Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in th...Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in this field using the bibliometric analysis.Publications in the PubMed and Web of Science databases were retrieved.Overall,there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer.Researchers from USA,Germany,Italy,China and England have greater studies than others.Top three publication institutions are University of California System,UDICE-French Research Universities and University of Texas System.Current research hotspots include oxidative stress,breast cancer,melatonin,cell cycle,calorie restriction,prostate cancer and NF-κB.In conclusion,results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer.These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.展开更多
The intricate relationship between cancer,circadian rhythms,and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression.Aging is a well-est...The intricate relationship between cancer,circadian rhythms,and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression.Aging is a well-established primary risk factor for cancer,while disruptions in circadian rhythms are intricately associated with the tumorigenesis and progression of various tumors.Moreover,aging itself disrupts circadian rhythms,leading to physiological changes that may accelerate cancer development.Despite these connections,the specific interplay between these processes and their collective impact on cancer remains inadequately explored in the literature.In this review,we systematically explore the physiological mechanisms of circadian rhythms and their influence on cancer development.We discuss how core circadian genes impact tumor risk and prognosis,highlighting the shared hallmarks of cancer and aging such as genomic instability,cellular senescence,and chronic inflammation.Furthermore,we examine the interplay between circadian rhythms and aging,focusing on how this crosstalk contributes to tumorigenesis,tumor proliferation,and apoptosis,as well as the impact on cellular metabolism and genomic stability.By elucidating the common pathways linking aging,circadian rhythms,and cancer,this review provides new insights into the pathophysiology of cancer and identifies potential therapeutic strategies.We propose that targeting the circadian regulation of cancer hallmarks could pave the way for novel treatments,including chronotherapy and antiaging interventions,which may offer important benefits in the clinical management of cancer.展开更多
Objective:The aim of this study is to develop a multimodal MRI radiomics-based model for predicting long-term overall survival in hypopharyngeal cancer patients undergoing definitive radiotherapy.Methods:We enrolled 2...Objective:The aim of this study is to develop a multimodal MRI radiomics-based model for predicting long-term overall survival in hypopharyngeal cancer patients undergoing definitive radiotherapy.Methods:We enrolled 207 hypopharyngeal cancer patients who underwent definitive radiotherapy and had 5-year overall survival outcomes from two major cancer centers in China.Pretreatment MRI images and clinical features were collected.Regions of interest(ROIs)for primary tumors and lymph node metastases(LNM)were delineated on T2 and contrast-enhanced T1(CE-T1)sequences.Principal component analysis(PCA),support vector machine(SVM),and 5-fold cross-validation were used to develop and evaluate the models.Results:Multivariate Cox regression analysis identified age under 50 years,advanced T stage,and N stage as risk factors for overall survival.Predictive models based solely on clinical features(Model A),single radiomics features(Model B),and their combination(Model C)performed poorly,with mean AUC values in the validation set of 0.663,0.772,and 0.779,respectively.The addition of multimodal LNM and CE-T1 radiomics features significantly improved prediction accuracy(Models D and E),with AUC values of 0.831 and 0.837 in the validation set.Conclusion:We developed a well-discriminating overall survival prediction model based on multimodal MRI radiomics,applicable to patients receiving definitive radiotherapy,which may contribute to personalized treatment strategies.展开更多
Adoptive immune cell-based therapies have shown promise in cancer treatment,yet their efficacy against solid tumors is often limited by the immunosuppressive tumor microenvironment(TME).To overcome these barriers,we d...Adoptive immune cell-based therapies have shown promise in cancer treatment,yet their efficacy against solid tumors is often limited by the immunosuppressive tumor microenvironment(TME).To overcome these barriers,we design an innovative immune cell cocktail as a combinatorial biomaterial platform,which harnessing the complementary functions of neutrophils and natural killer(NK)cells derived from human pluripotent stem cells(hPSCs).Using CRISPR/Cas9,we introduce an anti-fluorescein isothiocyanate(FITC)chimeric antigen receptor(CAR)construct into the AAVS1 safe harbor locus of hPSCs,allowing for the differentiation of CAR-modified neutrophils and NK cells.These CAR neutrophils exhibit robust anti-tumor activity,forming immune synapses with tumor cells tagged via a bispecific adapter(FITC-folate),even in hypoxic TMEs,while CAR NK cells demonstrate antigen-specific cytotoxicity.Together,the cocktail biomaterial composed of CAR neutrophils and CAR NK cells creates a synergistic anti-tumor effect:having neutrophils enhance TME modulation,and NK cells provide targeted cytotoxicity.This biomaterial offers a scalable and off-the-shelf solution for producing CAR neutrophils and CAR NK cells,potentially reducing needs for high-dose exogenous cytokines and minimizing immune-related toxicities.Our findings suggest that hPSC-derived CAR neutrophils and CAR NK cells may form an effective immuno-cocktail biomaterial,offering a feasible strategy for advancing solid tumor immunotherapy through cellular synergy and TME adaptation.展开更多
Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various cancers.However,limited immunological memory and access to sufficient numbers of allogenic donor cells ...Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various cancers.However,limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical applications.Here,we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein(FITC)single-chain variable fragment(scFv)to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid tumors.We next genetically engineer human pluripotent stem cells(hPSCs)with optimized CARs and differentiate them into functional dual CAR-NK cells.The tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3(pSTAT3)and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptorβ-chain(ΔIL-2Rβ)and STAT3-binding tyrosine-X-X-glutamine(YXXQ)motif.Anti-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor cells.Collectively,our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy.展开更多
Adoptive immunotherapy,notably involving chimeric antigen receptor(CAR)-T cells,has obtained Food and Drug Administration(FDA)approval as a treatment for various hematological malignancies,demonstrating promising prec...Adoptive immunotherapy,notably involving chimeric antigen receptor(CAR)-T cells,has obtained Food and Drug Administration(FDA)approval as a treatment for various hematological malignancies,demonstrating promising preclinical efficacy against cancers.However,the intricate and resource-intensive autologous cell processing,encompassing collection,expansion,engineering,isolation,and administration,hamper the efficacy of this therapeutic modality.Furthermore,conventional CAR T therapy is presently confined to addressing solid tumors due to impediments posed by physical barriers,the potential for cytokine release syndrome,and cellular exhaustion induced by the immunosuppressive and heterogeneous tumor microenvironment.Consequently,a strategic integration of adoptive immunotherapy with synergistic multimodal treatments,such as chemotherapy,radiotherapy,and vaccine therapy etc.,emerges as a pivotal approach to surmount these inherent challenges.This collaborative strategy holds the key to addressing the limitations delineated above,thereby facilitating the realization of more precise personalized therapies characterized by heightened therapeutic efficacy.Such synergistic strategy not only serves to mitigate the constraints associated with adoptive immunotherapy but also fosters enhanced clinical applicability,thereby advancing the frontiers of therapeutic precision and effectiveness.展开更多
The circadian clock is an internal timekeeper system that regulates biological processes through a central circadian clock and peripheral clocks controlling various genes.Basic helix-loop-helix ARNT-like 1(BMAL 1),als...The circadian clock is an internal timekeeper system that regulates biological processes through a central circadian clock and peripheral clocks controlling various genes.Basic helix-loop-helix ARNT-like 1(BMAL 1),also known as aryl hydrocarbon receptor nuclear translocator-like protein 1(ARNTL1),is a key component of the circadian clock.The deletion of BMAL1 alone can abolish the circadian rhythms of the human body.BMAL 1 plays a critical role in immune cell function.Dysregulation of BMAL 1 is linked to immune-related diseases such as autoimmune diseases,infectious diseases,and cancer,and vice versa.This review highlights the significant role of BMAL 1 in governing immune cells,including their development,differentiation,migration,homing,metabolism,and effector functions.This study also explores how dysregulation of BMAL1 can have far-reaching implications and potentially contribute to the onset of immune-related diseases such as autoimmune diseases,infectious diseases,cancer,sepsis,and trauma.Furthermore,this review discusses treatments for immune-related diseases that target BMAL 1 disorders.Understanding the impact of BMAL 1 on immune function can provide insights into the pathogenesis of immune-related diseases and help in the development of more effective treatment strategies.Targeting BMAL 1 has been demonstrated to achieve good efficacy in immune-related diseases,indicating its promising potential as a targetable therapeutic target in these diseases.展开更多
Hydrogels with particulates,including proteins,drugs,nanoparticles,and cells,enable the development of new and innovative biomaterials.Precise control of the spatial distribution of these particulates is crucial to pr...Hydrogels with particulates,including proteins,drugs,nanoparticles,and cells,enable the development of new and innovative biomaterials.Precise control of the spatial distribution of these particulates is crucial to produce advanced biomaterials.Thus,there is a high demand for manufacturing methods for particle-laden hydrogels.In this context,3D printing of hydrogels is emerging as a promising method to create numerous innovative biomaterials.Among the 3D printing methods,inkjet printing,so-called drop-on-demand(DOD)printing,stands out for its ability to construct biomaterials with superior spatial resolutions.However,its printing processes are still designed by trial and error due to a limited understanding of the ink behavior during the printing processes.This review discusses the current understanding of transport processes and hydrogel behaviors during inkjet printing for particulate-laden hydrogels.Specifically,we review the transport processes of water and particulates within hydrogel during ink formulation,jetting,and curing.Additionally,we examine current inkjet printing applications in fabricating engineered tissues,drug delivery devices,and advanced bioelectronics components.Finally,the challenges and opportunities for next-generation inkjet printing are also discussed.展开更多
基金supported by the Chinese Scholarship Council(No.202206240086)Zhejiang Province Public Welfare Technology Application Research Project in China(No.TGY23H160090 and No.LGF21H160029)+1 种基金Taizhou Science and Technology Project,Zhejiang Province(No.20ywb12)Program for Talents of Chongqing University Three Gorges Hospital(No.2022YJKYXM-036).
文摘Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in this field using the bibliometric analysis.Publications in the PubMed and Web of Science databases were retrieved.Overall,there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer.Researchers from USA,Germany,Italy,China and England have greater studies than others.Top three publication institutions are University of California System,UDICE-French Research Universities and University of Texas System.Current research hotspots include oxidative stress,breast cancer,melatonin,cell cycle,calorie restriction,prostate cancer and NF-κB.In conclusion,results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer.These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.
基金supported by the Chinese Scholarship Council(grant no.202206240086)a regional innovation cooperation project of Sichuan Province(grant no.23QYCX0136)。
文摘The intricate relationship between cancer,circadian rhythms,and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression.Aging is a well-established primary risk factor for cancer,while disruptions in circadian rhythms are intricately associated with the tumorigenesis and progression of various tumors.Moreover,aging itself disrupts circadian rhythms,leading to physiological changes that may accelerate cancer development.Despite these connections,the specific interplay between these processes and their collective impact on cancer remains inadequately explored in the literature.In this review,we systematically explore the physiological mechanisms of circadian rhythms and their influence on cancer development.We discuss how core circadian genes impact tumor risk and prognosis,highlighting the shared hallmarks of cancer and aging such as genomic instability,cellular senescence,and chronic inflammation.Furthermore,we examine the interplay between circadian rhythms and aging,focusing on how this crosstalk contributes to tumorigenesis,tumor proliferation,and apoptosis,as well as the impact on cellular metabolism and genomic stability.By elucidating the common pathways linking aging,circadian rhythms,and cancer,this review provides new insights into the pathophysiology of cancer and identifies potential therapeutic strategies.We propose that targeting the circadian regulation of cancer hallmarks could pave the way for novel treatments,including chronotherapy and antiaging interventions,which may offer important benefits in the clinical management of cancer.
基金CAMS Innovation Fund for Medical Sciences(CIFMS)under the Chinese Academy of Medical Sciences for Clinical and Translational Medicine Research Special Project(2023-I2M-C&T-B-072)Capital's Funds for Health Improvement and Research for the Beijing Municipal Health Development Scientific Research Special Project(2024-2-40212)。
文摘Objective:The aim of this study is to develop a multimodal MRI radiomics-based model for predicting long-term overall survival in hypopharyngeal cancer patients undergoing definitive radiotherapy.Methods:We enrolled 207 hypopharyngeal cancer patients who underwent definitive radiotherapy and had 5-year overall survival outcomes from two major cancer centers in China.Pretreatment MRI images and clinical features were collected.Regions of interest(ROIs)for primary tumors and lymph node metastases(LNM)were delineated on T2 and contrast-enhanced T1(CE-T1)sequences.Principal component analysis(PCA),support vector machine(SVM),and 5-fold cross-validation were used to develop and evaluate the models.Results:Multivariate Cox regression analysis identified age under 50 years,advanced T stage,and N stage as risk factors for overall survival.Predictive models based solely on clinical features(Model A),single radiomics features(Model B),and their combination(Model C)performed poorly,with mean AUC values in the validation set of 0.663,0.772,and 0.779,respectively.The addition of multimodal LNM and CE-T1 radiomics features significantly improved prediction accuracy(Models D and E),with AUC values of 0.831 and 0.837 in the validation set.Conclusion:We developed a well-discriminating overall survival prediction model based on multimodal MRI radiomics,applicable to patients receiving definitive radiotherapy,which may contribute to personalized treatment strategies.
基金supported by start-up package funding from The Hong Kong Polytechnic University(Y.C.)and the Shenzhen Science and Technology Program(No.JCYJ20241202130520027).
文摘Adoptive immune cell-based therapies have shown promise in cancer treatment,yet their efficacy against solid tumors is often limited by the immunosuppressive tumor microenvironment(TME).To overcome these barriers,we design an innovative immune cell cocktail as a combinatorial biomaterial platform,which harnessing the complementary functions of neutrophils and natural killer(NK)cells derived from human pluripotent stem cells(hPSCs).Using CRISPR/Cas9,we introduce an anti-fluorescein isothiocyanate(FITC)chimeric antigen receptor(CAR)construct into the AAVS1 safe harbor locus of hPSCs,allowing for the differentiation of CAR-modified neutrophils and NK cells.These CAR neutrophils exhibit robust anti-tumor activity,forming immune synapses with tumor cells tagged via a bispecific adapter(FITC-folate),even in hypoxic TMEs,while CAR NK cells demonstrate antigen-specific cytotoxicity.Together,the cocktail biomaterial composed of CAR neutrophils and CAR NK cells creates a synergistic anti-tumor effect:having neutrophils enhance TME modulation,and NK cells provide targeted cytotoxicity.This biomaterial offers a scalable and off-the-shelf solution for producing CAR neutrophils and CAR NK cells,potentially reducing needs for high-dose exogenous cytokines and minimizing immune-related toxicities.Our findings suggest that hPSC-derived CAR neutrophils and CAR NK cells may form an effective immuno-cocktail biomaterial,offering a feasible strategy for advancing solid tumor immunotherapy through cellular synergy and TME adaptation.
基金supported by startup funding from the Davidson School of Chemical Engineering and the College of Engineering at Purdue(X.B.)PICR Robbers New Investigators(X.B.),Showalter Research Trust(Young Investigator Award to X.B.)+2 种基金NSF CBET(grant no.2143064 to X.B.)NSF CBET(grant no.1943696 to X.L.L.)NIH NCI(grant no.R37CA265926 to X.B.).
文摘Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various cancers.However,limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical applications.Here,we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein(FITC)single-chain variable fragment(scFv)to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid tumors.We next genetically engineer human pluripotent stem cells(hPSCs)with optimized CARs and differentiate them into functional dual CAR-NK cells.The tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3(pSTAT3)and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptorβ-chain(ΔIL-2Rβ)and STAT3-binding tyrosine-X-X-glutamine(YXXQ)motif.Anti-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor cells.Collectively,our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy.
基金supported by start-up package funding from The Hong Kong Polytechnic University(Y.C.).
文摘Adoptive immunotherapy,notably involving chimeric antigen receptor(CAR)-T cells,has obtained Food and Drug Administration(FDA)approval as a treatment for various hematological malignancies,demonstrating promising preclinical efficacy against cancers.However,the intricate and resource-intensive autologous cell processing,encompassing collection,expansion,engineering,isolation,and administration,hamper the efficacy of this therapeutic modality.Furthermore,conventional CAR T therapy is presently confined to addressing solid tumors due to impediments posed by physical barriers,the potential for cytokine release syndrome,and cellular exhaustion induced by the immunosuppressive and heterogeneous tumor microenvironment.Consequently,a strategic integration of adoptive immunotherapy with synergistic multimodal treatments,such as chemotherapy,radiotherapy,and vaccine therapy etc.,emerges as a pivotal approach to surmount these inherent challenges.This collaborative strategy holds the key to addressing the limitations delineated above,thereby facilitating the realization of more precise personalized therapies characterized by heightened therapeutic efficacy.Such synergistic strategy not only serves to mitigate the constraints associated with adoptive immunotherapy but also fosters enhanced clinical applicability,thereby advancing the frontiers of therapeutic precision and effectiveness.
文摘The circadian clock is an internal timekeeper system that regulates biological processes through a central circadian clock and peripheral clocks controlling various genes.Basic helix-loop-helix ARNT-like 1(BMAL 1),also known as aryl hydrocarbon receptor nuclear translocator-like protein 1(ARNTL1),is a key component of the circadian clock.The deletion of BMAL1 alone can abolish the circadian rhythms of the human body.BMAL 1 plays a critical role in immune cell function.Dysregulation of BMAL 1 is linked to immune-related diseases such as autoimmune diseases,infectious diseases,and cancer,and vice versa.This review highlights the significant role of BMAL 1 in governing immune cells,including their development,differentiation,migration,homing,metabolism,and effector functions.This study also explores how dysregulation of BMAL1 can have far-reaching implications and potentially contribute to the onset of immune-related diseases such as autoimmune diseases,infectious diseases,cancer,sepsis,and trauma.Furthermore,this review discusses treatments for immune-related diseases that target BMAL 1 disorders.Understanding the impact of BMAL 1 on immune function can provide insights into the pathogenesis of immune-related diseases and help in the development of more effective treatment strategies.Targeting BMAL 1 has been demonstrated to achieve good efficacy in immune-related diseases,indicating its promising potential as a targetable therapeutic target in these diseases.
基金supported by grants from NIH(U01 CA274304 to BH)and NSF(MCB-2134603 to BH/GC).
文摘Hydrogels with particulates,including proteins,drugs,nanoparticles,and cells,enable the development of new and innovative biomaterials.Precise control of the spatial distribution of these particulates is crucial to produce advanced biomaterials.Thus,there is a high demand for manufacturing methods for particle-laden hydrogels.In this context,3D printing of hydrogels is emerging as a promising method to create numerous innovative biomaterials.Among the 3D printing methods,inkjet printing,so-called drop-on-demand(DOD)printing,stands out for its ability to construct biomaterials with superior spatial resolutions.However,its printing processes are still designed by trial and error due to a limited understanding of the ink behavior during the printing processes.This review discusses the current understanding of transport processes and hydrogel behaviors during inkjet printing for particulate-laden hydrogels.Specifically,we review the transport processes of water and particulates within hydrogel during ink formulation,jetting,and curing.Additionally,we examine current inkjet printing applications in fabricating engineered tissues,drug delivery devices,and advanced bioelectronics components.Finally,the challenges and opportunities for next-generation inkjet printing are also discussed.
