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Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin

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Science China Life Sciences 2024年第6期67卷 1226-1241页

作者： Zhengyang Guo Jiaqi Huang Xiao Huo Chen Huang Xiaotong Yu Yan Sun Yanfang Li Tianhui He Hongyan Guo Jianling Yang Lixiang Xue cancer center of peking university third hospital center of Basic Medical Research Institute of Medical Innovation and Research Peking University Third Hospital Peking University Third Hospital Cancer Center Department of Radiation Oncology Peking University Third Hospital Department of Obstetrics and Gynecology Peking University Third Hospital

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late. In ovarian cancer, multiple metabolic enzymes of lipid metabolism are abnormally expressed, resulting in metabolism disorder. As a characteristic pathway in polyunsaturated fatty acid(PUFA) metabolism, arachidonic acid(AA) metabolism is disturbed in ovarian cancer. Therefore, we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes. This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms(TCGA, ICGC, and GSE17260). The high association between the risk subgroups and clinical characteristics indicated a good performance of the model. Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer. Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer. Additionally, our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis, which contributes to the reduction of tumor-infiltrating CD8+T cells and immune escape in ovarian cancer. These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.

关键词： ovarian cancer polyunsaturated fatty acids prognostic risk model LTA4H tumor immunity CCL5

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Willingness of the General Public to Receive A COVID-19 Vaccine Booster—China,April–May 2021

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China CDC weekly 2022年第4期4卷 66-70页

作者： Xiaoxiao Wang Leyuan Liu Minyue Pei Xiaoguang Li Nan Li Research center of Clinical Epidemiology Peking University Third HospitalBeijingChina Department of Infectious Diseases Peking University Third HospitalBeijingChina

Summary What is already known about this topic?A coronavirus disease 2019(COVID-19)vaccine booster is planned for administration to eligible individuals.Understanding the factors that influence attitudes towards the booster shot will help to identify groups that will most readily accept a booster dose.What is added by this report?Of the individuals polled,75.2%reported they would receive a booster shot.Sociodemographic characteristics influencing booster vaccine acceptance included age,gender,occupation,and education.Moreover,those who had been vaccinated against influenza,who believed herd immunity would be effective against severe acute respiratory syndrome coronavirus 2,and who reported reduced anxiety after vaccination were more likely to accept a booster dose.What are the implications for public health practice?A booster shot of the COVID-19 vaccine could be widely accepted.Communicating about the effectiveness of the COVID-19 vaccine and the impact of infection on people’s health could help increase public willingness to get a booster dose.

关键词： occupation immunity COV

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Integrative single-cell multiomics analyses dissect molecular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer

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National Science Review 2023年第6期10卷 96-107页

作者： Shuhui Bian Yicheng Wang Yuan Zhou Wendong Wang Limei Guo Lu Wen Wei Fu Xin Zhou Fuchou Tang Biomedical Pioneering Innovation center School of Life Sciences Department of General Surgery Third Hospital Peking University State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Collaborative Innovation center for cancer Personalized Medicine Nanjing Medical University Beijing Advanced Innovation center for Genomics (ICG) Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Department of Pathology Peking University Third Hospital School of Basic Medical Science Peking University Health Science Center Peking University Third Hospital Cancer Center peking-Tsinghua center for Life Sciences Academy for Advanced Interdisciplinary Studies Peking University

Human gastric cancer is a highly lethal disease,but the underlying multiomic mole cular signatures remain largely uncle ar.Here,we performed multi-regional sampling,parallel single-cell multiomics sequencing and integrated analyses of human gastric cancer.We identified common transcrip tomic alterations of gastric cancer cells,such as aberrant down-regulation of genes associated with normal stomach function and up-regulation of KRT7,PI3,S100A4,etc.Surprisingly,aberrant and prevalent up-regulation of genes highly expressed in normal colorectal epithelial cells were also identified in cancer cells,which maybe partially regulated by promoter chromatin accessibility and DNA methylation levels.We reve aled the single-cell DNA methylome landscape of gastric cancer,and identified candidate DNA methylation biomarkers,such as hypermethylated promoters of TMEM240 and HAGLROS,and hypomethylated promoters of TRPM2-AS and HRH1.Additionally,the relationships between genetic lineages,D NA methylation and transcriptomic clusters were systematically revealed at single-cell level.We showed that DNA methylation heterogeneities were mainly among different genetic lineages of cancer cells.Moreover,we found that D NA methylation levels of cancer cells with poorer differentiation states tend to be higher than those of cancer cells with better differentiation states in the primary tumor within the same patient,although still lower than in normal gastric epithelial cells.cancer cells with poorer differentiation states also prevalently down-regulated MUC1 expression and immune-related pathways,and had poor infiltration of CD 8+T cells.Our study dissected the mole cular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer using integrative single-cell multiomics analyses.

关键词： gastric cancer single-cell multiomics analysis intratumoral heterogeneity tumor differentiation

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The protective effects and underlying mechanisms of dapagliflozin on diabetes-induced testicular dysfunction

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Asian Journal of Andrology 2023年第3期25卷 331-338页

作者： Zhi-Chao Luo Zi-Run Jin Ya-Fei Jiang Tian-Jiao Wei Ya-Lei Cao Zhe Zhang Rui Wei Hui Jiang Department of Urology Peking University Third HospitalBeijing 100191China Department of Endocrinology and Metabolism Peking University Third HospitalBeijing 100191China Department of Reproductive Medicine center Peking University Third HospitalBeijing 100191China

Male diabetic individuals present a marked impairment in fertility;however,knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory.The new hypoglycemic drug dapagliflozin has shown certain benefits,such as decreasing the risk of cardiovascular and renal events in patients with diabetes.Even so,until now,the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification.Here,we found that dapagliflozin lowered blood glucose levels,alleviated seminiferous tubule destruction,and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice.Moreover,the glucagon-like peptide-1 receptor(GLP-1R)antagonist exendin(9-39)had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice.We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2(BCL2)and X-linked inhibitor of apoptosis protein(XIAP)and inhibiting oxidative stress by enhancing the antioxidant status,including total antioxidant capacity,total superoxide dismutase(SOD)activity,and glutathione peroxidase(GPx)activity,as well as decreasing the level of 4-hydroxynonenal(4-HNE).Exendin(9-39)administration partially reversed these effects.Furthermore,dapagliflozin upregulated the glucagon-like peptide-1(GLP-1)level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog(Akt)phosphorylation in testicular tissue.Exendin(9-39)partially inhibited Akt phosphorylation.These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase(PI3K)/Akt signaling pathway.Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.

关键词： dapagliflozin diabetes glucagon-like peptide-1 receptor male infertility oxidative stress

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Advances in regulation and function of stearoyl-CoA desaturase 1 in cancer,from bench to bed

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Science China(Life Sciences) 2023年第12期66卷 2773-2785页

作者： Zhengyang Guo Xiao Huo Xianlong Li Changtao Jiang Lixiang Xue center of Basic Medical Research Institute of Medical Innovation and ResearchPeking University Third HospitalBeijing 100191China Department of Physiology and Pathophysiology School of Basic Medical SciencesPeking University and the Key Laboratory of Molecular Cardiovascular Science(Peking University)Ministry of EducationBeijing 100191China Peking University Third Hospital Cancer Center Department of Radiation OncologyPeking University Third HospitalBeijing 100191China

Stearoyl-CoA desaturase 1(SCD1)converts saturated fatty acids to monounsaturated fatty acids.The expression of SCD1 is increased in many cancers,and the altered expression contributes to the proliferation,invasion,stemness and chemoresistance of cancer cells.Recently,more evidence has been reported to further support the important role of SCD1 in cancer,and the regulation mechanism of SCD1 has also been focused.Multiple factors are involved in the regulation of SCD1,including metabolism,diet,tumor microenvironment,transcription factors,non-coding RNAs,and epigenetics modification.Moreover,SCD1 is found to be involved in regulating ferroptosis resistance.Based on these findings,SCD1 has been considered as a potential target for cancer treatment.However,the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity.This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment.

关键词： cancer metabolism SCD1 fatty acid lipid metabolism ferroptosis ER stress drug resistance cancer therapy

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Long-term outcomes of additional surgery versus non-gastrectomy treatment for early gastric cancer after non-curative endoscopic submucosal dissection: a meta-analysis

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Chinese Medical Journal 2023年第5期136卷 528-535页

作者： Sixuan Li Xueli Tian Jingyao Wei Yanyan Shi Hua Zhang Yonghui Huang Health Science center Peking UniversityBeijing 100191China Department of Gastroenterology Peking University Third HospitalBeijing 100191China Research center of Clinical Epidemiology Peking University Third HospitalBeijing 100191China

Background:Endoscopic resection is increasingly used in the treatment for early gastric cancer(EGC);however,about 15%of endoscopic submucosal dissection(ESD)cases report non-curative resection.The efficacy of different remedial interventions after non-curative ESD for EGC remains controversial.This meta-analysis aimed to compare the long-term outcomes of additional surgery and non-gastrectomy treatment for EGC patients who underwent non-curative ESD.Methods:All relevant studies published up to October 2021 were systematically searched in the PubMed,Web of Science,and Embase databases.The medical subject headings terms"early gastric cancer,""gastrectomy,""endoscopic submucosal dissection,"and their related free keywords were used to search relevant articles without restrictions on regions,publication types,or languages.The Newcastle–Ottawa Quality Assessment Scale was used to evaluate the quality of the included studies.Odds ratios(ORs)with 95%confidence intervals(CIs)of 5-year overall survival(OS),disease-specific survival(DSS),disease-free survival(DFS)and hazard ratios(HRs)with 95%CIs of OS were calculated using a random-or fixed-effects model.Results:This meta-analysis included 17 retrospective cohort studies with 5880 patients,of whom 3167 underwent additional surgery and 2713 underwent non-gastrectomy.We found that patients receiving additional gastrectomy had better 5-year OS(OR=3.63,95%CI=3.05–4.31),DSS(OR=3.22,95%CI=2.22–4.66),and DFS(OR=4.39,95%CI=1.78–10.82)outcomes than those receiving non-gastrectomy treatments.The pooled HR also showed that gastrectomy following non-curative ESD significantly improved OS(HR=0.40,95%CI=0.33–0.48).In addition,elderly patients benefited from additional surgery in consideration of the 5-year OS(HR=0.54,95%CI=0.41–0.72).Conclusions:Compared with non-gastrectomy treatments,additional surgery offered better long-term survival outcomes for patients with EGC who underwent non-curative ESD.

关键词： Endoscopic mucosal resection Stomach neoplasms Non-curative resection Additional surgery Non-gastrectomy treatment Disease-free survival

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COVID-19 pharmacological research trends:a bibliometric analysis

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Intelligent Medicine 2023年第1期3卷 1-9页

作者： Yanyan Shi Yahan Song Zhijun Guo Wei Yu Huiling Zheng Shigang Ding Siyan Zhan Research center of Clinical Epidemiology Peking University Third HospitalBeijing 100191China Library of peking university third hospital Beijing 100191China Department of Gastroenterology Peking University Third HospitalBeijing 100191China Department of Gastroenterology Affiliated Hospital of Jining Medical UniversityJiningShandong 272007China

Background:The coronavirus disease 2019(COVID-19)pandemic is ravaging the world.Many therapies have been explored to treat COVID-19.This report aimed to assess the global research trends for the development of COVID-19 therapies.Methods:We searched the relevant articles on COVID-19 therapies published from January 1,2020,to May 25,2022,in the Web of Science Core Collection Database(WOSCC).VOSviewer 1.6.18 software was used to assess data on the countries,institutions,authors,collaborations,keywords,and journals that were most implicated in COVID-19 pharmacological research.The latest research and changing trends in COVID-19-relevant pharmacological research were analyzed.Results:After manually eliminating articles that do not meet the requirements,a total of 5,289 studies authored by 32,932 researchers were eventually included in the analyses,which comprised 95 randomized controlled trials.3,044(57.6%)studies were published in 2021.The USA conducted the greatest number of studies,followed by China and India.The primary USA collaborators were China and England.The topics covered in the publications included:the general characteristics,the impact on pharmacists’work,the pharmacological research,broad-spectrum antiviral drug therapy and research,and promising targets or preventive measures,such as vaccine.The temporal diagram revealed that the current research hotspots focused on the vaccine,molecular docking,Mpro,and drug delivery keywords.Conclusion:Comprehensive bibliometric analysis could aid the rapid identification of the principal research topics,potential collaborators,and the direction of future research.Pharmacological research is critical for the development of therapeutic and preventive COVID-19-associated measures.This study may therefore provide valuable information for eradicating COVID-19.

关键词： Bibliometric analysis COVID-19 Pharmacological interventions Vaccine SARS-CoV-2

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Characteristics and Clinical Implication of UGT1A1 Heterozygous Mutation in Tumor

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中国肺癌杂志 2022年第3期25卷 137-146页

作者： Qian LI Tao SUN Hua ZHANG Wei LIU Yu XIAO Hongqi SUN Wencheng YIN Yanhong YAO Yangchun GU Yan'e LIU Fumei YI Qiqi WANG Jinyu YU Baoshan CAO Li LIANG Department of Medical Oncology and Radiation Sickness Peking University Third HospitalBeijing 100191China Department of General Surgery Peking University Third HospitalBeijing 100191China Research center of Clinical Epidemiology Peking University Third HospitalBeijing 100191China Department of Pharmacy Peking University Third HospitalBeijing 100191China

Background:The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1 A1 homozygous mutations,but the impact of UGT1 A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear.Methods:A total of 107 patients with UGT1 A1 heterozygous mutation or wild-type,who were treated with CPT-11 from January 2018 to September 2021 in peking university third hospital,were retrospectively enrolled.The adverse reaction spectra of patients with UGT1 A1*6 and UGT1 A1*28 mutations were analyzed.Adverse reactions were evaluated according to National cancer Institute Common Terminology Criteria for Adverse Events(NCI-CTCAE) 5.0.The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors(RECIST) 1.1.The genotypes of UGT1 A1*6 and UGT1 A1*28 were detected by digital fluorescence molecular hybridization.Results:There were 43 patients with UGT1 A1*6 heterozygous mutation,26 patients with UGT1 A1*28 heterozygous mutation,8 patients with UGT1 A1*6 and UGT1 A1*28 double heterozygous mutations,61 patients with heterozygous mutation at any gene locus of UGT1 A1*6 and UGT1 A1*28.Logistic regression analysis showed that the presence or absence of vomiting(P=0.013) and mucositis(P=0.005) was significantly correlated with heterozygous mutation of UGT1 A1*28,and the severity of vomiting(Pcancer,UGT1 A1*6 was significantly correlated to diarrhea(P=0.005),and the other adverse reactions spectrum was similar to that of the whole patient cohort,and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not.Conclusion:In clinical use,heterozygous mutations of UGT1 A1*6 and UGT1 A1*28 are related to the risk and severity of vomiting,diarrhea,neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy.In colorectal cancer,UGT1 A1*6 is significan

关键词： UGT1A1 Heterozygous mutation Adverse reaction

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A zero-sum game or an interactive frame?Iron competition between bacteriaand humans ininfectionwar

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Chinese Medical Journal 2022年第16期135卷 1917-1926页

作者： Zhenchao Wu Jiqi Shao Jiajia Zheng Beibei Liu Zhiyuan Li Ning Shen Department of Pulmonary and Critical Care Medicine Peking University Third HospitalBejing 100191China center for Infectious Diseases Peking University Third HospitalBejing 100191China center for Quantitative Biology Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China Department of Laboratory Medicine Peking University Third HospitalBejing 100191China.

Iron is an essential trace element for both humans and bacteria.It plays a vital role in life,such as in redox reactions and electron transport.Strict regulatory mechanisms are necessary to maintain iron homeostasis because both excess and insufficient iron are harmful to life.Competition for iron is a war between humans and bacteria.To grow,reproduce,colonize,and successfully cause infection,pathogens have evolved various mechanisms for iron uptake from humans,principally Fe^(3+)-siderophore and Fe^(2+)-heme transport systems.Humans have many innate immune mechanisms that regulate the distribution of iron and inhibit bacterial iron uptake to help resist bacterial invasion and colonization.Meanwhile,researchers have invented detection test strips and coupled antibiotics with siderophores to create tools that take advantage of this battle for iron,to help eliminate pathogens.In this review,we summarize bacterial and human iron metabolism,competition for iron between humans and bacteria,siderophore sensors,antibiotics coupled with siderophores,and related phenomena.We also discuss how competition for iron can be used for diagnosis and treatment of infection inthefuture.

关键词： Infection Iron metabolism Bacteria Siderophore Antibiotic

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Pregnancy and the disease recurrence of patients previously treated for differentiated thyroid cancer:A systematic review and meta analysis

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Chinese Medical Journal 2024年第5期137卷 547-555页

作者： Rui Shan Xin Li Ming Tao Wucai Xiao Jing Chen Fang Mei Shibing Song Bangkai Sun Chunhui Yuan Zheng Liu Department of Maternal and Child Health School of Public HealthPeking UniversityBeijing 100191China Department of General Surgery Peking University Third HospitalBeijing 100191China Department of Pathology Peking University Third HospitalSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Information Management and Big Data center Peking University Third HospitalBeijing 100191China

Background:Differentiated thyroid cancer(DTC)is commonly diagnosed in women of child-bearing age,but whether pregnancy influences the prognosis of DTC remains controversial.This study aimed to summarize existing evidence regarding the association of pregnancy with recurrence risk in patients previously treated for DTC.Methods:We searched PubMed,Embase,Web of Science,Cochrane,and Scopus based on the prespecified protocol registered at PROSPERO(CRD42022367896).After study selection,two researchers independently extracted data from the included studies.For quantitative data synthesis,we used random-effects meta-analysis models to pool the proportion of recurrence(for pregnant women only)and odds ratio(OR;comparing the risk of recurrence between the pregnancy group and the nonpregnancy group),respectively.Then we conducted subgroup analyses to explore whether risk of recurrence differed by response to therapy status or duration of follow-up time.We also assessed quality of the included studies.Results:A total of ten studies were included.The sample size ranged from 8 to 235,with participants’age at pregnancy or delivery ranging from 28 to 35 years.The follow-up time varied from 0.1 to 36.0 years.The pooled proportion of recurrence in all pregnant patients was 0.13(95%confidence intervals[CI]:0.06-0.25;I^(2):0.58).Among six included studies reporting response to therapy status before pregnancy,we observed a trend for increasingly higher risk of recurrence from excellent,indeterminate,and biochemically incomplete to structurally incomplete response to therapy(P trend0.05)or the OR of recurrence in studies with a comparison group(P>0.05).Two included studies that focused on patients with distant metastasis

关键词： Thyroid cancer Pregnancy Recurrence Women Systematic review Meta-analysis

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