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Development of PROTACS degrading KRAS and SOS1

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Oncology Research 2024年第8期32卷 1257-1264页

作者： GERHARD HAMILTON MARIE-THERESE EGGERSTORFER sandra stickler Institute of Pharmacology Medical University of ViennaVienna1090Austria

The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung ***,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of ***,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 *** approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of ***,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal *** of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not *** CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental *** to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin *** highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

关键词： Proteolysis-targeting chimeras(PROTACs) Kirsten rat sarcoma virus(KRAS) Son of sevenless 1(SOS1) Von Hippel-Lindau Cereblon

Changes of protein expression during tumorosphere formation of small cell lung cancer circulating tumor cells

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Oncology Research 2023年第1期31卷 13-22页

作者： sandra stickler BARBARA RATH MAXIMILIAN HOCHMAIR CLEMENS LANG LUKAS WEIGL GERHARD HAMILTON Institute of Pharmacology Medical University of ViennaViennaAustria Karl Landsteiner Institute of Lung Research and Pulmonary Oncology Klinik FloridsdorfViennaAustria Department of Trauma Surgery Sozialmedizinisches Zentrum OstDonauspitalViennaAustria Division of Special Anesthesia and Pain Medicine Medical University of ViennaViennaAustria

Small cell lung cancer(SCLC)is frequently disseminated and has a dismal prognosis with survival times of approximately two *** cancer responds well to initial chemotherapy but recurs within a short time as a globally chemoresistant *** tumor cells(CTCs)are held responsible for metastasis,the extremely high numbers of these cells in advanced SCLC allowed us to establish several permanent CTC cell *** CTCs are distinguished by the spontaneous formation of large spheroids,termed tumorospheres,in regular tissue *** contain quiescent and hypoxic cells in their interior and are associated with high chemoresistance compared to single cell *** CTC lines were compared for their expression of 84 proteins associated with cancer either as single cells or in the form of tumorospheres in Western blot *** the exception of the UHGc5 line,all other CTC lines express EpCAM and lack a complete EpCAM-negative,vimentin-positive epithelial-mesenchymal transition(EMT)*** formation of tumorospheres the expression of EpCAM,that mediates cell-cell adhesion is markedly *** such as E-Cadherin,p27 KIP1,Progranulin,BXclx,Galectin-3,and Survivin showed variable changes for the distinct CTC cell *** conclusion,EpCAM presents the most critical marker for individual SCLC CTCs and the assembly of highly chemoresistant tumorospheres.

关键词： SCLC Spheroid Chemoresistance EpCAM Topotecan Epirubicin

Brief Review and Reconsideration of Fatigue Crack Closure Effect in Materials

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Journal of Materials Science & Technology 1997年第1期13卷 1-14页

作者： Chen, DL Weiss, B stickler, R Wang, ZG ACAD SINICA INST MET RESSTATE KEY LAB FATIGUE & FRACTURE MATSHENYANG 110015PEOPLES R CHINA UNIV VIENNA INST PHYS CHEM MAT SCIA-1090 VIENNAAUSTRIA

The state-of-the-art of fatigue crack closure effect, involving the mechanisms, measurements, models, evaluation methods, influencing factors and existing problems is briefly reviewed. Attention is concentrated on a new consideration of closure effect and a re-definition of the effective driving force for the propagation of a fatigue crack. A theoretical basis for measuring the closure effect is established. The proposed closure concept takes into account the role of the tower portion of loading cycle below the opening load. The conventional closure concept is proven to be correct only for some extreme cases which are practically non-existent for engineering materials. A miniature strain gauge technique is developed to measure the crack closure. Stress-ratio-change tests at threshold level clearly indicate the shortcomings of the conventional closure concept, and the validity of the newly-proposed closure concept. The application of the proposed concept can give rise to a new method for the determination of the effective fatigue threshold of materials. If the fatigue threshold is measured at a sufficiently negative stress ratio (R

关键词： FINITE-WIDTH STRESS-RATIO THRESHOLD GROWTH LOAD PLATE

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Influence of Stress Ratio and Loading Condition on Near-threshold Fatigue Crack Growth Behaviour

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Journal of Materials Science & Technology 1993年第1期9卷 47-52页

作者： B.Weiss R.stickler University of Vienna Wahringer Street 42A-1090 ViennaAustria

Near-threshold fatigue crack propagation behaviour of a cold-worked copper tested with distinct fa- tigue testing systems under different stress ratios has been *** emphasis was placed on the evaluation of crack closure effect as well as the effective fatigue threshold,It was found that the fatigue threshold for R=0 is higher than those for R=-1 and R=0.4,for which almost the same threshold value was *** with the conventional closure evaluation method,the pro- posed new closure evaluation method can generally interpret the dependence of the fatigue thresh- old on stress ratio and loading condition,and leads to a higher and relatively constant effective fa- tigue threshold of about 3 MPa·m^(1/2) for the cold-worked copper at different stress ratios and loading conditions.

关键词： near-threshold fatigue crack stress ratio

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中英文电子搭档语言学习:前期准备及合作协调的作用(英文)

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汉语国际传播研究 2013年第2期 131-143,193页

作者： [英]阚茜 [奥]Ursula stickler 徐琤英国开放大学语言系北京交通大学远程与继续教育学院

在当今教育信息科技迅猛发展的时代,用语言搭档互助学外语也从传统的面对面走向了远程:搭档双方利用网络进行书面和口头交流。电子搭档语言学习近年来越来越引起外语教师和研究人员的重视。电子搭档学习和研究大多是在欧洲语言之间展开... 详细信息

在当今教育信息科技迅猛发展的时代,用语言搭档互助学外语也从传统的面对面走向了远程:搭档双方利用网络进行书面和口头交流。电子搭档语言学习近年来越来越引起外语教师和研究人员的重视。电子搭档学习和研究大多是在欧洲语言之间展开。近年来有了一些涉及汉语的电子搭档研究。本文介绍的为期六周的中英文电子搭档语言学习项目是由英国开放大学远程初级汉语教研室和北京交通大学远程教育学院合作进行的。本文重点探讨电子搭档语言学习项目前期准备和两所院校协调的作用。作者对收集到的数据进行了定性和定量分析,分析表明:项目前期准备和双方合作协调对电子搭档语言学习的成功起着至关重要的作用。

关键词：电子搭档语言学习远程汉语教学网络语言搭档项目设计合作协调

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临床儿科

国际护理学杂志 1988年第4期 155-156页

作者： stickler GB ,吴荫云

许多临床医学仍然建立在经验主义的基础上,在确立诊断时尤其如此,常凭有经验临床医生的直感。在此,我想提出一些我认为有用的规则。我希望它们能起到“抛砖引玉”的作用,掀起争鸣,导致这些规则的删除、添加和完善。1.确定出真正的“主诉... 详细信息

许多临床医学仍然建立在经验主义的基础上,在确立诊断时尤其如此,常凭有经验临床医生的直感。在此,我想提出一些我认为有用的规则。我希望它们能起到“抛砖引玉”的作用,掀起争鸣,导致这些规则的删除、添加和完善。1.确定出真正的“主诉”,而不要采用以前的诊断作为主诉。例如,一名因尿频、尿痛来就诊的患者,他(她)的主诉不是“尿路感染”。主诉必须以简洁的文字记录患儿或患儿家长来就诊的理由。2.仔细听取患儿母亲或主要看护人的叙述;这些人是最好的观察者,能把病情描述得很完善。如果病史不是由这些主要看护者申诉,或者有另外一些“感兴趣的人员”参与,如祖父母等,则此结果就可能搞得混乱不堪。3.根据家长理解的水平来确定他(她)们着急的原因;这一步对此后劝导他(她)们是非常重要的。

关键词：器质性疾病患儿采集病史病人病儿鉴别诊断病情

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输液与输电解质疗法的计划和实施

中华内科杂志 1957年第7期05卷 569-569,584页

作者： Moll,H.C. stickler,G.B. Daugherty,G.W. 邝贺龄

水与电解质平衡对于每个人都是重耍的;但需要医师处理的严重性平衡紊乱,则比较罕见。这是由于机体的巨大适应能力,借助于各项调节机转。虽没有

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