Objectives:High-grade serous ovarian cancer(HGSOC),the most common subtype of epithelial ovarian cancer(EOC),exhibits a mesenchymal phenotype characterized by fibrotic stroma and poor prognosis.Human epididymis protei...Objectives:High-grade serous ovarian cancer(HGSOC),the most common subtype of epithelial ovarian cancer(EOC),exhibits a mesenchymal phenotype characterized by fibrotic stroma and poor prognosis.Human epididymis protein 4(HE4),a key diagnostic biomarker for ovarian cancer,is involved in fibrotic processes in several non-malignant diseases.Given the clinical significance of stromal fibrosis in HGSOC and the potential link between HE4 and fibrosis,this study aimed to investigate the role of HE4 in the formation of stromal fibrosis in HGSOC.Methods:A total of 126 patients with gynecological conditions were included and divided into normal,benign,and EOC groups.Tissue stiffness was quantitatively measured and analyzed for its correlation with clinicopathological features.We further investigated the correlation between tumor stiffness and the expression levels of HE4 and fibroblast activation markers(α-smooth muscle actin(α-SMA)and fibroblast activation protein(FAP))in tumor tissues from 22 HGSOC patients.In vitro,primary fibroblasts were treated with recombinant HE4(rHE4)or conditioned media from HE4-knockdown ovarian cancer cells to assess fibroblasts activation and matrix contractility(Collagen gel contraction assays).In vivo,a subcutaneous xenograft model using HE4-knockdown cells was established to evaluate the effects of HE4 suppression on tumor growth and extensive extracellular matrix(ECM)remodeling.Results:Ovarian cancer tissues showed significantly increased stiffness compared to benign/normal groups,showing positive correlation with serum HE4 levels.High-stiffness HGSOC tumors exhibited upregulated expression of HE4,α-SMA,FAP,and collagen I.rHE4 stimulated fibroblast activation and enhanced matrix contractility,whereas HE4 knockdown in cancer cells abrogated these pro-fibrotic effects.In vivo,HE4-silenced xenografts displayed restricted tumor growth accompanied by reduced stromal expression ofα-SMA,FAP,and collagen I.Conclusion:Our findings suggest that HE4 may facilitate ECM remodeling in HGSOC through promoting fibroblast activation and increasing collagen deposition.展开更多
Blister wounds are featured with over-generated wound exudate and extensive skin peeling,call for breathable temporary skin with effective exudate management,and function as an extracellular matrix to accelerate regen...Blister wounds are featured with over-generated wound exudate and extensive skin peeling,call for breathable temporary skin with effective exudate management,and function as an extracellular matrix to accelerate regeneration of wound skin.Traditional extracellular matrix(ECM)mimicked nanofibrous 3D scaffold and corresponding hydrogel composites suffer from poor mechanical strength,and the wound exudate management behavior is seldom studied.Herein,we proposed the strategy to enhance the mechanical properties of a 3D nanofiber scaffold via constructing a long nanofiber(NF)and sodium alginate(SA)aerogel interpenetrated architecture(NF/SA).The as-prepared scaffold was then evaluated as temporary skin for a full-thickness defect wound.After absorption of blister fluid,the aerogel transferred into a hydrogel and imparted a wet wound care environment with a water-vapor transmission rate of(6001.90±522.04)g/(m^(2)·24 h),and Young s modulus of(2.97±0.38)MPa.The exudate was continuously refreshed by a directed and dynamic pump,followed by volatilization driven by Brownian motion.Meanwhile,the NF/SA scaffold exhibited decent compatibility with blister fluid.The basic fibroblast growth factor(bFGF)-loaded NF/SA improved the wound healing rate by 36.46%on Day 3 and 15.34%on Day 7 in the full-thickness defect wound model.展开更多
函数型主成分分析(Functional Principal Component Analysis,FPCA)是对函数型数据进行降维的常用技术,本文将考虑函数型数据的主成分联合选择问题。首先,本文给出了两函数型变量的主成分联合模型,并通过基函数展开法和极大惩罚似然法...函数型主成分分析(Functional Principal Component Analysis,FPCA)是对函数型数据进行降维的常用技术,本文将考虑函数型数据的主成分联合选择问题。首先,本文给出了两函数型变量的主成分联合模型,并通过基函数展开法和极大惩罚似然法对样本数据进行曲线平滑。在联合模型基础上,本文给出了确定函数型主成分个数的AIC准则,并提出了改进的ECME算法对模型参数进行估计。模拟显示AIC准则对应的主成分个数选择结果准确率更高,考虑两函数型数据之间相关信息的联合选择效果会比对各函数型数据主成分进行独立选择的结果有所提升。最后,本文将所提方法应用于老年人中医宗气数据的分析.展开更多
The small-molecule alkaloid halofuginone(HF)is obtained from febrifugine.Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic function...The small-molecule alkaloid halofuginone(HF)is obtained from febrifugine.Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions,which range from parasite infections and fibrosis to autoimmune diseases.In particular,HF is believed to play an excellent anticancer role by suppressing the proliferation,adhesion,metastasis,and invasion of cancers.This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF.In the studies covered in this review,the anticancer molecular mechanisms of HF mainly included transforming growth factor-β(TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2(Nrf2),serine/threonine kinase proteins(Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated(Wnt)/β-catenin,the exosomal microRNA-31(miR-31)/histone deacetylase 2(HDAC2)signaling pathway,and the interaction of the extracellular matrix(ECM)and immune cells.Notably,HF,as a novel type of adenosine triphosphate(ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase(ProRS)and amino acid starvation therapy(AAS)to suppress the formation of ribosome,further exerts a significant effect on the tumor microenvironment(TME).Additionally,the combination of HF with other drugs or therapies obtained universal attention.Our results showed that HF has significant potential for clinical cancer treatment.展开更多
The growth of Caenorhabditis elegans involves multiple molting processes,during which old cuticles are shed and new cuticles are rapidly formed.This process requires the regulated bulk secretion of cuticle components....The growth of Caenorhabditis elegans involves multiple molting processes,during which old cuticles are shed and new cuticles are rapidly formed.This process requires the regulated bulk secretion of cuticle components.The transmembrane protein-39(TMEM-39)mutant exhibits distinct dumpy and ruptured phenotypes characterized by notably thin cuticles.TMEM-39 primarily co-localizes with the coat protein II complex(COPII)in large vesicles rather than small COPII vesicles.These TMEM-39-associated large vesicles(TMEM-39-LVs)form robustly during the molting period and co-localize with various extracellular matrix components,including BLI-1 collagen,BLI-3 dual oxidase,and carboxypeptidases.Through immunoprecipitation using TMEM39A-FLAG and proteomics analysis in human sarcoma cells,we identify TMEM39A-associated proteins,including TMEM131.Knockdown of TMEM131 results in reduced TMEM39A-LV formation and collagen secretion in both C.elegans and human sarcoma cells,indicating a cooperative role between TMEM39A and TMEM131 in the secretion of extracellular components through the formation of large COPII vesicles.Given the conservation of TMEM39A and its associated proteins between C.elegans and humans,TMEM39A-LVs may represent a fundamental machinery for rapid and extensive secretion across metazoans.展开更多
文摘Objectives:High-grade serous ovarian cancer(HGSOC),the most common subtype of epithelial ovarian cancer(EOC),exhibits a mesenchymal phenotype characterized by fibrotic stroma and poor prognosis.Human epididymis protein 4(HE4),a key diagnostic biomarker for ovarian cancer,is involved in fibrotic processes in several non-malignant diseases.Given the clinical significance of stromal fibrosis in HGSOC and the potential link between HE4 and fibrosis,this study aimed to investigate the role of HE4 in the formation of stromal fibrosis in HGSOC.Methods:A total of 126 patients with gynecological conditions were included and divided into normal,benign,and EOC groups.Tissue stiffness was quantitatively measured and analyzed for its correlation with clinicopathological features.We further investigated the correlation between tumor stiffness and the expression levels of HE4 and fibroblast activation markers(α-smooth muscle actin(α-SMA)and fibroblast activation protein(FAP))in tumor tissues from 22 HGSOC patients.In vitro,primary fibroblasts were treated with recombinant HE4(rHE4)or conditioned media from HE4-knockdown ovarian cancer cells to assess fibroblasts activation and matrix contractility(Collagen gel contraction assays).In vivo,a subcutaneous xenograft model using HE4-knockdown cells was established to evaluate the effects of HE4 suppression on tumor growth and extensive extracellular matrix(ECM)remodeling.Results:Ovarian cancer tissues showed significantly increased stiffness compared to benign/normal groups,showing positive correlation with serum HE4 levels.High-stiffness HGSOC tumors exhibited upregulated expression of HE4,α-SMA,FAP,and collagen I.rHE4 stimulated fibroblast activation and enhanced matrix contractility,whereas HE4 knockdown in cancer cells abrogated these pro-fibrotic effects.In vivo,HE4-silenced xenografts displayed restricted tumor growth accompanied by reduced stromal expression ofα-SMA,FAP,and collagen I.Conclusion:Our findings suggest that HE4 may facilitate ECM remodeling in HGSOC through promoting fibroblast activation and increasing collagen deposition.
基金Natural Science Foundation of Shanghai(General Program,22ZR1409500)China Postdoctoral Science Foundation(23M742317,GZB240446)+3 种基金Shanghai Science and Technology Innovation Action Plan(22S31905500)Medical Engineering Fund of Fudan University(yg2021-032)Fundamental Research Project of CNTAC(J202104)Program of Introducing Talents of Discipline to Universities(BP0719035)。
文摘Blister wounds are featured with over-generated wound exudate and extensive skin peeling,call for breathable temporary skin with effective exudate management,and function as an extracellular matrix to accelerate regeneration of wound skin.Traditional extracellular matrix(ECM)mimicked nanofibrous 3D scaffold and corresponding hydrogel composites suffer from poor mechanical strength,and the wound exudate management behavior is seldom studied.Herein,we proposed the strategy to enhance the mechanical properties of a 3D nanofiber scaffold via constructing a long nanofiber(NF)and sodium alginate(SA)aerogel interpenetrated architecture(NF/SA).The as-prepared scaffold was then evaluated as temporary skin for a full-thickness defect wound.After absorption of blister fluid,the aerogel transferred into a hydrogel and imparted a wet wound care environment with a water-vapor transmission rate of(6001.90±522.04)g/(m^(2)·24 h),and Young s modulus of(2.97±0.38)MPa.The exudate was continuously refreshed by a directed and dynamic pump,followed by volatilization driven by Brownian motion.Meanwhile,the NF/SA scaffold exhibited decent compatibility with blister fluid.The basic fibroblast growth factor(bFGF)-loaded NF/SA improved the wound healing rate by 36.46%on Day 3 and 15.34%on Day 7 in the full-thickness defect wound model.
文摘函数型主成分分析(Functional Principal Component Analysis,FPCA)是对函数型数据进行降维的常用技术,本文将考虑函数型数据的主成分联合选择问题。首先,本文给出了两函数型变量的主成分联合模型,并通过基函数展开法和极大惩罚似然法对样本数据进行曲线平滑。在联合模型基础上,本文给出了确定函数型主成分个数的AIC准则,并提出了改进的ECME算法对模型参数进行估计。模拟显示AIC准则对应的主成分个数选择结果准确率更高,考虑两函数型数据之间相关信息的联合选择效果会比对各函数型数据主成分进行独立选择的结果有所提升。最后,本文将所提方法应用于老年人中医宗气数据的分析.
基金supported by the National Natural Science Foundation of China(Grant No.:32172918)the project funded by the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions,China,and the Key Projects of Natural Science Foundation of Anhui Provincial Department of Education,China(Grant No.:2023AH051017)the Anhui Agricultural University Talent Research Grant Project(Project No.:RC393302).
文摘The small-molecule alkaloid halofuginone(HF)is obtained from febrifugine.Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions,which range from parasite infections and fibrosis to autoimmune diseases.In particular,HF is believed to play an excellent anticancer role by suppressing the proliferation,adhesion,metastasis,and invasion of cancers.This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF.In the studies covered in this review,the anticancer molecular mechanisms of HF mainly included transforming growth factor-β(TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2(Nrf2),serine/threonine kinase proteins(Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated(Wnt)/β-catenin,the exosomal microRNA-31(miR-31)/histone deacetylase 2(HDAC2)signaling pathway,and the interaction of the extracellular matrix(ECM)and immune cells.Notably,HF,as a novel type of adenosine triphosphate(ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase(ProRS)and amino acid starvation therapy(AAS)to suppress the formation of ribosome,further exerts a significant effect on the tumor microenvironment(TME).Additionally,the combination of HF with other drugs or therapies obtained universal attention.Our results showed that HF has significant potential for clinical cancer treatment.
基金supported by the National Institutes of Health-Office of Research Infrastructure Programs(P40 OD010440)supported in part by grants from the National Cancer Center of Korea(NCC-2110160,NCC-2110263,and NCC-2310750)supported by the Basic Science Research Program of the National Research Foundation of Korea,funded by the Ministry of Science,ICT,and Future Planning(NRF-2015R1C1A1A01053611).
文摘The growth of Caenorhabditis elegans involves multiple molting processes,during which old cuticles are shed and new cuticles are rapidly formed.This process requires the regulated bulk secretion of cuticle components.The transmembrane protein-39(TMEM-39)mutant exhibits distinct dumpy and ruptured phenotypes characterized by notably thin cuticles.TMEM-39 primarily co-localizes with the coat protein II complex(COPII)in large vesicles rather than small COPII vesicles.These TMEM-39-associated large vesicles(TMEM-39-LVs)form robustly during the molting period and co-localize with various extracellular matrix components,including BLI-1 collagen,BLI-3 dual oxidase,and carboxypeptidases.Through immunoprecipitation using TMEM39A-FLAG and proteomics analysis in human sarcoma cells,we identify TMEM39A-associated proteins,including TMEM131.Knockdown of TMEM131 results in reduced TMEM39A-LV formation and collagen secretion in both C.elegans and human sarcoma cells,indicating a cooperative role between TMEM39A and TMEM131 in the secretion of extracellular components through the formation of large COPII vesicles.Given the conservation of TMEM39A and its associated proteins between C.elegans and humans,TMEM39A-LVs may represent a fundamental machinery for rapid and extensive secretion across metazoans.
