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Acute liver failure (ALF) is a complex syndrome characterized by overactivation of innate immunity, and the recruitment and differentiation of immune cells at inflammatory sites. The present study aimed to explore the role of microRNA (miRNA/miR)-21 and its potential mechanisms underlying inflammatory responses in ALF. Baseline serum miR-21 was analyzed in patients with ALF and healthy controls. In addition, miR-21 antagomir was injected via the tail vein into C57BL/6 mice, and lipopolysaccharide/D-galactosamine (LPS/GalN) was injected into mice after 48 h. The expression levels of miR-21, Krüppel-like-factor-6 (KLF6), autophagy-related proteins and interleukin (IL)-23, and hepatic pathology were then assessed in the liver tissue. Furthermore, THP-1-derived macrophages were transfected with a miRNA negative control, miR-21 inhibitor, miR-21 mimics or KLF6 overexpression plasmid, followed by treatment with or without rapamycin, and the expression levels of miR-21, KLF6, autophagy-related proteins and IL-23 were evaluated. The results revealed that baseline serum miR-21 levels were significantly upregulated in patients with ALF. In addition, LPS/GalN-induced ALF was attenuated in the antagomir-21 mouse group. KLF6 was identified as a target of miR-21-5p with one putative seed match site identified by TargetScan. A subsequent luciferase activity assay demonstrated a direct interaction between miR-21-5p and the 3′-UTR of KLF6 mRNA. Further experiments suggested that miR-21 promoted the expression of IL-23 via inhibiting KLF6, which regulated autophagy. In conclusion, in the present study, baseline serum miR-21 levels were highly upregulated in patients with ALF, antagomir-21 attenuated LPS/GalN-induced ALF in a mouse model, and miR-21 could promote the expression of IL-23 via inhibiting KLF6. [ABSTRACT FROM AUTHOR]

Carcinogenesis is one of the major complications for patients with inflammatory bowel disease (IBD) and causes poor prognosis. We aimed to describe cancer incidence in the Chinese IBD cohort compared to general population‐based cancer registration data and further explore associated risk factors for cancer occurrence in IBD patients. IBD inpatients from January 1998 to January 2018 in Peking Union Medical College Hospital (PUMCH) were included in our study. Patients were followed‐up from the date of IBD diagnosis until either the date of first cancer diagnosis or January 2019. Standardized incidence ratios (SIRs) of overall cancer and site‐specific cancers were calculated. A total of 869 Ulcerative Colitis (UC) and 516 Crohn's disease (CD) patients were finally included with median follow‐up time of 7 and 5 years, respectively. Fifty‐three cases developed malignancies. After standardization by age and gender, SIR of total cancer occurrence in IBD patients was 1.77 (95% CI, 1.33‐2.32). As for UC, digestive cancers (SIR 3.75; 95% CI, 2.29‐5.80), thyroid cancer (SIR 10.34; 95% CI, 4.72‐19.64) and hematological malignancies (SIR 6.25; 95% CI, 1.68‐16.00) had the highest incidence, which were prominent in young and middle‐aged patients. Use of steroids, immunosuppressants or infliximab did not present higher risk of malignancies in UC patients. There was no significant difference in cancer risk between CD patients and general population. In conclusion, the increased risks of multiple cancers are particularly prominent in Chinese UC patients and these findings can provide more targeted guidance for cancer monitoring in Chinese IBD patients. [ABSTRACT FROM AUTHOR]

Background and Aim: Behcet's disease is a systemic vasculitis that can involve gastrointestinal tract. This is a systematic review and meta‐analysis evaluating the efficacy and safety of anti‐tumor necrosis factor (TNF) agents in treating patients with intestinal Behcet's disease. Methods: We conducted searches on PubMed, Embase, and Cochrane. Data from eligible studies were used to calculate the pooled estimate of proportions of clinical remission, mucosal healing at Months 3, 6, 12, and 24 as well as the pooled incidence of adverse drug reactions. And subgroup analysis based on the specific type of anti‐TNF agents was performed. Results: Of the 828 studies initially identified, 13 were included finally, all of which were single‐arm cohort studies. The pooled proportions of clinical remission at Months 3, 6, 12, and 24 were 0.61 (95%CI 0.48–0.78), 0.51 (95%CI 0.40–0.66), 0.57 (95%CI 0.48–0.67), and 0.38 (95%CI 0.16–0.88), respectively. The pooled proportions of mucosal healing at Months 3, 6, 12, and 24 were 0.66 (95%CI 0.50–0.86), 0.82 (95%CI 0.48–0.98), 0.65 (95%CI 0.51–0.81), and 0.69 (95%CI 0.39–1.00), respectively. The pooled estimate of proportion of overall adverse drug reactions for infliximab was 0.22 (95%CI 0.07–0.69). Conclusions: Anti‐TNF agents, including infliximab and adalimumab, were an efficient therapy for intestinal Behcet's disease. The safety of anti‐TNF agents used in the treatment of intestinal Behcet's disease was acceptable. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) colitis brings great obstacles for treatment of ulcerative colitis (UC). We aimed to assess the impact of CMV colitis on prognostic outcomes and associated risk factors for UC patients. A consecutive 77 inpatients diagnosed as UC were collected retrospectively from January 2012 to December 2015. About 33 patients were defined with CMV colitis by histological tests of colon mucosa. Clinical characteristics and outcomes were compared between patients with CMV colitis or those without. The primary outcomes were UC-related colectomy or the first time of disease relapse after discharge. 33 CMV colitis patients had higher frequency of recent steroid treatment (81.8% vs. 31.8%, p <.001), older age of onset (45.3 ± 13.0 vs. 44.5 ± 15.7 years, p =.028) and more severe colitis (p <.001) characterized by lower hemoglobin (99.0 ± 23.2 vs. 114.6 ± 22.6 g/L, p =.004), albumin (29.7 ± 4.6 vs. 35.4 ± 6.5 g/L, p <.001), immunoglobulin G [8.8 (5.9–10.6) vs. 12.3 (9.3–16.2) g/L, p =.003] and higher C reactive protein [48.5 (21.6–73.8) vs. 9.1 (3.6–35.0) mg/L, p <.001]. The occurrence of UC-related colectomy in patients with CMV colitis was more frequent (48.5% vs 20.5%, p<.01) and CMV colitis was proved to be one of risk factors of colectomy with a hazard ratio of 3.15 (95%CI 1.387–7.171, p =.006), mainly in a short term period. UC-related complications almost occurred within 1 year since CMV colitis diagnosis. And UC patients with CMV colitis always experienced early relapse. CMV colitis increases the colectomy risk mainly in a short term due to severe inflammatory response, early-onset complications or medication treatment failure. There is also potential correlation between CMV colitis and early relapse. Short-term therapy for UC patients with CMV colitis should be more concerned on controlling systemic inflammation and reducing complications whereas long-term maintenance therapy may not require more aggressive intervention. [ABSTRACT FROM AUTHOR]

Background and Aim: Preoperative endoscopic markers have been extensively used for the localization of colonic neoplastic lesions in laparoscopic surgery. We conducted this respective cohort study to compare the localization accuracy of two commonly used endoscopic marker strategies (endoscopic clip plus abdominal plain film and endoscopic tattooing). Methods: Patients who received preoperative colonoscopy localization for colonic neoplasia and underwent an elective laparoscopic operation afterward between 2013 and 2020 were included in this retrospective study. The localization accuracy of the two endoscopic strategies was compared, and the predictors of successful endoscopic localization were identified by multivariate regression. Results: In total, 195 patients [average age 62.4 ± 9.2 years, 123 male (63.1%)] undergoing preoperative colonoscopy localization and subsequent laparoscopic colectomy for colonic neoplasms were included. Endoscopic localization was finally proven to be successful in 150 (76.9%) patients in the surgery. Compared to the tattooing group, patients who had successful localization for colonic lesions were fewer in the clip group (64 of 101 cases, 63.4% vs. 86 of 94 cases, 91.5%, p < 0.001). The multivariate regression analysis showed that the endoscopic tattooing strategy, endoscopic clip strategy, and lesion location were all predictors for successful localization (all with p < 0.001). Conclusion: Compared with endoscopic clip plus abdominal plain film, endoscopic tattooing had higher localization accuracy and less intraoperative colonoscopy counseling; the endoscopic clip strategy, tattooing strategy, and colonic lesion location were all predictors of successful endoscopic localization. [ABSTRACT FROM AUTHOR]

Background & Aims: The evaluation of the stage of liver fibrosis is essential in patients with chronic liver disease. However, due to the low quality of ultrasound images, the non‐invasive diagnosis of liver fibrosis based on ultrasound images is still an outstanding question. This study aimed to investigate the diagnostic accuracy of a deep learning‐based method in ultrasound images for liver fibrosis staging in multicentre patients. Methods: In this study, we proposed a novel deep learning‐based approach, named multi‐scale texture network (MSTNet), to assess liver fibrosis, which extracted multi‐scale texture features from constructed image pyramid patches. Its diagnostic accuracy was investigated by comparing it with APRI, FIB‐4, Forns and sonographers. Data of 508 patients who underwent liver biopsy were included from 4 hospitals. The area‐under‐the ROC curve (AUC) was determined by receiver operating characteristics (ROC) curves for significant fibrosis (≥F2) and cirrhosis (F4). Results: The AUCs (95% confidence interval) of MSTNet were 0.92 (0.87‐0.96) for ≥F2 and 0.89 (0.83‐0.95) for F4 on the validation group, which significantly outperformed APRI, FIB‐4 and Forns. The sensitivity and specificity of MSTNet (85.1% (74.5%‐92.0%) and 87.6% (78.0%‐93.6%)) were better than those of three sonographers in assessing ≥F2. Conclusions: The proposed MSTNet is a promising ultrasound image‐based method for the non‐invasive grading of liver fibrosis in patients with chronic HBV infection. [ABSTRACT FROM AUTHOR]

Whether patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo‐HSCT) benefit from pretransplant cytoreductive therapy remains controversial. Our study compared the outcomes of upfront transplantation with those of pretransplant cytoreductive therapy in the patients who received transplantation and those who dropped out due to cytoreductive therapy‐related adverse effects. Patients with MDS‐EB‐1 or MDS‐EB‐2 were enrolled and divided into three groups based on therapy pretransplantation: upfront transplantation (upfront, n = 54), induction chemotherapy (CT, n = 66) and hypomethylating agents (HMA, n = 37) alone. One hundred fifty‐seven patients were enrolled and 124 received allo‐HSCT, with 5.6%, 28.8% and 29.7% of drop‐out rate of transplantation in upfront, CT and HMA groups (P =.030), respectively. Overall therapy‐related mortality (TRM), cytoreductive therapy and transplant‐related mortality was 13.0%, 32.4% and 28.4% (P =.028), and 5‐year overall survival (OS) was 73.6%, 43.4% and 46.9% (P =.033). Multivariate analysis showed that CT and HMA were risk factors for TRM and OS, and transplantation was a protective factor for OS. In transplant patients, 3‐year cumulative incidence of relapse was 10.6%, 20.4% and 20.3% (P =.033), 5‐year TRM was 14.5%, 20.0% and 17.6% (P =.651), OS was 77.3%, 64.3% and 68.8% (P =.047) and DFS was 74.0%, 63.0% and 65.8% (P =.042). Multivariate analysis showed that CT was a risk factor for DFS, while CT, HMA and poor karyotype were risk factors for relapse. Results suggested that pretransplant cytoreductive therapy was not associated with better outcomes in the patients who had undergone transplantation. Therefore, upfront transplantation may be preferable for MDS patients. What's new? Whether patients with myelodysplastic syndrome undergoing allogeneic hematopoietic stem cell transplantation benefit from pre‐transplant cytoreductive therapy remains controversial. This study comparing the outcomes of upfront transplantation with those of pre‐transplant cytoreductive therapy includes both patients who ultimately received transplantation and those who dropped out due to cytoreductive therapy‐related adverse effects. The results suggest that pre‐transplant cytoreductive therapy did not improve survival because adverse effects led a proportion of patients to drop out of transplantation. Moreover, pre‐transplant cytoreductive therapy may increase relapse compared to upfront transplantation. Therefore, upfront transplantation may be preferable for myelodysplastic syndrome patients. [ABSTRACT FROM AUTHOR]

Background/Aims: Serum procalcitonin (PCT) is elevated in acute liver failure (ALF), but the expression of PCT in the liver has not been elucidated. We aimed to clarify the regulation of hepatic PCT expression and the cell sources in ALF. Methods: Human monocytic leukemia line U937 cells were treated with 12-O-tetradecanoylphorbol-l3-acetate (PMA) (100 ng/ mL) for 24 h to induce activated macrophages. In the presence of lipopolysaccharide (LPS, 1 μg/mL), activated macrophages and human hepatocyte line L02 cells were incubated with LPS or co-cultured for 0, 2, 6, and 24 h. In an in vivo experiment, male C57BL/6 mice were challenged with intraperitoneal LPS/D-galactosamine (LPS/D-GalN). Serum liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using an automatic chemical analyzer. Inflammatory mediators were measured by real-time PCR and liver histology was examined by hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). Results: LPS induced the upregulation of PCT mRNA in U937-activated macrophages but not in L02 cells. When co-cultured with L02 cells, the expression of PCT mRNA of activated macrophages was upregulated compared to controls; however, the activated macrophages did not induce the expression of PCT mRNA in L02 cells in the presence of LPS. Moreover, serum liver enzymes (ALT, AST), inflammation, necrosis, and hepatic expression of PCT were significantly elevated in the LPS/D-GalN-challenged ALF mouse model. IHC revealed that PCT expression was co-localized with hepatic macrophages. Conclusions: Hepatic PCT expression is upregulated in ALF. Hepatic macrophages but not hepatocytes are the cell source of hepatic PCT expression. [ABSTRACT FROM AUTHOR]

TRAF2 (Tumor necrosis factor receptor-associated factor 2) is a dual function protein, acting as an adaptor protein and a ubiquitin E3 ligase, which plays an essential role in mediating the TNFα-NFκB signal pathway. Dysregulated expression of TRAF2 has been reported in a variety of human cancers. Whether and how TRAF2 regulates the growth of liver cancer cells remains elusive. The goal of this study is to investigate potential dysregulation of TRAF2 and its biological function in liver cancer, and to elucidate the underlying mechanism, leading to validation of TRAF2 as an attractive liver cancer target. Here, we reported TRAF2 is up-regulated in human liver cancer cell lines and tissues, and high TRAF2 expression is associated with a poor prognosis of HCC patients. Proteomics profiling along with Co-immunoprecipitation analysis revealed that p62 is a new substrate of TRAF2, which is subjected to TRAF2-induced polyubiquitination via the K63 linkage at the K420 residue. A strong negative correlation was found between the protein levels of p62 and TRAF2 in human HCC samples. TRAF2 depletion inhibited growth and survival of liver cancer cells both in vitro and in vivo by causing p62 accumulation, which is partially rescued by simultaneous p62 knockdown. Mechanistically, TRAF2-mediated p62 polyubiquitylation activates the mTORC1 by forming the p62-mTORC1-Rag complex, which facilitates the lysosome localization of mTORC1. TRAF2 depletion inhibited mTORC1 activity through the disruption of interaction between p62 and the mTORC1 complex. In conclusion, our study provides the proof-of-concept evidence that TRAF2 is a valid target for liver cancer., (© 2023. The Author(s).)

Background: Ulcerative colitis (UC) is a disease characterized by chronic relapsing-remitting inflammatory disorders and is associated with environmental changes., Aim: To explore the disease patterns of Chinese UC patients and to determine controllable related environmental factors., Methods: This multicentre cross-sectional study was performed using a questionnaire survey. Data on clinical characteristics and environmental factors were collected. Patients with a disease course ≥5 years were defined as the long course group, and those with a disease course < 5 years were defined as the short course group., Results: A total of 588 effective questionnaires were collected. The proportion of the chronic continuous pattern was the highest among patients with a long disease course (46.8%), and in patients with a short disease course, the proportion of the active to remission pattern was the highest (53.3%). In patients with a long disease course, a higher proportion of patients with adequate sleep was found in the active to remission pattern than in the chronic intermittent (72.1% vs. 43.3%, p  = 0.008) and chronic continuous (72.1% vs. 52.4%, p  = 0.016) patterns. In patients with a short disease course, the frequency of shellfish and shrimp was higher in the chronic continuous pattern group than in the active to remission pattern group ( P  = 0.001 and 0.017 respectively)., Conclusions: For early diagnosis patients, dietary guidance should be actively carried out. With the prolongation of the disease course, attention should be given to the sleep quality of patients.

Introduction: Chronic gastritis is a common disease worldwide. Studies have consistently shown that chronic gastritis is usually associated with gastric microbial dysbiosis, especially the infection of Helicobacter pylori . However, the interaction between H. pylori and non- H. pylori bacteria in patients with chronic gastritis has not been clearly identified yet. Consequently, we designed a protocol for a systematic review and meta-analysis, which focused on identifying the changes in gastrointestinal microbiota composition between patients with H. pylori -infective and non-infective chronic gastritis., Method and Analysis: We will search PubMed, EMBASE and Cochrane Library databases to retrieve observational studies on humans. The eligible studies must include data about the relative abundance of the gastrointestinal microbiome in patients with H. pylori -infective or non-infective chronic gastritis. Only the data of adults aged over 18 years will be analysed. Two researchers will extract the data independently, and Newcastle-Ottawa Scale will be used to assess the risk of bias. Random-effects model will be performed in quantitative analyses. Correlation analysis, bioinformatics analysis and function analysis will be performed., Discussion: Currently, numerous studies have revealed the role of H. pylori in chronic gastritis. However, the alterations of non- H. pylori bacteria in patients with chronic gastritis remain an open question. The results of our study might provide new insights into future diagnosis and treatments., Ethics and Dissemination: This study is based on published documents, unrelated to personal data, so ethical approval is not in need. The results of this study are expected to be published in journals or conference proceedings., Prospero Registration Number: CRD42020205260; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There is no effective treatment for acute liver failure (ALF) except for an artificial liver support system (ALSS) and liver transplant. Bruton tyrosine kinase (Btk) plays important immunoregulatory roles in the inflammatory diseases, but its possible function in ALF remains to be characterized. In this study, we detected the phosphorylation level of Btk in ALF mouse liver and analyzed the protective effects of Btk inhibitor on survival rate and liver damage in ALF mouse models. We measured the expression levels of various inflammatory cytokines in the ALF mouse liver and primary human monocytes. In addition, we examined the expression of the NLRP3 inflammasome in mouse models with or without Btk inhibition. Clinically, we observed the dynamic changes of Btk expression in PBMCs of ALSS-treated patients. Our results showed that Btk was upregulated significantly in the experimental ALF mouse models and that Btk inhibition alleviated liver injury and reduced the mortality in these models. The protective effect of Btk inhibitors on ALF mice partially depended on the suppression of NLRP3 inflammasome signaling. Clinical investigations revealed that the dynamic changes of Btk expression in PBMCs could predict the effect of ALSS treatment. Our work shows that Btk inhibition is an effective therapeutic strategy for ALF. Moreover, Btk is a useful indicator to predict the therapeutic effect of ALSS on liver failure, which might have great value in clinical practice., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Background/aims: To investigate the relationship between elevated serum procalcitonin (PCT) and renal function in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF)., Methods: HBV-ACLF patients (n = 201) presenting to the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, from January 2013 to November 2016 were categorized into three groups according to serum PCT levels: (i) normal group (n = 74) had PCT of ≤ 0.5 ng/mL; (ii) elevated group (n = 85) had PCT in the range 0.5-1.0 ng/mL; and (iii) highly elevated group (n = 42) had PCT of > 1.0 ng/mL. Thirty-five cases received standard care after admission. Serum PCT levels and renal function were determined during a two-week follow-up., Results: Significant increases in serum creatinine (Cr) were recorded in male and female patients in the elevated group and highly elevated group compared with the normal group (P < 0.05). In addition, serum Cr levels in male and female patients were significantly higher in the highly elevated group than in the elevated group (P < 0.05). The glomerular filtration rate (GFR) was significantly lower in the highly elevated group (P < 0.05) and this group had the highest risk of altered Cr (45.9% in males; 80% in females) and abnormal GFR (37.5%). Serum PCT levels correlated significantly with all renal function parameters including homocysteine (Hcy), GFR, Cr, blood urea nitrogen, uric acid, and cystatin C at baseline and during treatment. Univariate and multivariate analyses indicated that serum PCT was a strong predictor of renal dysfunction., Conclusion: Serum PCT is closely related to renal dysfunction in HBV-ACLF., (© 2018 The Author(s). Published by S. Karger AG, Basel.)