Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflamm...Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.展开更多
Diabetic foot ulcers(DFUs)pose a critical medical challenge,significantly impairing the quality of life of patients.Adipose-derived stem cells(ADSCs)have been identified as a promising therapeutic approach for improvi...Diabetic foot ulcers(DFUs)pose a critical medical challenge,significantly impairing the quality of life of patients.Adipose-derived stem cells(ADSCs)have been identified as a promising therapeutic approach for improving wound healing in DFUs.Despite extensive exploration of the mechanical aspects of ADSC therapy against DFU,its clinical applications remain elusive.In this review,we aimed to bridge this gap by evaluating the use and advancements of ADSCs in the clinical management of DFUs.The review begins with a discussion of the classification and clinical management of diabetic foot conditions.It then discusses the current landscape of clinical trials,focusing on their geographic distribution,reported efficacy,safety profiles,treatment timing,administration techniques,and dosing considerations.Finally,the review discusses the preclinical strategies to enhance ADSC efficacy.This review shows that many trials exhibit biases in study design,unclear inclusion criteria,and intervention protocols.In conclusion,this review underscores the potential of ADSCs in DFU treatment and emphasizes the critical need for further research and refinement of therapeutic approaches,with a focus on improving the quality of future clinical trials to enhance treatment outcomes and advance the field of diabetic wound care.展开更多
Wound repair is a complex challenge for both clinical practitioners and researchers.Conventional approaches for wound repair have several limitations.Stem cell-based therapy has emerged as a novel strategy to address ...Wound repair is a complex challenge for both clinical practitioners and researchers.Conventional approaches for wound repair have several limitations.Stem cell-based therapy has emerged as a novel strategy to address this issue,exhibiting significant potential for enhancing wound healing rates,improving wound quality,and promoting skin regeneration.However,the use of stem cells in skin regeneration presents several challenges.Recently,stem cells and biomaterials have been identified as crucial components of the wound-healing process.Combination therapy involving the development of biocompatible scaffolds,accompanying cells,multiple biological factors,and structures resembling the natural extracellular matrix(ECM)has gained considerable attention.Biological scaffolds encompass a range of biomaterials that serve as platforms for seeding stem cells,providing them with an environment conducive to growth,similar to that of the ECM.These scaffolds facilitate the delivery and application of stem cells for tissue regeneration and wound healing.This article provides a comprehensive review of the current developments and applications of biological scaffolds for stem cells in wound healing,emphasizing their capacity to facilitate stem cell adhesion,proliferation,differentiation,and paracrine functions.Additionally,we identify the pivotal characteristics of the scaffolds that contribute to enhanced cellular activity.展开更多
Objective:This study investigated the clinical significance of DICER1 mutations in patients with distant metastatic follicular cell-derived thyroid cancer(FDTC).Methods:This study included 310 Chinese patients with di...Objective:This study investigated the clinical significance of DICER1 mutations in patients with distant metastatic follicular cell-derived thyroid cancer(FDTC).Methods:This study included 310 Chinese patients with distant metastatic FDTC.We analyzed the interactions between DICER1 mutations and other gene alterations and compared the clinicopathological characteristics of patients with pathogenic(P)or likely pathogenic(LP)DICER1 mutations(n=9),other gene alterations(n=253),and no gene alterations(n=37).To compare FDTCs with different drivers,isolated BRAFV600E,RAS mutations,and RET fusions were compared with isolated DICER1 mutations.Results:The prevalence of DICER1 mutations was 6.5%(20/310)in the patient cohort.Among patients with DICER1 mutations,45%(9/20)harbored P or LP DICER1 variants and 55%(11/20)harbored DICER1 variants of uncertain significance(VUS).The coexistence of DICER1 mutations and other gene alterations was detected in65%(13/20)of patients.Compared with VUS,P or LP DICER1 variants were almost mutually exclusive with early driver alterations(such as BRAFV600E)(11.1%vs.81.8%,P=0.002)and more coexisted with late-hit events,particularly TP53 mutations(44.4%vs.27.3%,P=0.642).Clinically,compared with the no alteration and other alteration groups,the DICER1 mutation group exhibited larger primary tumors,higher poorly differentiated thyroid cancer proportion,more extrathyroidal extension,more extrapulmonary metastases,and higher radioactive iodine-refractory proportion(all P<0.05).Cases with isolated DICER1 mutations differed from those with isolated BRAFV600E and RET fusions in terms of tumor size,poorly differentiated thyroid cancer proportion,and metastatic sites,but were similar to cases with isolated RAS mutations in the high proportion of follicular thyroid cancer,N0,and extrapulmonary metastases.Conclusions:Mutation of DICER1 gene is a non-negligible molecular event and it may represent an aggressive subset of FDTCs.DICER1 has RAS-like clinical characteristics and DICER1-mutant tumors exhibit more aggressive clinical behaviors compared with those with BRAFV600E and RET fusions.展开更多
Titin,the largest known protein in nature,is a giant sarcomeric protein that plays essential architectural,developmental,and regulatory roles in striated muscles.Mutations in the TTN gene(MIM:188840)that encodes titin...Titin,the largest known protein in nature,is a giant sarcomeric protein that plays essential architectural,developmental,and regulatory roles in striated muscles.Mutations in the TTN gene(MIM:188840)that encodes titin are related to a broad range of muscle diseases known as titinopathies,with diverse clinical manifestations including weakness,contractures,scoliosis,respiratory failure,and cardiomyopathy.1 In this case report,we describe two sisters with severe scoliosis,both carrying novel compound heterozygous variants in the TTN gene,yet presenting distinct clinical phenotypes,adding to the growing body of evidence linking TTN mutations to scoliosis and other titinrelated disorders.展开更多
Programmed death-1(PD-1)targeted immunotherapy has revolutionized cancer treatment but fails to induce durable responses in many patients,mainly due to restricted reversal of CD8^(+)T cell exhaustion.In cancer and chr...Programmed death-1(PD-1)targeted immunotherapy has revolutionized cancer treatment but fails to induce durable responses in many patients,mainly due to restricted reversal of CD8^(+)T cell exhaustion.In cancer and chronic infections,persistent antigens hinder effective immune clearance,leading CD8^(+)T cells into a dysfunctional and epigenetically stable state of"exhaustion"(Fig.1a)[1].展开更多
Background Mitochondria plays a pivotal role in cellular energy production,and their dysfunction can lead to a spectrum of mitochondrial diseases,affecting various organs with a wide range of clinical symptoms.Among t...Background Mitochondria plays a pivotal role in cellular energy production,and their dysfunction can lead to a spectrum of mitochondrial diseases,affecting various organs with a wide range of clinical symptoms.Among these,short stature is a notable manifestation,yet its pathogenesis related to mitochondrial dysfunction remains underexplored.Data sources A comprehensive literature search was conducted in the PubMed,Medline,and EMBASE databases from inception to November 2024.Patient demographics,genetic confirmation type,clinical features associated with short stature or growth abnormalities,and any interventions or treatments alongside treatment outcomes were extracted.Results Our article provides a comprehensive review of the clinical manifestations and delves into the molecular mechanisms of mitochondrial dysfunction that are associated with short stature.A total of 134 genetically confirmed cases with primary mitochondrial disease(PMD)associated with short stature with mtDNA(e.g.,m.3243A>G,large-scale deletions)and nDNA mutations(e.g.,NDUFB3,SURF1).Median age at short stature detection was 8 years,with 40%presenting earlier.Growth hormone deficiency(GHD)occurred in 15%of cases,showing variable responses to therapy.Pathogenesis involves mitochondrial dysfunction,growth plate impairment,and endocrine disorders.Early diagnosis relies on timely genetic testing.Management of PMD includes tailored dietary strategies,supplementation,and cautious GH therapy due to potential risks.Emerging gene therapy and multidisciplinary care are emphasized to address disease complexity and optimize outcomes.Conclusions Previous reviews have described the endocrine aspects of mitochondrial diseases.Although the list of endocrine diseases is comprehensive,it is not specific for short stature.This review focuses on short stature,and it is more specific than previous reviews in terms of etiology,pathogenesis,diagnosis,treatment,and prospects.展开更多
IgG4-related disease(IgG4-RD)is a chronic immune-mediated disorder characterized by progressive tissue fibrosis.Current treatments like glucocorticoids and rituximab focus on remission,yet reversing fibrosis remains c...IgG4-related disease(IgG4-RD)is a chronic immune-mediated disorder characterized by progressive tissue fibrosis.Current treatments like glucocorticoids and rituximab focus on remission,yet reversing fibrosis remains challenging[1,2].While interactions between immune cells and fibroblasts are known to drive fibrosis,the role of epithelial cells remains poorly understood[1].展开更多
Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function.Accumulating evidence implicates abnormal metabolism of T cells as playing a crit...Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function.Accumulating evidence implicates abnormal metabolism of T cells as playing a critical role in the pathogenesis of rheumatoid arthritis(RA).The deacetylase SIRT3 has been shown to directly regulate energy metabolism in nonimmune cells.However,the role of SIRT3 in T cells and whether it participates in RA process remain unclear.In this study,we demonstrated that T-cell glycolysis was inhibited after SIRT3 deficiency.Compared to wild-type mice,SIRT3 knockout mice exhibited more severe arthritis,cartilage erosion,and inflammation after immunization with antigen-induced arthritis(AIA).It is interesting to note that SIRT3 deficiency reduced the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3),a regulatory and rate-limiting enzyme in glycolysis.Overexpression of PFKFB3 was shown to restore the impaired ATP production caused by SIRT3 deficiency in T cells,and protects T cells from apoptosis.In summary,SIRT3 plays an important role in the regulation of T-cell metabolism in the pathogenesis of RA.SIRT3 deficiency decreases glycolysis,reduces ATP production,induces apoptosis in CD4+T cells,and further promotes AIA in mice.展开更多
基金the National Natural Science Foundation of China(82372412)the Social Development Project of Jiangsu Province(BE2022701)+4 种基金the Top Talent Support Program for Young and Middle-aged People of the Wuxi Health Committee(BJ2020044,BJ2020057,HB2020043)the Fundamental Research Funds of the Health and Family Planning Commission of Wuxi(M202024)the Special Program for Translational Medicine Research of the Wuxi Translational Medicine Center(2020DHYB07,2020DHYB03)the Key Special Project of Precision Medicine of the Wuxi Health Commission(J202101)peking union medical college hospital talent cultivation program(UHB50192).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.
基金Supported by National Key R&D Program of China,No.2020YFE0201600CAMS Innovation Fund for Medical Sciences,No.2020-I2MC&T-A-004National High Level Hospital Clinical Research Funding,No.2022-PUMCH-B-041,No.2022-PUMCH-A-210 and No.2022-PUMCH-C-025.
文摘Diabetic foot ulcers(DFUs)pose a critical medical challenge,significantly impairing the quality of life of patients.Adipose-derived stem cells(ADSCs)have been identified as a promising therapeutic approach for improving wound healing in DFUs.Despite extensive exploration of the mechanical aspects of ADSC therapy against DFU,its clinical applications remain elusive.In this review,we aimed to bridge this gap by evaluating the use and advancements of ADSCs in the clinical management of DFUs.The review begins with a discussion of the classification and clinical management of diabetic foot conditions.It then discusses the current landscape of clinical trials,focusing on their geographic distribution,reported efficacy,safety profiles,treatment timing,administration techniques,and dosing considerations.Finally,the review discusses the preclinical strategies to enhance ADSC efficacy.This review shows that many trials exhibit biases in study design,unclear inclusion criteria,and intervention protocols.In conclusion,this review underscores the potential of ADSCs in DFU treatment and emphasizes the critical need for further research and refinement of therapeutic approaches,with a focus on improving the quality of future clinical trials to enhance treatment outcomes and advance the field of diabetic wound care.
基金Supported by CAMS Innovation Fund for Medical Sciences,No.2020-I2M-C&T-A-004National High Level Hospital Clinical Research Funding,No.2022-PUMCH-A-210,No.2022-PUMCH-B-041,and No.2022-PUMCH-C-025and National Key R&D Program of China,No.2020YFE0201600.
文摘Wound repair is a complex challenge for both clinical practitioners and researchers.Conventional approaches for wound repair have several limitations.Stem cell-based therapy has emerged as a novel strategy to address this issue,exhibiting significant potential for enhancing wound healing rates,improving wound quality,and promoting skin regeneration.However,the use of stem cells in skin regeneration presents several challenges.Recently,stem cells and biomaterials have been identified as crucial components of the wound-healing process.Combination therapy involving the development of biocompatible scaffolds,accompanying cells,multiple biological factors,and structures resembling the natural extracellular matrix(ECM)has gained considerable attention.Biological scaffolds encompass a range of biomaterials that serve as platforms for seeding stem cells,providing them with an environment conducive to growth,similar to that of the ECM.These scaffolds facilitate the delivery and application of stem cells for tissue regeneration and wound healing.This article provides a comprehensive review of the current developments and applications of biological scaffolds for stem cells in wound healing,emphasizing their capacity to facilitate stem cell adhesion,proliferation,differentiation,and paracrine functions.Additionally,we identify the pivotal characteristics of the scaffolds that contribute to enhanced cellular activity.
基金supported by the National High Level Hospital Clinical Research Funding(No.2022-PUMCHB-072)。
文摘Objective:This study investigated the clinical significance of DICER1 mutations in patients with distant metastatic follicular cell-derived thyroid cancer(FDTC).Methods:This study included 310 Chinese patients with distant metastatic FDTC.We analyzed the interactions between DICER1 mutations and other gene alterations and compared the clinicopathological characteristics of patients with pathogenic(P)or likely pathogenic(LP)DICER1 mutations(n=9),other gene alterations(n=253),and no gene alterations(n=37).To compare FDTCs with different drivers,isolated BRAFV600E,RAS mutations,and RET fusions were compared with isolated DICER1 mutations.Results:The prevalence of DICER1 mutations was 6.5%(20/310)in the patient cohort.Among patients with DICER1 mutations,45%(9/20)harbored P or LP DICER1 variants and 55%(11/20)harbored DICER1 variants of uncertain significance(VUS).The coexistence of DICER1 mutations and other gene alterations was detected in65%(13/20)of patients.Compared with VUS,P or LP DICER1 variants were almost mutually exclusive with early driver alterations(such as BRAFV600E)(11.1%vs.81.8%,P=0.002)and more coexisted with late-hit events,particularly TP53 mutations(44.4%vs.27.3%,P=0.642).Clinically,compared with the no alteration and other alteration groups,the DICER1 mutation group exhibited larger primary tumors,higher poorly differentiated thyroid cancer proportion,more extrathyroidal extension,more extrapulmonary metastases,and higher radioactive iodine-refractory proportion(all P<0.05).Cases with isolated DICER1 mutations differed from those with isolated BRAFV600E and RET fusions in terms of tumor size,poorly differentiated thyroid cancer proportion,and metastatic sites,but were similar to cases with isolated RAS mutations in the high proportion of follicular thyroid cancer,N0,and extrapulmonary metastases.Conclusions:Mutation of DICER1 gene is a non-negligible molecular event and it may represent an aggressive subset of FDTCs.DICER1 has RAS-like clinical characteristics and DICER1-mutant tumors exhibit more aggressive clinical behaviors compared with those with BRAFV600E and RET fusions.
基金supported by the National Natural Science Foundation of China(No.82272446).
文摘Titin,the largest known protein in nature,is a giant sarcomeric protein that plays essential architectural,developmental,and regulatory roles in striated muscles.Mutations in the TTN gene(MIM:188840)that encodes titin are related to a broad range of muscle diseases known as titinopathies,with diverse clinical manifestations including weakness,contractures,scoliosis,respiratory failure,and cardiomyopathy.1 In this case report,we describe two sisters with severe scoliosis,both carrying novel compound heterozygous variants in the TTN gene,yet presenting distinct clinical phenotypes,adding to the growing body of evidence linking TTN mutations to scoliosis and other titinrelated disorders.
基金supported by the Beijing Natural Science Foundation(7252108)the National Science and Technology Major Project(2023ZD0502804)the Beijing Nova Program(20220484).
文摘Programmed death-1(PD-1)targeted immunotherapy has revolutionized cancer treatment but fails to induce durable responses in many patients,mainly due to restricted reversal of CD8^(+)T cell exhaustion.In cancer and chronic infections,persistent antigens hinder effective immune clearance,leading CD8^(+)T cells into a dysfunctional and epigenetically stable state of"exhaustion"(Fig.1a)[1].
基金We are grateful to National High Level Hospital Clinical Research Funding(2022-PUMCH-E-004).
文摘Background Mitochondria plays a pivotal role in cellular energy production,and their dysfunction can lead to a spectrum of mitochondrial diseases,affecting various organs with a wide range of clinical symptoms.Among these,short stature is a notable manifestation,yet its pathogenesis related to mitochondrial dysfunction remains underexplored.Data sources A comprehensive literature search was conducted in the PubMed,Medline,and EMBASE databases from inception to November 2024.Patient demographics,genetic confirmation type,clinical features associated with short stature or growth abnormalities,and any interventions or treatments alongside treatment outcomes were extracted.Results Our article provides a comprehensive review of the clinical manifestations and delves into the molecular mechanisms of mitochondrial dysfunction that are associated with short stature.A total of 134 genetically confirmed cases with primary mitochondrial disease(PMD)associated with short stature with mtDNA(e.g.,m.3243A>G,large-scale deletions)and nDNA mutations(e.g.,NDUFB3,SURF1).Median age at short stature detection was 8 years,with 40%presenting earlier.Growth hormone deficiency(GHD)occurred in 15%of cases,showing variable responses to therapy.Pathogenesis involves mitochondrial dysfunction,growth plate impairment,and endocrine disorders.Early diagnosis relies on timely genetic testing.Management of PMD includes tailored dietary strategies,supplementation,and cautious GH therapy due to potential risks.Emerging gene therapy and multidisciplinary care are emphasized to address disease complexity and optimize outcomes.Conclusions Previous reviews have described the endocrine aspects of mitochondrial diseases.Although the list of endocrine diseases is comprehensive,it is not specific for short stature.This review focuses on short stature,and it is more specific than previous reviews in terms of etiology,pathogenesis,diagnosis,treatment,and prospects.
基金supported by the National Natural Science Foundation of China(82271848,823B2037,and 82471829)the Beijing Natural Science Foundation(7232113)+2 种基金the National High Level Hospital Clinical Research Funding(2022-PUMCH-C-006)the National Key Research and Development Program of China(2022YFC2703104)the Peking Union Medical College Hospital Young Reserve Talent Development Program(UHB12076)。
文摘IgG4-related disease(IgG4-RD)is a chronic immune-mediated disorder characterized by progressive tissue fibrosis.Current treatments like glucocorticoids and rituximab focus on remission,yet reversing fibrosis remains challenging[1,2].While interactions between immune cells and fibroblasts are known to drive fibrosis,the role of epithelial cells remains poorly understood[1].
基金supported by grants from the National Key R&D Program of China(2022YFC3602000,2023YFC3403300)National High Level Hospital Clinical Research Funding(BJ-2022-116,BJ-2023-084,BJ-2024-141,BJ-2023-119,BJ-2024-243)+6 种基金National Natural Science Foundation of China(82230060,81801627,32141004,82100564,8210035244,92149305,82225007,82030017,and 82171798,32430036,32441093)Beijing Research Ward Excellence Program(BRWEP2024W234050100)Chinese Academy of Medical Science Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-017,2021-I2M-1040,2021-I2M-1-047,2021-I2M-1-016,2021-I2M-1-026,and 2022-I2M-2-002)National High Level Hospital Clinical Research Funding of Peking Union Medical College Hospital(2023PUMCH-F-004,2022-PUMCH-A-108,Young Reserve Talents of Peking Union Medical College Hospital(UHB12041)the Fundamental Research Funds for the Central Universities(3332018026)the fellowship of China Postdoctoral Science Foundation(2021T140069)Dongcheng District Outstanding Talent Nurturing Program(2023-dchrcpyzz-30)。
文摘Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function.Accumulating evidence implicates abnormal metabolism of T cells as playing a critical role in the pathogenesis of rheumatoid arthritis(RA).The deacetylase SIRT3 has been shown to directly regulate energy metabolism in nonimmune cells.However,the role of SIRT3 in T cells and whether it participates in RA process remain unclear.In this study,we demonstrated that T-cell glycolysis was inhibited after SIRT3 deficiency.Compared to wild-type mice,SIRT3 knockout mice exhibited more severe arthritis,cartilage erosion,and inflammation after immunization with antigen-induced arthritis(AIA).It is interesting to note that SIRT3 deficiency reduced the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3),a regulatory and rate-limiting enzyme in glycolysis.Overexpression of PFKFB3 was shown to restore the impaired ATP production caused by SIRT3 deficiency in T cells,and protects T cells from apoptosis.In summary,SIRT3 plays an important role in the regulation of T-cell metabolism in the pathogenesis of RA.SIRT3 deficiency decreases glycolysis,reduces ATP production,induces apoptosis in CD4+T cells,and further promotes AIA in mice.
