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Hepatobiliary & Pancreatic Diseases International 2024年第2期23卷 117-122页

作者： Xin Yang Lu Lu Wen-Wei Zhu Yi-Feng Tao Cong-Huan Shen Jin-Hong Chen Zheng-Xin Wang lun-xiu qin Hepatobiliary Surgery and Liver Transplantation Centers Department of General SurgeryHuashan Hospital&Cancer Metastasis InstituteFudan UniversityShanghai 200040China

Hepatectomy is still the major curative treatment for patients with liver malignancies.However,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the retrohepatic inferior vena cava and hepatic veins.Ex vivo liver resection and auto-transplantation(ELRA),a hybrid technique of the traditional liver resection and transplantation,has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation.Due to its technical difficulty,ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation.The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases,especially in the advanced alveolar echinococcosis.Recently,the application of ELRA for liver malignances has gained more attention.However,standardization of clinical practice norms and international consensus are still lacking.The prognostic impact in these oncologic patients also needs further evaluation.In this review,we summarized the principles and recent progresses on ELRA.

关键词： Ex vivo liver resection Liver auto-transplantation Oncology Liver malignancies

Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1690-1705页

作者： Yan Fu Keyu Shen Hao Wang Shun Wang Xufeng Wang Le Zhu Yan Zheng Tiantian Zou Hongfei Ci Qiongzhu Dong lun-xiu qin Hepatobiliary Surgery Department of General SurgeryHuashan Hospital&Cancer Metastasis InstituteFudan University200040 ShanghaiChina Center of Interventional Radiology and Vascular Surgery Department of RadiologyZhongda HospitalMedical SchoolSoutheast University87 Dingjiaqiao Road210009 NanjingChina institutes of Biomedical Sciences Fudan University200032 ShanghaiChina Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer Shanghai Municipal Health CommissionMinhang HospitalFudan UniversityShanghaiChina

Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis.Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment.However,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown.Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC progression.KN93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells.Above all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.

关键词： GSK3β metastasis Alpha

Strategies for improving the efflcacy of immunotherapy in hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2022年第5期21卷 420-429页

作者： Ying Zhu lun-xiu qin Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China

Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)have made great progress in the systemic treatment of HCC.However,anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and Check Mate 459 trials.It is urgent to understand the immunological rationale and explore novel ways to improve the efflcacy of immunotherapy.The combination of ICIs with other therapies,such as tyrosine kinase inhibitors(TKIs),monoclonal antibodies,or local therapy,has been demonstrated to improve overall response rate and survival.In addition,modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies.In this review,we summarized the latest findings in the immune microenvironment,the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs,as well as other kinds of immune treatment.

关键词： Hepatocellular carcinoma Tumor microenvironment Immune checkpoint inhibitors Interferon-α Programmed death receptor 1

Immunotherapy for hepatobiliary malignancies:Progress and prospective

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Hepatobiliary & Pancreatic Diseases International 2022年第5期21卷 409-412页

作者： lun-xiu qin Department of General Surgery Huashan HospitalFudan UniversityShanghai 200040China

Hepatobiliary malignancies include hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs).They are characterized by high heterozygosity,rapid progression,and difflcult to treat[1,2].Recent rapid progress in targeted therapeutic agents has brought new hope for those with advanced HCC[3-5].But there are problems such as lower response rate,or drug resistance(primary or acquired),as well as poor tolerance due to their side-effects,which make this treatment alone still face great challenges.

关键词： biliary malignancies prospective

Biomarkers for response to immunotherapy in hepatobiliary malignancies

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Hepatobiliary & Pancreatic Diseases International 2022年第5期21卷 413-419页

作者： Zhi-Fei Lin lun-xiu qin Jin-Hong Chen Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China

Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies.The identification of reliable predictors of the response to immunotherapy is urgently needed.Data sources:Literature search was conducted in Pub Med for relevant articles published up to May 2022.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence.Tumor programmed death-ligand 1(PD-L1)expression is the most widely studied biomarker in hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs),but there are conflicting results on its predictive potential.Tumor mutational burden(TMB)is generally low both in HCC and BTCs,and the clinical trials of TMB are rare in hepatobiliary malignancies.Promisingly,mismatch repair deficiency(dMMR)/high microsatellite instability(MSI-H)may be a predictive biomarker of response to antiPD-1 therapy in BTCs.Furthermore,some emerging biomarkers,such as gut microbiota,show predictive potential in the preliminary studies.Radiomics and liquid-biopsy biomarkers,including circulating tumor cells,circulating tumor DNA(ct DNA)and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response,showing a new promising direction.Conclusions:Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic.Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies.The identification of predictors for response to ICIs is an urgent need and major challenge.Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.

关键词： Biomarker Immunotherapy Hepatocellular carcinoma Biliary tract cancers

Expert consensus-promoting clinical excellence and ultimately benefitting patients

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Hepatobiliary Surgery and Nutrition 2023年第5期12卷 743-745页

作者： Jin-Hong Chen lun-xiu qin Hepatobiliary Surgery Department of General SurgeryHuashan HospitalFudan UniversityShanghaiChina

Evidence-based medicine serves as the cornerstone of modern healthcare.Based on current evidence in the field of evidence-based medicine,a team of authoritative experts in the industry engages in comprehensive discussions to develop expert consensus,following standardized procedures.The consensus serves as a foundation for clinical decision-making.However,the abundance of expert consensus varies in quality,and some viewpoints even contradict each other,leading to confusion in clinical decision-making.

关键词： Consensus guideline evidence-based medicine

A Prognostic Nomogram for Hepatocellular Carcinoma Based on Wound Healing and Immune Checkpoint Genes

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Journal of Clinical and Translational Hepatology 2022年第5期10卷 891-900页

作者： Beiyuan Hu Xiaotian Shen Wei qin Lan Zhang Tiantian Zou Qiongzhu Dong lun-xiu qin Department of General Surgery Huashan Hospital&Cancer Metastasis InstituteInstitutes of Biomedical SciencesFudan UniversityShanghaiChina

Background and Aims:Wound healing and tumor progression share some common biological features;however,how variations in wound healing patterns affect hepatocellular carcinoma(HCC)prognosis remains unclear.Methods:We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas(TCGA)and the International Cancer Genome Consortium(ICGC)and correlated them with immune infiltration and the expression levels of immune checkpoint genes.A risk score,which we named the“heal.immune”score,was established via stepwise Cox estimation.We constructed a nomogram based on age,sex,TNM stage,and heal.immune score and explored its predictive value for HCC prognosis.Seventy-four clinical patients were enrolled in this study,and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an independent validation group.Results:We identified two distinct wound healing patterns in HCC.The biological processes of healing cluster 1(C1)are related to metabolism,while those of healing cluster 2(C2)are related to the inflammatory response and immune cell accumulation.A total of 565 wound healing-related genes(based on Gene Ontology)and 25 immune checkpoint genes were considered.By analyzing differentially expressed genes and implementing a stepwise Cox estimation analysis,six genes with p values less than 0.02 in a multivariate Cox estimation were chosen as the“heal.immune”gene set(FCER1G,PLAT,ITGA5,CCNB1,CD86 and CD40).The“heal.immune”gene set,as an OS risk factor,was further validated in Fudan cohort.We constructed a nomogram to predict the 1-,3-and 5-year overall survival(OS)in the TCGA cohort.The area under curve vales of the receiver characteristic operator curves were 0.82,0.76 and 0.73 in the training group and 0.84,0.76 and 0.72 in the test group.Conclusions:We established a prognostic nomogram based on the heal.immune gene signature,which includes six wound healing-and immunity-related genes.This nomogram accurately predicts the OS of HCC patients.

关键词： Hepatocellular carcinoma Bioinformatics Immune checkpoint Wound healing Prognosis

New strategies for asymmetric photocatalysis: asymmetric organocatalytic/photoredox relay catalysis for efficient synthesis of polycyclic compounds containing vicinal amino alcohols

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Science China Chemistry 2024年第3期67卷 945-952页

作者： Jia-Lu Zhang Wen-Bo He xiu-qin Hu Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical EngineeringLanzhou UniversityLanzhou 730000China State Key Laboratory of Veterinary Etiological Biology College of Veterinary MedicineLanzhou UniversityLanzhou Veterinary Research InstituteChinese Academy of Agricultural SciencesLanzhou 730000China MOE Frontiers Science Center for Rare Isotopes Lanzhou UniversityLanzhou 730000China

An asymmetric catalytic strategy in photocatalysis utilizing a chirality-induced approach through an organocatalytic/photoredox relay catalysis strategy is successfully achieved for the rapid construction of polycyclic compounds containing vicinal amino alcohols in a one-pot protocol. This methodology facilitates the efficient synthesis of diverse substituted polycyclic tetrahydroquinoline and benzofuran-derived vicinal amino alcohols, each containing five consecutive chiral centers, with high yields,excellent diastereoselectivities and enantioselectivities(up to 95% yield, >20:1 dr and 98% ee), under mild reaction conditions driven by sequential bifunctional squaramide organocatalyst-catalyzed [4+2] annulation and photocatalyst-catalyzed ketyl radical addition cyclization reaction process. Furthermore, investigations into the stereoselectivity mechanism and high-resolution mass spectrometry(HRMS) experiments on free radical trapping have provided evidence for elucidating the detailed mechanism of chirality-induced processes and chiral intermediate conversions in this procedure.

关键词： enantioselective photocatalysis asymmetric organocatalytic/photocatalysis relay catalysis five consecutive chiral centers chirality-induced strategy chirality vicinal amino alcohols

In situ meso-tetra(4-carboxyphenyl) porphyrin ligand substitution in Hf-MOF for enhanced catalytic activity and stability in photoredox reactions

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Rare Metals 2024年第6期43卷 2682-2694页

作者： Jie Hu Hong-Xin Lao xiu-Wu Xu Wei-Kang Wang Le-Le Wang qin-qin Liu School of Materials Science and Engineering Jiangsu University College of Chemistry and Materials Engineering Research Center of Carbon NeutralityAnhui Normal University Fujian Provincial Key Laboratory of Ecology-Toxicological Effects and Control for Emerging Contaminants Putian University

Though there are numerous intrinsic merits of metal-organic frameworks（MOFs）,low charge separation efficiency has imposed heavy restrictions on their photocatalytic application.Herein,in situ porphyrin ligand substitution,as a strategy for improving the charge separation efficiency and increasing the amounts of active sites,has been designed and realized in a Hf-biphenyl dicarboxylic acid（BPDC） MOF.Specifically,a size and geometry matched meso-tetra（4-carboxyphenyl） porphyrin（TCPP）ligand was selected and doped into Hf-BPDC MOF by forming coordinating bonds with Hf centers,forming dualligand Hf-BPDC-TCPP MOF.The resultant Hf-BPDC-TCPP MOF showed significantly improved activity and chemical stability in the photocatalytic H2generation(261 μmol·g-1·h-1) and tetracycline（TC） degradation reactions（95.8%）,which was 48 and 1.47 folds higher than that of the Hf-BPDC MOF.Photophysical and electrochemical studies revealed that the introduction of porphyrin ligand could generate a stronger internal electric field for boosting the charge separation and transfer,increase the specific surface area for providing more active sites,and narrow the band gap to enhance the visible light absorption.This in situ ligand substitution method provides a promising approach to build a tunable platform for constructing high-performance MOF photocatalysts.

关键词： Ligand substitution Metal organic frameworks Meso-tetra(4-carboxyphenyl) porphyrin Hydrogen evolution reaction Tetracycline degradation

Stereodivergent synthesis ofα-fluoroα-azaarylγ-butyrolactones via cooperative copper and iridium catalysis

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Fundamental Research 2024年第1期4卷 77-85页

作者： Kui Tian Xin Chang Lu Xiao xiu-qin Dong Chun-Jiang Wang College of Chemistry and Molecular Sciences Engineering Research Center of Organosilicon Compounds&MaterialsMinistry of EducationWuhan UniversityWuhan 430072China State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryShanghai 230021China Suzhou Institute of Wuhan University Suzhou 215123China

The development of stereodivergent synthetic methods to access all four stereoisomers of biologically importantα-fluoroγ-butyrolactones containing vicinal stereocenters is of great importance and poses a formidable challenge owing to ring strain and steric hindrance.Herein,a novel asymmetric[3+2]annulation ofα-fluoroα-azaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization,affording a variety of enantioenrichedα-fluoroγ-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity(up to 98%yield,generally>20:1 dr and>99%ee).Notably,all four stereoisomers of these pharmaceutically valuable molecules could be accessed individually via simple permutations of two enantiomeric catalysts.In addition,other azaaryl acetates bearingα-methyl,α-chlorine orα-phenyl group were tolerated well in this transformation.Reaction mechanistic investigations were conducted to explore the process of this bimetallic catalysis based on the results of reaction intermediates,isotopic labelling experiments,and kinetic studies.

关键词： Asymmetric catalysis α-Fluoroγ-butyrolactones Synergistic catalysis Cascade reaction Stereodivergent synthesis