The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung cancer.Now,KRAS G12C mutated tumors can be successfully treated with inhibitors that cov...The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung cancer.Now,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS.However,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 months.One 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 activity.Accordingly,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 degradation.Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear.The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals.Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase.Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.展开更多
针对一类由众多组件系统集结而成的系统之系统(system of systems,SoS),以美国国防部体系结构框架(DoDAF)为标准,提出了一种基于面向对象思想的SoS体系结构DoDAF作战视图产品五阶段迭代设计方法。利用UML静态和动态建模机制的特点,采用...针对一类由众多组件系统集结而成的系统之系统(system of systems,SoS),以美国国防部体系结构框架(DoDAF)为标准,提出了一种基于面向对象思想的SoS体系结构DoDAF作战视图产品五阶段迭代设计方法。利用UML静态和动态建模机制的特点,采用自顶向下、自底向上相结合的方式实现SoS体系结构作战视图产品的面向对象描述。以一个战术导弹防御(tactical missile defense,TMD)系统为例,详细说明SoS体系结构DoDAF作战视图产品的面向对象设计过程,并总结了该方法的两大优越特性:横向通用性与纵向可复用性,以及由此给SoS体系结构带来的"柔性"优势。这是传统设计方法所不能实现的。展开更多
文摘The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung cancer.Now,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS.However,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 months.One 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 activity.Accordingly,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 degradation.Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear.The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals.Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase.Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.
文摘针对一类由众多组件系统集结而成的系统之系统(system of systems,SoS),以美国国防部体系结构框架(DoDAF)为标准,提出了一种基于面向对象思想的SoS体系结构DoDAF作战视图产品五阶段迭代设计方法。利用UML静态和动态建模机制的特点,采用自顶向下、自底向上相结合的方式实现SoS体系结构作战视图产品的面向对象描述。以一个战术导弹防御(tactical missile defense,TMD)系统为例,详细说明SoS体系结构DoDAF作战视图产品的面向对象设计过程,并总结了该方法的两大优越特性:横向通用性与纵向可复用性,以及由此给SoS体系结构带来的"柔性"优势。这是传统设计方法所不能实现的。
