Background/Aims: Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy. Methods: We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues. Results: We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts. Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.

Deep brain stimulation(DBS)has witnessed rapid advancement as a neurosurgical intervention over the past four decades,addressing movement disorders and a spectrum of neuropsychiatric conditions.Notably,subthalamic nucleus deep brain stimulation(STN-DBS)is widely implemented in the management of Parkinson's disease(PD)patients experiencing refractory motor fluctuations and complications,and has shown promise in ameliorating non-motor symptoms(NMS).However,the long-term efficacy of STN-DBS on NMS remains a subject of scholarly discourse.This review endeavors to synthesize current knowledge regarding the long-term impacts,underlying mechanisms,and future research directions of STN-DBS in the context of NMS in Parkinson's disease.

OBJECTIVES: To investigate the effect of hypaphorine (HYP) on Crohn's disease (CD)‑like colitis in mice and its molecular mechanism. METHODS: Thirty male C57BL/6J mice were equally randomized into WT, TNBS, and HYP groups, and in the latter two groups, mouse models of CD-like colitis were established using TNBS with daily gavage of 15 mg/kg HYP or an equivalent volume of saline. The treatment efficacy was evaluated by assessing the disease activity index (DAI), body weight changes, colon length and histopathology. The effect of HYP was also tested in a LPS-stimulated Caco-2 cell model mimicking intestinal inflammation by evaluating inflammatory responses and barrier function of the cells using qRT-PCR and immunofluorescence staining. GO and KEGG analyses were conducted to explore the therapeutic mechanism of HYP, which was validated in both the cell and mouse models using Western blotting. RESULTS: In the mouse models of CD-like colitis, HYP intervention obviously alleviated colitis as shown by significantly reduced body weight loss, colon shortening, DAI and inflammation scores, and expressions of pro-inflammatory factors in the colon tissues. HYP treatment also significantly increased the TEER values, reduced bacterial translocation to the mesenteric lymph nodes, liver, and spleen, lowered serum levels of I-FABP and FITC-dextran, increased the number of colonic tissue cup cells, and upregulated colonic expressions of MUC2 and tight junction proteins (claudin-1 and ZO-1) in the mouse models. In LPS-stimulated Caco-2 cells, HYP treatment significantly inhibited the expressions of pro-inflammatory factors and increased the expressions of tight junction proteins. Western blotting showed that HYP downregulated the expressions of the key proteins in the TLR4/MyD88 signaling pathway in both the in vitro and in vivo models. CONCLUSIONS HYP alleviates CD-like colitis in mice possibly by suppressing intestinal epithelial inflammation and improving gut barrier function.
Animals ; Male ; Mice, Inbred C57BL ; Crohn Disease/drug therapy* ; Mice ; Humans ; Caco-2 Cells ; Intestinal Mucosa/metabolism* ; Colitis/drug therapy* ; Disease Models, Animal ; Inflammation ; Toll-Like Receptor 4/metabolism* ; Myeloid Differentiation Factor 88/metabolism* ; Intestinal Barrier Function

Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.

Objective:To explore the mechanism through which the Ginkgo biloba extract(EGb)ameliorates depres-sion-like behaviors in chronic copper-exposed mice.Methods:A mouse model with depression was induced by chronic oral administration of copper sulfate solution(200 mg/L),followed by oral administration of the EGb(120 mg/L)for one month.Elevated plus-maze test,forced swimming test,and sucrose preference test were employed to detect the de-pression-like behaviors of mice.TUNEL staining was utilized to examine apoptosis in the hippocampal region of mice.Immunohistochemistry was adopted to detect the in situ expression of pro-brain-derived neurotrophic factor(proBDNF)and brain-derived neurotrophic factor(BDNF)in the hippocampal region.RT-qPCR was used to measure the expression of the BDNF mRNA.Western blot was utilized to determine the expressions of proteins such as proBDNF,mature BDNF(mBDNF),cAMP response element binding protein(CREB),phospho-CREB(p-CREB),tyrosine kinase receptor B(TrkB),p75 neurotrophin Receptor(p75NTR),furin,proprotein convertase subtilisin/kexin type 1(PCSK1),and matrix metalloproteinase-9(MMP9).Results:Chronic copper exposure led to depression-like behaviors in mice,in-creased neuronal apoptosis in the hippocampal region,enhanced proBDNF expression and reduced mBDNF expression(P＜0.05),decreased the expression of the downstream receptor protein TrkB and increased the expression of p75NTR(P＜0.05),and decreased the level of CREB and p-CREB(P＜0.05).Meanwhile,the expressions of intracellular proteases furin and PCSK1 in the hippocampal region of mice with depression-like behaviors decreased(P＜0.05),while the expression of extracellular protease MMP9 increased(P＜0.05).EGb was capable of alleviating depression-like behaviors and neuronal apoptosis in mice and partially reversing the abnormal expressions of BDNF,proBDNF,TrkB,p75NTR,CREB,p-CREB,furin,and PCSK1 proteins caused by copper exposure.Conclusion:Chronic copper exposure can lead to depression-like behaviors and apoptosis in mice.EGb can reverse these manifestations and corre-late with the balance of proBDNF/BDNF in the hippocampal region,which may offer novel insights for the treatment of depression.

Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.

ObjectiveTo investigate the recurrence of ischemic stroke (IS) and to analyze the association between four indices of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) and the risk of IS recurrence by analyzing the follow-up data related to IS in the community-based natural population of Songjiang District, Shanghai, so as to provide a scientific basis for improving the prognosis of stroke patients in the community and controlling IS recurrence. MethodsA prospective follow-up study was conducted among the IS patients in the community-based cohort population, collecting data about patient’s age, gender, disease history, biochemical indicators, and etc. Cox regression model and restricted cubic spline model were used to analyze the relationship between different levels of plasma lipids and the recurrence of IS in these patients. ResultsA total of 1 368 patients with IS were included. The total follow-up duration was 7 171.46 person-years, with a median follow-up time of 6.24 years. There were 420 cases of IS recurrence, resulting in a cumulative recurrence rate of 30.70%. The results of multivariate Cox regression analysis showed that the recurrence risk of IS was reduced when the baseline TC and LDL-C levels of IS patients were in the ranges of 4.65‒5.67 mmol·L^-1 and 2.52‒3.46 mmol·L^-1, respectively. The results of restricted cubic spline analysis showed a U-shaped relationship between baseline TC and LDL-C levels and the recurrence risk in IS patients. ConclusionThe cumulative recurrence rate of patients with IS in the community of Songjiang District in Shanghai is high, and the levels of TC and LDL-C at baseline survey are correlated with the recurrence of IS in these patients. It is suggested to pay more attention to the levels of LDL-C and TC in patients with IS, so as to improve the prognosis.

Deep brain stimulation(DBS)has witnessed rapid advancement as a neurosurgical intervention over the past four decades,addressing movement disorders and a spectrum of neuropsychiatric conditions.Notably,subthalamic nucleus deep brain stimulation(STN-DBS)is widely implemented in the management of Parkinson's disease(PD)patients experiencing refractory motor fluctuations and complications,and has shown promise in ameliorating non-motor symptoms(NMS).However,the long-term efficacy of STN-DBS on NMS remains a subject of scholarly discourse.This review endeavors to synthesize current knowledge regarding the long-term impacts,underlying mechanisms,and future research directions of STN-DBS in the context of NMS in Parkinson's disease.