背景与目的越来越多的癌症患者死于心血管疾病。三阴性乳腺癌(triple-negative breast cancer,TNBC)可选的治疗方法有限,因此化疗引起的心脏毒性对该类患者非常重要。心脏自噬是心脏毒性的重要机制之一。本研究旨在研究化疗对TNBC患者...背景与目的越来越多的癌症患者死于心血管疾病。三阴性乳腺癌(triple-negative breast cancer,TNBC)可选的治疗方法有限,因此化疗引起的心脏毒性对该类患者非常重要。心脏自噬是心脏毒性的重要机制之一。本研究旨在研究化疗对TNBC患者的心脏毒性,筛选易感人群,探讨心脏毒性与自噬相关基因多态性的相关性。方法在2450例I–III期TNBC患者中,有147例纳入了本研究。大多数患者在化疗周期前进行心电图(electrocardiography,ECG)检查,并根据临床需要进行超声心动图(echocardiography,UCG)检查。所有ECG和UCG资料均由阜外医院国家心血管病中心的心血管专家重新评判。根据美国国家生物技术信息中心数据库和癌症体细胞突变目录数据库,我们筛选了25个与自噬相关的单核苷酸多态性(single nucleotide polymorphisms,SNPs),并对147例TNBC患者进行了基因分型。采用配对样本T检验、卡方检验和logistic回归模型进行分析。结果每个化疗周期后,只有46(31.3%)例患者的ECG完全正常。在接受UCG的16例患者中,有2(12.5%)例患者左心室射血分数可逆性下降。使用蒽环类药物和过量饮酒是ECG异常的危险因素。随着化疗的持续,心率逐渐增加。蒽环类药物与QRS期持续异常有关(P=0.043)。我们对25个与自噬有关的SNP进行基因分型后发现,自噬相关基因13(ATG13)rs10838611的G等位基因与ECG异常显著相关(优势比=2.258,95%置信区间:1.318–3.869;P=0.003)。结论化疗引起的ECG异常在真实世界中很常见。自噬相关单核苷酸多态性与化疗引起的心脏毒性相关,本研究为自噬是化疗所致心脏损害的原因提供了新的证据。展开更多
Background:An increasing number of cancer patients die of cardiovascular diseases.The cardiotoxicity of chemo-therapy is particularly important in triple-negative breast cancer(TNBC)with limited therapeutic options.Ca...Background:An increasing number of cancer patients die of cardiovascular diseases.The cardiotoxicity of chemo-therapy is particularly important in triple-negative breast cancer(TNBC)with limited therapeutic options.Cardiac autophagy is an important mechanism of cardiotoxicity.This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC,screen the susceptible population,and determine the relationship between cardiotoxicity and autophagy-related polymorphisms.Methods:From a total of 2450 stage I-III TNBC patients,147 met the inclusion criteria and finally recruited.Electro-cardiography(ECG)was performed before most chemotherapy cycles,and echocardiography(UCG)was performed according to clinical needs.All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease,Fuwai Hospital.According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database,we selected 25 single nucleotide polymorphisms(SNPs)related to autophagy and genotyped the 147 TNBC patients.Paired-sample T tests,Chi squared tests,and logistic regression models were employed for the analysis.Results:Only 46(31.3%)patients had normal ECG records after every chemotherapy cycle.Among the 16 patients who underwent UCG,2(12.5%)had a reversible decrease of left ventricular ejection fraction.The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities.With the continuation of chemotherapy,heart rate gradually increased.Anthracyclines were associated with QRS duration abnormalities(P=0.043).After genotyping for 25 autophagy-related SNPs,we found that the G allele of autophagy-related 13(ATG13)rs10838611 was significantly associated with ECG abnormalities(odds ratio=2.258,95%confidence interval=1.318-3.869;P=0.003).Conclusion:ECG abnormalities caused by chemotherapy are common in the real world.Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity,thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.展开更多
Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high ...Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)infection.Here,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA.Mechanistically,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone acetylation.HDAC inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft models.These fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.展开更多
Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation ...Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined.Here,we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1(AFB1)targets.Among the most significant hits was the aryl hydrocarbon receptor(AHR),a ligand-binding transcription factor regulating cell metabolism,differentiation,and immunity.展开更多
Tongue-coating microbiome,as a part of oral microbiome,is an important part of commensal microbes in human body.Despite technical difficulties in gaining functional insights using metagenomic approaches due to high le...Tongue-coating microbiome,as a part of oral microbiome,is an important part of commensal microbes in human body.Despite technical difficulties in gaining functional insights using metagenomic approaches due to high levels of host DNA contaminations,a number of diseases have been found to be closely related to the alteration of oral microbial communities,including periodontal and caries diseases,cardiovascular disease,diabetes,rheumatoid arthritis.展开更多
Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistak...Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistake occurred during the production process in Fig.7 that needs to be corrected.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.展开更多
Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent.However,the lack of a clear understanding of the indications of metformin limits its efficacy.Here,we performed...Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent.However,the lack of a clear understanding of the indications of metformin limits its efficacy.Here,we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin.Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment(T18)compared to those of the untreated cells at day 0(T0)yielded candidate genes.Knockdown of a group of cyclin-dependent kinases(CDKs),including CDK1,CDK4,and CDK6,confirmed the results of the screen.Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo.Although cell cycle parameters were not further altered under the combination treatment,investigation of the metabolome revealed significant changes in cell metabolism,especially with regard to fatty acid oxidation,the tricarboxylic acid cycle and aspartate metabolism.Such changes appeared to be mediated through inhibition of the mTOR pathway.Collectively,our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.展开更多
Cancer is a leading cause of death in China with an estima- tion of nearly 2 million deaths every year （Chen and Fu, 2011b）. Matter of a public health importance in China and worldwide, the scientific community is s...Cancer is a leading cause of death in China with an estima- tion of nearly 2 million deaths every year （Chen and Fu, 2011b）. Matter of a public health importance in China and worldwide, the scientific community is still facing many obstacles to eradicate cancer： complexity of a mul- ti-factorial disease with organ-based specificities, high fail- ure rate of many anti-cancer drugs in clinical trials, lack of understanding of the cancer genesis factors.展开更多
Various molecular analytical techniques have provided more and more information which is necessary for the accurate classification of diseases.Such information has enabled researchers to shift from morphology-based cl...Various molecular analytical techniques have provided more and more information which is necessary for the accurate classification of diseases.Such information has enabled researchers to shift from morphology-based classification to molecular characteristics-based classification,also known as molecular classification.Molecular classifications of diseases can be carried out at the DNA,RNA,and protein levels.At the DNA level,for example,molecular classification can be done based on genetic mutation,polymorphisms,cytogenetic changes in genomes or DNA methylation differences.展开更多
Nasopharyngeal carcinoma （NPC） was mostly common in Guangdong Province and Guangxi Chuang Autonomous Region. This cancer jeopardized people＇s health in the above areas. In order to understand the mechanisms for NPC...Nasopharyngeal carcinoma （NPC） was mostly common in Guangdong Province and Guangxi Chuang Autonomous Region. This cancer jeopardized people＇s health in the above areas. In order to understand the mechanisms for NPC, and further promote NPC＇s early diagnosis and therapy, the molecular genetic analysis research of NPC in China and in its outbreak areas becomes an emergent topic. Since NPC is a rare disease in developed countries of Europe and America, the research in this field has not been well-recognized in these countries. Furthermore,展开更多
文摘背景与目的越来越多的癌症患者死于心血管疾病。三阴性乳腺癌(triple-negative breast cancer,TNBC)可选的治疗方法有限,因此化疗引起的心脏毒性对该类患者非常重要。心脏自噬是心脏毒性的重要机制之一。本研究旨在研究化疗对TNBC患者的心脏毒性,筛选易感人群,探讨心脏毒性与自噬相关基因多态性的相关性。方法在2450例I–III期TNBC患者中,有147例纳入了本研究。大多数患者在化疗周期前进行心电图(electrocardiography,ECG)检查,并根据临床需要进行超声心动图(echocardiography,UCG)检查。所有ECG和UCG资料均由阜外医院国家心血管病中心的心血管专家重新评判。根据美国国家生物技术信息中心数据库和癌症体细胞突变目录数据库,我们筛选了25个与自噬相关的单核苷酸多态性(single nucleotide polymorphisms,SNPs),并对147例TNBC患者进行了基因分型。采用配对样本T检验、卡方检验和logistic回归模型进行分析。结果每个化疗周期后,只有46(31.3%)例患者的ECG完全正常。在接受UCG的16例患者中,有2(12.5%)例患者左心室射血分数可逆性下降。使用蒽环类药物和过量饮酒是ECG异常的危险因素。随着化疗的持续,心率逐渐增加。蒽环类药物与QRS期持续异常有关(P=0.043)。我们对25个与自噬有关的SNP进行基因分型后发现,自噬相关基因13(ATG13)rs10838611的G等位基因与ECG异常显著相关(优势比=2.258,95%置信区间:1.318–3.869;P=0.003)。结论化疗引起的ECG异常在真实世界中很常见。自噬相关单核苷酸多态性与化疗引起的心脏毒性相关,本研究为自噬是化疗所致心脏损害的原因提供了新的证据。
基金supported by the National Natural Science Foundation of China(No.81472453).
文摘Background:An increasing number of cancer patients die of cardiovascular diseases.The cardiotoxicity of chemo-therapy is particularly important in triple-negative breast cancer(TNBC)with limited therapeutic options.Cardiac autophagy is an important mechanism of cardiotoxicity.This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC,screen the susceptible population,and determine the relationship between cardiotoxicity and autophagy-related polymorphisms.Methods:From a total of 2450 stage I-III TNBC patients,147 met the inclusion criteria and finally recruited.Electro-cardiography(ECG)was performed before most chemotherapy cycles,and echocardiography(UCG)was performed according to clinical needs.All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease,Fuwai Hospital.According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database,we selected 25 single nucleotide polymorphisms(SNPs)related to autophagy and genotyped the 147 TNBC patients.Paired-sample T tests,Chi squared tests,and logistic regression models were employed for the analysis.Results:Only 46(31.3%)patients had normal ECG records after every chemotherapy cycle.Among the 16 patients who underwent UCG,2(12.5%)had a reversible decrease of left ventricular ejection fraction.The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities.With the continuation of chemotherapy,heart rate gradually increased.Anthracyclines were associated with QRS duration abnormalities(P=0.043).After genotyping for 25 autophagy-related SNPs,we found that the G allele of autophagy-related 13(ATG13)rs10838611 was significantly associated with ECG abnormalities(odds ratio=2.258,95%confidence interval=1.318-3.869;P=0.003).Conclusion:ECG abnormalities caused by chemotherapy are common in the real world.Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity,thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.
基金supported by National Key R&D Program of China(2019YFA0110300,2017YFA0505600-04 to Q.L.)Innovative Research Team in University of Ministry of Education of China(IRT_17R15 to Q.L.)+7 种基金National Natural Science Foundation of China(81630005,81573025 to Q.L.,81773166 to Z.W.,81702683 to J.X.,81972594 to M.Y.,81402445 to C.W.,81502579 to Z.H.)Natural Science Foundation of Guangdong(2017A030313608 to Q.L,2018A0303130299,2020A1515010608 to M.Y.)the Science and Technology Planning Project of Guangzhou(201804020044 to Q.L.)the Key Project of Liaoning Natural Science Funding of China(201702031 to Q.L.)Fundamental Research Funds for the Central Universities(I9ykpy187 to M.Y.).EW-FL's work is supported by MRC(MR/N012097/1)CRUK(Al 2011)Breast Cancer Now(2012MayPR070,2012NovPhD016)the Cancer Research UK Imperial Centre,Imperial ECMC,and NIHR Imperial BRC.
文摘Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)infection.Here,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA.Mechanistically,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone acetylation.HDAC inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft models.These fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.
基金This work was supported by the National Key R&D Program of China(2018YFC1312100)the National Natural Science Foundation Fund(81772490)+1 种基金the National Key R&D Program of China(2020YFQ002705)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Grants 2016-I2M-1-001,2017-I2M-3-004,and 2019-I2M-1-003).
文摘Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined.Here,we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1(AFB1)targets.Among the most significant hits was the aryl hydrocarbon receptor(AHR),a ligand-binding transcription factor regulating cell metabolism,differentiation,and immunity.
基金supported by the Key Research Program of the Chinese Academy of Sciences under Grant KJZD-SW-L05 to Yixin Zeng and KJZD-SW-L05-04 to Hairong Chenthe Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Nos.ZYYCXTD-D-202001)to Jun Wang。
文摘Tongue-coating microbiome,as a part of oral microbiome,is an important part of commensal microbes in human body.Despite technical difficulties in gaining functional insights using metagenomic approaches due to high levels of host DNA contaminations,a number of diseases have been found to be closely related to the alteration of oral microbial communities,including periodontal and caries diseases,cardiovascular disease,diabetes,rheumatoid arthritis.
文摘Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistake occurred during the production process in Fig.7 that needs to be corrected.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.
基金supported by the National Natural Science Foundation Fund(81472559,81772490)the National Key R&D Program of China(2020YFC2002705,2018YFC0115204)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Grants 2016-I2M-1-001,2017-I2M-3-004,and 2019-I2M-1-003).
文摘Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent.However,the lack of a clear understanding of the indications of metformin limits its efficacy.Here,we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin.Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment(T18)compared to those of the untreated cells at day 0(T0)yielded candidate genes.Knockdown of a group of cyclin-dependent kinases(CDKs),including CDK1,CDK4,and CDK6,confirmed the results of the screen.Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo.Although cell cycle parameters were not further altered under the combination treatment,investigation of the metabolome revealed significant changes in cell metabolism,especially with regard to fatty acid oxidation,the tricarboxylic acid cycle and aspartate metabolism.Such changes appeared to be mediated through inhibition of the mTOR pathway.Collectively,our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.
文摘Cancer is a leading cause of death in China with an estima- tion of nearly 2 million deaths every year （Chen and Fu, 2011b）. Matter of a public health importance in China and worldwide, the scientific community is still facing many obstacles to eradicate cancer： complexity of a mul- ti-factorial disease with organ-based specificities, high fail- ure rate of many anti-cancer drugs in clinical trials, lack of understanding of the cancer genesis factors.
文摘Various molecular analytical techniques have provided more and more information which is necessary for the accurate classification of diseases.Such information has enabled researchers to shift from morphology-based classification to molecular characteristics-based classification,also known as molecular classification.Molecular classifications of diseases can be carried out at the DNA,RNA,and protein levels.At the DNA level,for example,molecular classification can be done based on genetic mutation,polymorphisms,cytogenetic changes in genomes or DNA methylation differences.
文摘Nasopharyngeal carcinoma （NPC） was mostly common in Guangdong Province and Guangxi Chuang Autonomous Region. This cancer jeopardized people＇s health in the above areas. In order to understand the mechanisms for NPC, and further promote NPC＇s early diagnosis and therapy, the molecular genetic analysis research of NPC in China and in its outbreak areas becomes an emergent topic. Since NPC is a rare disease in developed countries of Europe and America, the research in this field has not been well-recognized in these countries. Furthermore,
