The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironme...The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly understood.Here,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy.Our study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma composition.One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA.Furthermore,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins.Overall,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.展开更多
Background Immunization is a crucial preventive measure to safeguard children under five years old against a range of diseases.In China,the coverage rate of non-National Immunization Program(non-NIP)vaccines can be im...Background Immunization is a crucial preventive measure to safeguard children under five years old against a range of diseases.In China,the coverage rate of non-National Immunization Program(non-NIP)vaccines can be improved by leveraging the recommendation from public health workers.Hence,understanding the influencing factors of recommendation behaviors assume paramount importance.This study aims to investigate influencing factors of public health workers’recommendation behaviors towards non-NIP vaccines,with a particular emphasis on financial incentives.Methods A cross-sectional survey was conducted using a multi-stage sampling method in 2019 from August to October.627 public health workers were recruited from 148 community healthcare centers in ten provincial-level administrative divisions in China.An anonymous questionnaire was used to collect demographic information,attitudes towards vaccination,and recommendation behaviors towards non-NIP vaccines,includingHaemophilus influenzae type b(Hib)vaccine,pneumococcal conjugate vaccine,varicella vaccine,and rotavirus vaccine.Descriptive analysis and multivariate logistic regression analysis were adopted in this study.Results Of the 610 public health workers with complete survey data,53.8%,57.4%,84.1%,and 54.1%often recommended Hib vaccine,pneumococcal pneumonia vaccine(PCV),varicella vaccine,and rotavirus vaccine,respectively.Logistic regression revealed that gender(Hib vaccine:OR=0.4,95%CI:0.2-0.8;PCV:OR=0.4,95%CI:0.2-0.8;rotavirus vaccine:OR=0.3,95%CI:0.2-0.6),financial incentives for non-NIP vaccination(Hib vaccine:OR=1.9,95%CI:1.1-3.6;PCV:OR=2.1,95%CI:1.1-3.9;rotavirus vaccine:OR=2.0,95%CI:1.1-3.8)and perception of vaccine safety(Hib vaccine:OR=2.7,95%CI:1.1-7.0;PCV:OR=3.2,95%CI:1.2-8.0;rotavirus vaccine:OR=3.0,95%CI:1.2-7.7)were associated with public health workers’recommendation towards Hib vaccine,PCV and rotavirus vaccine.Conclusions The findings highlighted public health workers’recommendation behaviors of non-NIP vaccines in China and revealed strong association between vaccine recommendation and financial incentives.This highlights the importance of financial incentives in public health workers’recommendation toward non-NIP vaccines in China.Proper incentives are recommended for public health workers to encourage effective health promotion in immunization practices.展开更多
TP53 mutation(TP53^(mut))occurs in 10–20%of diffuse large B-cell lymphoma(DLBCL)cases and serves as an unfavorable biomarker of DLBCL progression.It confers resistance to immunochemotherapy,high-dose chemotherapy,aut...TP53 mutation(TP53^(mut))occurs in 10–20%of diffuse large B-cell lymphoma(DLBCL)cases and serves as an unfavorable biomarker of DLBCL progression.It confers resistance to immunochemotherapy,high-dose chemotherapy,autologous stem cell transplantation,and anti-CD19 chimeric antigen receptor T-cell therapy.Therapeutic targeting of TP53^(mut) remains a significant challenge in DLBCL treatment.Here we assessed TP53^(mut) in 667 patients with newly diagnosed DLBCL,including 576 patients treated with immunochemotherapy rituximab,cyclophosphamide,doxorubicin,vincristine,and prednisone(R-CHOP)and 91 patients with decitabine plus R-CHOP(DR-CHOP,NCT02951728 and NCT04025593).TP53^(mut) independently predicted an inferior prognosis in R-CHOP-treated DLBCL,although this could be mitigated by DR-CHOP treatment.In TP53^(mut) patients,multiple viral regulation pathways were repressed,resulting in the inhibition of immune modulation,as revealed by gene set enrichment analysis.TP53^(mut) DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation(H3K9me3),contributing to repression of endogenous retroviruses(ERVs)and immunosuppressive tumor microenvironment.In TP53^(mut) DLBCL cell lines,decitabine down-regulated SUV39H1,inhibited H3K9me3 occupancy on ERVs,and triggered ERV expression,thereby unleashing interferons program and CD4^(+)T/CD8^(+)T cell activation.Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression.In TP53^(mut) patient-derived xenograft models and TP53^(mut) patients,the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis.Collectively,our findings highlight an ERV regulatory circuitry in TP53^(mut) DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53^(mut)-driven cancers.展开更多
Dear Editor,Follicular lymphoma(FL)represents the most common subtype of indolent non-Hodgkin's lymphoma(NHL)with distinct pathological,cytogenetic,and molecular features,accounting for 9.7%of NHLs in China[1].FL ...Dear Editor,Follicular lymphoma(FL)represents the most common subtype of indolent non-Hodgkin's lymphoma(NHL)with distinct pathological,cytogenetic,and molecular features,accounting for 9.7%of NHLs in China[1].FL maintains a differentiation stage similar to germinal center(GC)B cells and is divided into grades 1,2,3A,and 3B[2].Up to 90%of FLs harbor the t(14;18)(q32;q21)/BCL2 apoptosis regula-tor(BCL2)-immunoglobulin heavy locus(IGH)transloca-tion and epigenetic modifier mutations,particularly lysine methyltransferase 2D(KMT2D)and CREB-binding pro-tein(CREBBP)[2].展开更多
We propose a computational workflow(I3)for intuitive integrative interpretation of complex genetic data mainly building on the self-organising principle.We illustrate the use in interpreting genetics of gene expressio...We propose a computational workflow(I3)for intuitive integrative interpretation of complex genetic data mainly building on the self-organising principle.We illustrate the use in interpreting genetics of gene expression and understanding genetic regulators of protein phenotypes,particularly in conjunction with information from human population genetics and/or evolutionary history of human genes.We reveal that loss-of-function intolerant genes tend to be depleted of tissue-sharing genetics of gene expression in brains,and if highly expressed,have broad effects on the protein phenotypes studied.We suggest that this workflow presents a general solution to the challenge of complex genetic data interpretation.I3 is available at http://suprahex.r-forge.r-project.org/I3.html.展开更多
基金supported by the State Key Laboratory of Medical Genomics,the Double First-Class Project(No.WF510162602)from the Ministry of Educationthe Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01)+5 种基金the Overseas Expertise Introduction Project for Discipline Innovation(111 Project,No.B17029)the National Natural Science Foundation of China(Nos.82230006 and 32170663)the Shanghai Clinical Research Center for Hematological disease(No.19MC1910700)the Shanghai Shenkang Hospital Development Center(No.SHDC2020CR5002)the Shanghai Major Project for Clinical Medicine(No.2017ZZ01002)the Innovative Research Team of High-level Local Universities in Shanghai and the Yangfan Program of the Science and Technology Commission of Shanghai Municipality(No.22YF1425500)。
文摘The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly understood.Here,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy.Our study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma composition.One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA.Furthermore,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins.Overall,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.
基金supported by the National Natural Science Foundation of China(82130004,81830007,and 82270194)the National Key Research and Development Program of China(2022YFC2502600)+7 种基金the Chang Jiang Scholars Program,the Shanghai Rising-Star Program(23QA1406100)the Shanghai Municipal Commission of Science and Technology Project(23141903100)the Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support(20152206,20152208,and 20161303)the Clinical Research Plan of Shanghai Hospital Development Center(SHDC 2020CR1032B)the Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine(DLY201601)the Multi-center Hematology-Oncology Protocols Evaluation System(M-HOPES)network from Chinathe Samuel Waxman Cancer Research Foundationthe Center for High Performance Computing at Shanghai Jiao Tong University。
基金This work was supported by the Bill&Melinda Gates Foundation(INV034554)。
文摘Background Immunization is a crucial preventive measure to safeguard children under five years old against a range of diseases.In China,the coverage rate of non-National Immunization Program(non-NIP)vaccines can be improved by leveraging the recommendation from public health workers.Hence,understanding the influencing factors of recommendation behaviors assume paramount importance.This study aims to investigate influencing factors of public health workers’recommendation behaviors towards non-NIP vaccines,with a particular emphasis on financial incentives.Methods A cross-sectional survey was conducted using a multi-stage sampling method in 2019 from August to October.627 public health workers were recruited from 148 community healthcare centers in ten provincial-level administrative divisions in China.An anonymous questionnaire was used to collect demographic information,attitudes towards vaccination,and recommendation behaviors towards non-NIP vaccines,includingHaemophilus influenzae type b(Hib)vaccine,pneumococcal conjugate vaccine,varicella vaccine,and rotavirus vaccine.Descriptive analysis and multivariate logistic regression analysis were adopted in this study.Results Of the 610 public health workers with complete survey data,53.8%,57.4%,84.1%,and 54.1%often recommended Hib vaccine,pneumococcal pneumonia vaccine(PCV),varicella vaccine,and rotavirus vaccine,respectively.Logistic regression revealed that gender(Hib vaccine:OR=0.4,95%CI:0.2-0.8;PCV:OR=0.4,95%CI:0.2-0.8;rotavirus vaccine:OR=0.3,95%CI:0.2-0.6),financial incentives for non-NIP vaccination(Hib vaccine:OR=1.9,95%CI:1.1-3.6;PCV:OR=2.1,95%CI:1.1-3.9;rotavirus vaccine:OR=2.0,95%CI:1.1-3.8)and perception of vaccine safety(Hib vaccine:OR=2.7,95%CI:1.1-7.0;PCV:OR=3.2,95%CI:1.2-8.0;rotavirus vaccine:OR=3.0,95%CI:1.2-7.7)were associated with public health workers’recommendation towards Hib vaccine,PCV and rotavirus vaccine.Conclusions The findings highlighted public health workers’recommendation behaviors of non-NIP vaccines in China and revealed strong association between vaccine recommendation and financial incentives.This highlights the importance of financial incentives in public health workers’recommendation toward non-NIP vaccines in China.Proper incentives are recommended for public health workers to encourage effective health promotion in immunization practices.
基金the National Natural Science Foundation of China(81830007,82130004,82170178,82200201,and 82070204)National Key R&D Program of China(2022YFC2502600)+4 种基金Chang Jiang Scholars Program,Shanghai Commission of Science and Technology(17PJ1405800)Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support(20152206,20152208,and 20171902)Clinical Research Plan of Shanghai hospital development center(SHDC,2020CR1032B)Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine(DLY201601)Samuel Waxman Cancer Research Foundation,and the Foundation of National Facility for Translational Medicine(Shanghai,TMSK-2020-115).
文摘TP53 mutation(TP53^(mut))occurs in 10–20%of diffuse large B-cell lymphoma(DLBCL)cases and serves as an unfavorable biomarker of DLBCL progression.It confers resistance to immunochemotherapy,high-dose chemotherapy,autologous stem cell transplantation,and anti-CD19 chimeric antigen receptor T-cell therapy.Therapeutic targeting of TP53^(mut) remains a significant challenge in DLBCL treatment.Here we assessed TP53^(mut) in 667 patients with newly diagnosed DLBCL,including 576 patients treated with immunochemotherapy rituximab,cyclophosphamide,doxorubicin,vincristine,and prednisone(R-CHOP)and 91 patients with decitabine plus R-CHOP(DR-CHOP,NCT02951728 and NCT04025593).TP53^(mut) independently predicted an inferior prognosis in R-CHOP-treated DLBCL,although this could be mitigated by DR-CHOP treatment.In TP53^(mut) patients,multiple viral regulation pathways were repressed,resulting in the inhibition of immune modulation,as revealed by gene set enrichment analysis.TP53^(mut) DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation(H3K9me3),contributing to repression of endogenous retroviruses(ERVs)and immunosuppressive tumor microenvironment.In TP53^(mut) DLBCL cell lines,decitabine down-regulated SUV39H1,inhibited H3K9me3 occupancy on ERVs,and triggered ERV expression,thereby unleashing interferons program and CD4^(+)T/CD8^(+)T cell activation.Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression.In TP53^(mut) patient-derived xenograft models and TP53^(mut) patients,the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis.Collectively,our findings highlight an ERV regulatory circuitry in TP53^(mut) DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53^(mut)-driven cancers.
基金The research described here was supported by the Program of the China Postdoctoral Science Foundation(Grant No.2021M690264 and 2021T140031)the Youth Talent Cultivation Program of Jiangsu University,and the State Key Laboratory of Special Functional Waterproof Materials(No.SKWL-2021KF10).
基金by research fund-ing from the National Natural Science Foundation of China(81830007 and 81900193)Chang Jiang Scholars Program,Shanghai Municipal Education Commission Gaofeng Clinical Medicine(20152206 and 20152208)+1 种基金Shanghai Sailing Program(19YF1430900),Clinical Research Plan of Shanghai Hospital Development Center(SHDC2020CR1032B)and Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine(DLY201601).
文摘Dear Editor,Follicular lymphoma(FL)represents the most common subtype of indolent non-Hodgkin's lymphoma(NHL)with distinct pathological,cytogenetic,and molecular features,accounting for 9.7%of NHLs in China[1].FL maintains a differentiation stage similar to germinal center(GC)B cells and is divided into grades 1,2,3A,and 3B[2].Up to 90%of FLs harbor the t(14;18)(q32;q21)/BCL2 apoptosis regula-tor(BCL2)-immunoglobulin heavy locus(IGH)transloca-tion and epigenetic modifier mutations,particularly lysine methyltransferase 2D(KMT2D)and CREB-binding pro-tein(CREBBP)[2].
基金the National Natural Science Foundation of China(Grant No.31301041 awarded to HF,and Grant Nos.81530003 and 81770153 awarded to KW).
文摘We propose a computational workflow(I3)for intuitive integrative interpretation of complex genetic data mainly building on the self-organising principle.We illustrate the use in interpreting genetics of gene expression and understanding genetic regulators of protein phenotypes,particularly in conjunction with information from human population genetics and/or evolutionary history of human genes.We reveal that loss-of-function intolerant genes tend to be depleted of tissue-sharing genetics of gene expression in brains,and if highly expressed,have broad effects on the protein phenotypes studied.We suggest that this workflow presents a general solution to the challenge of complex genetic data interpretation.I3 is available at http://suprahex.r-forge.r-project.org/I3.html.
