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Dabrafenib,an inhibitor of RIP3 kinase-dependent necroptosis,reduces ischemic brain injury

Neural Regeneration research 2018年第2期13卷 252-256页

作者： Shelly A.Cruz Zhaohong Qin Alexandre E R.Stewart Hsiao-Huei Chen ottawa hospital research institute OttawaCanada University of ottawa Brain and Mind InstituteOttawaCanada University of ottawa Heart institute OttawaCanada canadian Partnership for Storke Recovery OttawaCanada

Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.

关键词： ischemic brain injury inflammation macrophage Dabrafenib tumor necrosis factor-alpha photothrombosis receptor-interacting protein kinases necroptosis microgIia stroke neural regeneration

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Biomarker-guided drug therapy: personalized medicine for treating Alzheimer’s disease

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Neural Regeneration research 2021年第10期16卷 2010-2011页

作者： Charvi Syal Jing Wang Regenerative Medicine Program Ottawa Hospital Research InstituteOttawaONCanada Department of Cellular and Molecular Medicine Faculty of MedicineBrain and Mind Research InstituteUniversity of OttawaOttawaONCanada canadian Partnership for Stroke Recovery OttawaONCanada

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive *** is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril ***,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).

关键词： Alzheimer drugs Aβ

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Activation of tyrosine phosphatases in the progression of Alzheimer’s disease

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Neural Regeneration research 2020年第12期15卷 2245-2246页

作者： Alexandre F.R.Stewart Hsiao-Huei Chen University of ottawa Heart institute OttawaCanada ottawa hospital research institute OttawaCanada

Patients with Alzheimer’s disease(AD)have progressive memory loss,inability to reason,and display anxiety that accelerates disease *** points to two deficits:1)the brain fails to respond to insulin that regulates the formation of neuron connections required to store memories,and 2)deficits arise in the brain’s endogenous cannabinoid signaling that regulates mood and prevents anxiety(Aso and Ferrer,2014).In addition,leptin signaling,important in regulating hypothalamic synaptic plasticity and cognitive function is also affected in AD(McGregor and Harvey,2018).

关键词： Alzheimer endogenous arise

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N-methyl-D-aspartate receptor functions altered by neuronal PTP1B activation in Alzheimer’s disease and schizophrenia models

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Neural Regeneration research 2022年第10期17卷 2208-2210页

作者： Alexandre F.R.Stewart Hsiao-Huei Chen Department of Biochemistry Microbiology and ImmunologyUniversity of Ottawaand University of Ottawa Heart InstituteOttawaONCanada centre for Infection Immunity and InflammationOttawaONCanada Medicine Cellular and Molecular MedicineUniversity of Ottawa Brain and Mind InstituteOttawa Hospital Research InstituteOttawaONCanada

Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)*** AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane ***,NMDA receptors are only activated after repeated AMPA receptor activation by *** receptors are,for the most part,calcium-permeable *** influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.

关键词： PTP1B aspartate NMDA

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Neuronal protein-tyrosine phosphatase 1B hinders sensory-motor functional recovery and causes affective disorders in two different focal ischemic stroke models

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Neural Regeneration research 2021年第1期16卷 129-136页

作者： Shelly A.Cruz Zhaohong Qin Konrad M.Ricke Alexandre F.R.Stewart Hsiao-Huei Chen ottawa hospital research institute Neuroscience ProgramUniversity of OttawaOttawaONCanada Brain and Mind institute University of OttawaOttawaONCanada Department of Biochemistry Microbiology and ImmunologyUniversity of OttawaOttawaONCanada Cellular and Molecular Medicine University of OttawaOttawaONCanada Department of Medicine University of OttawaOttawaONCanada centre for Infection Immunity and InflammationUniversity of OttawaOttawaONCanada University of ottawa Heart institute OttawaONCanada

Ischemic brain injury causes neuronal death and *** activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after *** ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were *** stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 *** addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor ***-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated *** contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC *** together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after ***,PTP1B may represent a novel therapeutic target to improve stroke *** procedures for animal use were approved by the Animal Care and Use Committee of the University of ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.

关键词： adhesive removal test anxiety depression elevated plus maze forced swimming test Iba1 interleukin-1β microglia open field test tail suspension test tumor necrosis factor-α

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Re-evaluating the role of epithelial-mesenchymal-transition in cancer progression

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The Journal of Biomedical research 2018年第2期32卷 81-90页

作者： Andrew Sulaiman Zemin Yao Lisheng Wang Department of Biochemistry Microbiology and Immunology Faculty of Medicine University of Ottawa China-Canada centre of research for Digestive Diseases ottawa institute of Systems Biology University of Ottawa Regenerative Medicine Program Ottawa Hospital Research Institute

Epithelial-mesenchymal transition（EMT） and mesenchymal-epithelial transition（MET） are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells transit to mesenchymal-like tumor cells with great motility via EMT transcription factors; these mesenchymallike cells migrate through the circulation system, relocate to a suitable site and then convert back to an epithelial-like phenotype to regenerate the tumor. However, recent findings challenge this conventional model and support the existence of a stable hybrid epithelial/mesenchymal（E/M） tumor population. Hybrid E/M tumor cells exhibit both epithelial and mesenchymal properties, possess great metastatic and tumorigenic capacity and are associated with poorer patient prognosis. The hybrid E/M model and associated regulatory networks represent a conceptual change regarding tumor metastasis and organ colonization. It may lead to the development of novel treatment strategies to ultimately stop cancer progression and improve disease-free survival.

关键词： Epithelial-mesenchymal transition(EMT) mesenchymal-epithelial transition(MET) hybrid EMT/MET cancer metastasis

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Optimizing oncolytic virus design:a“Swiss army knife”approach to create a systemically delivered therapeutic

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1791-1792页

作者： Carolina S.Ilkow John Cameron Bell ottawa hospital research institute 501 Smyth RoadOttawaONK1H 8L6Canada

In a recent paper published in Nature Biotechnology,Chen et al.1 describe a multiplex oncolytic virus platform that coupled with adoptive T cell therapy could solve the problem of repeat,systemic delivery of virus based *** is widely accepted that multi-targeted therapeutic approaches attacking several facets of cancer biology are necessary to effectively deal with the tumor heterogeneity that exists within and between patients.

关键词： therapeutic al. targeted

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Consort观点：报告随机试验时变更结局的危害

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英国医学杂志中文版 2017年第9期20卷 491-494页

作者： Altman Douglas G Moher David Schulz Kenneth F 陈立敏(译者) centre for Statistics in Medicine and UK equator centre Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal SciencesUniversity of Oxford Oxford UK ottawa hospital research institute and canadian equator centre University of Ottawa Ottawa Canada FHI 360 Durham NC USA University of North Carolina School of Medicine Chapel Hill NC USAAccepted 13 January 2017 中华医学杂志英文版编辑部

严格而透明的临床试验可以增强试验结果的可信度。随机试验必须有一个研究方案，该方案需要给出计划进行的试验细节、概述预计采用的分析方法，并反映研究者间的重要想法。

关键词：医疗卫生行业临床试验医学研究分析方法

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Variability of Serum Concentration of Calcium, Phosphate and Parathyroid Hormone Depending on Time of Blood Draw for Patients on Nocturnal Home Hemodialysis

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Open Journal of Nephrology 2012年第4期2卷 65-71页

作者： Nasim Shahbazi Pierre A. Brown Ayub Akbari Deborah L. Zimmerman Department of Medicine Division of Nephrology Ottawa Hospital Ottawa Canada Department of Medicine Division of Nephrology Ottawa Hospital Ottawa Canada Kidney research centre of the ottawa hospital research institute Ottawa Canada Department of Medicine Division of Nephrology Thunder Bay Regional Health Sciences Centre Thunder Bay Canada

Background: Guidelines for patients treated with conventional hemodialysis patients have been written for target serum levels for calcium (Ca), phosphate (PO4) and intact parathyroid hormone (iPTH). No guidelines exist for nocturnal home hemodialysis (NHHD) patients for target values or timing of the blood sample draw. We undertook a prospective cohort study to examine the variability in pre, post and clinic (post-post) serum values for Ca, PO4, and iPTH in NHHD patients to determine if timing of blood draw could affect clinical decisions. Methods: Twenty prevalent NHHD patients collected blood pre and post their usual NHHD session with an additional blood sample drawn in clinic (post-post). Median and interquartile range of pre, post and clinic (post-post) values of iPTH, PO4 and Ca were calculated and compared with Freidman/Wilcoxon test. Serum concentrations were also categorized according to canadian Society of Nephrology (CSN) guidelines target values for pre and clinic (post-post) samples. The proportion of patients that would be categorized differently by clinic (post-post) samples was determined. Results: There was a significant difference between pre-serum values compared to post and clinic (post-post) values. Overall, iPTH, PO4 and Ca values would be misclassified in 25%, 70% and 50% respectively if blood was drawn at the clinic visit (post-post) compared to pre-HD as per CSN guidelines. Conclusions: Although no specific guideline has been written for NHHD patients, to ensure consistency of management compared to in-centre HD patients, lab values should be drawn pre-HD until clinical evidence suggests that the recommendations should be different for NHHD.

关键词： Nocturnal Hemodialysis Calcium Phosphate Parathyroid Hormone

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CONSORT 2010说明与详述:报告平行对照随机临床试验指南的更新

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中西医结合学报 2010年第8期8卷 701-741页

作者： David Moher Sally Hopewell Kenneth F Schulz Victor Montori Peter C Gφtzsche P J Devereaux Diana Elbourne Matthias Egger Douglas G Altman 周庆辉卞兆祥刘建平 ottawa Methods centre Clinical Epidemiology ProgramOttawa Hospital Research InstituteOttawa HospitalOttawaOntario centre for Statistics in Medicine University of Oxford Wolfson College Family Health International Research Triangle Park UK Knowledge and Encounter research Unit Mayo Clinic Rochester The Nordic Cochrane centre Rigshospitalet Blegdamsvej 9 McMaster University Health Sciences centre Hamilton Medical Statistics Unit London School of Hygiene and Tropical Medicine institute of Social and Preventive Medicine (ISPM) University of Bern

大量证据显示随机对照临床试验(randomised controlled trial,RCT)的报告质量不理想。报告不透明,则读者既不能评判试验结果是否真实可靠,也不能从中提取可用于系统综述的信息。最近的方法学分析表明,报告不充分和设计不合理与对治疗效... 详细信息

大量证据显示随机对照临床试验(randomised controlled trial,RCT)的报告质量不理想。报告不透明,则读者既不能评判试验结果是否真实可靠,也不能从中提取可用于系统综述的信息。最近的方法学分析表明,报告不充分和设计不合理与对治疗效果产生评价偏倚有关。这种系统误差对RCT损害严重,而RCT正是以其能减少或避免偏倚而被视为评价干预措施的金标准。为了提高RCT的报告质量,一个由专家和编辑组成的工作组制定了临床试验报告的统一标准(Consolidated Standards of Reporting Trials,CONSORT)声明。CONSORT声明于1996年首次发表,并于2001年更新。声明由对照检查清单和流程图组成,供作者在报告RCT时使用。许多核心医学期刊和主要国际性编辑组织都已认可CONSORT声明。该声明促进了对RCT的严格评价和解释。2001年,在对CONSORT进行修订时,人们就已经清楚地认识到,解释和说明制定CONSORT声明的原理,有助于研究人员等撰写或评价临床试验报告。一篇CONSORT说明与详述文章于2001年同2001版CONSORT声明一起发表。2007年1月的专家会议之后,对CONSORT声明作了进一步修订并已发表,即"CONSORT2010声明"。这次更新对原版对照检查清单作了文字上的修改,使其更为明晰,并收入了与一些新近才认识到的主题相关的建议,如选择性报告结局产生的偏倚。说明与详述文件旨在加强人们对CONSORT声明的理解、应用和传播,这次也作了大量修订,对每一项新增或更新的清单条目的含义和增改理由进行了解释,提供了优秀的报告实例,还尽可能地提供了相关的经验性研究的参考文献。文中收入了若干流程图实例。"CONSORT2010声明"、其说明与详述文件,以及相关网站(***),对于改进随机临床试验报告必将有所裨益。

关键词：临床试验随机对照试验指南 CONSORT

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