Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia

Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.     

Forecasting of electricity price through a functional prediction of sale and purchase curves

This work proposes a new approach for the prediction of the electricity price based on forecasting aggregated purchase and sale curves. The basic idea is to model the hourly purchase and the sale curves, to predict them and to find the intersection of the predicted curves in order to obtain the predicted equilibrium market price and volume. Modeling and forecasting of purchase and sale curves is performed by means of functional data analysis methods. More specifically, parametric (FAR) and nonparametric (NPFAR) functional autoregressive models are considered and compared to some benchmarks. An appealing feature of the functional approach is that, unlike other methods, it provides insights into the sale and purchase mechanism connected with the price and demand formation process and can therefore be used for the optimization of bidding strategies. An application to the Italian electricity market (IPEX) is also provided, showing that NPFAR models lead to a statistically significant improvement in the forecasting accuracy.     

稳定的复数域上状态反馈系统的几何结构

从信息几何的角度使用新的方法研究稳定的复数域上的状态反馈增益系统. 首先, 给出所有稳定的状态反馈增益集合的参数化. 进而,可知稳定的状态反馈增益集合微分同胚于满足一定代数条件的正定Hermite矩阵和反Hermite矩阵的笛卡尔积;其次, 探讨稳定矩阵中稳定的状态反馈增益系统的几何结构;然后,给出状态反馈增益的一个浸入;最后, 举例说明结果.      

企业研发团队知识共享影响因素的实证研究

基于知识共享理论和研发团队知识共享特征和影响因素,提出企业研发团队知识共享影响因素概念模型及理论假设,并运用调查问卷和结构方程模型对研发团队知识共享影响因素进行实证研究.结果表明,知识提供者、接受者、共享手段和共享双方关系4因素对研发团队知识共享水平有显著影响,而知识共享文化对知识共享水平影响作用不显著.提出了提高企业研发团队知识共享水平的对策与建议.     

基于Simulink的动态电路分析

介绍了Simulink应用于动态电路仿真分析的方法,以一个实例详述了图形输入式建模、参数设置、仿真配置、Matlab绘图分析等步骤．指出了联合运用To File、To Workspace和Scope模块,实现不同参数情况下仿真分析的优越性．     

数学分析在高等代数中的某些应用

高等代数中的某些问题,若用代数学的方法解决起来可能相当繁琐,但若结合数学分析的方法,则问题往往会迎刃而解．该文使用数学分析中的函数连续性和无穷区间的广义积分知识解决某些矩阵问题和二次型问题．     

Enhanced urease inhibition activity of Ag nanomaterials capped with N-substituted methyl 5-acetamido-β-resorcylate

Medically, bacterial ureases are important virulent factors and are used for treatment of peptic ulcers and urinary tones. Reported urease inhibitors are associated with various side effects including antibiotic resistance as a major one. Still there is an urgent need to synthesize new urease inhibitors. In this context we have synthesized new urease inhibitor i.e. AgL that is composed of Ag nanomaterials capped with N-substituted methyl 5-acetamido-β-resorcylate(L). The conjugation of L to silver was confirmed through FTIR, UV–vis and TEM analysis.Bare silver nanomaterials(Ag) were also prepared. The stability of AgL nanostructures was determined against various parameters(temperature, high salt concentration, pH) and found to be stable. The in vitro antimicrobial(antibacterial, antifungal), enzyme inhibition(xanthine oxidase, urease, carbonic anhydrase, α-chymotrypsin,cholinesterase) and antioxidant activities of AgL were investigated and compared with Ag, L and standard drugs.In comparison to other bioactivities, AgL shows statistically enhanced selective enzyme inhibition activity against urease enzyme. Urease inhibition activity of AgL was significantly greater than standard drug(thiourea),L and Ag. On a per weight basis, AgL required about 11–18 times less amount of L for inhibition of urease enzyme.     

A thyromimetic that decreases plasma cholesterol levels without increasing cardiac activity

A number of agents that mimic the ability of the thyroid hormone, T3, to decrease plasma cholesterol levels are described; one is as effective as T3 at reducing cholesterol levels and stimulating liver function, but has very little effect on cardiac function and is thus less likely to be toxic. The agent may be useful in the treatment of atherosclerosis.