目的探讨LMO4在弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)中的表达及其临床意义。方法应用免疫组化EnVision法检测123例DLBCL组织及60例反应性淋巴组织增生(reactive lymphoid hyperplasia,RLH)组织中LMO4蛋白的表达。...目的探讨LMO4在弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)中的表达及其临床意义。方法应用免疫组化EnVision法检测123例DLBCL组织及60例反应性淋巴组织增生(reactive lymphoid hyperplasia,RLH)组织中LMO4蛋白的表达。采用免疫细胞化学和Western blot法分别检测LMO4蛋白在DLBCL细胞株LY-10、SUDHL-4以及正常人外周血淋巴细胞中的表达。结果免疫组化结果显示LMO4蛋白在DLBCL中的高表达率明显高于RLH组织(66.7%vs 23.3%,P<0.05),其表达与肿瘤原发位置、免疫分型、IPI评分及Ann Arbor分期均有相关性(P<0.05),而与其他临床病理特征无明显相关性。免疫细胞化学和Western blot均显示LMO4在DLBCL细胞株LY-10和SUDHL-4中呈高表达,在正常人外周血淋巴细胞中呈低表达。结论DLBCL组织和细胞株中LMO4均呈高表达,在RLH和正常人外周血淋巴细胞中低表达,提示LMO4在DLBCL发生、发展中可能起重要作用。展开更多
High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials.Herein,we analyzed a published CRISPR activation screening to identify t...High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials.Herein,we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8^(+)T cells.Using IFN-γproduction as a proxy for CD8^(+)T cell terminal differentiation,LMO4 emerged among the top hits inhibiting the development of effectors cells.Consistently,we found that Lmo4 was downregulated upon CD8^(+)T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells.By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8^(+)T cells,we enabled selective expansion and enhanced persistence of transduced cells,while limiting their terminal differentiation and senescence.LMO4 overexpression promoted transcriptional programs regulating stemness,increasing the numbers of stem-like CD8^(+)memory T cells and enhancing their polyfunctionality and recall capacity.When tested in syngeneic and xenograft tumor models,LMO4 overexpression boosted CD8^(+)T cell antitumor immunity,resulting in enhanced tumor regression.Rather than directly modulating gene transcription,LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21,inducing the expression of target genes(Tcf7,Socs3,Junb,and Zfp36)crucial for memory responses.CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4,thereby abrogating the therapeutic benefit of LMO4 overexpression.These results establish LMO4 overexpression as an effective strategy to boost CD8^(+)T cell stemness,providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.展开更多
Potential advantages of active electrode nanomaterials have led to development of high energy and power density lithium-ion(Li-ion)batteries.However,under increasing demand for critical resources such as lithium and c...Potential advantages of active electrode nanomaterials have led to development of high energy and power density lithium-ion(Li-ion)batteries.However,under increasing demand for critical resources such as lithium and cobalt,it is necessary to use abundant raw materials,which can be obtained from industrial waste.In this work,purified Mg(OH)_(2)from waste generated in the production of Li2CO3 with natural brines from the Salar de Atacama(Chile)is used as a doping agent for synthesis of LiMn_(2)O_(4)(LMO)spinel octahedral nanoparticles co-doped with excess Li and Mg.Crystallization of a pure cubic spinel phase(Fd3m)takes place at 500℃and sintering temperature effect at 580 and 750℃,thus the elemental composition and the structural,morphological,and electrochemical properties are studied in detail.Optimum electrochemical performance at room temperature is obtained for Li_(1.03)Mg_(0.05)Mn_(1.92)O_(4)spinel sintered at 750℃with an initial discharge capacity of 121.3 mAh·g^(-1)and capacity retention of 94.0%after 100 cycles at C/3.A locally ordered spinel structure is obtained at 750℃,and doping with Mg^(2+)improves structural rigidity.Synergy between both effects resulted in a high Li^(+)diffusion rate(1.29×10^(-9)cm^(2)·s^(-1))significantly improving cycling performance at elevated C-rates in 50℃.展开更多
基金supported by the Deutsche Forschungsgemeinschaft(DFG)research grant(Project Nr.421981137)(to R.S.)DFG Sonderforschungsbereich Transregio 221 Gerok position(to R.S.and W.H.)+4 种基金the University Regensburg ReForM B grant(to R.S.)the Intramural Research Program of the US National Institutes of Health,National Cancer Institute(to L.G.)National Heart,Lung,and Blood Institute(to W.J.L.)the Italian Association for Cancer Research(AIRC)(IG 26305)AIRC Special Program 5x1000 IG 22737(to V.R.).
文摘High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials.Herein,we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8^(+)T cells.Using IFN-γproduction as a proxy for CD8^(+)T cell terminal differentiation,LMO4 emerged among the top hits inhibiting the development of effectors cells.Consistently,we found that Lmo4 was downregulated upon CD8^(+)T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells.By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8^(+)T cells,we enabled selective expansion and enhanced persistence of transduced cells,while limiting their terminal differentiation and senescence.LMO4 overexpression promoted transcriptional programs regulating stemness,increasing the numbers of stem-like CD8^(+)memory T cells and enhancing their polyfunctionality and recall capacity.When tested in syngeneic and xenograft tumor models,LMO4 overexpression boosted CD8^(+)T cell antitumor immunity,resulting in enhanced tumor regression.Rather than directly modulating gene transcription,LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21,inducing the expression of target genes(Tcf7,Socs3,Junb,and Zfp36)crucial for memory responses.CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4,thereby abrogating the therapeutic benefit of LMO4 overexpression.These results establish LMO4 overexpression as an effective strategy to boost CD8^(+)T cell stemness,providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.
基金Research presented in this article was funded by Programa Formacion de Capital Humano Avanzado from Comision Nacional de Investigación Cientifica and Tecnológica(No.CONICYT-PCHA/DoctoradoNacional/2015-21151464)Fondo de Financiamiento de Centros de Investigación enÁreas Prioritarias(No.ANID/FONDAP/15110019)+1 种基金Fondo Nacional de Desarrollo Cientifico and Tecnologico(No.FONDECYT REGULAR N°1191347)Programa Ingenieria 2030 from Corporación de Fomento de la Produccion(No.ING2030 CORFO 16ENI2-71940).
文摘Potential advantages of active electrode nanomaterials have led to development of high energy and power density lithium-ion(Li-ion)batteries.However,under increasing demand for critical resources such as lithium and cobalt,it is necessary to use abundant raw materials,which can be obtained from industrial waste.In this work,purified Mg(OH)_(2)from waste generated in the production of Li2CO3 with natural brines from the Salar de Atacama(Chile)is used as a doping agent for synthesis of LiMn_(2)O_(4)(LMO)spinel octahedral nanoparticles co-doped with excess Li and Mg.Crystallization of a pure cubic spinel phase(Fd3m)takes place at 500℃and sintering temperature effect at 580 and 750℃,thus the elemental composition and the structural,morphological,and electrochemical properties are studied in detail.Optimum electrochemical performance at room temperature is obtained for Li_(1.03)Mg_(0.05)Mn_(1.92)O_(4)spinel sintered at 750℃with an initial discharge capacity of 121.3 mAh·g^(-1)and capacity retention of 94.0%after 100 cycles at C/3.A locally ordered spinel structure is obtained at 750℃,and doping with Mg^(2+)improves structural rigidity.Synergy between both effects resulted in a high Li^(+)diffusion rate(1.29×10^(-9)cm^(2)·s^(-1))significantly improving cycling performance at elevated C-rates in 50℃.
