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Background: Postoperative recurrence is a vital reason for poor 5-year overall survival in hepatocellular carcinoma (HCC) patients. The ADV score is considered a parameter that can quantify HCC aggressiveness. This study aimed to identify HCC patients at high-risk of recurrence early using the ADV score. Methods: The medical data of consecutive HCC patients undergoing hepatectomy from The First Affiliated Hospital of Nanjing Medical University (TFAHNJMU) and Nanjing Drum Tower Hospital (NJDTH) were retrospectively reviewed. Based on the status of microvascular invasion and the Edmondson-Steiner grade, HCC patients were divided into three groups: low-risk group (group 1: no risk factor exists), medium-risk group (group 2: one risk factor exists), and high-risk group (group 3: coexistence of two risk factors). In the training cohort (TFAHNJMU), the R package nnet was used to establish a multi-categorical unordered logistic regression model based on the ADV score to predict three risk groups. The Welch's T-test was used to compare differences in clinical variables in three predicted risk groups. NJDTH served as an external validation center. At last, the confusion matrix was developed using the R package caret to evaluate the diagnostic performance of the model. Results: 350 and 405 patients from TFAHNJMU and NJDTH were included. HCC patients in different risk groups had significantly different liver function and inflammation levels. Density maps demonstrated that the ADV score could best differentiate between the three risk groups. The probability curve was plotted according to the predicted results of the multi-categorical unordered logistic regression model, and the best cut-off values of the ADV score were as follows: low-risk ≤ 3.4 log, 3.4 log < medium-risk ≤ 5.7 log, and high-risk > 5.7 log. The sensitivities of the ADV score predicting the high-risk group (group 3) were 70.2% (99/141) and 78.8% (63/80) in the training and external validation cohort, respectively. Conclusion: The ADV score might become a valuable marker for screening patients at high-risk of HCC recurrence with a cut-off value of 5.7 log, which might help surgeons, pathologists, and HCC patients make appropriate clinical decisions. [ABSTRACT FROM AUTHOR]

CD19+CD24hiCD27+ memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro , in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases. [ABSTRACT FROM AUTHOR]

CD19 + CD24 hi CD27 + memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro , in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro . Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Li, Gao, Zhou, Zhou, Deng, Lu, Rao, Ji, Gu, Yang, Xia and Wang.)

Background: Regulatory B cells (Bregs) play an essential role in inflammation and transplant tolerance. Several studies have reported a decreased number of Bregs in renal transplant patients with graft rejection. However, little is known about their role in the liver alloresponse., Methods: To investigate whether the circulating Bregs have been associated with acute allograft rejection (AR) in liver transplantation patients, 19 patients receiving liver allografts from donation after cardiac death (DCD) donors were retrospectively studied., Results: The postoperative proportions of circulating CD19 + CD24 hi CD38 hi transitional Bregs (tBregs) and CD19 + CD24 hi CD27 + memory Bregs (mBregs) in patients diagnosed with AR (AR group) and other patients with stable allograft liver function (SF group) were evaluated using flow cytometry (FCM) analysis. Results showed that while no significant changes were found regarding both the tBreg and mBreg, proportions across all time points in the SF group, the AR group showed significantly decreased proportions of mBregs. All of the five AR patients responded fine to the treatments, and the proportions of mBregs increased significantly after anti-rejection therapies. In addition, AR was suspected in four recipients, but gradually they were diagnosed with hemolytic or obstructive jaundice and showed no decrease in the proportion of mBregs., Conclusions: For the first time, our results suggested the potential role of a decreased proportion of circulating mBregs in predicting AR in patients with post liver transplantation., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Gallbladder perforation (GBP) represents a rare, but potentially life-threatening, complication of acute cholecystitis. GBP is subdivided into three categories whereas the development of biloma is extremely rare. The present case study reports on a 40-year-old man with a 10-year history of calculus cholecystitis, who was referred to The First Affiliated Hospital of Nanjing Medical University (Nanjing, China) for the surgical treatment of an emerging massive hepatic entity with insidious symptoms and normal laboratory tests. A preoperative imaging study demonstrated the collection with internal septations and mural nodules, but no visible communication with the biliary system. Given the suspected biliary cystic tumor, a laparotomy was performed and the lumen was scattered with papillae. An intraoperative frozen section examination illustrated a simple hepatic cyst. Biochemical analysis of the collection and histopathology of the gallbladder and capsule substantiated the diagnosis of biloma formation due to GBP. The purpose of the present case report was to demonstrate how a pinhole-sized perforation with extravasation of unconcentrated bile from the gallbladder may result in insidious clinical presentation and an undetected leak site. According to the clinicopathological characteristics and composition, formation of biloma should be classified as type IV GBP. To differentiate bilomas with intracystic septations and mural nodules from BCTs is difficult via a preoperative examination, and the definitive diagnosis should be based on a histological examination. Laparotomy with frozen section examination may be the optimal approach in such a case.