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Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

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Cancer Communications 2024年第2期44卷 226-250页

作者： Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi Department of liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationShanghaiP.R.China research Unit of liver cancer Recurrence and Metastasis Chinese Academy of Medical SciencesBeijingP.R.China State Key Laboratory of Medical Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijingP.R.China

Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic *** metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely ***,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat ***:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome *** on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was *** and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic *** proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA ***:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were *** metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic *** S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)*** the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)***:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing

关键词： diacylglycerol kinaseα intrahepatic cholangiocarcinoma MAPK signaling metabolic classifi-cation multiomics analysis phosphatidic acid metabolism

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Suppressing Wnt signaling of the blood-tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2716-2731页

作者： Yang Tong Pei An Puxian Tang Rui Mu Yuteng Zeng Hang Sun Mei Zhao Ziyan Lv Pan Wang Wanjun Han Chunshan Gui Xuechu Zhen Liang Han Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhou 215123China Jiangsu Province Engineering research center of Precision diagnostics and Therapeutics Development Soochow UniversitySuzhou 215123China

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid *** inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low ***,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@*** the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model *** combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy *** Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

关键词： Lipogenesis Brain metastases Blood-tumor barrier Wnt signaling Drug delivery Fatty acid synthase Nanoparticles Combination therapy

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Current status of liver transplantation for human immunodeficiency virus-infected patients in China's Mainland

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World Journal of Gastroenterology 2024年第14期30卷 1958-1962页

作者： Jian-Xin Tang Dong Zhao Department of liver Surgery and Organ Transplantation center Shenzhen Third People’s HospitalThe Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious DiseaseShenzhen 518000Guangdong ProvinceChina

According to the report from the Chinese center for Disease Control and Prevention,the prevalence of human immunodeficiency virus(HIV)infection exceeded 1.2 million individuals by the year 2022,with an annual increase of about 80000 *** overall prevalence of hepatitis B surface antigen among individuals co-infected with HIV reached 13.7%,almost twice the rate of the general population in *** addition to the well-documented susceptibility to opportunistic infections and new malignancies,HIV infected patients frequently experience liver-related organ damage,with the liver and kidneys being the most commonly *** often leads to the development of end-stage liver and kidney ***,organ transplantation has emerged as an important part of active treatment for HIV infected ***,the curative effect is not *** infection has been considered a contraindication for organ *** the emergence of highly active anti-retroviral therapy in 1996,the once intractable replication of retrovirus was effectively *** prolonged survival,the failure of important organs has become the main cause of death among HIV ***,transplant centers worldwide have resu-med exploration of organ transplantation for HIV-infected individuals and reached a positive *** study provides an overview of the current landscape of HIV-positive patients receiving liver transplantation(LT)in main-land *** date,our transplant center has conducted LT for eight end-stage liver disease patients co-infected with HIV,and all but one,who died two months postoperatively due to sepsis and progressive multi-organ failure,have *** analysis with hepatitis B virus-infected patients during the same period revealed no statistically significant differences in acute rejection reactions,cytomegalovirus infection,bacteremia,pulmonary infections,acute kidney injury,new-onset cancers,or vascular and biliary co

关键词： liver transplantation Human immunodeficiency virus Infection Hepatitis B virus End-stage liver disease China'Mainland

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Pulmonary Bacterial Infection and liver Cirrhosis: Current Status and Treatment

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Infectious Microbes & Diseases 2024年第1期6卷 5-10页

作者： Yingying Zhao Song Yang Huichun Xing center of liver Diseases Division 3 Beijing Ditan HospitalCapital Medical UniversityBeijingChina

liver cirrhosis has a higher incidence rate and mortality when complicated with bacterial *** bacterial infections,especially bacterial pneumonia,increase the susceptibility of cirrhotic patients to decompensation,with a higher likelihood of *** pneu-monia is often overlooked in patients with liver cirrhosis,although it can impact the clinical progress and *** diagnosis and inappropriate antibiotic treatments are associated with poor prognosis and increased *** understanding of mechanisms and appropriate antibiotic treatments for cirrhosis-related bacterial pneumonia remain ***,we reviewed the epidemiology,clinical characteristics and treatment of pulmonary bacterial infections in cirrhotic patients to provide suggestions for clinical practice.

关键词： bacterial pneumonia liver cirrhosis epidemiology characteristics treatment

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Diagnosis and therapy of tacrolimus toxicity in a liver transplant recipient during COVID-19 treatment

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 326-330页

作者： Feng Zhu Yi-Ming Wang Ming Ni Yuan Liang Jie-Hui Huang Xue-Hao Wang Feng Cheng Ling Lu Hepatobiliary center The First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Liver TransplantationResearch Unit of Liver Transplantation and Transplant ImmunologyChinese Academy of Medical SciencesNanjing 210000China Department of Respiratory and Critical Care Medicine Wuxi Fifth People’s HospitalWuxi 214000China Jiangsu Key Laboratory of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjing 210000China

To the Editor:SARS-CoV-2,the pathogen responsible for the pandemic of coronavirus disease 2019(COVID-19),has had profound impacts on human health,and its antagonist Paxlovid is a commonly used treatment option[1].However,treatment selection for immunosuppressed patients,such as liver recipients,remains uncertain due to potential drug interactions and the risk of immunosuppressant dosage adjustment,which can cause liver injury[2].

关键词： dosage treatment antagonist

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Hepatitis B virus genotypes in precision medicine of hepatitis Brelated hepatocellular carcinoma:Where we are now

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1097-1103页

作者： Caecilia H C Sukowati Sri Jayanti Turyadi Turyadi David H Muljono Claudio Tiribelli Eijkman research center for Molecular Biology Research Organization for HealthNational Research and Innovation Agency of IndonesiaJakarta 10340Indonesia liver Cancer Unit Fondazione Italiana Fegato ONLUSTrieste 34149Italy Faculty of Medicine Hasanuddin UniversityMakassar 90245South SulawesiIndonesia Faculty of Medicine and Health University of SydneySydney 2050Australia

Hepatitis B virus(HBV)infection is a major player in chronic hepatitis B that may lead to the development of hepatocellular carcinoma(HCC).HBV genetics are diverse where it is classified into at least 9 genotypes(A to I)and 1 putative genotype(J),each with specific geographical distribution and possible different clinical outcomes in the *** diversity may be associated with the precision medicine for HBV-related HCC and the success of therapeutical approaches against HCC,related to different pathogenicity of the virus and host *** Editorial discusses recent updates on whether the classification of HBV genetic diversity is still valid in terms of viral oncogenicity to the HCC and its precision medicine,in addition to the recent advances in cellular and molecular biology technologies.

关键词： Hepatitis B virus Hepatocellular carcinoma Genotypes Pathogenesis Precision medicine

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Gastroesophageal reflux after per-oral endoscopic myotomy:Management literature

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World Journal of Gastroenterology 2024年第23期30卷 2947-2953页

作者： Ahmed Tawheed Ibrahim Halil Bahcecioglu Mehmet Yalniz Mohamed El-Kassas Department of Endemic Medicine Faculty of MedicineHelwan UniversityCairo 11795Egypt Department of Gastroenterology Faculty of MedicineFirat UniversityElazig 23119Türkiye liver Disease research center College of MedicineKing Saud UniversityRiyadh 7805Saudi Arabia

In this editorial,we respond to a review article by Nabi et al,in which the authors discussed gastroesophageal reflux(GER)following peroral endoscopic myotomy(POEM).POEM is presently the primary therapeutic option for achalasia,which is both safe and effective.A few adverse effects were documented after POEM,including *** diagnostic criteria were not clear enough because approximately 60%of patients have a long acid exposure time,while only 10%experience reflux *** predictors of high disease incidence have been identified,including old age,female sex,obesity,and a baseline lower esophageal sphincter pressure of less than 45 *** technical steps during the procedure,such as a lengthy or full-thickness myotomy,may further enhance the *** pump inhibitors are currently the first line of *** voices are increasingly advocating for the routine combining of POEM with an endoscopic fundoplication method,such as peroral endoscopic fundoplication or transoral incisionless ***,more research is necessary to determine the safety and effectiveness of these procedures in the long term for patients who have undergone them.

关键词： Achalasia Per-oral endoscopic myotomy Gastroesophageal reflux disease Transoral incisionless fundoplication Peroral endoscopic fundoplication

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Single-domain antibodies as therapeutics for solid tumor treatment

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2854-2868页

作者： Mingkai Wang Tianlei Ying Yanling Wu MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology School of Basic Medical SciencesDepartment of Pulmonary and Critical Care MedicineDepartment of Liver Surgery and TransplantationZhongshan HospitalFudan UniversityShanghai 200032China Shanghai Engineering research center for Synthetic Immunology Shanghai 200032China

Single-domain antibodies(sdAbs),initially identified in camelids or sharks and commonly referred to as nanobodies or VNARs,have emerged as a promising alternative to conventional therapeutic *** sdAbs have many superior physicochemical and pharmacological properties,including small size,good solubility and thermostability,easier accessible epitopes,and strong tissue ***,the inherent challenges associated with the animal origin of sdAbs limit their clinical *** recent years,various innovative humanization technologies,including complementarity-determining region(CDR)grafting or complete engineering of fully human sdAbs,have been developed to mitigate potential immunogenicity issues and enhance their *** review provides a comprehensive exploration of sdAbs,emphasizing their distinctive features and the progress in humanization *** addition,we provide an overview of the recent progress in developing drugs and therapeutic strategies based on sdAbs and their potential in solid tumor treatment,such as sdAbedrug conjugates,multispecific sdAbs,sdAb-based delivery systems,and sdAb-based cell therapy.

关键词： Single-domain antibody Nanobody Humanization Fully human singledomain antibody Solid tumor

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Chinese expert consensus on refined diagnosis,treatment,and management of advanced primary liver cancer(2023 edition)

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肝脏研究（英文） 2024年第2期8卷 61-71页

作者： Xiufeng Liu Feng Xia Yue Chen Huichuan Sun Zhengqiang Yang Bo Chen Ming Zhao Xinyu Bi Tao Peng Aizier Ainiwaer Zhiwen Luo Fusheng Wang Yinying Lu National Clinical research center for Infectious Diseases Society of Hepatology,Beijing Medical Association Translational Medicine Branch,China Association of Gerontology and Geriatrics Department of Medical Oncology Bayi Hospital Affiliated to Nanjing Chinese Medical University NanjingJiangsuChina Department of Hepatobiliary Surgery Southwest HospitalArmy Medical University ChongqingChina Senior Department of Hepatology The Fifth Medical Center of PLA General HospitalBeijingChina Department of liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina Department of Interventional Therapy National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Radiation Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Minimally Invasive Interventional Therapy Liver Cancer Study and Service GroupSun Yat-sen University Cancer CenterGuangzhouGuangdongChina Department of Hepatobiliary Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Hepatobiliary Surgery The First Affiliated Hospital of Guangxi Medical UniversityNanningGuangxiChina Senior Department of Infectious Diseases The Fifth Medical Center of PLA General HospitalBeijingChina Comprehensive liver Cancer center The Fifth Medical Center of PLA General HospitalBeijingChina

Hepatocellular carcinoma(HCC),commonly known as primary liver cancer,is a major cause of malignant tumors and cancer-related deaths in China,accounting for approximately 85％of all cancer cases in the *** guidelines have been used to diagnose and treat liver ***,these guidelines provide a broad definition for classifying advanced liver cancer,with an emphasis on a singular approach,without considering treatment options for individual ***,it is necessary to establish a comprehensive and practical expert consensus,specifically for China,to enhance the diagnosis and treatment of HCC using the Delphi *** classification criteria were refined for Chinese patients with HCC,and the corresponding optimal treatment regimen recommendations were *** recommendations took into account various factors,including tumor characteristics,vascular tumor thrombus grade,distant metastasis,liver function status,portal hypertension,and the hepatitis B virus replication status of patients with primary HCC,along with treatment *** findings and rec-ommendations provide detailed,scientific,and reasonable individualized diagnosis and treatment strategies for clinicians.

关键词： Hepatocellular carcinoma (HCC) Targeted therapy Immunotherapy Refined diagnosis and treatment Expert consensus

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Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression

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Frontiers of Medicine 2024年第3期18卷 430-445页

作者： Yue Ma Hongwei Lv Fuxue Xing Wei Xiang Zixin Wu Qiyu Feng Hongyang Wang Wen Yang Cancer research center First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei230027China National center for liver Cancer Naval Medical University(Second Military Medical University)Shanghai201805China International Co-operation Laboratory on Signal Transduction Eastern Hepatobiliary Surgery HospitalNaval Medical University(Second Military Medical University)Shanghai200438China Shanghai Key Laboratory of Hepato-biliary Tumor Biology Shanghai200438China Key Laboratory of Signaling Regulation and Targeting Therapy of liver Cancer Ministry of EducationShanghai200438China

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression.A tumor subpopulation called liver cancer stem cells(CSCs)significantly accounts for the initiation,metastasis,therapeutic resistance,and recurrence of liver *** evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy *** review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression,as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their ***,we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

关键词： liver cancer cancer stem cell immune cell immunotherapy

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