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Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders

Translational neurodegeneration 2014年第1期3卷 180-203,179页

作者： Kristi M Anderson katherine E Olson katherine A Estes Ken Flanagan Howard E Gendelman R Lee Mosley Department of Pharmacology and Experimental neuroscience Center for Neurodegenerative DisordersThe University of Nebraska Medical CenterOmahaNE 68198USA Prothena Biosciences Inc.650 Gateway BoulevardSouth San FranciscoCA 94080USA

Inappropriate T cell responses in the central nervous system(CNS)affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include,but are not limited to,multiple sclerosis,amyotrophic lateral sclerosis,Alzheimer’s disease and Parkinson’s *** the one hand immune responses can exacerbate neurotoxic responses;while on the other hand,they can lead to neuroprotective *** temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent ***,immune responses that affect neurodegeneration may occur within or outside the *** of antigen-specific CD4+T cells from the periphery to the CNS and consequent immune cell interactions with resident glial cells affect neuroinflammation and neuronal *** destructive or protective mechanisms of these interactions are linked to the relative numerical and functional dominance of effector or regulatory T ***,immune responses at disease onset or during progression may exhibit a differential balance of immune responses in the periphery and within the *** responses with predominate T cell subtypes may differentially manifest migratory,regulatory and effector functions when triggered by endogenous misfolded and aggregated proteins and cell-specific *** final result is altered glial and neuronal behaviors that influence the disease ***,discovery of neurodestructive and neuroprotective immune mechanisms will permit potential new therapeutic pathways that affect neuronal survival and slow disease progression.

关键词： neurodegeneration neuroprotection Migration MPTP MCAM Regulatory T cell Effector T cell,neuroinflammation

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Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

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Frontiers of Chemical Science and Engineering 2016年第2期10卷 186-195页

作者： Andrew Best katherine James Gerald Hysenaj Alison Tyson-Capper David J. Elliott Institute of Genetic Medicine Newcastle University Newcastle NE1 3BZ UK Interdisciplinary Computing and Complex BioSystems Research Group and Centre for Bacterial Cell Biology Newcastle University Newcastle NE1 3BZ UK Institute for Cellular Medicine Newcastle University Newcastle NE2 4HH UK

Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and the highly similar Tra2a protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2fl reduces splicing inclu- sion of a poison exon in the mRNA encoding Tra2a, thereby up-regulating Tra2a protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2fl alone. Discovery of this cross-regulation pathway, and its by-pass by joint deple- tion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 （CHK1） gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.

关键词： RNA splicing gene expression breast cancer,DNA damage CHK1

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代谢相关药物对3T3-L1脂肪细胞促酰化蛋白分泌的影响

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细胞与分子免疫学杂志 2012年第10期28卷 1051-1054页

作者：高颖 katherine Cianflone Danny Gauvreau Wei Cui 马依彤新疆医科大学第一附属医院心脏中心新疆乌鲁木齐830011 Centre de Recherche Institut Universitaire de Cardiologie et dePneumologie de Quebec(CRIUCPQ) Laval UniversityQuebecQuebecCanada

目的:建立使用3T3-L1脂肪细胞评价药物影响促酰化蛋白(ASP)分泌的细胞模型和测定ASP分泌的ELISA方法,观察代谢相关药物二甲双胍、罗格列酮钠及立莫那班对ASP分泌的影响及机制,以及与补体C3、非酯化脂肪酸(ne-FA)释放、甘油三酯总量(TG m... 详细信息

目的:建立使用3T3-L1脂肪细胞评价药物影响促酰化蛋白(ASP)分泌的细胞模型和测定ASP分泌的ELISA方法,观察代谢相关药物二甲双胍、罗格列酮钠及立莫那班对ASP分泌的影响及机制,以及与补体C3、非酯化脂肪酸(ne-FA)释放、甘油三酯总量(TG mass)、脂肪酸摄取量的关系。方法:以3T3-L1前脂肪细胞为实验对象,诱导细胞分化,分别加入乳糜微粒、二甲双胍、罗格列酮钠及立莫那班作用48 h。采用ELISA法测定ASP、C3含量,使用酶标比色法测定neFA含量,脂肪细胞FA摄取速度在荧光酶标仪进行动力学方法测量,采用分光光度法测定TG含量,考马斯亮蓝染料结合法测定细胞总蛋白。结果:乳糜微粒刺激ASP分泌(达411%±133%P<0.05);罗格列酮钠和立莫那班抑制ASP产生(-53%～-85%,P<0.05),同时抑制前体蛋白C3分泌(-37%～-65%,P<0.05);二甲双胍抑制ASP分泌(-54%～-100%,P<0.05),对前体蛋白C3分泌无影响;二甲双胍降低TG含量(达-60%,P<0.05)和FA摄取速度(达-75%,P<0.05)。结论:成功建立了评价药物影响促酰化蛋白(ASP)分泌的3T3-L1前脂肪细胞模型,并建立了测定ASP分泌的ELISA方法。

关键词： 3T3-L1脂肪细胞促酰化蛋白药物

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An open-label multiyear study of sargramostim-treated Parkinson’s disease patients examining drug safety,tolerability,and immune biomarkers from limited case numbers

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Translational neurodegeneration 2023年第1期12卷 529-545页

作者： katherine E.Olson Mai M.Abdelmoaty Krista L.Namminga Yaman Lu Helen Obaro Pamela Santamaria R.Lee Mosley Howard E.Gendelman Department of Pharmacology and Experimental neuroscience Center for Neurodegenerative DisordersUniversity of Nebraska Medical CenterOmahaNE 68198USA Great Plains Center for Clinical and Translational Research Nebraska MedicineOmahaNEUSA neurology Consultants of nebraska PC and Nebraska MedicineOmahaNEUSA

Background The clinical utility and safety of sargramostim has previously been reported in cancer,acute radiation syndrome,autoimmune disease,inflammatory conditions,and Alzheimer’s *** safety,tolerability,and mecha-nisms of action in Parkinson’s disease(PD)during extended use has not been *** As a primary goal,safety and tolerability was assessed in five PD patients treated with sargramostim(Leukine®,granulocyte-macrophage colony-stimulating factor)for 33 *** goals included numbers of CD4+T cells and monocytes and motor ***,metabolic,immune,and neurological evaluations were assessed during a 5-day on,2-day off therapeutic regimen given at 3μg/*** 2 years,drug use was discon-tinued for 3 *** was then followed by an additional 6 months of *** Sargramostim-associated adverse events included injection-site reactions,elevated total white cell counts,and bone *** drug,blood analyses and metabolic panels revealed no untoward side effects linked to long-term *** Parkinson’s Disease Rating Scale scores remained stable throughout the study while regulatory T cell number and function were *** the initial 6 months of treatment,transcriptomic and proteomic mono-cyte tests demonstrated autophagy and sirtuin *** finding paralleled anti-inflammatory and antioxidant activities within both the adaptive and innate immune profile *** Taken together,the data affirmed long-term safety as well as immune and anti-inflammatory responses reflecting clinical stability in PD under the sargramostim *** in larger patient populations is planned in a future phase II evaluation.

关键词： Parkinson’s disease Granulocyte-macrophage colony-stimulating factor Unified Parkinson’s Disease Rating Scale Regulatory T cells neuroprotection Sargramostim therapy

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Screening and Purification of Natural Products from Actinomycetes that Induce a“Rounded”Morphological Phenotype in Fission Yeast

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Natural Products and Bioprospecting 2021年第4期11卷 431-445页

作者： Richard Alexander Lewis Jenileima Devi katherine Green Juanjuan Li Adam Hopkins Jacqueline Hayles Paul Nurse Jeff Errington Nicholas Edward Ellis Allenby Demuris Ltd The BiosphereDraymans WayNewcastle HelixNewcastle upon Tyne NE45BXUK University of Southampton University RoadSouthampton SO171BJUK Cell Cycle Laboratory The Francis Crick Institute1 Midland RoadLondon NW11ATUK

This study was designed to identify and investigate bioactive natural product compounds that alter the cellular shape of the fission yeast Schizosaccharomyces pombe and induce a“rounded”or“small”cellular morphological *** using a range of antifungal agents against a multidrug-sensitive fission yeast strain,SAK950 showed that many induced a“rounded”*** then investigated whether 46 of the actinomycete strains identified in our previous study as inducing a similar phenotype produced antifungal agents of similar *** show that five of the strains produced streptothricin and that 26 strains produced polyenes,including fungichromin,filipin and candicidin,the last of which was produced by 24 strains.A taxonomic study of the strains indicated that the majority of the candicidin only producers were Streptomyces hydrogenans and *** whilst those that additionally produced streptothricin were related to ***.A follow-up study to investigate the natural products made by related strains indicated that they followed a similar *** identification of several compounds from the actinomycete strains similar to the antifungal agents initially tested confirm the validity of an approach using the *** morphological phenotype and actinomycete taxonomy as a predictive tool for natural product identification.

关键词： Actinomycetes Schizosaccharomyces pombe Morphology Phenotype Antifungal Polyene

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改善门诊抗生素使用利用数据的力量

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英国医学杂志中文版 2019年第6期22卷 311-312页

作者： Lauri A Hicks Laura M King katherine E Fleming-Dutra 于东豪(译) 曹彬(校) Office of Antibiotic Stewardship Division of Healthcare Quality PromotionNational Center for Emerging and Zoonotic Infectious DiseasesCenters for Disease Control and Prevention1600 Clifton Road NEMailstop A-31 AtlantaGA 30329USA 首都医科大学附属北京潞河医院呼吸与危重症医学科中日友好医院呼吸与危重症医学科

据估算,门诊处方占据了85%~95%的抗生素使用,而在门诊背景下,抗生素常常被滥用或误用1-3.人们越来越多的意识到优化门诊环境下的抗生素使用是提高患者安全的潜在机会4。THE BMJ的两项研究描述了如何利用门诊抗生素处方数据的力量来提高... 详细信息

据估算,门诊处方占据了85%~95%的抗生素使用,而在门诊背景下,抗生素常常被滥用或误用1-3.人们越来越多的意识到优化门诊环境下的抗生素使用是提高患者安全的潜在机会4。THE BMJ的两项研究描述了如何利用门诊抗生素处方数据的力量来提高管理质量5-6.数据对于确定改进的机会以采取通报行动,追溯和上报抗生素的使用,并评估干预措施的影响十分重要4。

关键词：门诊处方抗生素力量数管理质量 BMJ

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