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Fibroblast growth factor 21(FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB(TFEB)-regulated lipophagy

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Journal of zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第6期24卷 485-495页

作者： Zhensheng ZHANG Li XU Xun QIU Xinyu YANG Zhengxing LIAN Xuyong WEI Di LU Xiao XU zhejiang University School of medicine Hangzhou 310058China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Hangzhou 310006China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Institute of Organ Transplantation Zhejiang UniversityHangzhou 310003China NHC key laboratory of Combined Multi-organ Transplantation Hangzhou 310003China Westlake laboratory of Life Sciences and Biomedicine Hangzhou 310024China

Tacrolimus(TAC),also called FK506,is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation.However,it has been proved to be associated with post-transplant hyperlipemia.The mechanism behind this is unknown,and it is urgent to explore preventive strategies for hyperlipemia after transplantation.Therefore,we established a hyperlipemia mouse model to investigate the mechanism,by injecting TAC intraperitoneally for eight weeks.After TAC treatment,the mice developed hyperlipemia(manifested as elevated triglyceride(TG)and low-density lipoprotein cholesterol(LDL-c),as well as decreased high-density lipoprotein cholesterol(HDL-c)).Accumulation of lipid droplets was observed in the liver.In addition to lipid accumulation,TAC induced inhibition of the autophagy-lysosome pathway(microtubule-associated protein 1light chain 3β(LC3B)II/I and LC3B II/actin ratios,transcription factor EB(TFEB),protein 62(P62),and lysosomal-associated membrane protein 1(LAMP1))and downregulation of fibroblast growth factor 21(FGF21)in vivo.Overexpression of FGF21may reverse TAC-induced TG accumulation.In this mouse model,the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway.We conclude that TAC downregulates FGF21and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway.Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.

关键词： Autophagy Fibroblast growth factor 21(FGF21) Lipid Lipophagy Lysosome Tacrolimus Transcription factor EB(TFEB)

The difficulty of medical decision-making:should patients be involved?

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Hepatobiliary Surgery and Nutrition 2023年第3期12卷 407-409页

作者： Junbin Zhou Xiao Xu zhejiang University School of medicine HangzhouChina Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province HangzhouChina Institute of Organ Transplantation Zhejiang UniversityHangzhouChina

Introduction The success or failure of treatment has long been attributed to the doctors alone,but the role of patients in the medical decision-making(MDM)process has often been ignored.As medical development and health needs increase,the desire of patients to participate in MDM continues to grow.This raises the question:should patients be involved in such a highly professional medical activity?How can their involvement bring better clinical benefits?

关键词： Communication decision making patient participation physician-patient relations

RNA binding protein-based risk score model for prognosis prediction of patients with hepatocellular carcinoma

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Chinese Medical Journal 2022年第23期135卷 2890-2892页

作者： Shengjun Xu Ning Ding Sheng Zheng Jun Chen Yafeng Wan Sunbin Ling Xiao Xu 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 Department of Gastroenterology The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China Institute of Organ Transplantation Zhejiang UniversityHangzhouZhejiang 310003China

To the Editor:Liver cancer is estimated to be the sixth most lethal tumor,representing approximately 5.0%of all cancer-related deaths.[1]Mainly due to the high rate of infection with hepatitis B virus,liver cancer remains a serious health concern in China,severely limiting the extension of human life expectancy.In China,the number of new cases and deaths from liver cancer is projected to exceed 400,000 in 2022.[2]Hepatocellular carcinoma(HCC)is the major histological type of liver cancer and is a complex and highly heterogeneous disease.Due to the lack of early symptoms,patients with HCC are usually diagnosed at an advanced stage,thus losing the opportunity for surgical resection or liver transplantation.Tumor recurrence and metastasis are major bafflements that limit the efficiency of surgical therapeutics.It is urgent to explore the molecular mechanism of HCC to develop effective methods for early diagnosis and identify patients at high risk of tumor recurrence and metastasis.

关键词： patients diagnosis prediction

Visual analysis of mesenchymal stem cell research in liver disease based on bibliometrics

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iLIVER 2022年第4期1卷 283-291页

作者： Chengzuo Han Rui Wang Nan Xu Xuyong Wei Qiang Wei Xiao Xu 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 MedicineHangzhou310006China Westlake laboratory of Life Sciences and Biomedicine Hangzhou310024China

The research of mesenchymal stem cells(MSCs)in the field of liver diseases has received more and more attention.This paper introduces the current situation,hot spots,and development trends in this field.Compre-hensive searches were conducted using Web of Science Core Collection from January 1,2000 to December 13,2021 with the following keywords:TS(topic)¼(liver*OR hepatic*OR hepatocyte)AND TS(topic)¼(Mesen-chymal stem cell*).VOSviewer(version 1.6.16)and CiteSpace V are used as bibliometric tools to analyze and visualize the knowledge graph.A total of 4452 papers were included in this study,and the number of research papers on MSCs in the field of liver diseases increased from January 2000 to December 2020.Eighty-four countries and regions have published articles on research in this field,among which China and the United States are the main two countries of publication.Based on the keyword burst detection,we find that the research in this field has shifted from basic research to clinical application,from medical research to interdisciplinary research.Tissue engineering and regenerative medicine are the frontier fields of MSCs research in liver diseases.Multicountry,multi-author cooperation,and multi-disciplinary intersection are the research trends in this field.Exocrine body,obesity,and tissue engineering are the hotspots in this field.

关键词： Mesenchymal stem cells Liver disease Bibliometrics Visualization

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

Double-negative T cells:a promising avenue of adoptive cell therapy in transplant oncology

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Journal of zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第5期24卷 387-396页

作者： Zhihang HU Modan YANG Hao CHEN Chiyu HE Zuyuan LIN Xinyu YANG Huigang LI Wei SHEN Di LU Xiao XU zhejiang University School of medicine Hangzhou 310058China Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou 310006China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Hangzhou 310006China Institute of Organ Transplantation Zhejiang UniversityHangzhou 310003China NHC key laboratory of Combined Multi-organ Transplantation Hangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhou 310004China

Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer.In addition to the common mechanisms underlying tumor recurrence,another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis.Transplant oncology is an emerging field that addresses oncological challenges in transplantation.In this context,a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients.Double-negative T cells(DNTs)are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor(TCR)type.Among them,TCRαβ^(+)DNTs are considered to induce immune suppression in immune-mediated diseases,while TCRγδ^(+)DNTs are widely recognized as tumor killers.As a composite cell therapy,healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host.In this work,we summarized the biological characteristics and functions of DNTs in oncology,immunology,and transplantation.Based on the multiple roles of DNTs,we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy(ACT).

关键词： Double-negative T cell(DNT) Adoptive cell therapy(ACT) Liver cancer Liver transplantation oncology

Role of surgical treatments in high-grade or advanced gastroenteropancreatic neuroendocrine neoplasms

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World Journal of Gastrointestinal Surgery 2022年第5期14卷 397-408页

作者： Qing-Yang Que Lin-Cheng Zhang Jia-Qi Bao Sun-Bin Ling Xiao Xu Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Hangzhou 310006Zhejiang ProvinceChina zhejiang University Cancer Center Hangzhou 310006Zhejiang ProvinceChina NHC key laboratory of Combined Multi-organ Transplantation Hangzhou 310006Zhejiang ProvinceChina Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou 310006Zhejiang ProvinceChina Institute of Organ Transplantation Zhejiang UniversityHangzhou 310003Zhejiang ProvinceChina

Over the last 40 years,the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have continued to increase.Compared to other epithelial neoplasms in the same organ,GEP-NENs exhibit indolent biological behavior,resulting in more chances to undergo surgery.However,the role of surgery in high-grade or advanced GEP-NENs is still controversial.Surgery is associated with survival improvement of well-differentiated highgrade GEP-NENs,whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers.Additionally,surgery also plays an important role in locally advanced and metastatic disease.For locally advanced GEP-NENs,isolated major vascular involvement is no longer an absolute contraindication.In the setting of metastatic GEP-NENs,radical intended surgery is recommended for patients with low-grade and resectable metastases.For unresectable metastatic disease,a variety of surgical approaches,including cytoreduction of liver metastasis,liver transplantation,and surgery after neoadjuvant treatment,show survival benefits.Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control,prolonged survival,and improved sensitivity toward systemic therapies.Although there is no established neoadjuvant or adjuvant strategy,increasing attention has been given to this emerging research area.Some studies have reported that neoadjuvant therapy effectively reduces tumor burden,improves the effectiveness of subsequent surgery,and decreases surgical complications.

关键词： Gastroenteropancreatic neuroendocrine neoplasms Neuroendocrine carcinomas Surgery Hepatic debulking Liver transplant Transplant oncology

LncFASA promotes cancer ferroptosis via modulating PRDX1 phase separation

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Science China(Life Sciences) 2024年第3期67卷 488-503页

作者： Xiao Fan Fangzhou Liu Xiang Wang Ying Wang Yu Chen Chengyu Shi Xinwan Su Manman Tan Qingfeng Yan Jinrong Peng Jianzhong Shao Yan Xiong Aifu Lin MOE laboratory of Biosystem Homeostasis and Protection College of Life SciencesZhejiang UniversityHangzhou 310058China key laboratoryof Cancer Prevention and Intervention China National Ministry of EducationHangzhou 310009China Cancer Center Zhejiang UniversityHangzhou 310058China key laboratory for Cell and Gene Engineering of zhejiang province Hangzhou 310058China Department of Central laboratory the First People's Hospital of HuzhouHuzhou 313000China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Affiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou 310006China MOE key laboratory for Molecular Animal Nutrition College of Animal SciencesZhejiang UniversityHangzhou 310058China Department of Orthopedic Surgery the Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310000China Breast Center of the First Affiliated Hospital School of MedicineZhejiang UniversityHangzhou 310003China International School of medicine International Institutes of MedicineThe 4th Affiliated Hospital of Zhejiang University School of MedicineYiwu 322000China

Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA(lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer(TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1(PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.

关键词： long non-coding RNA peroxiredoxin liquid-liquid phase separation ferroptosis breast cancer

Applications of neural networks in liver transplantation

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iLIVER 2022年第2期1卷 101-110页

作者： Jinwen Meng Zhikun Liu Xiao Xu 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 MedicineHangzhou310006China Westlake laboratory of Life Sciences and Biomedicine Hangzhou310024China NHC key laboratory of Combined Multi-organ Transplantation Hangzhou310003China Institute of Organ Transplantation Zhejiang UniversityHangzhou310003China

The use of neural networks(NNs)as a cutting-edge technique in the medical field has drawn considerable attention.NN models“learn”from a large amount of data and then find corresponding clinical patterns that are challenging for clinicians to recognize.In this study,we focus on liver transplantation(LT),which is an effective treatment for end-stage liver diseases.The management before and after LT produces a massive quantity of medical data,which can be fully processed by NNs.We describe recent progress in the clinical application of NNs to LT in five respects:pre-transplantation evaluation of the donor and recipient,recipient outcome prediction,allocation system development,operation monitoring,and post-transplantation complication prediction.This review provides clinicians and researchers with a description of forefront applications of NNs in the field of LT and discusses prospects and pitfalls.

关键词： Artificial intelligence Liver transplantation Machine learning Neural network Deep learning