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蛋白激酶A（PKA-C）突变L205R的致癌机制与特性抑制剂设计

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蛋白激酶A（PKA-C）突变L205R的致癌机制与特性抑制剂设计

Postpartum meloxicam administration alters plasma haptoglobin, polyunsaturated fatty acid, and oxylipid concentrations in postpartum ewes

第十一届全国化学生物学学术会议

作者：王英杰 caitlin Walker 高加力 Gianluigi Veglia 深圳湾实验室系统生物学研究所 Department of Chemistry and BMBB University of Minnesota

蛋白质激酶的突变是诸多癌症的直接诱因,因而激酶抑制剂是当前癌症靶向治疗的一线药物。最近研究发现蛋白激酶A催化亚基（PKA-C）的诸多突变可直接导致库欣综合征,其中最主要的L205R点突变晶体结构与野生型几乎没有差异,因而其致癌机理... 详细信息

蛋白质激酶的突变是诸多癌症的直接诱因,因而激酶抑制剂是当前癌症靶向治疗的一线药物。最近研究发现蛋白激酶A催化亚基（PKA-C）的诸多突变可直接导致库欣综合征,其中最主要的L205R点突变晶体结构与野生型几乎没有差异,因而其致癌机理尚未定论,同时也给临床治疗带来了诸多困难。我们综合采用分子动力学模拟,结合蛋白质核磁共振实验及多种热力学定量测量方法,共同阐明了该突变对蛋白质运动及别构效应改变的物理化学基础。尤为关键的是,我们发现L205R突变减弱了激酶与原生蛋白抑制剂（PKI）的结合力,同时改变了PKA-C的底物选择性,从而重构了别构网络和信号转导。基于对该机制的理解,我们结合计算与实验,设计了针对L205R的特异抑制多肽,相较于PKI,其对L205R的选择性抑制提升了600多倍。该项研究表明,针对激酶致癌突变的机制性研究有助于研发新一代更具特异性和选择性的激酶抑制剂。

关键词：激酶分子动力学模拟 NMR 别构

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Journal of Animal Science and Biotechnology 2020年第4期11卷 1047-1060页

作者： Katie EOlagaray Barry J.Bradford Lorraine M.Sordillo Jeffery C.Gandy Laman K.Mamedova Turner H.Swartz Trey D.Jackson Emma K.Persoon caitlin S.Shugart Curtis R.Youngs Department of Animal Sciences and Industry Kansas State UniversityManhattan 66506USA College of Veterinary Medicine Michigan State University2265K Anthony HallEast LansingMI 48824-1225USA Department of Animal Science Iowa State UniversityAmesIAUSA.

Background: Postpartum inflammation is a natural and necessary response;however, a dysfunctional inflammatory response can be detrimental to animal productivity. The objective of this study was to determine the effects of a non-steroidal anti-inflammatory drug(meloxicam) on ewe postpartum inflammatory response, ewe plasma polyunsaturated fatty acid and oxylipid concentrations, and lamb ***: After lambing, 36 Hampshire and Hampshire × Suffolk ewes were sequentially assigned within type of birth to control(n = 17) or meloxicam orally administered on d 1 and 4 of lactation(MEL;90 mg, n = 19). Milk and blood samples were collected on d 1(prior to treatment) and d 4. Milk glucose-6-phosphate was not affected by MEL. Plasma haptoglobin(Hp) concentrations were less for MEL ewes;control ewes with greater d 1 Hp concentrations had elevated Hp on d 4, but this was not the case for MEL-treated ewes. Treatment with MEL increased plasma arachidonic acid concentration by more than 4-fold in ewes rearing singles but decreased concentrations of 9,10-dihydroxyoctadecenoic acid, prostaglandin F2α, 8-iso-prostaglandin E2, and 8,9-dihydroxyeicosatetraenoic acid. Nine oxylipids in plasma had interactions of treatment with d 1 Hp concentration,all of which revealed positive associations between d 1 Hp and d 4 oxylipid concentrations for CON, but neutral or negative relationships for MEL. MEL decreased 13-hydroxyoctadecadienoic acid:13-oxooctadecadienoic acid ratio and tended to increase 9-hydroxyoctadecadienoic acid:9-oxooctadecadienoic acid ratio(both dependent on d 1 values), indicating progressive metabolism of linoleic acid-derived oxylipids occurred by enzymatic oxidation after MEL treatment. Meloxicam reduced oxylipids generated across oxygenation pathways, potentially due to an improved redox ***: Postpartum MEL treatment of ewes decreased plasma concentrations of Hp and several oxylipids,with the greatest impact in ewes with biomarkers reflecting a greate

关键词： Eicosanoid Inflammation Lactation Nonsteroidal anti-inflammatory drug Sheep

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蛋白激酶A（PKA-C）突变L205R的致癌机制与特性抑制剂设计

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蛋白激酶A（PKA-C）突变L205R的致癌机制与特性抑制剂设计

中国化学会第六届全国生物物理化学会议（NCBPC-6）

作者：王英杰 caitlin Walker 高加力 Gianluigi Veglia 深圳湾实验室系统生物学研究所 Department of Chemistry and BMBB University of Minnesota

＜正＞蛋白质激酶的突变是诸多癌症的直接诱因,因而激酶抑制剂是当前癌症靶向治疗的一线药物。最近研究发现蛋白激酶A催化亚基（PKA-C）的诸多突变可直接导致库欣综合征,其中最主要的L205R点突变晶体结构与野生型几乎没有差异,因而其致...

＜正＞蛋白质激酶的突变是诸多癌症的直接诱因,因而激酶抑制剂是当前癌症靶向治疗的一线药物。最近研究发现蛋白激酶A催化亚基（PKA-C）的诸多突变可直接导致库欣综合征,其中最主要的L205R点突变晶体结构与野生型几乎没有差异,因而其致癌机理尚未定论,同时也给临床治疗带来了诸多困难。我们综合采用分子动力学模拟,结合蛋白质核磁共振实验及多种热力学定量测量方法,共同阐明了该突变对蛋白质运动及别构效应改变的物理化学基础。尤为关键的是,我们发现L205R突变减弱了激酶与原生蛋白抑制剂（PKI）的结合力,同时改变了PKA-C的底物选择性,从而重构了别构网络和信号转导。基于对该机制的理解,我们结合计算与实验,设计了针对L205R的特异抑制多肽,相较于PKI,其对L205R的选择性抑制提升了600逾倍。该项研究表明,针对激酶致癌突变的机制性研究有助于研发新一代更具特异性和选择性的激酶抑制剂。

关键词：

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漫画欣赏《铲屎官和猫》

视野 2017年第13期 28-29页

作者： caitlin Major

当铲屎官和猫主互换身份,会出现怎样奇异的画风?漫画家caitlin Major用画笔实现了"虐猫"。在这组漫画里,主角叫Manfried,一只虎斑人,是个不拘小节、赤身裸体的糙汉子;而铲屎官却是一只俄罗斯蓝猫,有点宅,但是很爱它的小人Manfried。

关键词：漫画讽刺画绘画

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公关传播界的重要挑战及应对思路

公关世界 2014年第10期 12-13页

作者： caitlin Carragee

美通社最近参加了2014美国公关协会国际会议,Golin公司CEO Fred Cooke在接受PRSA2014金砧奖时做了一个引起在场人士深思的演讲,演讲提出了公关传播界面临的重要挑战,并对如何迎接挑战提出了思路。很长一段时间还有很多人一直认为公关不... 详细信息

美通社最近参加了2014美国公关协会国际会议,Golin公司CEO Fred Cooke在接受PRSA2014金砧奖时做了一个引起在场人士深思的演讲,演讲提出了公关传播界面临的重要挑战,并对如何迎接挑战提出了思路。很长一段时间还有很多人一直认为公关不相信数据,公关没有精确的报告,并且在一些极端的案例中,公关没有对公司价值之关键产生积极的影响。参

关键词：公关工作公关传播数据点

Biological implications of 2-chlorocyclohexa-2,5-diene-1,4-dione toward ribonuclease A

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Advances in Bioscience and Biotechnology 2013年第1期4卷 22-28页

作者： Albert R. Vaughn caitlin B. Redman Sophia M. Kang Jisook Kim Department of Chemistry University of Tennessee at Chattanooga Chattanooga USA

2-Chlorocyclohexa-2,5-diene-1,4-dione (CBQ) or 2-chloro1,4-benzquinone is one of the common metabolites of polycyclic aromatic hydrocarbons generated through industrial processes. This report describes the biological effects of CBQ toward ribonuclease A (RNase). We also investigated the inhibition of RNase modifications and the reactivity of CBQ toward selected amino acids. The study was carried out by incubating RNase or amino acids with CBQ in a concentration- and a time-dependent manner at 37°C and pH 7.0. SDS-PAGE results showed oligomerization as well as polymeric aggregation of RNase when incubated with CBQ as early as in 10 min. CBQ-induced RNase modifications were inhibited in the presence of NADH or ascorbic acid. CBQ reactivity toward selected amino acids was also evaluated by determining the second-order rate constants for the reactions of CBQ with selected amino acids. It was found that the reactivity toward CBQ decreased in the order of lysine > threonine > serine >> aspartate > cysteine.

关键词： Chlorobenzoquinone PAH Protein Modification Ribonuclease A

Prognostic and Predictive Value of Pretreatment Derived Neutrophil-to-Lymphocyte Ratio in Non-Small-Cell Lung Cancer Patients Treated with an Immune Checkpoint Inhibitor

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Journal of Cancer Therapy 2018年第1期9卷 23-34页

作者： John Kucharczyk caitlin Sullivan Jonathan Lu Andrew Kolomensky Edward Peters Marc R. Matrana NYU Winthrop Hospital Internal Medicine Residency Program NYU Winthrop Hospital Mineola NY USA The University of Queensland School of Medicine Ochsner Clinical School New Orleans LA USA Ochsner Medical Oncology Fellowship Program Ochsner Clinic Foundation New Orleans LA USA Louisiana State University School of Public Health New Orleans LA USA Ochsner Cancer Institute Ochsner Clinic Foundation New Orleans LA USA

Background: Immune checkpoint inhibitors produce prolonged responses in select non-small cell lung cancer (NSCLC) patients, however the identification of patients most likely to benefit is difficult. Pretreatment derived neutrophil-to-lymphocyte ratio (dNLR) is an easily calculated marker available in routine clinical care that has shown prognostic value in many cancer treatment settings, but its association with survival in NSCLC patients treated with immune-checkpoint inhibitors is less understood. Patients and Methods: We retrospectively reviewed 72 NSCLC patients receiving either nivolumab or pembrolizumab between 3/1/15 and 3/1/17 with a median follow-up time of 5.1 months. Patients were compared using Cox proportional hazards models to detect an association between pretreatment dNLR 3 vs ≥3 on overall survival (OS), progression-free survival (PFS) and overall response rate. Results: Median age was 65 (range: 41 - 86), 65% were male, 40% received ≥ 2 prior systemic therapies and 14% had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2. Pretreatment dNLR ≥ 3 was independently associated with shortened OS (median 3.6 vs 8.5 months;HR: 5.4;95% CI: 2.0 - 14.6;p = 0.001) and PFS (median 2.1 vs 3.4;HR: 2.3;95% CI: 1.1 - 4.8;p = 0.027). Conclusion: Pretreatment dNLR ≥ 3 was independently associated with inferior survival in NSCLC treated with immune checkpoint inhibitors in routine practice. Prospective verification of this marker is warranted as it could serve as an inexpensive and widely-available marker for identifying NSCLC patients most likely to benefit from PD-1 inhibitors.

关键词： Clinical Marker PD-1 Inhibitor Immunotherapy Nivolumab Pembrolizumab

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6岁盲童钢琴奇才走红世界（英文）

疯狂英语（新悦读） 2019年第6期 18-19,62页

作者： caitlin O’Kane 不详

Avett Ray Maness is a 6-year-old piano *** taught himself to play piano by *** he is *** moment he could pull himself to reach the piano,he was playing the melody to Twinkle Twinkle Little *** was when he was just 11 ... 详细信息

关键词：奇才钢琴盲童世界

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重新认识蛋白表达

科学新闻 2020年第1期 55-58页

作者： caitlin Smith 李楠中国科学院深圳先进技术研究院

蛋白质表达之前只是作为生物学研究的一种重要工具,而现在它作为生物治疗的一种药物生产方式变得越来越重要。CRISPR/Cas9系统等基因组编辑工具的出现,为科学家提供了一种成本低廉、易于获取、且相对简单的改变基因的方法。通过结构和... 详细信息

蛋白质表达之前只是作为生物学研究的一种重要工具,而现在它作为生物治疗的一种药物生产方式变得越来越重要。CRISPR/Cas9系统等基因组编辑工具的出现,为科学家提供了一种成本低廉、易于获取、且相对简单的改变基因的方法。通过结构和翻译后修饰来精确控制蛋白表达,在表达治疗性蛋白(如处方药)方面同样十分重要。而控制其他物种(如蚊子)的蛋白质表达,甚至可

关键词： CRISPR 重新认识细胞系 RNA 基因组编辑大肠杆菌表达