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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

TIMP-1 Promotes Expression of MCP-1 and Macrophage Migration by Inducing Fli-1 in Experimental liver Fibrosis

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Journal of Clinical and Translational Hepatology 2024年第7期12卷 634-645页

作者： Xiaoli Huang Xiaofan Wang Yanhong Wang Shuangjun Shen Wei Chen Tianhui Liu Ping Wang Xu Fan Lin Liu Jidong Jia Min Cong liver Research Center Beijing Friendship HospitalCapital Medical UniversityBeijingChina beijing key laboratory of Translational Medicine in liver cirrhosis and National Clinical Research Center of Digestive Disease BeijingChina Dongying People’s Hospital DongyingShandongChina Experimental and Translational Research Center Beijing Friendship HospitalCapital Medical UniversityBeijingChina

Background and Aims:Tissue inhibitor of metalloproteinase-1(TIMP-1)plays a role in the excessive generation of extracellular matrix in liver *** study aimed to explore the pathways through which TIMP-1 controls monocyte chemoattractant protein-1(MCP-1)expression and promotes hepatic macrophage ***:liver fibrosis was triggered through carbon tetrachloride,and an adenoassociated virus containing small interfering RNA targeting TIMP-1(siRNA-TIMP-1)was administered to both rats and *** assessed the extent of fibrosis and macrophage *** molecular mechanisms regulating macrophage recruitment by TIMP-1 were investigated through transwell migration assays,luciferase reporter assays,the use of pharmacological modulators,and an analysis of extracellular vesicles(EVs).Results:siRNA-TIMP-1 alleviated carbon tetrachloride-induced liver fibrosis,reducing macrophage migration and MCP-1 ***-culturing macrophages with hepatic stellate cells(HSCs)post-TIMP-1 downregulation inhibited macrophage *** siRNATIMP-1-treated HSCs,microRNA-145(miRNA-145)expression increased,while the expression of Friend leukemia virus integration-1(Fli-1)and MCP-1 was *** of Fli-1 led to decreased MCP-1 expression,whereas Fli-1 overexpression increased MCP-1 expression within *** with miRNA-145 mimics reduced the expression of both Fli-1 and MCP-1,while miRNA-145 inhibitors elevated the expression of both Fli-1 and MCP-1 in ***-145 bound directly to the 3'-UTR of Fli-1,and mi RNA-145-EN-riched EVs secreted by HSCs after TIMP-1 downregulation influenced macrophage ***:TIMP-1 induces Fli-1 expression through miRNA-145,subsequently increasing MCP-1 expression and macrophage ***-145-enriched EVs from HSCs can transmit biological information and magnify the function of TIMP-1.

关键词： TIMP-1 Fli-1 MCP-1 miRNA-145 liver fibrosis Extracellular vesicles

Exploring the potential of extrachromosomal DNA as a novel oncogenic driver

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Science China Life Sciences 2024年

作者： Huanbo Zhu Longtao Huangfu Junbing Chen Jiafu Ji Xiaofang Xing key laboratory of Carcinogenesis and Translational Research (Ministry of Education/beijing) Division of Gastrointestinal Cancer Translational Research Laboratory Peking University Cancer Hospital &Institute Department of Gastrointestinal cancer Center Peking University Cancer Hospital & Institute Department of liver Surgery & Transplantation Liver Cancer Institute Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education State key laboratory of Holistic Integrative Management of Gastrointestinal cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Division of Gastrointestinal Cancer Translational Research Laboratory Peking University Cancer Hospital & Institute

Extrachromosomal DNA(ecDNA) is a form of circular DNA mostly found in tumor cells. Unlike the typical chromosomal DNA, ecDNA is circular, self-replicating, and carries complete or partial gene fragments. Although ecDNA occurrence remains a rare event in cancer, recent studies have shown that oncogene amplification on ecDNA is widespread throughout many types of cancer, implying that ecDNA plays a central role in accelerating tumor evolution. ecDNA has also been associated with increased tumor mutation burden, chromosomal instability, and even tumor microenvironment remodeling. ecDNA may be crucial in influencing tumor heterogeneity, drug sensitivity,oncogenic senescence, and tumor immunogenicity, leading to a worsening prognosis for tumor patients. In this way, several clinical trials have been conducted to investigate the importance of ecDNA in clinical treatment. In this review, we summarize the biogenesis, characteristics, and current research methods of ecDNA, discuss the vital role of ecDNA-caused tumor heterogeneity in cancers, and highlight the potential role of ecDNA in cancer therapy.

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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

Value of multiple models of diffusion-weighted imaging to predict hepatic lymph node metastases in colorectal liver metastases patients

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World Journal of Gastroenterology 2024年第4期30卷 308-317页

作者： Hai-Bin Zhu Bo Zhao Xiao-Ting Li Xiao-Yan Zhang Qian Yao Ying-Shi Sun key laboratory of Carcinogenesis and Translational Research(Ministry of Education/beijing) Department of RadiologyPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and Translational Research(Ministry of Education/beijing) Department of PathologyPeking University Cancer Hospital and InstituteBeijing 100142China

BACKGROUND About 10%-31% of colorectal liver metastases(CRLM)patients would concomitantly show hepatic lymph node metastases(LNM),which was considered as sign of poor biological behavior and a relative contraindication for liver *** to now,there’s still lack of reliable preoperative methods to assess the status of hepatic lymph nodes in patients with CRLM,except for pathology examination of lymph node after *** To compare the ability of mono-exponential,bi-exponential,and stretchedexponential diffusion-weighted imaging(DWI)models in distinguishing between benign and malignant hepatic lymph nodes in patients with CRLM who received neoadjuvant chemotherapy prior to *** In this retrospective study,97 CRLM patients with pathologically confirmed hepatic lymph node status underwent magnetic resonance imaging,including DWI with ten b values before and after *** parameters,such as the apparent diffusion coefficient from the mono-exponential model,and the true diffusion coefficient,the pseudo-diffusion coefficient,and the perfusion fraction derived from the intravoxel incoherent motion model,along with distributed diffusion coefficient(DDC)andαfrom the stretched-exponential model(SEM),were *** parameters before and after chemotherapy were compared between positive and negative hepatic lymph node groups.A nomogram was constructed to predict the hepatic lymph node *** reliability and agreement of the measurements were assessed using the coefficient of variation and intraclass correlation *** Multivariate analysis revealed that the pre-treatment DDC value and the short diameter of the largest lymph node after treatment were independent predictors of metastatic hepatic lymph nodes.A nomogram combining these two factors demonstrated excellent performance in distinguishing between benign and malignant lymph nodes in CRLM patients,with an area under the curve of ***,parameters from SEM sho

关键词： Colorectal cancer Individualized treatment Diffusion magnetic resonance imaging Intravoxel incoherent motion liver

Helicobacter pylori and immunotherapy for gastrointestinal cancer

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The Innovation 2024年第2期5卷 51-60页

作者： Keren Jia Yang Chen Yi Xie Xicheng Wang Yajie Hu Yu Sun Yanshuo Cao Liyan Zhang Yakun Wang Zhenghang Wang Zhihao Lu Jian Li Xiaotian Zhang Lin Shen key laboratory of Carcinogenesis and Translational Research(Ministry of Education/beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China key laboratory of Carcinogenesis and Translational Research(Ministry of Education/beijing) Department of PathologyPeking University Cancer Hospital&InstituteBeijing 100142China

Helicobacter pylori infection is associated with the risk of gastrointestinal(GI)cancers;however,its impact on immunotherapy for GI cancers remains *** this study,we included 10,122 patients who underwent ^(13)C-urea breath *** 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer(GC)who were treated with anti-PD-1/PD-L1 therapy,***–positive patients exhibited significantly longer immune-related progression-free survival(irPFS)compared with ***–negative patients(6.97 months versus 5.03 months,pliver cancer and pancreatic cancer *** summary,our findings supported that *** infection is a beneficial factor for GC immunotherapy by shaping hot tumor ***,in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients,*** adversely affects the efficacy of immunothera

关键词： immunotherapy gastrointestinal pylori

Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers:An open-label,non-randomized,phase II clinical trial

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World Journal of Gastroenterology 2024年第30期30卷 3564-3573页

作者： Ling-Xiao Xu Jia-Jia Yuan Ran Xue Jun Zhou Department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing)Peking University Cancer Hospital and InstituteBeijing 100142China

BACKGROUND Biliary tract cancers(BTCs)are a heterogeneous group of tumors with high malignancy,poor prognosis,and limited treatment *** To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic *** This open-label,non-randomized,double-center,phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at beijing cancer Hospital and the First Hospital of China Medical *** patients were administered nab-paclitaxel(150 mg/m^(2),day 1)and capecitabine(2000 mg/m^(2),twice daily,days 1-7)in 14-day cycles until experiencing intolerable toxicity or disease *** primary outcome was the objective response rate(ORR).The secondary outcomes included the disease control rate(DCR),overall survival(OS),progression-free survival(PFS),and *** A total of 44 patients successfully completed the trial,with a median age of 64.00 years(interquartile range,35.00-76.00),and 26(59.09%)were *** response assessment was impeded for one patient due to premature demise from tumor *** the remaining 43 patients undergoing at least one imaging assessment,the ORR was 23.26%[95%confidence interval(CI):11.80%-38.60%],and the DCR was 69.77%(95%CI:53.90%-82.80%).The median OS was 14.1 months(95%CI:8.3-19.9),and the median PFS was 4.4 months(95%CI:2.5-6.3).A total of 41 patients(93.18%)experienced at least one adverse event(AE),with 10 patients(22.73%)encountering grade≥3 AEs,and the most frequent AEs of any grade were alopecia(79.50%),leukopenia(54.55%),neutropenia(52.27%),and liver dysfunction(40.91%),and no treatment-related deaths were *** Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

关键词： Nab-paclitaxel Capecitabine Biliary tract cancer Objective response rate Phase II clinical trial

Clinicopathological significance and immunotherapeutic outcome of claudin 18.2 expression in advanced gastric cancer:A retrospective study

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Chinese Journal of cancer Research 2024年第1期36卷 78-89页

作者： Changsong Qi Xiaoyi Chong Ting Zhou Mingyang Ma Jifang Gong Miao Zhang Jian Li Jun Xiao Xiaohui Peng Zhen Liu Zonghai Li Lin Shen Xiaotian Zhang State key laboratory of Holistic Integrative Management of Gastrointestinal cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China key laboratory of Carcinogenesis and Translational Research(Ministry of Education/beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China CARsgen Therapeutics Co. LtdShanghai 200231China CARsgen Life Sciences Co. LtdShanghai 200131China

Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in ***: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression ***: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of *** death-ligand 1(PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of ***18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(Pliver metastasis(P<0.001)was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive ***: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.

关键词： Gastric cancer claudin18.2 CT041 PD-L1 immunotherapy

Trends in Mortality of cirrhosis in China: An Analysis of the China Death Surveillance Database from 2008 to 2020

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Journal of Clinical and Translational Hepatology 2024年第3期12卷 236-244页

作者： Xiaoxiao Wang Huixin Liu Jinlei Qi Lijun Wang Peng Yin Feng Liu Lai Wei Yu Wang Maigeng Zhou Huiying Rao Peking University People’s Hospital Peking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijing International Cooperation Base for Science and Technology on NAFLD DiagnosisBeijingChina Department of Clinical Epidemiology and Biostatistics Peking University People’s HospitalBeijingChina National Center for Chronic Noncommunicable Disease Control and Prevention Chinese Center for Disease Control and PreventionBeijingChina beijing Tsinghua Changgung Hospital Tsinghua UniversityBeijingChina Chinese Foundation for Hepatitis Prevention and Control BeijingChina

Background and Aims:China accounts for 14.9%of total cirrhosis deaths worldwide.A detailed and comprehensive understanding of the contemporary status of cirrhosis mortality in China is crucial for establishing strategies for intervention and decreasing the disease burden of cirrhosis *** study aimed to report the cirrhosis mortality rates in our whole country or province over ***:Mortality data from 2008 to 2020 were retrieved from the Disease Surveillance Point System(DSPs)of the Chinese Center for Disease Control and *** crude mortality rate and age-standardized mortality rate of patients with cirrhosis were stratified by sex,residential location,and *** average annual percentage change(AAPC)in cirrhosis mortality rates from 2008 to 2020 was also ***:The crude mortality rate of cirrhosis was 4.57/100,000 people in *** with females and individuals living in urban areas,males and people living in rural areas had greater age-standardized *** crude mortality rate and age-standardized mortality rate in provinces in Southwest China(Guangxi,Yunnan,Guizhou,and Qinghai)were greater than those in other ***,with increasing age,the age-specific mortality rate increased *** 2008 to 2020,the mortality rate of cirrhosis in China decreased except for in males aged 50–59 years,females aged 45–49 years and females aged 80–84 ***:The mortality rate of patients with cirrhosis in China decreased from 2008 to *** the future,interventions of cirrhosis mortality control need to pay more attention to all males,females aged 45–49 and 80–84 years,and people living in rural areas and in provinces in Southwest China.

关键词： cirrhosis Mortality Trend China