carcinogenic effects on normal cells, dual effects on tumor cells. Liver cancer is one of the most common malignant tumors in China and even globally, with hepatocellular carcinoma (HCC) being the most common histological subtype. Copper exhibits dualism in HCC, as it both contributes to the growth and invasion of HCC cells, and exerts anticancer effects by inducing cuproptosis. Also, cuproptosis-related genes can be the evaluation of immunotherapy effect and the construction of prognostic models. Clarifying the role of copper death in liver cancer can help explore new methods for liver cancer screening, treatment, and prognosis evaluation.

Endoscopic Submucosal Dissection for Treatment of Early-Stage Cancer or Precancerous Lesion in the Upper Gastrointestinal Tract in Patients with Liver Cirrhosis.

(1) Background: Endoscopic submucosal dissection (ESD) has been widely accepted as the standard method for treating early-stage cancer or precancerous lesions in the upper gastrointestinal tract; however, it may be difficult in patients with liver cirrhosis due to clinical challenges such as coagulation dysfunction, presence of gastroesophageal varices, etc. We aimed to demonstrate the safety and efficacy of ESD in these populations. (2) Methods: The clinical data of patients were retrospectively collected and analyzed. Inclusion criteria of the study were: a. patients with liver cirrhosis; b. patients who underwent ESD; c. patients who were diagnosed with early-stage cancer or precancerous lesions in the upper gastrointestinal tract. (3) Results: Eight patients were enrolled from April 2019 to April 2023, of whom three were male and five were female, with ages ranging from 43 to 70 years old. Seven lesions were located in the stomach and one other lesion was in the esophagus. ESD was performed successfully in all eight patients, and the resected lesion size ranged from 2 to 6 cm. Only one patient encountered postoperative complications, namely, chest pain and fever. No recurrence was noticed during a follow-up of 3 to 45 months. (4) Conclusions: ESD may serve as a safe and effective method for treating upper gastrointestinal early-stage cancer or precancerous lesions in patients with liver cirrhosis.

Systemic immune-inflammation index as a potential biomarker to monitor ulcerative colitis.

OBJECTIVE: The treat-to-target strategy is recommended by Selecting Therapeutic Targets in Inflammatory Bowel Disease II (STRIDE-II) for treating ulcerative colitis (UC), and monitoring remission status is crucial during this management. The systemic immune-inflammation index (SII), defined as platelet * neutrophil/lymphocyte, is a complete blood count-based index reflecting the balance of immune and inflammatory status. This study aims to investigate the feasibility of SII for diagnosing UC and monitoring UC disease activity. METHODS: This study retrospectively analyzed patients with UC and controls. Relationships between SII and Mayo clinical score, Mayo Endoscopic Score (MES), and Nancy Histological Index (NHI) were evaluated. RESULTS: 167 patients with UC and 106 controls were included. SII significantly increased in patients with UC and was closely correlated with the Mayo clinical score, MES, and NHI. SII diagnosed UC with a cut-off value of 619.1 × 109/L (area under the curve = 0.861, p < 0.0001, sensitivity 79.64%, specificity 77.36%), evaluated clinical remission status with a cut-off value of 1068 × 109/L (area under the curve = 0.691, p < 0.05, sensitivity 55.71%, specificity 81.48%), endoscopic improvement with a cut-off value of 981.3 × 109/L (area under the curve = 0.819, p < 0.0001, sensitivity 65.22%, specificity 89.66%), and histological healing with a cut-off value of 689.3 × 109/L (area under the curve = 0.898, p < 0.0001, sensitivity 88.89%, specificity 95.83%). CONCLUSION: SII is a potential biomarker for diagnosing UC and monitoring UC disease severity, especially in evaluating mucosal and histological healing during the long-term management in treat-to-target strategy. However, further research is needed to confirm its usefulness and optimize its clinical application.

Researchers studied an index calculated from a blood test, named the "systemic immune-inflammation index" (SII), to see if it can identify and track the activity of a bowel condition called ulcerative colitis (UC).They reviewed health records of UC patients and compared them to people without this condition. They specifically checked if the SII test's results aligned with other common tests that show the severity of UC.People with UC tended to have higher SII results. The SII test results were consistent with other tests for UC. Specific scores from the SII test, like 619.1 × 10⁹/L, can indicate someone might have UC. What's more, this test can give clues about inflammation in the bowel, saving some from more invasive tests like a colonoscopy or biopsy.The SII test could be a promising way for doctors to diagnose UC and gauge its activity without needing more intrusive tests. However, more studies are required to fully trust this approach.

Role of Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA) in the Diagnosis of Suspicious Malignant Esophageal Strictures.

(1) Background: The accurate diagnosis of esophageal strictures is quite critical for optimizing medical intervention. However, the diagnosis of suspicious malignant esophageal strictures with intact mucosa appearance and negative biopsy results is challenging. This study aimed to evaluate the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the diagnosis of suspicious esophageal strictures. (2) Methods: We retrospectively analyzed the cases with suspicious malignant esophageal strictures that underwent EUS-FNA, with or without rapid on-site evaluation (ROSE), in our hospital from April 2017 to September 2022. Their clinical manifestations, imaging examinations, gastroscopic examinations, EUS-FNA results, and therapeutic strategies were retrospectively recorded and analyzed. (3) Results: A total of 23 patients (15 male and 8 female) were enrolled in this study. Based on EUS-FNA results, 18 patients were diagnosed with malignancies, including 16 cases of primary esophageal cancer (13 squamous carcinomas and 3 adenocarcinomas), 1 case of mediastinal cancer, and 1 case of metastatic esophageal cancer; 1 case of tuberculosis was also confirmed by EUS-FNA. Among 4 cases of ambiguous diagnosis with EUS-FNA, 1 was diagnosed with an esophageal glomus tumor after surgical removal, and 2 patients survived for several years without medical intervention, which hinted at the possibility of benign esophageal strictures. No major complications, including bleeding or perforation, were observed. (4) Conclusions: EUS-FNA may serve as a safe and effective diagnostic tool in suspicious malignant esophageal strictures with accurate specimen acquisition, especially for biopsy-negative cases.

Endoscopic ultrasound guided lauromacrogol sclerotherapy for a large splenic cyst.

Symptomatic splenic cyst is usually managed by surgical resection or ultrasound-guided percutaneous sclerotherapy. In the present case, we demonstrated the safety and feasibility of endoscopic ultrasound-guided sclerotherapy for treatment of splenic cyst. As far as we known. This is the first case report concerning EUS-guided sclerotherapy for splenic cyst.

Peroral Endoscopic Myotomy for Achalasia in Older Adults: A Retrospective Analysis of 39 Cases with a Minimum Follow-Up of 5 Years.

Peroral endoscopic myotomy (POEM) has demonstrated favorable short-term safety and efficacy in older adults, while a comprehensive understanding of the long-term outcomes were vague. We aimed to evaluate clinical outcomes in older adults' 5-year postop after undergoing POEM to treatment achalasia. Older adults from a single hospital who received POEM between January 2010 and January 2017 were analyzed. Older persons were reached to evaluate their symptoms at present and encouraged repeat examinations for objective follow-up. The clinical success, POEM-related indicators, POEM-related adverse events, and quality of life were assessed. Thirty-nine older adults with a mean age of 70.82 ± 4.72 who underwent POEM were studied at a mean 84.23 ± 25.06 month follow-up. The preoperative diagnosis was achalasia type I in 7 older adults, achalasia type II in 26 older adults, and achalasia type III in 2 older adults. Sixteen older adults had prior treatment and 21 older adults suffered from comorbidities. The median operative time was 50 (25-120) minutes, and perioperative adverse events were recorded in four older adults. The current Eckardt scores were significantly lower than that before POEM (2.08 ± 2.12 vs. 6.58 ± 1.78, P < 0.001). Besides, long-term clinical success was gained in 66.7% of older adults. Three older adults received postop treatment for symptom recurrence. Ultimately, 80.6% of old adults expressed satisfaction with POEM, while 27.8% of older adults suffered from symptomatic reflux. In conclusion, POEM can provide symptomatic improvement in a large proportion of older adults with achalasia at 5-year postop.

Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease.

The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness's role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed.

Statin can reduce the risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.

Currently, nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and liver-related mortality worldwide. Hepatocellular carcinoma (HCC) is a fatal complication in patients with NAFLD. However, whether statins can reduce the risk of HCC in patients with NAFLD remains controversial. We aimed to determine the relationship between statin use and HCC occurrence among patients with NAFLD. We independently retrieved related studies from PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrial.gov (from 1 January 2000 to 27 February 2022). The main outcome was the development of HCC. A fixed-effects model was used to merge odds ratio (OR) in the meta-analysis. Five studies involving 684 363 patients were included. The results of the meta-analysis suggested a significantly lower risk of HCC among statin users with NAFLD [OR = 0.59; 95% confidence interval (CI), 0.39-0.89; I2 = 87.90%]. Additionally, a lower risk of HCC was observed among patients with NAFLD aged less than 65 years (OR = 0.59; 95% CI, 0.46-0.77; I2 = 20.50%). Statins can reduce the risk of HCC in patients aged less than 65 years with NAFLD.

Clinicopathological characteristics of gastrointestinal schwannomas: A retrospective analysis of 78 cases.

Introduction: Schwannomas are tumors arising from Schwan cells of the neural sheath, which rarely occur in the gastrointestinal tract. The aim of the present study was to analyze the clinicopathological features and treatment outcomes of gastrointestinal schwannomas (GISs). Methods: Patients who were diagnosed with GISs in our hospital from January 2010 to December 2021 were selected. Data about demographic characteristics, clinical symptoms, treatment methods and outcomes, pathological results, and follow-up results were retrospectively collected and analyzed. Results: A total of 78 patients with 79 GISs were included, the female-to-male ratio was 55:23, and the average age was 52.12 ± 12.26 years. One-third (26/78) of the patients were asymptomatic. A total of 79 GISs were removed, and the average size was 3.63 ± 2.03 cm (range, 0.3-10 cm). As for tumor location, 54 GISs were located in the stomach, 14 in the esophagus, 2 in the duodenum, 6 in the colorectum (4 in the colon and 2 in the rectum), and the other 3 in the small intestine. A total of 23 and 55 patients underwent endoscopic and surgical resections, respectively. Compared with surgical resection, endoscopic resection is associated with a smaller diameter, lower cost, and shorter hospital stay. Pathological results revealed that S100 was positive in all the GISs. No recurrence was noticed during a median follow-up of 45 months (range, 6-148 months). Conclusion: GISs are rare gastrointestinal tumors with favorable prognoses, which are most commonly seen in the stomach and diagnosed by pathological findings with immunohistochemical staining. Surgical resection remains the standard method for removing GISs, while endoscopic resection may serve as an alternative method for selected patients with GISs and may be attempted in GISs with a diameter of <3 cm and no signs of malignancy.