With the advent of safer and more efficient gene transfer methods, gene therapy has become a viable solution for many inherited and acquired disorders. Hematopoietic stem cells(HSCs) are a prime cell compartment for g...With the advent of safer and more efficient gene transfer methods, gene therapy has become a viable solution for many inherited and acquired disorders. Hematopoietic stem cells(HSCs) are a prime cell compartment for gene therapy aimed at correcting blood-based disorders, as well as those amenable to metabolic outcomes that can effect cross-correction. While some resounding clinical successes have recently been demonstrated, ample room remains to increase the therapeutic output from HSC-directed gene therapy. In vivo amplification of therapeutic cells is one avenue to achieve enhanced gene product delivery. To date, attempts have been made to provide HSCs with resistance to cytotoxic drugs, to include druginducible growth modules specific to HSCs, and to increase the engraftment potential of transduced HSCs. This review aims to summarize amplification strategies that have been developed and tested and to discuss their advantages along with barriers faced towards their clinical adaptation. In addition, next-generation strategies to circumvent current limitations of specific amplification schemas are discussed.展开更多
Brassica napus(cv.Madrigal)seedlings pre-treated with ascospores of Leptosphaeria biglobosa or foliar sprays of either acibenzolar-S-methyl(ASM)or menadione sodium bisulphite(MSB)were chal- lenge inoculated with L.mac...Brassica napus(cv.Madrigal)seedlings pre-treated with ascospores of Leptosphaeria biglobosa or foliar sprays of either acibenzolar-S-methyl(ASM)or menadione sodium bisulphite(MSB)were chal- lenge inoculated with L.maculans ascospores and assessed for phoma leaf spot development and tissue morphology and gene expression responses to infection.Rates of increase in phoma leaf spot area 8―21 d after challenge inoculation were significantly greater on water pre-treated plants than on plants pre-treated with L.biglobosa,ASM or MSB on both pre-treated leaves(local effect)and younger leaves without pre-treatment(systemic effect).Ninety-six h after challenge inoculation,the invasive hyphae of L.maculans were encircled by rings of necrotic mesophyll cells on leaves pre-treated with L. biglobosa,ASM or MSB but not those pre-treated with water.Quantification of transcript levels of genes commonly used as markers of the major defence signalling pathways(PDF1.2,PR-1,NPR1,APX, CHB4)0–96 h after L.maculans challenge inoculation showed expression patterns indicating prefer- ential activation of the jasmonate/ethylene pathway and involved induction of NPR1 locally and sys- temically in leaves of plants pre-treated with L.biglobosa ascospores.展开更多
目的探讨药物性肝损伤(DILI)患者临床转归的影响因素,构建列线图模型并进行内部验证。方法回顾性分析哈尔滨工业大学附属黑龙江省医院2017年1月—2022年12月收治的188例DILI患者的一般资料和实验室数据,根据患者临床转归分为结局良好组(...目的探讨药物性肝损伤(DILI)患者临床转归的影响因素,构建列线图模型并进行内部验证。方法回顾性分析哈尔滨工业大学附属黑龙江省医院2017年1月—2022年12月收治的188例DILI患者的一般资料和实验室数据,根据患者临床转归分为结局良好组(n=146)和不良结局组(n=42)。正态分布计量资料两组间比较采用成组t检验;非正态分布计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ^(2)检验。通过单因素和多因素Logistic回归分析筛选DILI患者临床转归相关的独立影响因素。R Studio 4.1.2软件构建列线图模型,通过校准曲线、受试者工作特征曲线(ROC曲线)和决策曲线分析(DCA)对模型进行内部验证。结果单因素Logistic回归分析结果显示,肝活检诊断DILI、PLT、ChE、Alb、PTA、IgM和IgG与DILI患者不良结局相关(P值均<0.05)。多因素Logistic回归分析结果显示,肝活检诊断DILI(OR=0.072,95%CI:0.022~0.213,P<0.001)、临床分型(OR=0.463,95%CI:0.213~0.926,P=0.039)、ALT(OR=0.999,95%CI:0.998~1.000,P=0.025)、PTA(OR=0.973,95%CI:0.952~0.993,P=0.011)和Ig M(OR=1.456,95%CI:1.082~2.021,P=0.015)是DILI患者临床转归的独立影响因素。构建列线图,经验证校准曲线接近参考曲线,ROC曲线下面积为0.829,决策曲线分析显示该模型具有良好的临床净收益。结论构建的列线图模型对评估DILI患者的临床转归具有较好的临床校准度、鉴别能力和应用价值。展开更多
基金Supported by Canadian Institutes of Health Research Grant to Medin JA,No.MOP-123528
文摘With the advent of safer and more efficient gene transfer methods, gene therapy has become a viable solution for many inherited and acquired disorders. Hematopoietic stem cells(HSCs) are a prime cell compartment for gene therapy aimed at correcting blood-based disorders, as well as those amenable to metabolic outcomes that can effect cross-correction. While some resounding clinical successes have recently been demonstrated, ample room remains to increase the therapeutic output from HSC-directed gene therapy. In vivo amplification of therapeutic cells is one avenue to achieve enhanced gene product delivery. To date, attempts have been made to provide HSCs with resistance to cytotoxic drugs, to include druginducible growth modules specific to HSCs, and to increase the engraftment potential of transduced HSCs. This review aims to summarize amplification strategies that have been developed and tested and to discuss their advantages along with barriers faced towards their clinical adaptation. In addition, next-generation strategies to circumvent current limitations of specific amplification schemas are discussed.
基金Supported by a Rothamsted International Fellowship to LIU ShengYi,a Royal Society China Fellowship to LIU RenHu,the UK Biotechnology and Biological Sciences Research Council(BBSRC),Department for Environment,Food and Rural Affairs(Defra),the Chadacre Trust,UK and the Ministry of Agriculture,P.R.China
文摘Brassica napus(cv.Madrigal)seedlings pre-treated with ascospores of Leptosphaeria biglobosa or foliar sprays of either acibenzolar-S-methyl(ASM)or menadione sodium bisulphite(MSB)were chal- lenge inoculated with L.maculans ascospores and assessed for phoma leaf spot development and tissue morphology and gene expression responses to infection.Rates of increase in phoma leaf spot area 8―21 d after challenge inoculation were significantly greater on water pre-treated plants than on plants pre-treated with L.biglobosa,ASM or MSB on both pre-treated leaves(local effect)and younger leaves without pre-treatment(systemic effect).Ninety-six h after challenge inoculation,the invasive hyphae of L.maculans were encircled by rings of necrotic mesophyll cells on leaves pre-treated with L. biglobosa,ASM or MSB but not those pre-treated with water.Quantification of transcript levels of genes commonly used as markers of the major defence signalling pathways(PDF1.2,PR-1,NPR1,APX, CHB4)0–96 h after L.maculans challenge inoculation showed expression patterns indicating prefer- ential activation of the jasmonate/ethylene pathway and involved induction of NPR1 locally and sys- temically in leaves of plants pre-treated with L.biglobosa ascospores.
文摘目的探讨药物性肝损伤(DILI)患者临床转归的影响因素,构建列线图模型并进行内部验证。方法回顾性分析哈尔滨工业大学附属黑龙江省医院2017年1月—2022年12月收治的188例DILI患者的一般资料和实验室数据,根据患者临床转归分为结局良好组(n=146)和不良结局组(n=42)。正态分布计量资料两组间比较采用成组t检验;非正态分布计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ^(2)检验。通过单因素和多因素Logistic回归分析筛选DILI患者临床转归相关的独立影响因素。R Studio 4.1.2软件构建列线图模型,通过校准曲线、受试者工作特征曲线(ROC曲线)和决策曲线分析(DCA)对模型进行内部验证。结果单因素Logistic回归分析结果显示,肝活检诊断DILI、PLT、ChE、Alb、PTA、IgM和IgG与DILI患者不良结局相关(P值均<0.05)。多因素Logistic回归分析结果显示,肝活检诊断DILI(OR=0.072,95%CI:0.022~0.213,P<0.001)、临床分型(OR=0.463,95%CI:0.213~0.926,P=0.039)、ALT(OR=0.999,95%CI:0.998~1.000,P=0.025)、PTA(OR=0.973,95%CI:0.952~0.993,P=0.011)和Ig M(OR=1.456,95%CI:1.082~2.021,P=0.015)是DILI患者临床转归的独立影响因素。构建列线图,经验证校准曲线接近参考曲线,ROC曲线下面积为0.829,决策曲线分析显示该模型具有良好的临床净收益。结论构建的列线图模型对评估DILI患者的临床转归具有较好的临床校准度、鉴别能力和应用价值。
