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Molecular phenotypes reveal heterogeneous engraftments of patient-derived hepatocellular carcinoma xenografts

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Chinese Journal of Cancer Research 2021年第4期33卷 470-479页

作者： Jianyong Zhuo Di Lu Jianguo Wang Zhengxing Lian Jiali Zhang Huihui Li Beini Cen Xuyong Wei Qiang Wei haiyang xie Xiao Xu Department of Hepatobiliary and Pancreatic Surgery The Center for Integrated Oncology and Precision MedicineAffiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China National Health Commission Key Laboratory of Combined Multi-organ Transplantation Institute of Organ TransplantationZhejiang UniversityHangzhou 310003China

Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been ***:HCC tumor samples from 76 patients were implanted in immunodeficient *** molecular expression was evaluated by *** and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square *** independent prediction parameters were identified by logistic regression ***:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment *** with poor differentiation and vascular invasion were related to engraftment *** positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment *** regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX *** with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)***:Successful engraftment of HCC PDXs was significantly related to molecular *** with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.

关键词： Hepatocellular carcinoma patient-derived xenografts heterogeneous establishment molecular phenotype

Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening

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Bioactive Materials 2022年第12期7卷 164-177页

作者： Haijiang Dong Zequn Li Suchen Bian Guangyuan Song Wenfeng Song Mingqi Zhang haiyang xie Shusen Zheng Xuxu Yang Tiefeng Li Penghong Song Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineZhejiang ProvinceHangzhou310003China NHC Key Laboratory of Combined Multi-organ Transplantation Zhejiang ProvinceHangzhou310003China 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 Sciences(2019RU019)Zhejiang ProvinceHangzhou310003China Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesZhejiang ProvinceHangzhou310003China Department of Hepatopancreatobiliary Surgery and Minimally Invasive Surgery Zhejiang Provincial People’s Hospital(People’s Hospital of Hangzhou Medical College)Zhejiang ProvinceHangzhou310014China Center for X-Mechanics Department of Engineering MechanicsZhejiang UniversityZhejiang ProvinceHangzhou310007China Key Laboratory of Soft Machines and Smart Devices of Zhejiang Province Zhejiang ProvinceHangzhou310007China

A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug *** economical and high-efficiency simulation of the liver tumor microenvironment(TME)in a drug-screening model has high value yet challenging to ***,we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters,and the culture of patient-derived tumor organoids(PDTOs)for personalized pre-clinical drug *** hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in *** a result,18 of the 28 patient-derived multicellular clusters were successfully cultured as *** PDTOs,along with hepatocyte growth factor(HGF)of non-cellular components,preserve stromal cells,including cancer-associated fibroblasts(CAFs)and vascular endothelial cells(VECs).They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver ***,including cabazitaxel,oxaliplatin,and sorafenib,were tested in *** sensitivity of PDTOs to these drugs differs between *** sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging(MRI)and biochemical tests after oxaliplatin clinical treatment of the corresponding ***,this approach is promising for economical,accurate,and high-throughput drug screening for personalized treatment.

关键词： Multicellular clusters Hydrogel capsules Tumor microenvironment Tumor heterogeneity Patient-derived tumor organoids Personalized pre-clinical drug screening

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 *** family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many *** this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer ***: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 *** 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 *** methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and *** 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 ***-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using ***:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA ***2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver ***2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and ***/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with ***,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,***,EGFR was activated in liver cancer cells after sorafenib treatment,and SER

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

Severity of early allograft dysfunction following donation after circulatory death liver transplantation:a multicentre study

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Hepatobiliary Surgery and Nutrition 2021年第1期10卷 9-19页

作者： Kun Wang Di Lu Yuhui Liu Wangyao Li Li Zhuang Zhenyu Ma Qinfen xie Binhua Pan Yichao Wu Junli Chen Lidan Lin Xiaowen Feng Qiang Wei Xuyong Wei haiyang xie Zhengxin Wang Shusen Zheng Xiao Xu Department of Hepatobiliary and Pancreatic Surgery First Affiliated HospitalZhejiang University School of MedicineHangzhouChina Key Lab of Combined Multi-Organ Transplantation Ministry of Public HealthHangzhouChina Department of Surgery Dezhou People’s HospitalDezhouChina Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhouChina Department of General Surgery Huashan HospitalFudan UniversityShanghaiChina China Liver Transplant Registry HangzhouChina

Background:Early allograft dysfunction(EAD)is associated with decreased graft and patient survival *** study aimed to identify the severity of EAD and develop a predictive model for EAD after donation after circulatory death(DCD)liver transplantation(LT).Furthermore,the influence of operative time on EAD incidence was also ***:In this retrospective,multicentre cohort study,nomograms were established based on a single-centre training cohort(n=321)and validated in a 3-center validation cohort(n=501).Results:The incidence rate of EAD was 46.4%(149/321)in the training cohort and 40.5%(203/501)in the validation *** the 149 EAD patients in the training cohort,77 patients with either elevated alanine aminotransferase(ALT)or aspartate aminotransferase(AST)were classified as having EAD type A,and the rest of the EAD patients were classified as having EAD type *** with EAD type B had lower graft and patient survival rates than recipients with EAD type A(P=0.043 and 0.044,respectively).We further developed a nomogram to predict EAD(graft weight,cold ischemia time,donor age,model for end-stage liver disease(MELD)score)and another nomogram to predict EAD type B(graft weight,cold ischemia time,MELD score).The nomograms for the prediction of EAD and EAD type B had good discrimination[concordance index(C-index)=0.712(0.666-0.758),0.707(0.641-0.773)]and calibration[Hosmer-Lemeshow(HL)P=0.384,P=0.425]in the validation *** increased operative time(>6 h)was associated with increased EAD and EAD type B incidence in the high-risk group(P=0.005,P=0.020,respectively).Conclusions:EAD type B was associated with decreased graft and patient survival *** novel nomograms effectively predicted the incidence of EAD and EAD type B in DCD LT patients.

关键词： Liver transplantation donation after circulatory death early allograft dysfunction(EAD)

Down regulation of Glutathione peroxidase 3 is associated with graft non-function after liver transplantation

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Down regulation of Glutathione peroxidase 3 is associated wi...

档案学语境下直隶非物质文化遗产数字化保护与传播策略研究

2013年浙江省肠外肠内营养学学术年会

作者： Chunyang Xing haiyang xie Lin Zhou Shusen Zheng Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang University Key Laboratory of Combined Multi-organ Transplantation Ministry of Public Health

Body:Background:Arachidonic acid(AA) and its metabolic pathway have generated a heightened interest due to their significant role in primary graft non-function after liver transplantation(LT),but the mechanisms are far from *** purpose of this study was to identify whether there are genes in AA pathway that have similar expression changes after *** so,we would try to reveal the potential biological pathways of these genes by metaanalysis to find the underlying mechanisms of them their actions in LT.

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档案学研究 2018年第4期 97-101页

作者：谢海洋华北电力大学机械工程系

从区域文化而非单纯从局部或行政区划的视角研究直隶非物质文化遗产的保护问题,是在特定文化生态环境下对文化遗产进行整体化保护的积极思路。文章运用档案学前端控制理论和档案记忆观等思想,结合文化生态学、信息生态学和计算机科学等... 详细信息

从区域文化而非单纯从局部或行政区划的视角研究直隶非物质文化遗产的保护问题,是在特定文化生态环境下对文化遗产进行整体化保护的积极思路。文章运用档案学前端控制理论和档案记忆观等思想,结合文化生态学、信息生态学和计算机科学等学科相关理论和技术方法,从分类标准体系建设、数据库建设、基于GIS技术的直隶非物质文化遗产地理信息系统建设、基于Tag技术的直隶非物质文化遗产网上信息资源的组织与共享机制建设等几个方面,探讨了直隶非物质文化遗产的档案式保护和数字化传承与传播策略。这有助于提升文化认同感和区域文化软实力,从文化层面促进京津冀协同发展。

关键词：非物质文化遗产直隶文化区域文化地理信息系统社会标签

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脉冲消融在心房颤动治疗中的研究进展

武汉大学学报（医学版） 2023年第10期44卷 1199-1203页

作者：谢海扬谢双伦中山大学孙逸仙纪念医院广东广州510120

脉冲电场是近年来新兴的心脏导管消融能量源。相较射频和冷冻消融而言,脉冲电场消融具有快速且特异性损伤心肌的优势。脉冲消融应用前景广阔,将可能成为治疗心房颤动的一大利器。本文将综合近年国内外研究资料,介绍脉冲消融的基本原理... 详细信息

脉冲电场是近年来新兴的心脏导管消融能量源。相较射频和冷冻消融而言,脉冲电场消融具有快速且特异性损伤心肌的优势。脉冲消融应用前景广阔,将可能成为治疗心房颤动的一大利器。本文将综合近年国内外研究资料,介绍脉冲消融的基本原理、以及其在心脏消融治疗中的应用进展、优势和局限性。

关键词：脉冲消融心房颤动导管消融

Hepatic stellate cells promote immunotolerance following liver transplantation in rats via inducing T cells apoptosis and regulating cell cytokines

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Hepatic stellate cells promote immunotolerance following liv...

The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

2012中国器官移植大会

作者： Zhijun Jiang,Ying Chen,Xiaonin Feng,haiyang xie,Lin Zhou,Shusen Zheng 浙江大学医学院附属第一医院肝胆胰外科

【Background/Aims】Recently,the hepaticstellate cells(HSCs) have been demonstrated to have immune inhibitory activity. The aim of this study is to investigate the role of hepatic stellate cells in the development of immunotolerance after liver transplantation.【Methods】we established a rat livertransplantation model of tolerance(donor Lewis into recipient DA) andrejection(donor DA into recipient Lewis).On the 7th day aftertransplantation,the hepatic stellate cells and T cells were isolated from rats of either tolerance or rejection group and cultured together.24 hours later,the apoptosis rate of T cells was determined by flow

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Signal Transduction and Targeted Therapy 2024年第10期9卷 4614-4627页

作者： Qiaonan Shan Lu Yin Qifan Zhan Jiongjie Yu Sheng Pan Jianyong Zhuo Wei Zhou Jiaqi Bao Lincheng Zhang Jiachen Hong Jianan Xiang Qingyang Que Kangchen Chen Shengjun Xu Jingrui Wang Yangbo Zhu Bin He Jingbang Wu haiyang xie Shusen Zheng Tingting Feng Sunbin Ling Xiao Xu Department of Hepatobiliary and Pancreatic Surgery NHC Key Laboratory of Combined Multi-organ TransplantationThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310058China Department of Hepatobiliary and Pancreatic Surgery The Center for Integrated Oncology and Precision MedicineAffiliated Hangzhou First People’s HospitalSchool of MedicineWestlake UniversityHangzhou310006China Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital)School of Clinical MedicineHangzhou Medical CollegeHangzhou314408China Institute of Translational Medicine Zhejiang UniversityHangzhou310009China Zhejiang Cancer Hospital Hangzhou310022China

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently *** this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment *** established an HCC model of acquired *** counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC *** and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying ***-derived HCC models and HCC samples from patients were used to demonstrate clinical *** identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1α)pathway activation is responsible for acquired LR in *** non-muscle myosin heavy chain 9(MYH9)at Ser1943,p-MYH9(Ser1943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1αin lenvatinib-resistant ***,p-MYH9(Ser1943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in ***,the p-MYH9(Ser1943)/USP22/HIF-1αaxis is critical for LR and cancer *** the diagnosis and treatment of LR in HCC,p-MYH9(Ser1943),USP22,and HIF-1αmight be valuable as novel biomarkers and targets.

关键词： USP22 hepatocellular diagnosis