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Targeting KRAS in pancreatic cancer

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Oncology Research 2024年第5期32卷 799-805页

作者： SANDRA STICKLER BARBARA RATH gerhard HAMILTON Institute of Pharmacology Medical University of ViennaViennaA-1090Austria

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient *** Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for ***,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung *** G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of ***,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in *** other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives *** agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

关键词： Pancreatic cancer PDAC KRAS SOS1 PROTAC

Translocator protein and neurodegeneration: insights from Alzheimer’s disease

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Neural Regeneration Research 2025年第4期20卷 1090-1091页

作者： Arpit Kumar Pradhan Rainer Rupprecht gerhard Rammes Klinik für Anaesthesiologie und Intensivmedizin der Technischen Universität München Klinikum rechts der IsarMunichGermany Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität MünchenMartinsriedGermany Department of Psychiatry and Psychotherapy University RegensburgRegensburgGermany

The 18 kDa translocator protein(TSPO)located on the outer mitochondrial membrane regulates several key cellular processes including mitochondrial homeostasis,cholesterol transport,apoptosis,cell proliferation,and maintenance of mitochondrial health(Rupprecht et al.,2022,2023).TSPO is expressed in both peripheral organs and the central nervous system,with a more pronounced expression in tissues that produce *** main reason why TSPO has garnered so much attention is because it plays a key role in neurosteroidogenesis by transferring cholesterol from the outer to the inner mitochondrial membrane,which is the rate-limiting step in neurosteroid synthesis.A cholesterol-recognizing amino acid consensus domain has been identified in the cytosolic C terminus of the TSPO protein by both in vitro and site-directed mutagenesis experiments(Li et al.,2001).However,the role of TSPO in the process of neurosteroid synthesis has been challenged by several studies,particularly TSPO knockout models,which suggest that TSPO removal does not affect the phenotype or the system’s viability(Tu et al.,2014).However,ligands targeting TSPO have been shown to enhance levels of neurosteroids which suggests that neurosteroidogenesis is one of the major functional roles mediated by the TSPO protein.

关键词： cholesterol organs

限量供油条件下微柱阵列束油表面润滑增效特性研究

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摩擦学学报（中英文） 2024年第2期44卷 117-128页

作者：孙建欣刘成龙郭峰 POLL gerhard 柏林清栗心明青岛理工大学机械与汽车工程学院山东青岛266520 莱布尼兹-汉诺威大学机械设计与摩擦学研究所 Welfengarten130167汉诺威德国

在润滑轨道两侧制备以防指纹油涂层(Anti-fingerprint coating,AFC)修饰的微柱阵列(Micropillar array,MA),形成润湿性梯度束油的润滑增效表面.使用点接触光弹流润滑油膜测量仪测量了该表面在限量供油往复运动条件下的油膜厚度以及油池... 详细信息

在润滑轨道两侧制备以防指纹油涂层(Anti-fingerprint coating,AFC)修饰的微柱阵列(Micropillar array,MA),形成润湿性梯度束油的润滑增效表面.使用点接触光弹流润滑油膜测量仪测量了该表面在限量供油往复运动条件下的油膜厚度以及油池形态,探究了往复频率、束油轨道宽度和载荷对润滑性能的影响,同时与未经AFC修饰的微柱阵列束油表面和仅以AFC形成的束油表面进行了对比.结果表明:制备的经AFC修饰的微柱阵列束油表面比其他2个束油表面有更好的润滑特性,往复运动条件(4 Hz)下明显改善了行程中点及两端点处的润滑状态,相对原始未处理表面行程中点处中心油膜厚度最高提升了51.4%.表面在束油轨道宽度接近Hertz接触区宽度时集油效果最强,随着轨道宽度增加集油效果减弱.载荷对微柱束油阵列表面的集油效果影响显著,随着载荷增大轨道机械分离作用变强、毛细回流作用减弱,造成集油能力和油膜厚度下降.

关键词：微柱阵列润湿性梯度油膜厚度往复运动限量供油

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Anomalies in the short-range local environment and atomic diffusion in single crystalline equiatomic CrMnFeCoNi highentropy alloy

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Nano Research 2024年第6期17卷 5336-5348页

作者： Alevtina Smekhova Daniel Gaertner Alexei Kuzmin Ana Guilherme Buzanich Goetz Schuck Ivo Zizak gerhard Wilde Kirill V.Yusenko Sergiy Divinski Helmholtz-Zentrum Berlin für Materialien und Energie(HZB) D-12489 BerlinGermany Institute of Materials Physics University of MünsterD-48149 MünsterGermany Institute of Solid State Physics University of LatviaLV-1063 RigaLatvia Bundesanstalt für Materialforschung und–prüfung(BAM) D-12489 BerlinGermany

Multi-edge extended X-ray absorption fine structure(EXAFS)spectroscopy combined with reverse Monte Carlo(RMC)simulations was used to probe the details of element-specific local coordinations and component-dependent structure relaxations in single crystalline equiatomic CrMnFeCoNi high-entropy alloy as a function of the annealing *** representative states,namely a high-temperature state,created by annealing at 1373 K,and a low-temperature state,produced by long-term annealing at 993 K,were compared in *** features identified in atomic configurations of particular principal components indicate variations in the local environment distortions connected to different degrees of compositional disorder at the chosen representative *** detected changes provide new atomistic insights and correlate with the existence of kinks previously observed in the Arrhenius dependencies of component diffusion rates in the CrMnFeCoNi high-entropy alloy.

关键词： high-entropy alloys diffusion short-range order extended X-ray absorption fine structure(EXAFS) reverse Monte Carlo

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

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不同环境温度下滚动轴承脂润滑性能台架测试

轴承 2024年第5期 44-50页

作者：陈凯栗心明金旭阳郭峰 gerhard Poll 青岛理工大学机械与汽车工程学院山东青岛266520 德国莱布尼茨汉诺威大学机械设计与摩擦学研究所德国汉诺威30167

采用台架测量装置测试了不同环境温度下滚动轴承润滑脂的性能,研究环境温度、轴承转速、载荷和润滑脂锥入度对轴承力矩和温度的影响。结果表明:环境温度较低时,轴承启动力矩和运行力矩整体较高,轴承温度变化较为明显,润滑状态较差;随环... 详细信息

采用台架测量装置测试了不同环境温度下滚动轴承润滑脂的性能,研究环境温度、轴承转速、载荷和润滑脂锥入度对轴承力矩和温度的影响。结果表明:环境温度较低时,轴承启动力矩和运行力矩整体较高,轴承温度变化较为明显,润滑状态较差;随环境温度升高,轴承力矩和温度变化幅度均下降,轴承的润滑状态好转;高速乏油和重载条件下,轴承的力矩和温度增大,润滑状态变差。不同环境温度下润滑脂的表观黏度差异、不同转速下润滑脂的受剪切程度以及由此引起的润滑脂分油率的不同,是轴承呈现不同润滑状态的主要原因。

关键词：滚动轴承角接触球轴承环境温度锂基润滑脂台架试验力矩

离心力作用下轴承滚道润滑剂流失与定量补油数值模拟

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摩擦学学报 2024年

作者：高军斌杨萍栗心明高志伟郭峰 gerhard Poll 青岛理工大学机械与汽车工程学院德国莱布尼茨汉诺威大学

采用自由表面薄膜流动模型，数值模拟了高速轴承壁面润滑剂在离心力作用下的流动过程，并通过外部定量补油对壁面油层厚度和润滑状态进行了调控。结果表明：高速下离心力的作用可使轴承壁面的润滑剂呈现出非线性衰退，使轴承处于乏油润... 详细信息

采用自由表面薄膜流动模型，数值模拟了高速轴承壁面润滑剂在离心力作用下的流动过程，并通过外部定量补油对壁面油层厚度和润滑状态进行了调控。结果表明：高速下离心力的作用可使轴承壁面的润滑剂呈现出非线性衰退，使轴承处于乏油润滑状态；与离心力相比，由表面张力引起的润滑剂回填几乎可以忽略，需依靠外部供油对轴承壁面油层进行增补；通过调整供油时间间隔，可实现轴承壁面润滑剂流动的供失平衡；采用多次微量供油，可将壁面油层厚度和接触区润滑状态调控在一定范围内，进而使轴承处于最佳的润滑状态。

关键词：油层衰退离心力润滑剂补充滚动轴承

考虑接触点运动的偏心轮-滚子副运动学及润滑特性研究

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摩擦学学报 2024年

作者：高园杰郭峰 gerhard Poll 李书义晁珅青岛理工大学机械与汽车工程学院汉诺威莱布尼茨大学机械设计与摩擦学研究所内燃机可靠性国家重点实验室潍柴动力股份有限公司

在凸轮-滚子副润滑分析中，为求解接触区的卷吸速度对凸轮-滚子单元进行运动学分析，发现接触点除了绕凸轮轴轴心作定轴转动外，还会因为滚子升程的变化来回摆动，产生牵连运动。卷吸速度的计算会采用忽略接触点运动的简化处理方法，但... 详细信息

在凸轮-滚子副润滑分析中，为求解接触区的卷吸速度对凸轮-滚子单元进行运动学分析，发现接触点除了绕凸轮轴轴心作定轴转动外，还会因为滚子升程的变化来回摆动，产生牵连运动。卷吸速度的计算会采用忽略接触点运动的简化处理方法，但产生的误差鲜有研究。使用点的合成运动法，将复杂运动转化为简单运动的叠加，简化了计算过程。为更好的厘清凸轮与滚子间的运动学关系，将偏心轮-滚子作为凸轮-滚子的1个特例进行运动学分析，得到考虑接触点运动的卷吸速度解析解。结果表明：考虑接触点运动的卷吸速度最大相对误差为8.89%，接触点的运动对卷吸速度计算的影响不可忽略。讨论了偏心轮-滚子单元偏心距、偏心轮半径、滚子半径和偏心轮转速对卷吸速度计算结果的影响，发现偏心距较大时接触点运动的卷吸速度相对误差影响较大。建立偏心轮-滚子副非牛顿点接触时变润滑模型，数值模拟了接触点的运动对润滑状态的影响。发现偏心轮角度为0°时，y/a=0截面的中心膜厚差距最明显，相对误差可达6.30%，同时接触点的运动会给第二压力峰带来细微变化，因此不可以忽略接触点运动带来的影响。

关键词：偏心轮-滚子副接触点的运动卷吸速度运动学分析润滑状态

Epidemiology of work-related hand and wrist injuries in a referral center: A descriptive study

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World Journal of Orthopedics 2024年第7期15卷 650-659页

作者： Angélica M Rodríguez Ginna P Tocanchón Jessica T Villalba Luis M Pombo Aníbal A Teherán Gabriel Camero-Ramos Karen P Ayala gerhard M Acero Research Center Fundación Universitaria Juan N.CorpasBogotá111321Colombia Red Cross Cruz Roja Colombiana-Seccional Cundinamarca BogotáBogotá111221Colombia Vigilancia Epidemiológica Instituto Nacional de SaludBogotá111321Colombia

BACKGROUND Occupational hand and wrist injuries(OHWIs)account for 25%of work-related accidents in low-and middle-income *** Colombia,more than 500000 occupational accidents occurred in 2021,and although the rate declined to less than 5%in 2020 and 2021,at least one in four accidents involved a hand or wrist *** To describe the OHWIs in workers seen at the emergency room at a second-level hospital in *** An observational study was performed using data from workers who experienced OHWIs and attended a second-level hospital,between June,2020 and May,*** overall frequency of OHWIs,as well as their distribution by sociodemo-graphic,clinical,and occupational variables,are ***,association patterns between sex,anatomical area(fingers,hand,wrist),and type of job were analyzed by correspondence analysis(CA).RESULTS There were 2.101 workers treated for occupational accidents,423(20.3%)were cases of OHWIs,which mainly affected men(93.9%)with a median age of 31 years and who worked mainly in mining(75.9%).OHWIs were more common in the right upper extremity(55.3%)and comprised different types of injuries,such as contusion(42.1%),laceration(27.9%),fracture(18.7%),and crush injury(15.6%).They primarily affected the phalanges(95.2%),especially those of the first finger(25.7%).The CAs showed associations between the injured anatomical area and the worker’s job that differed in men and women(explained variance>90%).CONCLUSION One out of five workers who suffered occupational accidents in Cundinamarca,Columbia had an OHWI,affecting mainly males employed in *** occupational profile is likely to lead to prolonged rehabilitation,and permanent functional *** results might be useful for adjusting preventive measures in cluster risk groups.

关键词： Accidents Occupational Epidemiology Hand injuries Wrist injuries Occupational health