Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3

Oncogenic tyrosine kinases have proved to be promising targets for the development of highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (HER) family show only limited activity against HER2-driven breast cancers, despite effective inhibition of epidermal growth factor receptor (EGFR) and HER2 in vivo. The reasons for this are unclear. Signalling in trans is a key feature of this multimember family and the critically important phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 (refs 9, 10). Here we show that HER3 and consequently PI(3)K/Akt signalling evade inhibition by current HER-family TKIs in vitro and in tumours in vivo. This is due to a compensatory shift in the HER3 phosphorylation-dephosphorylation equilibrium, driven by increased membrane HER3 expression driving the phosphorylation reaction and by reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt-mediated negative-feedback signalling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target. However, because HER3 signalling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to silence oncogenic HER2 signalling effectively. The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation.     

长江水质评价和预测的模型研究

本文研究长江水质的评价与预测的模型。对长江近两年水质总体情况和地区分布进行了定性和定量分析。根据近10年(水文年)的主要统计数据进行分析,给出了I—V类、劣V类水无量纲百分比发展趋势和污水排放量发展趋势的超越函数混合模型和趋势图,由此预测未来长江水污染的情势。最后对解决长江水质污染问题提出了几点建议。     

冷链运输装备开门渗风试验及温度场分析

冷藏运输与配送过程中开、关门进行装卸作业易造成货物温度波动,从而影响食品质量,亟待规范.研究对30℃/-18℃条件下冷链配送过程中存在问题进行分析,对装卸时间、是否安装门帘、装卸时是否开启循环风机等状况进行对比试验.在此基础上有针对性地提出完善及规范化的操作方案.认为开门时间长短是影响运输装备内部温度最重要的因素之一,在装卸作业时对大门开启处进行适当的保护则能大大降低冷量的损失,此外,装卸作业时车内循环风机以关闭为宜.     

构建农村经济安全体系的思考

近年来农村经济的发展出现了减缓趋势,农村面临的经济安全问题,必须引起我们高度重视。全面建设小康社会重点在农村,关键是发展农村经济。为了保证农村经济安全、健康、持续的发展,必须构建农村经济安全保障体系。     

论和谐社会构建中体育之促进作用

采用文献资料、逻辑推理、理论等方法,分析了和谐社会的构建拓宽了体育的功能范围,并对体育在和谐社会构建中的作用进行了论述,旨在更新观念,树立“和谐”意识。