Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(...Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.展开更多
Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conse...Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conserved thrombospondin family,THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions.Through dynamic interactions with various ECM components,THBS4 plays pivotal roles in cell adhesion,proliferation,inflammation regulation,and tissue remodeling,establishing it as a key modulator of microenvironmental organization.The transcription and translation of THBS4 gene,as well as the activity of the THBS4 protein,are tightly regulated by multiple signaling pathways and extracellular cues.Positive regulators of THBS4 include transforming growth factorβ(TGF-β),interferonγ(IFNγ),granulocyte-macrophage colony-stimulating factor(GM-CSF),bone morphogenetic proteins(BMP12/13),and other regulatory factors(such as B4GALNT1,ITGA2/ITGB1,PDGFRβ,etc.),which upregulate THBS4 at the mRNA and/or protein level.Conversely,oxidized low-density lipoprotein(OXLDL)acts as a potent negative regulator of THBS4.This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to diverse physiological and pathological stimuli.Functionally,THBS4 acts as a critical signaling hub,influencing multiple downstream pathways essential for cellular behavior and tissue homeostasis.The best-characterized pathways include:(1)the PI3K/AKT/mTOR axis,which THBS4 modulates through both direct and indirect interactions with integrins and growth factor receptors;(2)Wnt/β-catenin signaling,where THBS4 functions as either an activator or inhibitor depending on the cellular context;(3)the suppression of DBET/TRIM69,contributing to its diverse regulatory roles.These signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes.Substantial evidence links aberrant THBS4 expression to a range of pathological conditions,including neoplastic diseases,cardiovascular disorders,fibrotic conditions,neurodegenerative diseases,musculoskeletal disorders,and atopic dermatitis.In cancer biology,THBS4 exhibits context-dependent roles,functioning either as a tumor suppressor or promoter depending on the tumor type and microenvironment.In the cardiovascular system,THBS4 contributes to both adaptive remodeling and maladaptive fibrotic responses.Its involvement in fibrotic diseases arises from its ability to regulate ECM deposition and turnover.The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine.As a biomarker,THBS4 expression patterns correlate significantly with disease progression and patient outcomes.Therapeutically,targeting THBS4-mediated pathways offers novel opportunities for precision medicine approaches,including anti-fibrotic therapies,modulation of the tumor microenvironment,and enhancement of tissue repair.This comprehensive review systematically explores three key aspects of THBS4 research:(1)the fundamental biological functions of THBS4 in ECM organization;(2)its mechanistic involvement in various disease pathologies;(3)its emerging potential as both a diagnostic biomarker and therapeutic target.By integrating recent insights from molecular studies,animal models,and clinical investigations,this review provides a framework for understanding the multifaceted roles of THBS4 in health and disease.The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts.Given its unique position at the intersection of ECM biology and cellular signaling,THBS4 represents a promising frontier for the development of novel diagnostic tools and therapeutic strategies in precision medicine.展开更多
OBJECTIVE To investigate the contribution of B cell activating factor of TNF family(BAFF)in the proliferation and activation of B cell in rheumatoid arthritis(RA),and to clarify whether high levels of BAFF is associat...OBJECTIVE To investigate the contribution of B cell activating factor of TNF family(BAFF)in the proliferation and activation of B cell in rheumatoid arthritis(RA),and to clarify whether high levels of BAFF is associated with clinical variables and lab parameters.METHODS Blood samples and peripheral blood mononuclear cells from RA patients and healthy controls(HCs)were collected and isolated respectively.Clinical variables and lab parameters,BAFF level,cytokines and immunoglobulins in serum were evaluated at entry.B cell subpopulations,BAFF receptors(BAFFR,BCMA,TACI),and alternative and canonical NF-κB pathway in B cell were analyzed in vivo and in vitro.RESULTS In RA patients,BAFF level and activated B cell subsets increased significantly.BAFF level was associated with CRP,RF,DAS28,swollen joint counts and tender joint counts.BAFFR,BCMA,TACI on B cells in RA over expressed.The expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52 were higher than that in HCs.In vitro,BAFF up regulated activated B cell subset and the expressions of BAFFR,BCMA and TACI.BAFF also enhanced the expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52.CONCLUSION Increased BAFF in serum is associated with the disease activity of RA,BAFF involves in the proliferation and activation of B cell in RA through alternative and canonical NF-κB pathway,indicating that BAFF might be a novel biomarker of diagnosis and therapy.展开更多
文摘Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.
文摘Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conserved thrombospondin family,THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions.Through dynamic interactions with various ECM components,THBS4 plays pivotal roles in cell adhesion,proliferation,inflammation regulation,and tissue remodeling,establishing it as a key modulator of microenvironmental organization.The transcription and translation of THBS4 gene,as well as the activity of the THBS4 protein,are tightly regulated by multiple signaling pathways and extracellular cues.Positive regulators of THBS4 include transforming growth factorβ(TGF-β),interferonγ(IFNγ),granulocyte-macrophage colony-stimulating factor(GM-CSF),bone morphogenetic proteins(BMP12/13),and other regulatory factors(such as B4GALNT1,ITGA2/ITGB1,PDGFRβ,etc.),which upregulate THBS4 at the mRNA and/or protein level.Conversely,oxidized low-density lipoprotein(OXLDL)acts as a potent negative regulator of THBS4.This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to diverse physiological and pathological stimuli.Functionally,THBS4 acts as a critical signaling hub,influencing multiple downstream pathways essential for cellular behavior and tissue homeostasis.The best-characterized pathways include:(1)the PI3K/AKT/mTOR axis,which THBS4 modulates through both direct and indirect interactions with integrins and growth factor receptors;(2)Wnt/β-catenin signaling,where THBS4 functions as either an activator or inhibitor depending on the cellular context;(3)the suppression of DBET/TRIM69,contributing to its diverse regulatory roles.These signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes.Substantial evidence links aberrant THBS4 expression to a range of pathological conditions,including neoplastic diseases,cardiovascular disorders,fibrotic conditions,neurodegenerative diseases,musculoskeletal disorders,and atopic dermatitis.In cancer biology,THBS4 exhibits context-dependent roles,functioning either as a tumor suppressor or promoter depending on the tumor type and microenvironment.In the cardiovascular system,THBS4 contributes to both adaptive remodeling and maladaptive fibrotic responses.Its involvement in fibrotic diseases arises from its ability to regulate ECM deposition and turnover.The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine.As a biomarker,THBS4 expression patterns correlate significantly with disease progression and patient outcomes.Therapeutically,targeting THBS4-mediated pathways offers novel opportunities for precision medicine approaches,including anti-fibrotic therapies,modulation of the tumor microenvironment,and enhancement of tissue repair.This comprehensive review systematically explores three key aspects of THBS4 research:(1)the fundamental biological functions of THBS4 in ECM organization;(2)its mechanistic involvement in various disease pathologies;(3)its emerging potential as both a diagnostic biomarker and therapeutic target.By integrating recent insights from molecular studies,animal models,and clinical investigations,this review provides a framework for understanding the multifaceted roles of THBS4 in health and disease.The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts.Given its unique position at the intersection of ECM biology and cellular signaling,THBS4 represents a promising frontier for the development of novel diagnostic tools and therapeutic strategies in precision medicine.
基金The project supported by National Natural Science Foundation of China(81473223,31100640,81302517 and 81330081)China Postdoctoral Science Foundation(2013M540509)
文摘OBJECTIVE To investigate the contribution of B cell activating factor of TNF family(BAFF)in the proliferation and activation of B cell in rheumatoid arthritis(RA),and to clarify whether high levels of BAFF is associated with clinical variables and lab parameters.METHODS Blood samples and peripheral blood mononuclear cells from RA patients and healthy controls(HCs)were collected and isolated respectively.Clinical variables and lab parameters,BAFF level,cytokines and immunoglobulins in serum were evaluated at entry.B cell subpopulations,BAFF receptors(BAFFR,BCMA,TACI),and alternative and canonical NF-κB pathway in B cell were analyzed in vivo and in vitro.RESULTS In RA patients,BAFF level and activated B cell subsets increased significantly.BAFF level was associated with CRP,RF,DAS28,swollen joint counts and tender joint counts.BAFFR,BCMA,TACI on B cells in RA over expressed.The expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52 were higher than that in HCs.In vitro,BAFF up regulated activated B cell subset and the expressions of BAFFR,BCMA and TACI.BAFF also enhanced the expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52.CONCLUSION Increased BAFF in serum is associated with the disease activity of RA,BAFF involves in the proliferation and activation of B cell in RA through alternative and canonical NF-κB pathway,indicating that BAFF might be a novel biomarker of diagnosis and therapy.
