Traditional Chinese medicine （TCM） is commonly used in treating liver diseases worldwide, especially in China. The advantages of using TCM for treatment of liver diseases include： protecting hepatocytes, inhibiting...Traditional Chinese medicine （TCM） is commonly used in treating liver diseases worldwide, especially in China. The advantages of using TCM for treatment of liver diseases include： protecting hepatocytes, inhibiting hepatic inflammation and antifibrosis in the liver. In this article, we introduce TCM herbal preparations from the Chinese materia medica （such as Fuzheng Huayu） that are typically used for the treatment of liver diseases. Literature surrounding the mechanisms of TCM therapy for treatment of liver diseases is presented and discussed. We propose that side effects of herbal compounds are often under-appreciated, and that more care should be taken in the prescription of potentially hepatotoxic medicines. Further, to deepen the understanding of TCM mechanisms, new techniques and methodologies must be developed. Future studies will lead to the enhancement of clinical outcomes of TCM. As complementary and alternative therapies, TCMs will play an expanding role in the future of liver disease treatment.展开更多
To the Editor:SARS-CoV-2,the pathogen responsible for the pandemic of coronavirus disease 2019(COVID-19),has had profound impacts on human health,and its antagonist Paxlovid is a commonly used treatment option[1].Howe...To the Editor:SARS-CoV-2,the pathogen responsible for the pandemic of coronavirus disease 2019(COVID-19),has had profound impacts on human health,and its antagonist Paxlovid is a commonly used treatment option[1].However,treatment selection for immunosuppressed patients,such as liver recipients,remains uncertain due to potential drug interactions and the risk of immunosuppressant dosage adjustment,which can cause liver injury[2].展开更多
AIM： To study the relationship of human leukocyte antigen （HLA）-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon （IFN） in HBV-infected patients. METHODS： Low...AIM： To study the relationship of human leukocyte antigen （HLA）-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon （IFN） in HBV-infected patients. METHODS： Low-resolution DNA typing kit was used to determine HLA-DR-1 and -DQB1 genes in 72 patients with chronic hepatitis B （CHB） and HLA-DRB1 in 200 healthy people ready to donate their bone marrow in Shanghai. Among CHB patients, 35 were treated with IFNα-1b for 24 wk. RESULTS： The frequencies of HLA-DRBI＊06, DRBI＊08 and DRB1＊16 alleles in 72 patients were higher than in 200 healthy people （2.08% vs0%, OR = 3.837, P= 0.018; 11.11% vs5.50%, OR = 2.148, P= 0.034; and 6.94% vs 3.00%, OR = 0.625, P = 0.049, respectively）; whereas that of DRBI＊07 allele was lower （2.78% vs 7.75%, OR = 0.340, P= 0.046）. The frequency of HLA-DRBI＊ 14 allele was higher in 11 responders to IFN compared with 24 non-responders （18.18% vs2.08%, OR = 10.444, P = 0.031）, whereas that of DQBI＊07 allele was inverse （9.09% vs37.50%, OR = 0.167, P= 0.021）. CONCLUSION： The polymorphism of HLA class II may influence the susceptibility to HBV infection and the response to IFN in studied CHB patients. Compared with other HLA-DRB1 alleles, HLA-DRBI＊06, DRBI＊08, and DRB1＊16 may be associated with chronicity of HBV infection, HLA-DRBI＊07 with protection against HBV infection, and HLA-DRB1＊14 allele may be associated with a high rate of the response of CHB patients to IFN treatment. Compared with other HLA-DQB1 alleles, HLA-DQBI＊07 may be associated with low response rate to IFN. 2005 The WJG Press and Elsevier Inc. All rights reserved展开更多
Decision-making based on artificial intelligence(AI)methodology is increasingly present in all areas of modern medicine.In recent years,models based on deep-learning have begun to be used in organ transplantation.Taki...Decision-making based on artificial intelligence(AI)methodology is increasingly present in all areas of modern medicine.In recent years,models based on deep-learning have begun to be used in organ transplantation.Taking into account the huge number of factors and variables involved in donor-recipient(DR)matching,AI models may be well suited to improve organ allocation.AI-based models should provide two solutions:complement decision-making with current metrics based on logistic regression and improve their predictability.Hundreds of classifiers could be used to address this problem.However,not all of them are really useful for D-R pairing.Basically,in the decision to assign a given donor to a candidate in waiting list,a multitude of variables are handled,including donor,recipient,logistic and perioperative variables.Of these last two,some of them can be inferred indirectly from the team’s previous experience.Two groups of AI models have been used in the D-R matching:artificial neural networks(ANN)and random forest(RF).The former mimics the functional architecture of neurons,with input layers and output layers.The algorithms can be uni-or multi-objective.In general,ANNs can be used with large databases,where their generalizability is improved.However,they are models that are very sensitive to the quality of the databases and,in essence,they are black-box models in which all variables are important.Unfortunately,these models do not allow to know safely the weight of each variable.On the other hand,RF builds decision trees and works well with small cohorts.In addition,they can select top variables as with logistic regression.However,they are not useful with large databases,due to the extreme number of decision trees that they would generate,making them impractical.Both ANN and RF allow a successful donor allocation in over 80%of D-R pairing,a number much higher than that obtained with the best statistical metrics such as model for end-stage liver disease,balance of risk score,and survival outcomes following liver transplantation scores.Many barriers need to be overcome before these deeplearning-based models can be included for D-R matching.The main one of them is the resistance of the clinicians to leave their own decision to autonomous computational models.展开更多
In this review we outline the different mechanisms mediating hepatocarcinogenesis. We also discuss possible targets of bioactive herbal agents at different stages of hepatocarcinogenesis and highlight their role at ea...In this review we outline the different mechanisms mediating hepatocarcinogenesis. We also discuss possible targets of bioactive herbal agents at different stages of hepatocarcinogenesis and highlight their role at each individual stage. We gathered information on the most common herbal prescriptions and extracts thought to be useful in prevention or sensitization for chemotherapy in management of hepatocellular carcinoma (HCC). The value of this topic may seem questionable compared to the promise offered for HCC management by chemotherapy and radiation. However, we would recommend the use of herbal preparations not as alternatives to common chemo /and or radiotherapy, but rather for prevention among atrisk individuals, given that drug/herb interactions are still in need of extensive clarification. The bioactive constituents of various herbs seem to be promising targets for isolation, cancer activity screening and clinical evaluation. Finally, herbal preparations may offer a cost effective protective alternative to individuals known to have a high risk for HCC and possibly other cancers, through maintaining cell integrity, reversingoxidative stress and modulating different molecular pathways in preventing carcinogenesis.展开更多
AIM: To increase inspiratory muscle strength and improve the quality of life of candidates for liver transplantation.METHODS: Twenty-three candidates for liver transplantation participated in the control group and 14 ...AIM: To increase inspiratory muscle strength and improve the quality of life of candidates for liver transplantation.METHODS: Twenty-three candidates for liver transplantation participated in the control group and 14 made up the intervention group. The control group consisted of 18 men and 5 women, body mass index(BMI) 27.3 ± 4.5 kg/m2 and Model for End-Stage Liver Disease(MELD) 18.2 ± 6.1. The intervention group consisted of 11 men and 3 women, BMI 28.6 ± 5.4 kg/m2 and MELD 18 ± 4.5. The presence or absence of ascites was identified in the first patient evaluation and after three months. We evaluated maximal inspiratory pressure(MIP) and maximal expiratory pressure, spirometry, root mean square(RMS) of diaphragm and rectus abdominis, and the quality of life. The exercises were performed daily by patients at home for three months and were supervised at distance monthly. The manual consisted of diaphragmatic breathing exercises, diaphragmatic isometric exercise, Threshold IMT®, lifting upper limbs with a bat and strengthening the abdomen. RESULTS: There was significant difference(P = 0.01) between the first(initial) and the third month(final) MIP in the control group and in the intervention group, but there was no difference(P = 0.45) between the groups.The RMS of the diaphragm was lower(P = 0.001) and the functional capacity was higher(P = 0.006) in the intervention group compared to the control. The general health and mental health domains received higher scores after three months in the control group(P = 0.01) and the intervention group(P = 0.004), but there was no significant difference between them. The comparison between the presence of initial ascites with the presence of ascites was performed after three months in the control group(P = 0.083) and intervention group(P = 0.31). There was no significant difference, in relation to the presence of ascites after three months between groups(P = 0.21). In the intervention group, patients with ascites at the end of the time period had decreased scores on the social aspects SF-36 domain(P = 0.023) compared to those who had no ascites. CONCLUSION: The proposed exercises provide an increase in the inspiratory muscle strength and improve functional capacity, consequently bettering the quality of life of liver disease patients.展开更多
Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immun...Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.展开更多
AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors(mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclospori...AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors(mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine.METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation(OLT), including all liver recipients with worsening renal function before conversion to mTORi(n = 55 patients) and recipients with normal renal function who converted to m TORi for other reasons(n = 31 patients). We identified patients with diabetes mellitus(n = 28), arterial hypertension(n = 27), proteinuria(n = 27) and all three factors(n = 8)(some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus(DM), hypertension(HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction.RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function(2.14 to 1.77 mg/dL)(P = 0.02). Patients with DM showed no improvement of serum creatinine levels(1.31 mg/dL to 1.37 mg/dL) compared with non DM patients(1.31 mg/dL to 1.15 mg/dL)(P = 0.01), HT patients(1.48 mg/dL to 1.5 mg/dL) with non HT patients(1.21mg/d L to 1.08 mg/dL) and patients with proteinuria(1.44 mg/dL to 1.41 mg/dL) and no proteinuria(1.31 mg/dL to 1.11 mg/dL). CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to m TORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to m TORi; it also stabilizes renal function. Conversion to m TORi should only be avoided in patients with diabetes, hypertension and proteinuria.展开更多
AIM： To analyze the polygraphic sleep patterns during cirrhosis progression in a rat model by repeated CCh administration. METHODS： Male Wistar rats received three weekly injections of CCl4 for 11 wk, and were analy...AIM： To analyze the polygraphic sleep patterns during cirrhosis progression in a rat model by repeated CCh administration. METHODS： Male Wistar rats received three weekly injections of CCl4 for 11 wk, and were analyzed before and during the induction of cirrhosis. Rats were im- planted with electrodes to record their sleep patterns. Polygraph recordings were made weekly over 11 wk for 8 h, during the light period. After a basal recording, rats received three weekly injections of CCl4. Histological confirmation of cirrhosis was performed after 11 wk. RESULTS： The results showed a progressive decrease in total wake time that reached statistical significance from the second week of treatment. In addition, there was an increase in total time of slow wave sleep （SWS）Ⅱ and rapid eye movement sleep （REM sleep） in most of the 11 wk. SWS I showed no significant variations. During the final weeks, a significant increase in REM sleep frequency was also observed. Histological analyses of the livers showed unequivocal signs of cirrhosis. CONCLUSION： These data suggest that hepatic failure produced by CCh administration is capable of modifying the sleep pattern even after only a few doses.展开更多
Liver transplantation(LT)remains the primary treatment for irreversible liver failure.However,challenges in organ preservation,particularly ischemia-reperfusion injury and donor liver vulnerability,contribute to poor ...Liver transplantation(LT)remains the primary treatment for irreversible liver failure.However,challenges in organ preservation,particularly ischemia-reperfusion injury and donor liver vulnerability,contribute to poor post-transplant outcomes.[1,2]The accumulation of reactive oxygen species(ROS)exacerbates these issues,leading to inflammation,tissue damage,and impaired graft function.[3]Ceria nanoparticles have gained attention for their antioxidant,antibacterial,and antifibrotic properties and exhibited multiple enzymatic activities,including those of superoxide dismutase and catalase.[4]We developed an innovative system for organ preservation using dextran-coated ceria nanoparticles(CeO2NPs)incorporated into the University of Wisconsin(UW)solution,aiming to enhance liver preservation by reducing oxidative stress and inflammation and adjusting macrophage polarization.展开更多
Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma(HCC)patients,resistance in most individuals necessitates additional investigation.For this study,we collected tumor tissue...Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma(HCC)patients,resistance in most individuals necessitates additional investigation.For this study,we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing.These findings revealed significant upregulation of GSDME,which is predominantly expressed by tumor-associated macrophages(TAMs),in anti-PD1-resistant patients.Furthermore,patients with elevated levels of GSDME+macrophages in HCC tissues presented a poorer prognosis.The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment(TIME)of HCC while concurrently augmenting the cytotoxicity of CD8+T cells.The non-N-terminal fragment of GSDME within macrophages combines with PDPK1,thereby activating the PI3K-AKT pathway and facilitating M2-like polarization.The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1.The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc+/+;Alb-Cre+/+mice and in a hydrodynamic tail vein injection model,which provides a promising strategy for novel combined immunotherapy.展开更多
Aim:This study aims to evaluate the feasibility of examining circulating tumor DNA(ctDNA)in urine samples from hepatocellular carcinoma(HCC)patients by droplet digital PCR(ddPCR)and to assess its value in predicting H...Aim:This study aims to evaluate the feasibility of examining circulating tumor DNA(ctDNA)in urine samples from hepatocellular carcinoma(HCC)patients by droplet digital PCR(ddPCR)and to assess its value in predicting HCC recurrence after surgery.Methods:HCC cases who accepted surgical resection were included.Perioperative urine,tissue and peripheral blood specimens were collected.Four hotspot mutants[TP53-rs28934571(c.747G>T),TRET-rs1242535815(c.1-124C>T),CTNNB1-rs121913412(c.121A>G),and CTNNB1-rs121913407(c.133T>C)]were chosen for ctDNA analysis,and mutant allele frequency(MAF)was worked out.Sanger sequencing was performed on matched tumor tissues and peripheral blood mononuclear cells(PBMCs).The patients’clinicopathologic characteristics were retrospectively analyzed.The predictive abilities of urine ctDNA for postoperative recurrence were evaluated using the Kaplan-Meier method.Results:Forty-six patients were enrolled,and 18 patients(39.1%,18/46)exhibited detectable circulating mutants,with the MAF in the range of 0.07%to 0.91%.The consistency test indicated moderate to substantial concordance between urine and paired tumor tissue mutations.The mutation level dropped dramatically or disappeared after surgery.Positive urine ctDNA before surgery was closely related to greater tumor size and recurrence.Kaplan-Meier curves revealed significantly shorter disease-free survival(DFS)for ctDNA-positive patients.Multivariate analysis identified detectable urine ctDNA as an independent risk factor for tumor recurrence.More than that,receiver operating characteristic(ROC)curves demonstrated that urine ctDNA had the largest area under the curve(AUC)for predicting HCC recurrence.Conclusion:Detecting ctDNA in urine using ddPCR is feasible and holds significant potential for predicting and monitoring HCC recurrence.展开更多
Serine arginine-rich splicing factor 1(SRSF1)is a key oncogenic splicing factor in various cancers,promoting abnormal gene expression through post-translational regulation.Although the protumoral function of SRSF1 is ...Serine arginine-rich splicing factor 1(SRSF1)is a key oncogenic splicing factor in various cancers,promoting abnormal gene expression through post-translational regulation.Although the protumoral function of SRSF1 is well-established,the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8+T cell-mediated antitumor immunity remain unclear.Our findings indicate that depleting SRSF1 in CD8+T cells improve antitumor immune function,glycolytic metabolism,and the efficacy of adoptive T cell therapy.The inactivation of SRSF1 in tumor cells reduces transcription factors,including c-Jun,c-myc,and JunB,facilitating glycolytic metabolism reprogramming,which restores CD8+T cell function and inhibits tumor growth.The small-molecule inhibitor TN2008 targets SRSF1,boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models.We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8+T cells.展开更多
Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic strategies.The metabolic reprogramming of tumor cells plays an essential role in the devel...Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic strategies.The metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely unknown.Here,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat iCCA.Methods:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome anal-ysis.Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was determined.Survival and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic subtypes.Cell proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA cells.Results:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were identified.These metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic alterations.The S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)mutations.Among the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)signaling.Conclusion:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing that the S2 subtype exhibited the poorest survival outcomes.We further identified DGKA as a potential target for the S2 subtype.展开更多
Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumo...Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumors,their impact on tumor immunology remains unclear.This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.Methods:To identify the key genes associated with immunotherapy resistance,we conducted single-nuclear RNA sequencing,multiplex immunofluorescence,and The Cancer Genome Atlas and Gene Expression Omnibus database analyses.We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems,flow cytometry,various tumor-bearing mouse models,and patient-derived organotypic tumor spheroids.Results:SRSF10 was upregulated in various tumors and associated with poor prognosis.Moreover,SRSF10 positively regulated lactate production,and SRSF10/glycolysis/histone H3 lysine 18 lactylation(H3K18la)formed a positive feedback loop in tumor cells.Increased lactate levels promoted M2 macrophage polarization,thereby inhibiting CD8^(+)T cell activity.Mechanistically,SRSF10 interacted with the 3′-untranslated region of MYB,enhancing MYB RNA stability,and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1(GLUT1),hexokinase 1(HK1),lactate dehydrogenase A(LDHA),resulting in elevated intracellular and extracellular lactate levels.Lactate accumulation induced histone lactylation,which further upregulated SRSF10 expression.Additionally,lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages,thereby activating transcription and enhancing pro-tumor macrophage activity.M2 macrophages,in turn,inhibited the enrichment of CD8^(+)T cells and the proportion of interferon-γ+CD8^(+)T cells in the tumor microenvironment(TME),thus creating an immunosuppressive TME.Clinically,SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1(PD-1)monoclonal antibodies(mAbs)in both murine and human preclinical models.Conclusions:The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance.Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.展开更多
Regulatory T cell(Tregs)predominantly maintain the immune balance and prevent autoimmunity via their immunosuppressive functions.However,tumor-infiltrating Tregs(TI-Tregs)may mediate tumor immune tolerance in complex ...Regulatory T cell(Tregs)predominantly maintain the immune balance and prevent autoimmunity via their immunosuppressive functions.However,tumor-infiltrating Tregs(TI-Tregs)may mediate tumor immune tolerance in complex tumor microenvironments,resulting in poor prognosis.Distinguishing specific TI-Treg subpopulations from peripheral Tregs and intratumoral conventional T cells(Tconvs)has recently emerged as an important topic in antitumor therapy.In this review,we summarize novel therapeutic approaches targeting both the metabolic pathways and hallmarks of TI-Tregs in preclinical and clinical studies.Although the phenotypic and functional diversity of TI-Tregs remains unclear,our review provides new insights into TI-Tregbased therapies and facilitates precision medicine for tumor treatment.展开更多
基金supported by the National Basic Research Program(973 Program)of China(No.2006CB504800)National Natural Science Foundation of China(No.30271657 and No.30672489)+3 种基金Leading Academic Discipline Project of Shanghai Municipal Education Commission(No.J50307)Innovation Research Team in Universities,Shanghai Municipal Education CommissionLeading Academic Discipline of Hepatology of State Administration of TCM China(No.2010sh)Three-year Action Plan of Shanghai TCM Development(No.ZYSNXD-CC-YJXYY)
文摘Traditional Chinese medicine （TCM） is commonly used in treating liver diseases worldwide, especially in China. The advantages of using TCM for treatment of liver diseases include： protecting hepatocytes, inhibiting hepatic inflammation and antifibrosis in the liver. In this article, we introduce TCM herbal preparations from the Chinese materia medica （such as Fuzheng Huayu） that are typically used for the treatment of liver diseases. Literature surrounding the mechanisms of TCM therapy for treatment of liver diseases is presented and discussed. We propose that side effects of herbal compounds are often under-appreciated, and that more care should be taken in the prescription of potentially hepatotoxic medicines. Further, to deepen the understanding of TCM mechanisms, new techniques and methodologies must be developed. Future studies will lead to the enhancement of clinical outcomes of TCM. As complementary and alternative therapies, TCMs will play an expanding role in the future of liver disease treatment.
基金The study was supported by grants from the National Natural Science Foundation of China(81871259,81971495,82070675,81530048,82200731 and 81570562)the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials,and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘To the Editor:SARS-CoV-2,the pathogen responsible for the pandemic of coronavirus disease 2019(COVID-19),has had profound impacts on human health,and its antagonist Paxlovid is a commonly used treatment option[1].However,treatment selection for immunosuppressed patients,such as liver recipients,remains uncertain due to potential drug interactions and the risk of immunosuppressant dosage adjustment,which can cause liver injury[2].
基金Supported by the Development Fund of Shanghai Science and Technology Committee, No. 014119052
文摘AIM： To study the relationship of human leukocyte antigen （HLA）-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon （IFN） in HBV-infected patients. METHODS： Low-resolution DNA typing kit was used to determine HLA-DR-1 and -DQB1 genes in 72 patients with chronic hepatitis B （CHB） and HLA-DRB1 in 200 healthy people ready to donate their bone marrow in Shanghai. Among CHB patients, 35 were treated with IFNα-1b for 24 wk. RESULTS： The frequencies of HLA-DRBI＊06, DRBI＊08 and DRB1＊16 alleles in 72 patients were higher than in 200 healthy people （2.08% vs0%, OR = 3.837, P= 0.018; 11.11% vs5.50%, OR = 2.148, P= 0.034; and 6.94% vs 3.00%, OR = 0.625, P = 0.049, respectively）; whereas that of DRBI＊07 allele was lower （2.78% vs 7.75%, OR = 0.340, P= 0.046）. The frequency of HLA-DRBI＊ 14 allele was higher in 11 responders to IFN compared with 24 non-responders （18.18% vs2.08%, OR = 10.444, P = 0.031）, whereas that of DQBI＊07 allele was inverse （9.09% vs37.50%, OR = 0.167, P= 0.021）. CONCLUSION： The polymorphism of HLA class II may influence the susceptibility to HBV infection and the response to IFN in studied CHB patients. Compared with other HLA-DRB1 alleles, HLA-DRBI＊06, DRBI＊08, and DRB1＊16 may be associated with chronicity of HBV infection, HLA-DRBI＊07 with protection against HBV infection, and HLA-DRB1＊14 allele may be associated with a high rate of the response of CHB patients to IFN treatment. Compared with other HLA-DQB1 alleles, HLA-DQBI＊07 may be associated with low response rate to IFN. 2005 The WJG Press and Elsevier Inc. All rights reserved
基金supported by a grant from Mutua Madrile?a XVIII Convovatoria de ayudas a la investigación。
文摘Decision-making based on artificial intelligence(AI)methodology is increasingly present in all areas of modern medicine.In recent years,models based on deep-learning have begun to be used in organ transplantation.Taking into account the huge number of factors and variables involved in donor-recipient(DR)matching,AI models may be well suited to improve organ allocation.AI-based models should provide two solutions:complement decision-making with current metrics based on logistic regression and improve their predictability.Hundreds of classifiers could be used to address this problem.However,not all of them are really useful for D-R pairing.Basically,in the decision to assign a given donor to a candidate in waiting list,a multitude of variables are handled,including donor,recipient,logistic and perioperative variables.Of these last two,some of them can be inferred indirectly from the team’s previous experience.Two groups of AI models have been used in the D-R matching:artificial neural networks(ANN)and random forest(RF).The former mimics the functional architecture of neurons,with input layers and output layers.The algorithms can be uni-or multi-objective.In general,ANNs can be used with large databases,where their generalizability is improved.However,they are models that are very sensitive to the quality of the databases and,in essence,they are black-box models in which all variables are important.Unfortunately,these models do not allow to know safely the weight of each variable.On the other hand,RF builds decision trees and works well with small cohorts.In addition,they can select top variables as with logistic regression.However,they are not useful with large databases,due to the extreme number of decision trees that they would generate,making them impractical.Both ANN and RF allow a successful donor allocation in over 80%of D-R pairing,a number much higher than that obtained with the best statistical metrics such as model for end-stage liver disease,balance of risk score,and survival outcomes following liver transplantation scores.Many barriers need to be overcome before these deeplearning-based models can be included for D-R matching.The main one of them is the resistance of the clinicians to leave their own decision to autonomous computational models.
文摘In this review we outline the different mechanisms mediating hepatocarcinogenesis. We also discuss possible targets of bioactive herbal agents at different stages of hepatocarcinogenesis and highlight their role at each individual stage. We gathered information on the most common herbal prescriptions and extracts thought to be useful in prevention or sensitization for chemotherapy in management of hepatocellular carcinoma (HCC). The value of this topic may seem questionable compared to the promise offered for HCC management by chemotherapy and radiation. However, we would recommend the use of herbal preparations not as alternatives to common chemo /and or radiotherapy, but rather for prevention among atrisk individuals, given that drug/herb interactions are still in need of extensive clarification. The bioactive constituents of various herbs seem to be promising targets for isolation, cancer activity screening and clinical evaluation. Finally, herbal preparations may offer a cost effective protective alternative to individuals known to have a high risk for HCC and possibly other cancers, through maintaining cell integrity, reversingoxidative stress and modulating different molecular pathways in preventing carcinogenesis.
文摘AIM: To increase inspiratory muscle strength and improve the quality of life of candidates for liver transplantation.METHODS: Twenty-three candidates for liver transplantation participated in the control group and 14 made up the intervention group. The control group consisted of 18 men and 5 women, body mass index(BMI) 27.3 ± 4.5 kg/m2 and Model for End-Stage Liver Disease(MELD) 18.2 ± 6.1. The intervention group consisted of 11 men and 3 women, BMI 28.6 ± 5.4 kg/m2 and MELD 18 ± 4.5. The presence or absence of ascites was identified in the first patient evaluation and after three months. We evaluated maximal inspiratory pressure(MIP) and maximal expiratory pressure, spirometry, root mean square(RMS) of diaphragm and rectus abdominis, and the quality of life. The exercises were performed daily by patients at home for three months and were supervised at distance monthly. The manual consisted of diaphragmatic breathing exercises, diaphragmatic isometric exercise, Threshold IMT®, lifting upper limbs with a bat and strengthening the abdomen. RESULTS: There was significant difference(P = 0.01) between the first(initial) and the third month(final) MIP in the control group and in the intervention group, but there was no difference(P = 0.45) between the groups.The RMS of the diaphragm was lower(P = 0.001) and the functional capacity was higher(P = 0.006) in the intervention group compared to the control. The general health and mental health domains received higher scores after three months in the control group(P = 0.01) and the intervention group(P = 0.004), but there was no significant difference between them. The comparison between the presence of initial ascites with the presence of ascites was performed after three months in the control group(P = 0.083) and intervention group(P = 0.31). There was no significant difference, in relation to the presence of ascites after three months between groups(P = 0.21). In the intervention group, patients with ascites at the end of the time period had decreased scores on the social aspects SF-36 domain(P = 0.023) compared to those who had no ascites. CONCLUSION: The proposed exercises provide an increase in the inspiratory muscle strength and improve functional capacity, consequently bettering the quality of life of liver disease patients.
基金supported by grants from the National Natural Science Foundation of China(81971495 and 91442117)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-035)+2 种基金the National Science Foundation of Jiangsu Province(BRA2017533 and BK20191490)the State Key Laboratory of Reproductive Medicine(SKLRM-K202001)the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials。
文摘Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.
文摘AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors(mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine.METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation(OLT), including all liver recipients with worsening renal function before conversion to mTORi(n = 55 patients) and recipients with normal renal function who converted to m TORi for other reasons(n = 31 patients). We identified patients with diabetes mellitus(n = 28), arterial hypertension(n = 27), proteinuria(n = 27) and all three factors(n = 8)(some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus(DM), hypertension(HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction.RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function(2.14 to 1.77 mg/dL)(P = 0.02). Patients with DM showed no improvement of serum creatinine levels(1.31 mg/dL to 1.37 mg/dL) compared with non DM patients(1.31 mg/dL to 1.15 mg/dL)(P = 0.01), HT patients(1.48 mg/dL to 1.5 mg/dL) with non HT patients(1.21mg/d L to 1.08 mg/dL) and patients with proteinuria(1.44 mg/dL to 1.41 mg/dL) and no proteinuria(1.31 mg/dL to 1.11 mg/dL). CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to m TORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to m TORi; it also stabilizes renal function. Conversion to m TORi should only be avoided in patients with diabetes, hypertension and proteinuria.
基金Supported by Grant 50633 from CONACyT to Jiménez-Anguiano A
文摘AIM： To analyze the polygraphic sleep patterns during cirrhosis progression in a rat model by repeated CCh administration. METHODS： Male Wistar rats received three weekly injections of CCl4 for 11 wk, and were analyzed before and during the induction of cirrhosis. Rats were im- planted with electrodes to record their sleep patterns. Polygraph recordings were made weekly over 11 wk for 8 h, during the light period. After a basal recording, rats received three weekly injections of CCl4. Histological confirmation of cirrhosis was performed after 11 wk. RESULTS： The results showed a progressive decrease in total wake time that reached statistical significance from the second week of treatment. In addition, there was an increase in total time of slow wave sleep （SWS）Ⅱ and rapid eye movement sleep （REM sleep） in most of the 11 wk. SWS I showed no significant variations. During the final weeks, a significant increase in REM sleep frequency was also observed. Histological analyses of the livers showed unequivocal signs of cirrhosis. CONCLUSION： These data suggest that hepatic failure produced by CCh administration is capable of modifying the sleep pattern even after only a few doses.
文摘Liver transplantation(LT)remains the primary treatment for irreversible liver failure.However,challenges in organ preservation,particularly ischemia-reperfusion injury and donor liver vulnerability,contribute to poor post-transplant outcomes.[1,2]The accumulation of reactive oxygen species(ROS)exacerbates these issues,leading to inflammation,tissue damage,and impaired graft function.[3]Ceria nanoparticles have gained attention for their antioxidant,antibacterial,and antifibrotic properties and exhibited multiple enzymatic activities,including those of superoxide dismutase and catalase.[4]We developed an innovative system for organ preservation using dextran-coated ceria nanoparticles(CeO2NPs)incorporated into the University of Wisconsin(UW)solution,aiming to enhance liver preservation by reducing oxidative stress and inflammation and adjusting macrophage polarization.
基金supported by the National Natural Science Foundation of China(No.82372946,No.82072670,and No.81871916)the Leading Project of the Science and Technology Committee of Shanghai Municipality(No.21Y21900100)the Project of Shanghai Municipal Health Commission(No.202140269).
文摘Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma(HCC)patients,resistance in most individuals necessitates additional investigation.For this study,we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing.These findings revealed significant upregulation of GSDME,which is predominantly expressed by tumor-associated macrophages(TAMs),in anti-PD1-resistant patients.Furthermore,patients with elevated levels of GSDME+macrophages in HCC tissues presented a poorer prognosis.The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment(TIME)of HCC while concurrently augmenting the cytotoxicity of CD8+T cells.The non-N-terminal fragment of GSDME within macrophages combines with PDPK1,thereby activating the PI3K-AKT pathway and facilitating M2-like polarization.The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1.The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc+/+;Alb-Cre+/+mice and in a hydrodynamic tail vein injection model,which provides a promising strategy for novel combined immunotherapy.
基金supported by National Natural Science Foundation of China(82150004)Shanghai Municipal Health Commission(20224Y0285,R2022-010)+4 种基金Shanghai“Rising Stars of Medical Talent”Youth Development Program(Outstanding Youth Medical Talents)the Projects from the Shanghai Science and Technology Commission(19441905000 and 21140900300)Natural Science Funds of Shanghai(21ZR1413800,20ZR1473100)the Projects from Science Foundation of Zhongshan Hospital,Fudan University(2021ZSCX28,2020ZSLC31)the Shanghai Municipal Science and Technology Major Project,and the Shanghai Municipal Key Clinical Specialty.
文摘Aim:This study aims to evaluate the feasibility of examining circulating tumor DNA(ctDNA)in urine samples from hepatocellular carcinoma(HCC)patients by droplet digital PCR(ddPCR)and to assess its value in predicting HCC recurrence after surgery.Methods:HCC cases who accepted surgical resection were included.Perioperative urine,tissue and peripheral blood specimens were collected.Four hotspot mutants[TP53-rs28934571(c.747G>T),TRET-rs1242535815(c.1-124C>T),CTNNB1-rs121913412(c.121A>G),and CTNNB1-rs121913407(c.133T>C)]were chosen for ctDNA analysis,and mutant allele frequency(MAF)was worked out.Sanger sequencing was performed on matched tumor tissues and peripheral blood mononuclear cells(PBMCs).The patients’clinicopathologic characteristics were retrospectively analyzed.The predictive abilities of urine ctDNA for postoperative recurrence were evaluated using the Kaplan-Meier method.Results:Forty-six patients were enrolled,and 18 patients(39.1%,18/46)exhibited detectable circulating mutants,with the MAF in the range of 0.07%to 0.91%.The consistency test indicated moderate to substantial concordance between urine and paired tumor tissue mutations.The mutation level dropped dramatically or disappeared after surgery.Positive urine ctDNA before surgery was closely related to greater tumor size and recurrence.Kaplan-Meier curves revealed significantly shorter disease-free survival(DFS)for ctDNA-positive patients.Multivariate analysis identified detectable urine ctDNA as an independent risk factor for tumor recurrence.More than that,receiver operating characteristic(ROC)curves demonstrated that urine ctDNA had the largest area under the curve(AUC)for predicting HCC recurrence.Conclusion:Detecting ctDNA in urine using ddPCR is feasible and holds significant potential for predicting and monitoring HCC recurrence.
基金funded by the National Natural Science Foundation of China(Grant No.).This research was supported by grants from the National Natural Science Foundation of China(Grant Nos.82073217,82403555,82073218,82003084)the National Key Research and Development Program of China(Grant No.2018YFC1312100)+3 种基金the Shanghai Municipal Key Clinical Specialty,and the CAMS Innovation Fund for Medical Sciences(CIFMS 2019-I2M-5-058)the Leading Project of the Science and Technology Commission of Shanghai Municipality(No.21Y21900100)the Project of the Shanghai Municipal Health Commission This research was also supported by the Outstanding Resident Clinical Postdoctoral Program at Zhongshan Hospital,Fudan University,and the China Postdoctoral Science Foundation(KLF152165,202140269)The authors appreciated for the technical assistance in the virtual screening job described in this study by Prof.Renxiao Wang,School of Pharmacy,Fudan University.
文摘Serine arginine-rich splicing factor 1(SRSF1)is a key oncogenic splicing factor in various cancers,promoting abnormal gene expression through post-translational regulation.Although the protumoral function of SRSF1 is well-established,the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8+T cell-mediated antitumor immunity remain unclear.Our findings indicate that depleting SRSF1 in CD8+T cells improve antitumor immune function,glycolytic metabolism,and the efficacy of adoptive T cell therapy.The inactivation of SRSF1 in tumor cells reduces transcription factors,including c-Jun,c-myc,and JunB,facilitating glycolytic metabolism reprogramming,which restores CD8+T cell function and inhibits tumor growth.The small-molecule inhibitor TN2008 targets SRSF1,boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models.We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8+T cells.
基金This project was supported by grants from the National Natural Science Foundation of China(82273387,82273386,82073217,32270711,82073218 and 82003084)the National Key Research and Develop-ment Program of China(2018YFC1312100)+3 种基金Beijing Nova Program(20220484230)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Shanghai Municipal Key Clinical Specialty,CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-058)the State Key Laboratory of Proteomics(SKLP-K202004).
文摘Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic strategies.The metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely unknown.Here,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat iCCA.Methods:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome anal-ysis.Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was determined.Survival and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic subtypes.Cell proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA cells.Results:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were identified.These metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic alterations.The S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)mutations.Among the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)signaling.Conclusion:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing that the S2 subtype exhibited the poorest survival outcomes.We further identified DGKA as a potential target for the S2 subtype.
基金supported by the National Natural Science Foundation of China(No.82372946 and No.82072670)the 12 Leading Project of the Science and Technology Committee of Shanghai Municipality(No.21Y21900100)the Project of Shanghai Municipal Health Commission(No.202140269).
文摘Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumors,their impact on tumor immunology remains unclear.This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.Methods:To identify the key genes associated with immunotherapy resistance,we conducted single-nuclear RNA sequencing,multiplex immunofluorescence,and The Cancer Genome Atlas and Gene Expression Omnibus database analyses.We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems,flow cytometry,various tumor-bearing mouse models,and patient-derived organotypic tumor spheroids.Results:SRSF10 was upregulated in various tumors and associated with poor prognosis.Moreover,SRSF10 positively regulated lactate production,and SRSF10/glycolysis/histone H3 lysine 18 lactylation(H3K18la)formed a positive feedback loop in tumor cells.Increased lactate levels promoted M2 macrophage polarization,thereby inhibiting CD8^(+)T cell activity.Mechanistically,SRSF10 interacted with the 3′-untranslated region of MYB,enhancing MYB RNA stability,and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1(GLUT1),hexokinase 1(HK1),lactate dehydrogenase A(LDHA),resulting in elevated intracellular and extracellular lactate levels.Lactate accumulation induced histone lactylation,which further upregulated SRSF10 expression.Additionally,lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages,thereby activating transcription and enhancing pro-tumor macrophage activity.M2 macrophages,in turn,inhibited the enrichment of CD8^(+)T cells and the proportion of interferon-γ+CD8^(+)T cells in the tumor microenvironment(TME),thus creating an immunosuppressive TME.Clinically,SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1(PD-1)monoclonal antibodies(mAbs)in both murine and human preclinical models.Conclusions:The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance.Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.
基金supported by grants from the National Natural Science Foundation of China(Nos.81971495,82171759,and 82101873)the CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5-035)Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.SJCX23_0706).
文摘Regulatory T cell(Tregs)predominantly maintain the immune balance and prevent autoimmunity via their immunosuppressive functions.However,tumor-infiltrating Tregs(TI-Tregs)may mediate tumor immune tolerance in complex tumor microenvironments,resulting in poor prognosis.Distinguishing specific TI-Treg subpopulations from peripheral Tregs and intratumoral conventional T cells(Tconvs)has recently emerged as an important topic in antitumor therapy.In this review,we summarize novel therapeutic approaches targeting both the metabolic pathways and hallmarks of TI-Tregs in preclinical and clinical studies.Although the phenotypic and functional diversity of TI-Tregs remains unclear,our review provides new insights into TI-Tregbased therapies and facilitates precision medicine for tumor treatment.
