Myosin light chain 9 mediates graft fibrosis after pediatric liver transplantation through TLR4/MYD88/NF-κB signaling.

Background & Aims: The incidence of graft fibrosis is elevated following pediatric liver transplantation (pLT) and is influenced by cold ischemic time (CIT). Myosin light chain 9 (MYL9), a member of the myosin family, could act on hepatic stellate cells (HSCs) and induce a transition to active phase. We hypothesized that cold ischemic injury could stimulate MYL9 expression and lead to graft fibrosis.

Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice.

Objectives: Previous studies elucidated that capecitabine (CAP) works as an anti-tumor agent with putative immunosuppressive effects. However, the intricate mechanisms underpinning these effects remain to be elucidated. In this study, we aimed to unravel the molecular pathways by which CAP exerts its immunosuppressive effects to reduce allograft rejection.

A Protein Complex of Liver Origin Activates a Pro-inflammatory Program That Drives Hepatic and Intestinal Injury in Alcohol-Associated Liver Disease.

Background & Aims: There is limited information on how the liver-to-gut axis contributes to alcohol-associated liver disease (AALD). We previously identified that high-mobility group box-1 (HMGB1) undergoes oxidation in hepatocytes and demonstrated elevated serum levels of oxidized HMGB1 ([O] HMGB1) in alcoholic patients. Since interleukin-1 beta (IL-1B) increases in AALD, we hypothesized hepatocyte-derived [O] HMGB1 could interact with IL-1B to activate a pro-inflammatory program that, besides being detrimental to the liver, drives intestinal barrier dysfunction.

Ablation of secreted phosphoprotein-1 in hepatocytes increases fatty acid oxidation and ameliorates alcohol-associated liver disease.

Background: Previously, we demonstrated that Spp1 mice exhibit a greater susceptibility to alcohol-induced liver injury than wild-type (WT) mice. Notably, alcohol triggers the expression of osteopontin (encoded by SPP1) in hepatocytes. However, the specific role of hepatocyte-derived SPP1 in either mitigating or exacerbating alcohol-associated liver disease (AALD) has yet to be elucidated.

Basiliximab Induction and Postoperative Steroid-free Immunosuppression With Tacrolimus in Pediatric Liver Transplantation: A Randomized Clinical Trial.

Background: Optimizing the immunosuppressive regimen is essential to improve the long-term outcomes of pediatric liver transplant recipients.

Methods: We conducted a prospective, randomized, open-label study to compare the safety and efficacy of 2 treatment approaches during pediatric liver transplantation: tacrolimus monotherapy following basiliximab induction (the study group) and a dual regimen of tacrolimus plus steroids (the control group). A total of 150 patients were enrolled, with 75 patients allocated to each group.

Overexpression of HMGB1 in hepatocytes accelerates PTEN inactivation-induced liver cancer.

Background: Liver cancer is increasing due to the rise in metabolic dysfunction-associated steatohepatitis (MASH). High-mobility group box-1 (HMGB1) is involved in the pathogenesis of chronic liver disease, but its role in MASH-associated liver cancer is unknown. We hypothesized that an increase in hepatocyte-derived HMGB1 in a mouse model of inactivation of PTEN that causes MASH could promote MASH-induced tumorigenesis.

Redox-sensitive high-mobility group box-1 isoforms contribute to liver fibrosis progression and resolution in mice.

Background & Aims: High-mobility group box-1 (HMGB1) significantly increases and undergoes post-translational modifications (PTMs) in response to liver injury. Since oxidative stress plays a major role in liver fibrosis and induces PTMs in proteins, we hypothesized that redox-sensitive HMGB1 isoforms contribute to liver fibrosis progression and resolution.

Methods: We used ESI-LC-MS (electrospray ionization-liquid chromatography-mass spectrometry) to study PTMs of HMGB1 during fibrosis progression and resolution.

Serum CXCL8 Concentration Can Be Used as a Noninvasive Marker of Subclinical Rejection After Pediatric Liver Transplantation.

Background: This study aimed to explore whether serum CXCL8 concentration can be used as a noninvasive marker of subclinical rejection (SCR) after pediatric liver transplantation (pLT).

Methods: Firstly, RNA sequencing (RNA-seq) was performed on 22 protocol liver biopsy samples. Secondly, several experimental methods were used to verify the RNA-seq results.

Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis.

Background: Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death.

Safety and Effectiveness of Rasagiline in Chinese Patients with Parkinson's Disease: A Prospective, Multicenter, Non-interventional Post-marketing Study.

Introduction: Rasagiline is indicated for treating idiopathic Parkinson's disease (PD) as monotherapy and adjunct therapy to levodopa in patients.

Objectives: To assess the post-marketing safety and tolerability of rasagiline in Chinese PD patients, as well as its effectiveness in improving motor symptoms.

Methods: This prospective, non-interventional, multicenter, cohort study included PD patients administered rasagiline monotherapy or adjunct therapy to levodopa.

Matrisome gene-based subclassification of patients with liver fibrosis identifies clinical and molecular heterogeneities.

Background Aims: Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology.

Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis.

Background & Aims: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether MF-derived OPN affects NASH progression is unknown.

Methods: We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose, and cholesterol diet mimicking the Western diet, to induce NASH.

Deficiency of neutrophil high-mobility group box-1 in liver transplant recipients exacerbates early allograft injury in mice.

Background And Aims: Early allograft dysfunction (EAD) is a severe event leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury remains elusive.

Hepatocellular carcinomas, exhibiting intratumor fibrosis, express cancer-specific extracellular matrix remodeling and WNT/TGFB signatures, associated with poor outcome.

Background And Aims: HCC, the third leading cause of cancer-related death, arises in the context of liver fibrosis. Although HCC is generally poorly fibrogenic, some tumors harbor focal intratumor extracellular matrix (ECM) deposits called "fibrous nests." To date, the molecular composition and clinical relevance of these ECM deposits have not been fully defined.

Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice.

Hydrodynamic tail vein injection (HTV) is the "gold standard" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene.

HBsAg seroconversion in de novo hepatitis B virus-infected paediatric liver transplant recipients with anti-viral therapy.

We investigated the clinical characteristics and therapeutic strategies for paediatric liver transplant (PLT) recipients who experienced de novo hepatitis B virus infection and the features of HBsAg seroconversion. A total of 821 PLT were performed in HBV-free recipients between January 2013 and January 2019 in Paediatric Organ Transplant Center, Tianjin First Central Hospital. Twenty-one recipients developed de novo HBV infection, the clinical data were analysed.

Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function.

Background & Aims: The gut-liver axis plays a key role in the pathogenesis of alcohol-associated liver disease (ALD). We demonstrated that Opn develop worse ALD than wild-type (WT) mice; however, the role of intestinal osteopontin (OPN) in ALD remains unknown. We hypothesized that overexpression of OPN in intestinal epithelial cells (IECs) could ameliorate ALD by preserving the gut microbiome and the intestinal barrier function.

Outcome of split-liver transplantation from pediatric donors weighing 25 kg or less.

The lower limit of body weight for "splitable" liver grafts remains unknown. To examine the outcome of split-liver transplantation (SLT) from pediatric donors ≤25 kg relative to conventional graft-type liver transplantation from deceased donors under corresponding conditions, a total of 158 patients who received primary liver transplantation, including 22 SLTs from donors ≤25 kg, 46 SLTs from donors >25 kg, 76 whole-liver transplantations, and 14 reduced-liver transplantations in donors ≤25 kg between January 2018 and December 2019, were included in the study. There was no significant difference in the complications, patient survival, and graft survival between each of the latter three groups and the SLT ≤25 kg group.

Ablation of high-mobility group box-1 in the liver reduces hepatocellular carcinoma but causes hyperbilirubinemia in Hippo signaling-deficient mice.

Silencing the Hippo kinases mammalian sterile 20-like 1 and 2 (MST1/2) activates the transcriptional coactivator yes-associated protein (YAP) in human hepatocellular carcinoma (HCC). Hepatocyte-derived high-mobility group box-1 (HMGB1) regulates YAP expression; however, its contribution to HCC in the context of deregulated Hippo signaling is unknown. Here, we hypothesized that HMGB1 is required for hepatocarcinogenesis by activating YAP in Hippo signaling-deficient (Mst1/2 ) mice.

Outflow reconstruction of left lateral graft with two widely spaced hepatic veins in pediatric living donor liver transplantation.

Background: Living donor liver transplantation using the left lateral segment of the liver is the most common type of pediatric liver transplantation. An appropriate surgical approach is crucial for decreasing the risk of vascular complications using these grafts with anatomical variations.

Methods: Between January 2017 and December 2020, 631 living donor liver transplantations using left lateral segment grafts were performed at Tianjin First Central Hospital.

Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis.

Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte-derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis.

The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wild-type mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks.

Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect.

Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage.