Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical b...Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice.Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes.The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities.In this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies.We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy.Specifically,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.展开更多
Atherosclerosis(AS)is the main underlyingpathology of atherosclerotic cardiovascular disease(ASCVD),which is the leading cause of mortality inthe worldwide[1,2].Since the 19th century,Virchowhas already stated that AS...Atherosclerosis(AS)is the main underlyingpathology of atherosclerotic cardiovascular disease(ASCVD),which is the leading cause of mortality inthe worldwide[1,2].Since the 19th century,Virchowhas already stated that AS is a chronic inflammatorystate induced by cholesterol.After that,it took at leastthree decades’worth of study to establish the multipleinflammatory pathways related to AS.展开更多
Neoatherosclerosis(NA)within stents has become an important clinical problem after coronary artery stent implantation.In-stent restenosis and in-stent thrombosis are the two major complications following coronary sten...Neoatherosclerosis(NA)within stents has become an important clinical problem after coronary artery stent implantation.In-stent restenosis and in-stent thrombosis are the two major complications following coronary stent placement and seriously affect patient prognosis.As the common pathological basis of these two complications,NA plaques,unlike native atherosclerotic plaques,often grow around residual oxidized lipids and stent struts.The main components are foam cells formed by vascular smooth muscle cells(VSMCs)engulfing oxidized lipids at lipid residue sites.Current research mainly focuses on optical coherence tomography(OCT)and intravascular ultrasound(IVUS),but the specific pathogenesis of NA is still unclear.A thorough understanding of the pathogenesis and pathological features of NA provides a theoretical basis for clinical treatment.This article reviews the previous research of our research group and the current situation of domestic and foreign research.展开更多
Objective Vascular smooth muscle cell(VSMC)differentiation from stem cells is one source of the increasing number of VSMCs that are involved in vascular remodeling-related diseases such as hypertension,atherosclerosis...Objective Vascular smooth muscle cell(VSMC)differentiation from stem cells is one source of the increasing number of VSMCs that are involved in vascular remodeling-related diseases such as hypertension,atherosclerosis,and restenosis.MicroRNA-146a(miR-146a)has been proven to be involved in cell proliferation,migration,and tumor metabolism.However,little is known about the functional role of miR-146a in VSMC differentiation from embryonic stem cells(ESCs).This study aimed to determine the role of miR-146a in VSMC differentiation from ESCs.Methods Mouse ESCs were differentiated into VSMCs,and the cell extracts were analyzed by Western blotting and RT-qPCR.In addition,luciferase reporter assays using ESCs transfected with miR-146a/mimic and plasmids were performed.Finally,C57BL/6J female mice were injected with mimic or miR-146a-overexpressing ESCs,and immunohistochemistry,Western blotting,and RT-qPCR assays were carried out on tissue samples from these mice.Results miR-146a was significantly upregulated during VSMC differentiation,accompanied with the VSMC-specific marker genes smooth muscle-alpha-actin(SMαA),smooth muscle 22(SM22),smooth muscle myosin heavy chain(SMMHC),and h1-calponin.Furthermore,overexpression of miR-146a enhanced the differentiation process in vitro and in vivo.Concurrently,the expression of Kruppel-like factor 4(KLF4),predicted as one of the top targets of miR-146a,was sharply decreased in miR-146a-overexpressing ESCs.Importantly,inhibiting KLF4 expression enhanced the VSMC-specific gene expression induced by miR-146a overexpression in differentiating ESCs.In addition,miR-146a upregulated the mRNA expression levels and transcriptional activity of VSMC differentiation-related transcription factors,including serum response factor(SRF)and myocyte enhancer factor 2c(MEF-2c).Conclusion Our data support that miR-146a promotes ESC-VSMC differentiation through regulating KLF4 and modulating the transcription factor activity of VSMCs.展开更多
Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoi...Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.展开更多
This study examined the changes of activities of vitamin K-dependent clotting factors(VKDCF) under various pathological conditions and explored the relationship between acquired deficiency of VKDCFs and hemorrhage.Cli...This study examined the changes of activities of vitamin K-dependent clotting factors(VKDCF) under various pathological conditions and explored the relationship between acquired deficiency of VKDCFs and hemorrhage.Clinical data of 35 patients who were diagnosed as having acquired deficiency of VKDCF were retrospectively analyzed.Coagulation factors involved in the intrinsic and extrinsic pathways were detected in these patients and 41 control subjects.The results showed that the average activities of VKDCFs were decreased in the patients in comparison to the control subjects and significantly increased after treatment of these patients with vitamin K and blood products.Multivariate regression analysis indicated that decreased activity of VKDCF was not an independent risk factor for bleeding disorders owing to deficiency or metabolic disturbance of vitamin K.It was concluded that acquired deficiency of VKDCF occurs under a variety of pathologic conditions and is closely associated with hemorrhagic events.Administration of vitamin K and transfusion of blood products containing high concentrations of VKDCFs helps alleviate the hemorrhagic diseases.展开更多
Since the discovery of Stimulator of Interferon Genes(STING)as an important pivot for cytosolic DNA sensation and interferon(IFN)induction,intensive efforts have been endeavored to clarify the molecular mechanism of i...Since the discovery of Stimulator of Interferon Genes(STING)as an important pivot for cytosolic DNA sensation and interferon(IFN)induction,intensive efforts have been endeavored to clarify the molecular mechanism of its activation,its physiological function as a ubiquitously expressed protein,and to explore its potential as a therapeutic target in a wide range of immune-related diseases.With its orthodox ligand 2’3’-cyclic GMP–AMP(2’3’-cGAMP)and the upstream sensor 2’3’-cGAMP synthase(cGAS)to be found,STING acquires its central functionality in the best-studied signaling cascade,namely the cGAS–STING–IFN pathway.However,recently updated research through structural research,genetic screening,and biochemical assay greatly extends the current knowledge of STING biology.A second ligand pocket was recently discovered in the transmembrane domain for a synthetic agonist.On its downstream outputs,accumulating studies sketch primordial and multifaceted roles of STING beyond its cytokine-inducing function,such as autophagy,cell death,metabolic modulation,endoplasmic reticulum(ER)stress,and RNA virus restriction.Furthermore,with the expansion of the STING interactome,the details of STING trafficking also get clearer.After retrospecting the brief history of viral interference and the milestone events since the discovery of STING,we present a vivid panorama of STING biology taking into account the details of the biochemical assay and structural information,especially its versatile outputs and functions beyond IFN induction.We also summarize the roles of STING in the pathogenesis of various diseases and highlight the development of small-molecular compounds targeting STING for disease treatment in combination with the latest research.Finally,we discuss the open questions imperative to answer.展开更多
Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T...Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood.This study aims to explore the molecular deter-minants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.Methods:The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing.The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells.In addition,the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models.Results:The CRISPR/Cas9-based knockout screening showed that the enrich-ment of autophagy-related genes(ATG3,BECN1,and RB1CC1)provided protec-tion of cancer cells from CD19 CAR-T cell-mediated cytotoxicity.These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy.Notably,higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer respon-siveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy.Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell ther-apy.Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma.Moreover,our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation.Conclusions:These findings confirm that autophagy signaling in B-cell malig-nancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.展开更多
Human microorganisms,including bacteria,fungi,and viruses,play key roles in several physiological and pathological processes.Some studies discovered that tumour tissues once considered sterile actually host a variety ...Human microorganisms,including bacteria,fungi,and viruses,play key roles in several physiological and pathological processes.Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms,which have been confirmed to be closely related to oncogenesis.The concept of intratumoural microbiota was subsequently proposed.Microbiota could colonise tumour tissues through mucosal destruction,adjacent tissue migration,and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment.Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations,affecting epigenetic modifications,promoting inflammation response,avoiding immune destruction,regulating metabolism,and activating invasion and metastasis.Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging,new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination.In addition,interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy,especially immunotherapy,although there are some inevitable challenges.Here,we aim to provide an extensive review of the concept,development history,potential sources,heterogeneity,and carcinogenic mechanisms of intratumoural microorganisms,explore the potential role of microorganisms in tumour prognosis,and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.展开更多
To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithromb...To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithrombin （TAT） complex. Thirty normal pregnant women served as controls. ELISA was employed for the detection. The results showed that the TAFI antigen levels in normal pregnancy group, gestational hypertension group and PE group were （85.35±24.69）%, （99.65±18.27）%, （110.12±23.36）%; （97.06±21.40）%, （114.08±27.76）%, （125.49±24.70）%; （106.6±19.21）%, （129.2±25.07）%, （139.1±30.12）%, in the 1st, 2nd and 3rd trimester respectively. No significant differences were found between the normal pregnancy group and gestational hypertension group but significant difference existed between normal pregnancy group and PE group in each trimester （P〈0.05）. TAT complexes were significantly higher in patients with PE than that in controls （P〈0.05）, but no correlation was found between TAT and TAFI. It is concluded that TAFI may contributed to the impairment of fibrinolysis in the patients with PE and may serves as a sensitive indicator for PE, but it may not help in the diagnosis of the gestational hypertension.展开更多
The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,which has accelerated the progress of immunotherapy.S...The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,which has accelerated the progress of immunotherapy.Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers,including stem cell transplantation,immune checkpoint inhibitors,antigen-targeted antibodies,antibody-drug conjugates,tumor vaccines,and adoptive cell therapies.These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success.Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed.To provide clinicians with timely information on these revolutionary therapeutic approaches,the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy.Here,we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies.We further discuss the specific mechanisms of action,summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies,as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.展开更多
Myocardial ischemia–reperfusion injury(MIRI)is a major hindrance to the success of cardiac reperfusion therapy.Although increased neutrophil infiltration is a hallmark of MIRI,the subtypes and alterations of neutroph...Myocardial ischemia–reperfusion injury(MIRI)is a major hindrance to the success of cardiac reperfusion therapy.Although increased neutrophil infiltration is a hallmark of MIRI,the subtypes and alterations of neutrophils in this process remain unclear.Here,we performed single-cell sequencing of cardiac CD45^(+)cells isolated from the murine myocardium subjected to MIRI at six-time points.We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI.Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations,including Ccl3^(hi)Neu and Ym-1^(hi)Neu,which were increased at 6 h and 1 d after reperfusion,respectively.Ym-1^(hi)Neu selectively expressed genes with protective effects and was,therefore,identified as a novel specific type of cardiac cell in the injured heart.Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues,especially instructing the response of macrophages.The abundance of Ym-1^(hi)Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D(Ly6G)or anti-Intercellular cell adhesion molecule-1(ICAM-1)neutralizing antibodies.In addition,a neutrophil subtype with the same phenotype as Ym-1^(hi)Neu was detected in clinical samples and correlated with prognosis.Ym-1 inhibition exacerbated myocardial injury,whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice,which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue.Overall,our findings reveal the antiinflammatory phenotype of Ym-1^(hi)Neu and highlight its critical role in myocardial protection during the early stages of MIRI.展开更多
Heart failure(HF)remains a rising global epidemic worldwide[1,2].It is widely recognized that immune cells play important roles in the pathogenesis of HF.The hearts of HF patients are characterized by persistent low-g...Heart failure(HF)remains a rising global epidemic worldwide[1,2].It is widely recognized that immune cells play important roles in the pathogenesis of HF.The hearts of HF patients are characterized by persistent low-grade inflammation,which has been linked to adverse ventricular remodeling as it promotes interstitial fibrosis and cardiomyocyte dysfunction and loss.展开更多
Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases(CVDs).Regulatory T cells(Tregs)are typical immune regulatory cells with recognized immunosuppressive properties.Despi...Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases(CVDs).Regulatory T cells(Tregs)are typical immune regulatory cells with recognized immunosuppressive properties.Despite the immunosuppressive properties,researchers have acknowledged the significance of Tregs in maintaining tissue homeostasis and facilitating repair/regeneration.Previous studies unveiled the heterogeneity of Tregs in the heart and aorta,which expanded in CVDs with unique transcriptional phenotypes and reparative/regenerative function.This review briefly summarizes the functional principles of Tregs,also including the synergistic effect of Tregs and other immune cells in CVDs.We discriminate the roles and therapeutic potential of Tregs in CVDs such as atherosclerosis,hypertension,abdominal arterial aneurysm,pulmonary arterial hypertension,Kawasaki disease,myocarditis,myocardial infarction,and heart failure.Tregs not only exert anti-inflammatory effects but also actively promote myocardial regeneration and vascular repair,maintaining the stability of the local microenvironment.Given that the specific mechanism of Tregs functioning in CVDs remains unclear,we reviewed previous clinical and basic studies and the latest findings on the function and mechanism of Tregs in CVDs.展开更多
基金National Key Research and Development Program of China(2022YFC2502700)National Natural Science Foundation of China(8187343482100190).
文摘Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice.Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes.The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities.In this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies.We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy.Specifically,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.
文摘Atherosclerosis(AS)is the main underlyingpathology of atherosclerotic cardiovascular disease(ASCVD),which is the leading cause of mortality inthe worldwide[1,2].Since the 19th century,Virchowhas already stated that AS is a chronic inflammatorystate induced by cholesterol.After that,it took at leastthree decades’worth of study to establish the multipleinflammatory pathways related to AS.
基金supported by grants from the National Natural Science Foundation of China(Nos.82070376 and 81873491).
文摘Neoatherosclerosis(NA)within stents has become an important clinical problem after coronary artery stent implantation.In-stent restenosis and in-stent thrombosis are the two major complications following coronary stent placement and seriously affect patient prognosis.As the common pathological basis of these two complications,NA plaques,unlike native atherosclerotic plaques,often grow around residual oxidized lipids and stent struts.The main components are foam cells formed by vascular smooth muscle cells(VSMCs)engulfing oxidized lipids at lipid residue sites.Current research mainly focuses on optical coherence tomography(OCT)and intravascular ultrasound(IVUS),but the specific pathogenesis of NA is still unclear.A thorough understanding of the pathogenesis and pathological features of NA provides a theoretical basis for clinical treatment.This article reviews the previous research of our research group and the current situation of domestic and foreign research.
基金funded by the National Natural Science Foundation of China(No.82070376 and No.81873491)the Natural Science Foundation of Zhejiang Province(No.LY21H020005)+1 种基金the Zhejiang Medical Science and Technology Project(No.2019KY376 and No.2018KY071)a Ningbo Science and Technology Project(No.202002N3173).
文摘Objective Vascular smooth muscle cell(VSMC)differentiation from stem cells is one source of the increasing number of VSMCs that are involved in vascular remodeling-related diseases such as hypertension,atherosclerosis,and restenosis.MicroRNA-146a(miR-146a)has been proven to be involved in cell proliferation,migration,and tumor metabolism.However,little is known about the functional role of miR-146a in VSMC differentiation from embryonic stem cells(ESCs).This study aimed to determine the role of miR-146a in VSMC differentiation from ESCs.Methods Mouse ESCs were differentiated into VSMCs,and the cell extracts were analyzed by Western blotting and RT-qPCR.In addition,luciferase reporter assays using ESCs transfected with miR-146a/mimic and plasmids were performed.Finally,C57BL/6J female mice were injected with mimic or miR-146a-overexpressing ESCs,and immunohistochemistry,Western blotting,and RT-qPCR assays were carried out on tissue samples from these mice.Results miR-146a was significantly upregulated during VSMC differentiation,accompanied with the VSMC-specific marker genes smooth muscle-alpha-actin(SMαA),smooth muscle 22(SM22),smooth muscle myosin heavy chain(SMMHC),and h1-calponin.Furthermore,overexpression of miR-146a enhanced the differentiation process in vitro and in vivo.Concurrently,the expression of Kruppel-like factor 4(KLF4),predicted as one of the top targets of miR-146a,was sharply decreased in miR-146a-overexpressing ESCs.Importantly,inhibiting KLF4 expression enhanced the VSMC-specific gene expression induced by miR-146a overexpression in differentiating ESCs.In addition,miR-146a upregulated the mRNA expression levels and transcriptional activity of VSMC differentiation-related transcription factors,including serum response factor(SRF)and myocyte enhancer factor 2c(MEF-2c).Conclusion Our data support that miR-146a promotes ESC-VSMC differentiation through regulating KLF4 and modulating the transcription factor activity of VSMCs.
基金Supported by a grant from the National Natural Science Founda-tion of China(no.82200319).
文摘Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.
基金supported by grants from the Ministry of Health of China(No.[2007]353)the National Natural Sciences Foundation of China (N0.30700332)+1 种基金the National Outstanding Youth Foundation(No.30825018)the National Basic Research Program(973 Program,No.2007CB935803)
文摘This study examined the changes of activities of vitamin K-dependent clotting factors(VKDCF) under various pathological conditions and explored the relationship between acquired deficiency of VKDCFs and hemorrhage.Clinical data of 35 patients who were diagnosed as having acquired deficiency of VKDCF were retrospectively analyzed.Coagulation factors involved in the intrinsic and extrinsic pathways were detected in these patients and 41 control subjects.The results showed that the average activities of VKDCFs were decreased in the patients in comparison to the control subjects and significantly increased after treatment of these patients with vitamin K and blood products.Multivariate regression analysis indicated that decreased activity of VKDCF was not an independent risk factor for bleeding disorders owing to deficiency or metabolic disturbance of vitamin K.It was concluded that acquired deficiency of VKDCF occurs under a variety of pathologic conditions and is closely associated with hemorrhagic events.Administration of vitamin K and transfusion of blood products containing high concentrations of VKDCFs helps alleviate the hemorrhagic diseases.
基金supported by the National Key Research and Development Program of China(No.2019YFC1316204)the National Natural Science Foundation of China(Nos.81974249,82070136).
文摘Since the discovery of Stimulator of Interferon Genes(STING)as an important pivot for cytosolic DNA sensation and interferon(IFN)induction,intensive efforts have been endeavored to clarify the molecular mechanism of its activation,its physiological function as a ubiquitously expressed protein,and to explore its potential as a therapeutic target in a wide range of immune-related diseases.With its orthodox ligand 2’3’-cyclic GMP–AMP(2’3’-cGAMP)and the upstream sensor 2’3’-cGAMP synthase(cGAS)to be found,STING acquires its central functionality in the best-studied signaling cascade,namely the cGAS–STING–IFN pathway.However,recently updated research through structural research,genetic screening,and biochemical assay greatly extends the current knowledge of STING biology.A second ligand pocket was recently discovered in the transmembrane domain for a synthetic agonist.On its downstream outputs,accumulating studies sketch primordial and multifaceted roles of STING beyond its cytokine-inducing function,such as autophagy,cell death,metabolic modulation,endoplasmic reticulum(ER)stress,and RNA virus restriction.Furthermore,with the expansion of the STING interactome,the details of STING trafficking also get clearer.After retrospecting the brief history of viral interference and the milestone events since the discovery of STING,we present a vivid panorama of STING biology taking into account the details of the biochemical assay and structural information,especially its versatile outputs and functions beyond IFN induction.We also summarize the roles of STING in the pathogenesis of various diseases and highlight the development of small-molecular compounds targeting STING for disease treatment in combination with the latest research.Finally,we discuss the open questions imperative to answer.
基金National Key R&D Program of China,Grant/Award Number:2022YFC2502700National Natural Science Foundation of China,Grant/Award Numbers:81873434,82100190,82200145China Postdoctoral Innovative Talent Support Foundation,Grant/Award Number:BX2021106
文摘Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood.This study aims to explore the molecular deter-minants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.Methods:The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing.The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells.In addition,the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models.Results:The CRISPR/Cas9-based knockout screening showed that the enrich-ment of autophagy-related genes(ATG3,BECN1,and RB1CC1)provided protec-tion of cancer cells from CD19 CAR-T cell-mediated cytotoxicity.These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy.Notably,higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer respon-siveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy.Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell ther-apy.Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma.Moreover,our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation.Conclusions:These findings confirm that autophagy signaling in B-cell malig-nancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.
基金supported by the National Natural Science Foundation of China(No.82330003,No.82070099,No.82102496,No.82001988)National Science and Technology Major Project of the Ministry of Science and Technology of China(2022YFF1203300)+1 种基金Major Project of the Department of Science and Technology of Hubei(2022BCA016)Hubei Key Laboratory of Biological Targeted Therapy(2022swbx009).
文摘Human microorganisms,including bacteria,fungi,and viruses,play key roles in several physiological and pathological processes.Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms,which have been confirmed to be closely related to oncogenesis.The concept of intratumoural microbiota was subsequently proposed.Microbiota could colonise tumour tissues through mucosal destruction,adjacent tissue migration,and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment.Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations,affecting epigenetic modifications,promoting inflammation response,avoiding immune destruction,regulating metabolism,and activating invasion and metastasis.Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging,new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination.In addition,interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy,especially immunotherapy,although there are some inevitable challenges.Here,we aim to provide an extensive review of the concept,development history,potential sources,heterogeneity,and carcinogenic mechanisms of intratumoural microorganisms,explore the potential role of microorganisms in tumour prognosis,and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.
基金a grant from the Key Program of Clinical Sciences of Ministry of Health of China (No. WGCF468)
文摘To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithrombin （TAT） complex. Thirty normal pregnant women served as controls. ELISA was employed for the detection. The results showed that the TAFI antigen levels in normal pregnancy group, gestational hypertension group and PE group were （85.35±24.69）%, （99.65±18.27）%, （110.12±23.36）%; （97.06±21.40）%, （114.08±27.76）%, （125.49±24.70）%; （106.6±19.21）%, （129.2±25.07）%, （139.1±30.12）%, in the 1st, 2nd and 3rd trimester respectively. No significant differences were found between the normal pregnancy group and gestational hypertension group but significant difference existed between normal pregnancy group and PE group in each trimester （P〈0.05）. TAT complexes were significantly higher in patients with PE than that in controls （P〈0.05）, but no correlation was found between TAT and TAFI. It is concluded that TAFI may contributed to the impairment of fibrinolysis in the patients with PE and may serves as a sensitive indicator for PE, but it may not help in the diagnosis of the gestational hypertension.
基金This work was supported by grants from the National Key R&D Program of China(2022YFC2502700)the National Natural Science Foundation of China(81873434+1 种基金82100190)the China Postdoctoral Innovative Talent Support Foundation(BX2021106).All the figures were created by the website tool BioRender(https://www.biorender.com/).
文摘The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,which has accelerated the progress of immunotherapy.Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers,including stem cell transplantation,immune checkpoint inhibitors,antigen-targeted antibodies,antibody-drug conjugates,tumor vaccines,and adoptive cell therapies.These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success.Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed.To provide clinicians with timely information on these revolutionary therapeutic approaches,the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy.Here,we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies.We further discuss the specific mechanisms of action,summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies,as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.
基金supported by the National Natural Science Foundation of China(82022076,81974249,82070136,82104488,and 82305194)the Postdoctoral Science Foundation of China(2023M731222,and 2020T130040ZX)the Foundation of Hubei Key Laboratory of Biological Targeted Therapy(2023swbx021)。
文摘Myocardial ischemia–reperfusion injury(MIRI)is a major hindrance to the success of cardiac reperfusion therapy.Although increased neutrophil infiltration is a hallmark of MIRI,the subtypes and alterations of neutrophils in this process remain unclear.Here,we performed single-cell sequencing of cardiac CD45^(+)cells isolated from the murine myocardium subjected to MIRI at six-time points.We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI.Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations,including Ccl3^(hi)Neu and Ym-1^(hi)Neu,which were increased at 6 h and 1 d after reperfusion,respectively.Ym-1^(hi)Neu selectively expressed genes with protective effects and was,therefore,identified as a novel specific type of cardiac cell in the injured heart.Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues,especially instructing the response of macrophages.The abundance of Ym-1^(hi)Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D(Ly6G)or anti-Intercellular cell adhesion molecule-1(ICAM-1)neutralizing antibodies.In addition,a neutrophil subtype with the same phenotype as Ym-1^(hi)Neu was detected in clinical samples and correlated with prognosis.Ym-1 inhibition exacerbated myocardial injury,whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice,which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue.Overall,our findings reveal the antiinflammatory phenotype of Ym-1^(hi)Neu and highlight its critical role in myocardial protection during the early stages of MIRI.
基金supported by grants from the National Natural Science Foundation of China(82030016,82230011,82170394,82300447 and 82170282)the Department of Science and Technology of Hubei Province(2023AFA113).
文摘Heart failure(HF)remains a rising global epidemic worldwide[1,2].It is widely recognized that immune cells play important roles in the pathogenesis of HF.The hearts of HF patients are characterized by persistent low-grade inflammation,which has been linked to adverse ventricular remodeling as it promotes interstitial fibrosis and cardiomyocyte dysfunction and loss.
基金National Natural Science Foundation of China(Nos.82030016 and 82230011 to Xiang Cheng and No.82000443 to Jingyong Li)
文摘Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases(CVDs).Regulatory T cells(Tregs)are typical immune regulatory cells with recognized immunosuppressive properties.Despite the immunosuppressive properties,researchers have acknowledged the significance of Tregs in maintaining tissue homeostasis and facilitating repair/regeneration.Previous studies unveiled the heterogeneity of Tregs in the heart and aorta,which expanded in CVDs with unique transcriptional phenotypes and reparative/regenerative function.This review briefly summarizes the functional principles of Tregs,also including the synergistic effect of Tregs and other immune cells in CVDs.We discriminate the roles and therapeutic potential of Tregs in CVDs such as atherosclerosis,hypertension,abdominal arterial aneurysm,pulmonary arterial hypertension,Kawasaki disease,myocarditis,myocardial infarction,and heart failure.Tregs not only exert anti-inflammatory effects but also actively promote myocardial regeneration and vascular repair,maintaining the stability of the local microenvironment.Given that the specific mechanism of Tregs functioning in CVDs remains unclear,we reviewed previous clinical and basic studies and the latest findings on the function and mechanism of Tregs in CVDs.
