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Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease

Science China(Life Sciences) 2024年第6期67卷 1183-1198页

作者： Shiman Jiang Lvwan Xu Yanfei Chen Zheyue Shu Longxian Lv Yuxi Zhao Kefan Bi Sisi Yang Qiangqiang Wang Lanjuan Li State Key Laboratory for Diagnosis and Treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Division of hepatobiliary and pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Liver disease,a major health concern worldwide,is a serious and progressive disorder.Herein,we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut mycobiome.As liver disease advanced,gut integrity was disrupted,and the mycobiota was disturbed in the mouse models.The metabolites associated with hepatocellular carcinoma(HCC)differed from those associated with the cirrhotic phase as follows:levels of stercobilin and aflatoxin B1 dialcohol were reduced,while levels of triterpenoids,bafilomycin A1,and DHEA were increased in the HCC group.The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in HCC.Based on the results from clinical human samples,the genus Candida(Ascomycota)(in humans)and the genus Kazachstania(Ascomycota)(in mice)occupied a dominant position in the HCC group,while other fungi were depleted.The increased abundance of C.albicans and depletion of S.cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC.Moreover,the administration of C.albicans and S.cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC.Therefore,gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.

关键词： gut mycobiome liver disease longitudinal studies hepatocarcinogenesis fungal biomarker

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Recent advances in cancer-associated fibroblast:Biomarkers,signaling pathways,and therapeutic opportunities

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Chinese Medical Journal 2024年第6期137卷 638-650页

作者： Donger Zhou Lei Zheng Department of hepatobiliary-pancreatic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Sidney Kimmel Comprehensive Cancer center The Skip Viragh Pancreatic Cancer Center for Clinical Research and Careand The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of MedicineBaltimoreMD 21287USA

Anti-cancer therapies usually focus on tumor cells,but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression,which may be the prognostic factors and potential therapeutic targets.Cancer-associated fibroblasts(CAFs)are the essential component in the tumor environment,exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis,immune systems,and metabolism.Single-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity,and many subtypes have been defined.However,the precise functions of these subtypes need to be studied and validated.Studies of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic targets.Some clinical trials,including phase III trials targeting CAFs,have been performed recently.However,few of these trials have generated promising results,which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown,and in-depth investigations of CAFs should be performed.This review summarizes the research on CAFs,focusing on the heterogeneity of their phenotypes and functions,specific signaling pathways,and the therapeutic strategies involving CAFs.Additionally,we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.

关键词： Cancer-associated fibroblasts Tumor microenvironment Anti-cancer therapy Targeted therapy

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Imaging, pathology, and diagnosis of solitary fibrous tumor of the pancreas: A case report and review of literature

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World Journal of clinical Cases 2024年第5期12卷 995-1003页

作者： Wen-Wen Wang Shu-Ping Zhou Xiang Wu Luo-Luo Wang Yi Ruan Jun Lu Hai-Li Li Xu-Ling Ni Li-Li Qiu Xin-Hua Zhou Department of hepatobiliary and pancreatic Surgery The Affiliated Li Huili HospitalNingbo University School of MedicineNingbo 315000Zhejiang ProvinceChina Ningbo College of Health Sciences Ningbo College of Health SciencesNingbo 315000Zhejiang ProvinceChina Health Science center Ningbo UniversityNingbo 315000Zhejiang ProvinceChina Department of hepatobiliary and pancreatic Surgery The Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou310006Zhejiang ProvinceChina Department of Diagnosis Ningbo Diagnostic Pathology CenterNingbo 315000Zhejiang ProvinceChina

BACKGROUND A solitary fibrous tumor(SFT)is often located in the pleura,while SFT of the pancreas is extremely rare.Here,we report a case of SFT of the pancreas and discuss imaging,histopathology,and immunohistochemistry for accurate diagnosis and treatment.CASE SUMMARY A 54-year-old man presented to our hospital with pancreatic occupancy for over a month.There were no previous complaints of discomfort.His blood pressure was normal.Blood glucose,tumor markers,and enhanced computed tomography(CT)suggested a malignant tumor.Because the CT appearance of pancreatic cancer varies,we could not confirm the diagnosis;therefore,we performed endoscopic ultrasound-guided fine-needle biopsy(EUS-FNB).Pathology and immunohistochemistry were consistent with SFT of the pancreas.The posto-perative pathology and immunohistochemistry were consistent with the puncture results.The patient presented for a follow-up examination one month after discharge with no adverse effects.CONCLUSION Other diseases must be excluded in patients with a pancreatic mass that cannot be diagnosed.CT and pathological histology have diagnostic value for pancreatic tumors.Endoscopic puncture biopsy under ultrasound can help diagnose pancreatic masses that cannot be diagnosed preoperatively.Surgery is an effective treatment for SFT of the pancreas;however,long-term follow-up is strongly recommended because of the possibility of malignant transformation of the tumor.

关键词： Pancreas Neoplasm fibrous tumor Endoscopic ultrasound-guided fine-needle biopsy Treatment Case report

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SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation

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Cancer Communications 2024年第3期44卷 384-407页

作者： Shiyu Zhang Xing Jia Haojiang Dai Xingxin Zhu Wenfeng Song Suchen Bian Hao Wu Shinuo Chen Yangbo Tang Junran Chen Cheng Jin Mengqiao Zhou Haiyang Xie Shusen Zheng Penghong Song Division of hepatobiliary and pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China National Health Commission Key Laboratory of Combined Multi-organ Transplantation HangzhouZhejiangP.R.China Key Laboratory of the Diagnosis and Treatment of Organ Transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical SciencesHangzhouZhejiangP.R.China Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiangP.R.China State Key Laboratory for Diagnosis and Treatment of Infectious diseases First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China

Background:Liver cancer is a malignancy with high morbidity and mortality rates.Serpin family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many tumors.In this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.Methods:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver can-cer.Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of patients.DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells.RNA sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis.Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.Results:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA methylation.SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer.SERPINE2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and angiogenesis.IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with EGFR.Mechanistically,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,c-Cbl.Additionally,EGFR was activated in liver cancer cells after sorafenib treatment,and SER-PINE2 knockdown-induced EGFR downregulation sig

关键词： liver cancer metastasis DNA methylation SERPINE2 EGFR c-Cbl ubiquitination

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clinical review and literature analysis of hepatic epithelioid angiomyolipoma in alcoholic cirrhosis: A case report

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World Journal of clinical Cases 2024年第14期12卷 2382-2388页

作者： Jing-Qiang Guo Jia-Hui Zhou Kun Zhang Xin-Liang Lv Chao-Yong Tu Department of hepatobiliary and pancreatic Surgery Lishui Municipal Central HospitalLishui 323000Zhejiang ProvinceChina Department of Pathology Lishui Municipal Central HospitalLishui 323000Zhejiang ProvinceChina Department of General Surgery The Fifth Affiliated Hospital of Wenzhou Medical UniversityLishui 323000Zhejiang ProvinceChina

BACKGROUND Hepatic epithelioid angiomyolipoma(HEA)has a low incidence and both clinical manifestations and imaging lack specificity.Thus,it is easy to misdiagnose HEA as other tumors of the liver,especially in the presence of liver diseases such as hepatitis cirrhosis.This article reviewed the diagnosis and treatment of a patient with HEA and alcoholic cirrhosis,and analyzed the literature,in order to improve the understanding of this disease.CASE SUMMARY A 67-year-old male patient with a history of alcoholic cirrhosis was admitted due to the discovery of a space-occupying lesion in the liver.Based on the patient’s history,laboratory examinations,and imaging examinations,a malignant liver tumor was considered and laparoscopic partial hepatectomy was performed.Postoperative pathology showed HEA.During outpatient follow-up,the patient showed no sign of recurrence.CONCLUSION HEA is difficult to make a definite diagnosis before surgery.HEA has the poten-tial for malignant degeneration.If conditions permit,surgical treatment is recom-mended.

关键词： Hepatic epithelioid angiomyolipoma Alcoholic cirrhosis Magnetic resonance imaging Computed tomography Immunohistochemistry Misdiagnose analysis Case report

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Predicting the prognosis of hepatic arterial infusion chemotherapy in hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2380-2393页

作者： Qi-Feng Wang Zong-Wei Li Hai-Feng Zhou Kun-Zhong Zhu Ya-Jing Wang Ya-Qin Wang Yue-Wei Zhang Department of hepatobiliary pancreatic center Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua UniversityBeijing 102218China Department of hepatobiliary and pancreatic Surgery Qinghai University Affiliated HospitalXining 810000Qinghai ProvinceChina

Hepatic artery infusion chemotherapy(HAIC)has good clinical efficacy in the treatment of advanced hepatocellular carcinoma(HCC);however,its efficacy varies.This review summarized the ability of various markers to predict the efficacy of HAIC and provided a reference for clinical applications.As of October 25,2023,51 articles have been retrieved based on keyword predictions and HAIC.Sixteen eligible articles were selected for inclusion in this study.Comprehensive literature analysis found that methods used to predict the efficacy of HAIC include serological testing,gene testing,and imaging testing.The above indicators and their combined forms showed excellent predictive effects in retrospective studies.This review summarized the strategies currently used to predict the efficacy of HAIC in middle and advanced HCC,analyzed each marker's ability to predict HAIC efficacy,and provided a reference for the clinical application of the prediction system.

关键词： Hepatocellular carcinoma Hepatic artery infusion chemotherapy Prediction Prognosis Imaging Biomarkers Genomics

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Pre-MASLD:Should it be defined separately?

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hepatobiliary & pancreatic diseases International 2024年第1期23卷 1-3页

作者： Hang-Kai Huang You-Ming Li Cheng-Fu Xu Department of Gastroenterology Zhejiang Provincial Clinical Research Center for Digestive Diseasesthe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases,yet it has not received sufficient attention[1].Over the past two decades,the overall global prevalence of NAFLD has risen from 25%to 37%[2].The disease burden of NAFLD is fueled by the epidemic of obesity and diabetes[3].It is estimated that more than half of patients with diabetes have NAFLD.

关键词： NAFLD liver diseases

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A prognostic four-gene signature and a therapeutic strategy for hepatocellular carcinoma:Construction and analysis of a circRNA-mediated competing endogenous RNA network

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hepatobiliary & pancreatic diseases International 2024年第3期23卷 272-287页

作者： Hai-Yan Zhang Jia-Jie Zhu Zong-Ming Liu Yu-Xuan Zhang Jia-Jia Chen Ke-Da Chen zhejiang Chinese Medical University Hangzhou 310053China Shulan International Medical College Zhejiang Shuren UniversityHangzhou 310015China State Key Laboratory for Diagnosis and Treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China

Background:Hepatocellular carcinoma(HCC)has a poor long-term prognosis.The competition of circular RNAs(circRNAs)with endogenous RNA is a novel tool for predicting HCC prognosis.Based on the alterations of circRNA regulatory networks,the analysis of gene modules related to HCC is feasible.Methods:Multiple expression datasets and RNA element targeting prediction tools were used to construct a circRNA-microRNA-mRNA network in HCC.Gene function,pathway,and protein interaction analyses were performed for the differentially expressed genes(DEGs)in this regulatory network.In the proteinprotein interaction network,hub genes were identified and subjected to regression analysis,producing an optimized four-gene signature for prognostic risk stratification in HCC patients.Anti-HCC drugs were excavated by assessing the DEGs between the low-and high-risk groups.A circRNA-microRNA-hub gene subnetwork was constructed,in which three hallmark genes,KIF4A,CCNA2,and PBK,were subjected to functional enrichment analysis.Results:A four-gene signature(KIF4A,CCNA2,PBK,and ZWINT)that effectively estimated the overall survival and aided in prognostic risk assessment in the The Cancer Genome Atlas(TCGA)cohort and International Cancer Genome Consortium(ICGC)cohort was developed.CDK inhibitors,PI3K inhibitors,HDAC inhibitors,and EGFR inhibitors were predicted as four potential mechanisms of drug action(MOA)in high-risk HCC patients.Subsequent analysis has revealed that PBK,CCNA2,and KIF4A play a crucial role in regulating the tumor microenvironment by promoting immune cell invasion,regulating microsatellite instability(MSI),and exerting an impact on HCC progression.Conclusions:The present study highlights the role of the circRNA-related regulatory network,identifies a four-gene prognostic signature and biomarkers,and further identifies novel therapy for HCC.

关键词： Hepatocellular carcinoma circRNA-related ceRNA network Biomarker Least absolute shrinkage and selection operator Bioinformatics

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FGF21-mediated autophagy:Remodeling the homeostasis in response to stress in liver diseases

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Genes & diseases 2024年第3期11卷 264-274页

作者： Wei Shen Modan Yang Hao Chen Chiy He Huigang Li Xinyu Yang Jianyong Zhuo Zuyuan Lin Zhihang Hu Di Lu Xiao Xu zhejiang University School of Medicine HangzhouZhejiang 310058China Key Laboratory of Integrated Oncology and Intelligent Medicine of zhejiang province Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouZhejiang 310006China The Institute for Organ Repair and Regenerative Medicine of Hangzhou HangzhouZhejiang 310006China Institute of Organ Transplantation Zhejiang UniversityHangzhouZhejiang 310003China National center for Healthcare Quality Management in Liver Transplant HangzhouZhejiang 310003China

Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum stress.The exact interplay between stress and liver diseases remains unclear.Autophagy plays an essential role in maintaining homeostasis,and recent studies indicate tight crosstalk between stress and autophagy in liver diseases.Once the bal-ance between damage and autophagy is broken,autophagy can no longer resist injury or main-tain homeostasis.In recent years,FGF21(fibroblast growth factor 21)-induced autophagy has attracted much attention.FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress.Also,increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role.This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.

关键词： Autophagy Fibroblast growth factor 21 Liver diseases mTOR Stress

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Metal nanoparticles for cancer therapy:Precision targeting of DNA damage

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1132-1149页

作者： Qian Chen Chunyan Fang Fan Xia Qiyue Wang Fangyuan Li Daishun Ling Institute of Pharmaceutics Hangzhou Institute of Innovative MedicineCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Frontiers Science center for Transformative Molecules School of Chemistry and Chemical EngineeringNational Center for Translational MedicineShanghai Jiao Tong UniversityShanghai 200240China World Laureates Association(WLA)Laboratories Shanghai 201203China Key Laboratory of Precision Diagnosis and Treatment for hepatobiliary and pancreatic Tumor of zhejiang province Hangzhou 310009China

Cancer,a complex and heterogeneous disease,arises from genomic instability.Currently,DNA damage-based cancer treatments,including radiotherapy and chemotherapy,are employed in clinical practice.However,the efficacy and safety of these therapies are constrained by various factors,limiting their ability to meet current clinical demands.Metal nanoparticles present promising avenues for enhancing each critical aspect of DNA damage-based cancer therapy.Their customizable physicochemical properties enable the development of targeted and personalized treatment platforms.In this review,we delve into the design principles and optimization strategies of metal nanoparticles.We shed light on the limitations of DNA damage-based therapy while highlighting the diverse strategies made possible by metal nanoparticles.These encompass targeted drug delivery,inhibition of DNA repair mechanisms,induction of cell death,and the cascading immune response.Moreover,we explore the pivotal role of physicochemical factors such as nanoparticle size,stimuli-responsiveness,and surface modification in shaping metal nanoparticle platforms.Finally,we present insights into the challenges and future directions of metal nanoparticles in advancing DNA damage-based cancer therapy,paving the way for novel treatment paradigms.

关键词： DNA damage Metal nanoparticles Nucleus-targeting DNA repair inhibition Immune response Size optimization Stimuli-responsiveness Surface modification

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