RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.     

铝合金隔热型材传热系数试验研究

传热系数是铝合金隔热型材热工性能的一个重要节能评价指标,通过试验分析热冷室空气温差、热冷室平均空气温度、试件投影面积、试件安装方式等因素对铝合金隔热型材传热系数的影响,为制定符合实际生产状况的铝合金隔热型材节能评价指标提供参考依据.     

基于CC2430芯片的动物机器人遥控导航系统

提出一种基于CC2430芯片的动物机器人遥控导航系统,该系统分手持控制器和机器人节点2部分,手持控制器由有机发光二极管(OLED)显示器、键盘模块、CC2430芯片及电源模块组成,机器人节点由刺激模块、CC2430芯片和电源模块等组成.该系统采用点对点通信模式,利用循环冗余码(CRC)校验和地址识别功能,能有效地保障通...     

基于流场数值模拟的多级泵转子动力学分析

根据多级泵零件二维图,应用Pro/E软件对转子系统主要部件进行实体建模,采用FLUENT软件对多级泵内部流场进行数值模拟,分析了轴向力及径向力随不同工况的变化情况,基于ANSYS软件对转子系统施加静力载荷,进行静力学、谐响应和瞬态动力学等分析.结果表明:转子系统在第1阶临界转速下的安全区运行,转子系统的振幅与转速变化呈...     

Clothing Colour Preferences in A Hospital Environment in Hong Kong:Part Ⅱ-Paediatric Nurses’Preferences of Colour on Their Uniform

The present study investigated nurses'colour prefer-ences on their uniform in paediatric wards.Results ofthe study provided guidelines for the selecting of ap-propriate colours for nurses'uniforms for paediatricwards,and the comparison of nurses'preferences ofcolours on their uniform and child patients'colourpreferences of nurses'uniform was drawn.     

喷浆机器人微机控制电液位置伺服系统

介绍了喷浆机器人每个关节的电液位置伺服系统的单片微机闭环控制，较详细地讨论了系统的数学模型及其具体设计与实现方法。     

化学物质对香石竹切花品质保持的研究

化学物质对保持香石竹切花品质和延长其瓶插寿命有较大影响。在试验所用的化学物质中我们认为较为有效的成分及其浓度为８－ＨＱ３００ｐｐｍ＋Ｂ－９５００ｐｐｍ＋ＢＡ２０ｐｐｍ＋３％蔗糖。该配方可显著延长香石竹切花的瓶插寿命，处理后切花的直径与对照相比有明显增大。对上述配方进行稀释可有效防止切花茎基部变褐、组织干缩和花色变暗等现象。其最佳稀释倍数为４倍（８－ＨＱ７５ｐｐｍ＋Ｂ－９１２５ｐｐｍ＋ＢＡ５ｐｐｍ＋３％蔗糖）。     

三种不育剂对山楂叶螨的不育效应

为了有效防治山楂叶螨（Tetranychus viennensis)，以喷蒸馏水为对照，配制3种不育剂（MSA，CSⅡ，MSC）对山楂叶螨进行不育效应的室内试验，MSA，CSⅡ，MSC的试验浓度（3个重复）分别是0．2％，0．5％，1．0％；0．4％，0．8％，1．2％，1倍原液，2倍原液，原液，喷不良剂后，每天对产卵，卵的孵化，交尾，寿命等观察和记载，持续3个月，结果表明，以0．8％的CSⅡ可湿性粉剂喷雾使用为最好，与对照相比，此浓度可将该叶螨的每雌产卵量（粒），孵化率（％）及第2代,雄蠕数量（头）降低，分别为7．17，3．66，1．00和0．50；对照组为73．3，84．06，32．00和70．67。     

可加混料模型参数估计A—最优正交区组设计

对于含有过程变量的二阶可加混料模型，研究了参数估计的Ａ－最优正交区组设计，借助计算机求解非线性规划问题，一般地给出了ｑ分量二阶可加料模型的Ａ－最优正交区组设计。     

γ-辐照降解偶氮染料水溶液的研究

以２．９６×１０１４Ｂｑ６０Ｃｏ为辐照源，对直接耐晒大红４ＢＳ等五种偶氮染料水溶液进行γ－辐照。结果表明，它们能有效降解和脱色，剂量为１２ＫＧｙ时，其降解度为３０～８０％，脱色度均超过８０％，ＣＯＤ去除率为５０％～６０％。另外，还做了吸收剂量、乙醇和Ｈ２Ｏ２的影响试验，并对结果进行了讨论