Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However...Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity.We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.Methods We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1.Then,we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1.Furthermore,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.Results We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and UL39.Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor cells.More importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.Conclusions Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.展开更多
The discovery of the Higgs boson with its mass around 125 GeV by the ATLAS and CMS Collaborations marked the beginning of a new era in high energy physics.The Higgs boson will be the subject of extensive studies of th...The discovery of the Higgs boson with its mass around 125 GeV by the ATLAS and CMS Collaborations marked the beginning of a new era in high energy physics.The Higgs boson will be the subject of extensive studies of the ongoing LHC program.At the same time,lepton collider based Higgs factories have been proposed as a possible next step beyond the LHC,with its main goal to precisely measure the properties of the Higgs boson and probe potential new physics associated with the Higgs boson.The Circular Electron Positron Collider(CEPC)is one of such proposed Higgs factories.The CEPC is an e^+e^- circular collider proposed by and to be hosted in China.Located in a tunnel of approximately 100 km in circumference,it will operate at a center-of-mass energy of 240 GeV as the Higgs factory.In this paper,we present the first estimates on the precision of the Higgs boson property measurements achievable at the CEPC and discuss implications of these measurements.展开更多
In the version of this article initially published,a grant name and the acknowledgment information were missing.The grant name and acknowledgment information have been added at the end of Acknowledgments:J.L.is suppor...In the version of this article initially published,a grant name and the acknowledgment information were missing.The grant name and acknowledgment information have been added at the end of Acknowledgments:J.L.is supported by WU Jieping Medical Foundation(320.6750.2021-17-12).We thank Dr.Chunfu Zheng for providing the HSV-1 BAC plasmid.The results and conclusions were not affected.展开更多
基金This project was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-047 and 2019-I2M-5-049)National Science Funds of China(82073181,81802870 and 82102371)+5 种基金Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-PT310-006,2019XK310002 and 2018TX31001)as well as NIH R01AI069120,AI158154,and AI140718 grants,the UCLA AIDS InstituteUCLA David Geffen School of Medicine-Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award ProgramH.Y.is supported by science funds from Jiangsu Province(BK20211554,BK20170407)the Innovative and Entrepreneurial Team grant(2018-2021)from Jiangsu ProvinceL.L.is supported by Innovative and Entrepreneurial Doctor grant(2020-2022)from Jiangsu Province.
文摘Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity.We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.Methods We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1.Then,we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1.Furthermore,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.Results We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and UL39.Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor cells.More importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.Conclusions Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.
基金Supported by the National Key Program for S&T Researh and Development(2016YFA0400400)CAS Center for Excellence in Particle Physics+12 种基金Yifang Wang’s Science Studio of the Ten Thousand Talents Projectthe CAS/SAFEA International Partnership Program for Creative Research Teams(H751S018S5)IHEP Innovation Grant(Y4545170Y2)Key Research Program of Frontier Sciences,CAS(XQYZDY-SSW-SLH002)Chinese Academy of Science Special Grant for Large Scientific Project(113111KYSB20170005)the National Natural Science Foundation of China(11675202)the Hundred Talent Programs of Chinese Academy of Science(Y3515540U1)the National 1000 Talents Program of ChinaFermi Research Alliance,LLC(DE-AC02-07CH11359)the NSF(PHY1620074)by the Maryland Center for Fundamental Physics(MCFP)Tsinghua University Initiative Scientific Research Programthe Beijing Municipal Science and Technology Commission project(Z181100004218003)
文摘The discovery of the Higgs boson with its mass around 125 GeV by the ATLAS and CMS Collaborations marked the beginning of a new era in high energy physics.The Higgs boson will be the subject of extensive studies of the ongoing LHC program.At the same time,lepton collider based Higgs factories have been proposed as a possible next step beyond the LHC,with its main goal to precisely measure the properties of the Higgs boson and probe potential new physics associated with the Higgs boson.The Circular Electron Positron Collider(CEPC)is one of such proposed Higgs factories.The CEPC is an e^+e^- circular collider proposed by and to be hosted in China.Located in a tunnel of approximately 100 km in circumference,it will operate at a center-of-mass energy of 240 GeV as the Higgs factory.In this paper,we present the first estimates on the precision of the Higgs boson property measurements achievable at the CEPC and discuss implications of these measurements.
文摘In the version of this article initially published,a grant name and the acknowledgment information were missing.The grant name and acknowledgment information have been added at the end of Acknowledgments:J.L.is supported by WU Jieping Medical Foundation(320.6750.2021-17-12).We thank Dr.Chunfu Zheng for providing the HSV-1 BAC plasmid.The results and conclusions were not affected.
