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targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted therapy 2024年第1期9卷 105-149页

作者： Yumin Wang Jing Hu Shuang Wu Joshua S.Fleishman Yulin Li Yinshi Xu Wailong Zou Jinhua Wang Yukuan Feng Jichao Chen Hongquan Wang Department of Respiratory and Critical Care Medicine Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Department of Pathogen Biology School of Basic Medical SciencesTianjin Medical UniversityTianjin 300060PR China Department of Neurology Zhongnan Hospital of Wuhan UniversityWuhan 430000PR China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Department of Outpatient Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Beijing key laboratory of Drug Target and Screening Research Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050PR China Department of Pancreatic cancer Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060PR China

Ferroptosis,a unique modality of cell death with mechanistic and morphological differences from other cell death modes,plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug *** epigenetic modifications and posttranslational modifications(PTMs)promote anticancer drug resistance,cancer progression,and *** studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases(NSDs),cardiovascular diseases(CVDs),liver diseases,lung diseases,and kidney *** this review,we first summarize the core molecular mechanisms of ***,the roles of epigenetic processes,including histone PTMs,DNA methylation,and noncoding RNA regulation and PTMs,such as phosphorylation,ubiquitination,SUMOylation,acetylation,methylation,and ADP-ribosylation,are concisely *** roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases,including cancers,NSD,CVDs,liver diseases,lung diseases,and kidney diseases,as well as the application of epigenetic and PTM modulators in the therapy of these diseases,are then discussed in *** the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other *** addition,these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

关键词： diseases epigenetic overcome

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Distinct Immune Signatures in Peripheral Blood Predict Chemosensitivity in Intrahepatic Cholangiocarcinoma Patients

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Engineering 2021年第10期7卷 1381-1392页

作者： Tong Wu Ying-Cheng Yang Bo Zheng Xue-Bing Shi Wei Li Wen-Cong Ma Shan Wang Zhi-Xuan Li Yan-Jing Zhu Jian-Min Wu Kai-Ting Wang Yan Zhao Rui Wu Cheng-Jun Sui Si-Yun Shen Xuan Wu Lei Chen Zhen-Gang Yuan Hong-Yang Wang International Cooperation laboratory on Signal Transduction&key laboratory of signaling regulation and targeting therapy of liver cancer Ministry of Education&Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China National Center for liver cancer Shanghai 201805China Department of Hepatobiliary Surgery Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China Fudan University Shanghai cancer Center Shanghai 200032China Institute of Metabolism and Integrative Biology Fudan UniversityShanghai 200433China Department of laboratory Medicine The Tenth People’s Hospital of ShanghaiTongji UniversityShanghai 200072China key laboratory of signaling regulation and targeting therapy of liver cancer Ministry of EducationShanghai 200438China Department of Oncology Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China

Intrahepatic cholangiocarcinoma(ICC)is the second most common liver *** remains the main therapeutic strategy for advanced ICC patients,but chemosensitivity varies ***,we applied cytometry by time-of-flight(CyTOF)to establish the immune profile of peripheral blood mononuclear cells(PBMCs)on the single-cell level at indicated time points before,during,and after *** immunofluorescence staining was applied to examine the spatial distribution of certain immune *** microarrays(TMAs)were used for prognostic evaluation.A total of 20 ICC patients treated with gemcitabine(GEM)were enrolled in our study,including eight cases with good response(R)and 12 cases with non-response(NR).Tremendous changes in PBMC composition,including an increased level of CD4/CD8 double-positive T cells(DPT),were observed after *** with higher level of CD4^(+)CD45RO^(+)CXCR3^(+)T cells before treatment had a favorable response to *** study identified a positive correlation between the percentage of T cell subpopulations and clinical response after chemotherapy,which suggests that it is practical to predict the potential response before treatment by evaluating the proportions of the cell population in PBMCs.

关键词： Intrahepatic cholangiocarcinoma Gemcitabine Chemosensitivity Peripheral blood mononuclear cells

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Pan-cancer analysis of ORAI family proteins and their genomic alterations

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Medical Data Mining 2024年第4期7卷 41-49页

作者： Zhan-Bo Wu Wen-Shuai Zhang Dan-Yang Ren Xin Li Department of cancer Immunotherapy Tianjin Cancer Hospital Airport HospitalTianjin 300308China Tianjin Medical University cancer Institute and Hospital National Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin’s Clinical Research Center for CancerTianjin 300060China Department of Pathology Tianjin Cancer Hospital Airport HospitalTianjin 300308China

Background:The ORAI family of proteins,comprising ORAI1,ORAI2,and ORAI3,plays a crucial role in the regulation of intracellular calcium signaling,which is essential for various cellular functions including proliferation,differentiation,and *** of calcium signaling has been implicated in cancer pathogenesis,influencing tumor progression,metastasis,and resistance to *** study aims to provide a comprehensive analysis of the ORAI family members across a broad spectrum of ***:Publicly available datasets from The cancer Genome Atlas and the Gene Expression Omnibus were *** sequencing data,mutation profiles,copy number variation data,and methylation data across different cancer types were *** expression analysis,survival analysis,copy number variation analysis,mutation analysis,methylation analysis,immune cell infiltration analysis using the Cibersort algorithm,and gene set enrichment analysis were conducted using R ***:ORAI1 and ORAI3 were significantly upregulated in glioblastoma multiforme,whereas ORAI2 was notably downregulated in kidney chromophobe and pancreatic ***2 exhibited higher mutation rates and copy number gains in multiple cancers compared to ORAI1 and *** hypermethylation of ORAI2 in head and neck squamous cell carcinoma,esophageal carcinoma,and glioblastoma multiforme negatively correlated with its gene ***1 and ORAI3 expression positively correlated with regulatory T cells infiltration,whereas ORAI2 showed a negative correlation with CD8^(+)T cell *** set enrichment analysis revealed that ORAI1 and ORAI2 are associated with immune-related pathways,while ORAI3 is linked to MYC targets and oxidative ***:Our pan-cancer analysis reveals significant differential expression,genomic alterations,and epigenetic regulation of ORAI family members across various ***1 and ORAI3 appear to promote an immunosuppr

关键词： ORAI family calcium signaling cancer progression immune cell infiltration gene expression

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A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

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Acta Pharmaceutica Sinica B 2024年第1期14卷 223-240页

作者： Lei Sun Arabella H.Wan Shijia Yan Ruonian Liu Jiarui Li Zhuolong Zhou Ruirui Wu Dongshi Chen Xianzhang Bu Jingxing Ou Kai Li Xiongbin Lu Guohui Wan Zunfu Ke Department of Pathology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China National-Local Joint Engineering laboratory of Druggability and New Drug Evaluation National Engineering Research Center for New Drug and Druggability(Cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA Department of Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Department of Hepatic Surgery and liver Transplantation Center Third Affiliated HospitalOrgan Transplantation InstituteSun Yat-sen UniversityOrgan Transplantation Research Center of Guangdong ProvinceGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhou 510630China Guangdong Provincial key laboratory of liver Disease Research Guangzhou 510630China Department of Ultrasound Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Melvin and Bren Simon Comprehensive cancer Center Indiana UniversityIndianapolisIN 46202USA

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug ***,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant *** and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing *** screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO ***,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX ***,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

关键词： Lenvatinib Drug resistance High-throughput screening Drug discovery Patient-derived model Romidepsin EGFR liver cancer

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Regulatory role of electroacupuncture on satellite glial cell activity in the colon and dorsal root ganglion of rats with irritable bowel syndrome

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Journal of Traditional Chinese Medicine 2024年第5期44卷 981-990页

作者： ZHANG Fang YAN Cuina WENG Zhijun WU Luyi QI Li ZHAO Min XIN Yuhu WU Huangan LIU Huirong key laboratory of Acupuncture and Immunological Effects Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese Medicine Shanghai Research Institute of Acupuncture and Meridian Shanghai University of Traditional Chinese Medicine cancer Hospital Fudan University

OBJECTIVE: To investigate the role of satellite glial cells in irritable bowel syndrome(IBS) and the effect of electroacupuncture(EA) at the Tianshu(ST25) and Shangjuxu(ST37) combination. METHODS: A model for visceral hypersensitivity in IBS was induced through colorectal distension(CRD) stimulation. Clean-grade male Sprague-Dawley(SD) rats were randomly divided into four groups: a normal group(NG), a model group(MG), an electroacupuncture group(EA), and a glial cell inhibitor group(FCA). Bilateral EA(2/100 Hz, 1 mA, 30 min) was administered at the Tianshu(ST25) and Shangjuxu(ST37) in week 6. Abdominal withdrawal reflex(AWR) scores were used to assess the behavioral response associated with visceral hyperalgesia, while hematoxylin-eosin staining was employed to evaluate pathological changes in the colon. The protein and mRNA levels of glial fibrillary acidic protein(GFAP) in the colon and colon-related dorsal root ganglion(DRG) were analyzed using immun-ofluorescence, immunohistochemistry, Western blotting, real-time polymerase chain reaction. The impact of EA on electrophysiological properties of colon-related DRG neurons was observed through whole-cell patch clamp analysis. RESULTS: EA significantly reduced the visceral pain behavior scores in rats with IBS in response to graded(20, 40, 60, 80 mm Hg) CRD stimulation. Additionally, EA downregulated the protein and mRNA expression levels of GFAP in the colon and colon-related DRG of rats with IBS. EA also regulated the resting membrane potential, rheobase and action potential of colon-related DRG neurons in rats with IBS. CONCLUSIONS: EA can regulate the excitatory properties of colon-related DRG neurons by downregulating the protein and mRNA expression of GFAP in the colon and colon-related DRG, indicating a potential neurobiological mechanism by which EA relieves visceral hypersensitivity in rats with IBS.

关键词： electroacupuncture glial fibrillary acidic proteinSupporting information irritable bowel syndrome satellite glial cell visceral hypersensitivity

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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 *** 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

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Comprehensive analysis of the potential pathogenesis of COVID-19 infection and liver cancer

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 436-457页

作者： Yao Rong Ming-Zheng Tang Song-Hua Liu Xiao-Feng Li Hui Cai First Clinical Medical College Gansu University of Chinese MedicineLanzhou 730000Gansu ProvinceChina General Surgery Clinical Medical Center Gansu Provincial HospitalLanzhou 730000Gansu ProvinceChina key laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province Gansu Provincial HospitalLanzhou 730000Gansu ProvinceChina NHC key laboratory of Diagnosis and therapy of Gastrointestinal Tumor Gansu Provincial HospitalLanzhou 730000Gansu ProvinceChina

BACKGROUND A growing number of clinical examples suggest that coronavirus disease 2019(COVID-19)appears to have an impact on the treatment of patients with liver cancer compared to the normal population,and the prevalence of COVID-19 is significantly higher in patients with liver ***,this mechanism of action has not been *** sets for COVID-19(GSE180226)and liver cancer(GSE87630)were obtained from the Gene Expression Omnibus *** identifying the common differentially expressed genes(DEGs)of COVID-19 and liver cancer,functional enrichment analysis,protein-protein interaction network construction and scree-ning and analysis of hub genes were ***,the validation of the differential expression of hub genes in the disease was performed and the regulatory network of transcription factors and hub genes was *** Of 518 common DEGs were obtained by screening for functional *** hub genes including aurora kinase B,cyclin B2,cell division cycle 20,cell division cycle associated 8,nucleolar and spindle associated protein 1,etc.,were further identified from DEGs using the“cytoHubba”*** enrichment analysis of hub genes showed that these hub genes are associated with P53 signalling pathway regulation,cell cycle and other functions,and they may serve as potential molecular markers for COVID-19 and liver ***,we selected 10 of the hub genes for in vitro expression validation in liver cancer *** Our study reveals a common pathogenesis of liver cancer and *** common pathways and key genes may provide new ideas for further mechanistic studies.

关键词： COVID-19 liver cancer Differentially expressed genes Hub genes Pathogenesis

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Analysis of the potential biological value of pyruvate dehydrogenase E1 subunitβin human cancer

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World Journal of Gastrointestinal Oncology 2024年第1期16卷 144-181页

作者： Yao Rong Song-Hua Liu Ming-Zheng Tang Zhi-Hang Wu Guo-Rong Ma Xiao-Feng Li Hui Cai First Clinical Medical College Gansu University of Chinese MedicineLanzhou 730000Gansu ProvinceChina General Surgery Clinical Medical Center Gansu Provincial HospitalLanzhou 730000Gansu ProvinceChina key laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province Gansu Provincial HospitalLanzhou 730000Gansu ProvinceChina NHC key laboratory of Diagnosis and therapy of Gastrointestinal Tumor Gansu Provincial HospitalLanzhou 730000Gansu ProvinceChina

BACKGROUND The pyruvate dehydrogenase E1 subunitβ(PDHB)gene which regulates energy metabolism is located in ***,few studies have elucidated the role and mechanism of PDHB in different *** To comprehensive pan-cancer analysis of PDHB was performed based on bioinformatics approaches to explore its tumor diagnostic and prognostic value and tumor immune relevance in *** vitro experiments were performed to examine the biological regulation of PDHB in liver *** Pan-cancer data related to PDHB were obtained from the cancer Genome Atlas(TCGA)*** of the gene expression profiles of PDHB was based on TCGA and Genotype Tissue Expression Dataset *** regression analysis and Kaplan-Meier methods were used to assess the correlation between PDHB expression and survival prognosis in cancer *** correlation between PDHB and receiver operating characteristic diagnostic curve,clinicopathological staging,somatic mutation,tumor mutation burden(TMB),microsatellite instability(MSI),DNA methylation,and drug susceptibility in pan-cancer was also *** algorithms were used to analyze the correlation between PDHB and immune cell infiltration and tumor chemotaxis environment,as well as the co-expression analysis of PDHB and immune checkpoint(ICP)*** expression and functional phenotype of PDHB in single tumor cells were studied by single-cell sequencing,and the functional enrichment analysis of PDHB-related genes was *** study also validated the level of mRNA or protein expression of PDHB in several ***,in vitro experiments verified the regulatory effect of PDHB on the proliferation,migration,and invasion of liver *** PDHB was significantly and differently expressed in most *** was significantly associated with prognosis in patients with a wide range of cancers,including kidney renal clear cell carcinoma,kidney renal papillary cell carcinoma,breast invasive carcinom

关键词： Cuprotosis Pyruvate dehydrogenase E1 subunitβ Pan-cancer Prognosis liver cancer

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SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors

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Signal Transduction and Targeted therapy 2024年第5期9卷 2285-2297页

作者： Hui Qian Chen-Hong Ding Fang Liu Shi-Jie Chen Chen-Kai Huang Meng-Chao Xiao Xia-Lu Hong Ming-Chen Wang Fang-Zhi Yan Kai Ding Ya-Lu Cui Bai-Nan Zheng Jin Ding Cheng Luo Xin Zhang Wei-Fen Xie Department of Gastroenterology Changzheng HospitalNaval Medical UniversityShanghaiChina Department of Gastroenterology Shanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina Drug Discovery and Design Center CAS Key Laboratory of Receptor ResearchState Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina Department of Gastroenterology First Affiliated Hospital of Nanchang UniversityNanchangChina Clinical cancer Institute Center for Translational MedicineNaval Medical UniversityShanghaiChina

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor ***,the precise molecular mechanisms governing the nuclear import of YAP are not fully *** this study,we have uncovered a crucial role of SOX9 in the activation of ***9 promotes the nuclear translocation of YAP by direct ***,we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of ***,we have discovered a novel asymmetrical dimethylation of YAP at Arg-124(YAP-R124me2a)catalyzed by ***-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple ***,we disrupted the interaction between SOX9 and YAP using a competitive peptide,S-A1,which mimics anα-helix of SOX9 containing Asp-125.S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor *** study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

关键词： interaction interaction precise

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One-versus two-stage partial hepatectomy for large resectable solitary hepatocellular carcinomas determined preoperatively to have a narrow resection margin:a propensity score matching analysis

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Hepatobiliary Surgery and Nutrition 2022年第5期11卷 662-674页

作者： Yao Li Peng-Peng Li Da-Peng Sun Jun-Sheng Ni Hui Liu Ze-Ya Pan Yuan Yang Ling-Hao Zhao Wan Yee Lau Gang Huang Wei-Ping Zhou The Third Department of Hepatic Surgery Eastern Hepatobiliary Surgery HospitalShanghaiChina Faculty of Medicine The Chinese University of Hong KongPrince of Wales HospitalShatinHong KongChina key laboratory of signaling regulation and targeting therapy of liver cancer(SMMU) Ministry of EducationShanghaiChina Shanghai key laboratory of Hepatobiliary Tumor Biology(EHBH) ShanghaiChina

Background:For patients with a large but resectable solitary hepatocellular carcinoma(HCC)of>5 cm in diameter,it is often difficult to achieve a sufficient resection *** is still no study on whether a two-stage hepatectomy to increase a narrow resection margin would be ***:From August 2014 to February 2017,patients with a large but resectable solitary HCC of>5 cm and a preoperative estimated resection margin of5 cm,and resulted in significantly better long-term survival outcomes after partial hepatectomy.

关键词： One-stage hepatectomy two-stage hepatectomy large solitary hepatocellular carcinoma(HCC) resection margin

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