Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.

Acquired resistance to selective FLT3 inhibitors is an emerging clinical problem in the treatment of FLT3-ITD(+) acute myeloid leukaemia (AML). The paucity of valid pre-clinical models has restricted investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. We generated selective FLT3 inhibitor-resistant cells by treating the FLT3-ITD(+) human AML cell line MOLM-13 in vitro with the FLT3-selective inhibitor MLN518, and validated the resistant phenotype in vivo and in vitro. The resistant cells, MOLM-13-RES, harboured a new D835Y tyrosine kinase domain (TKD) mutation on the FLT3-ITD(+) allele. Acquired TKD mutations, including D835Y, have recently been identified in FLT3-ITD(+) patients relapsing after treatment with the novel FLT3 inhibitor, AC220. Consistent with this clinical pattern of resistance, MOLM-13-RES cells displayed high relative resistance to AC220 and Sorafenib. Furthermore, treatment of MOLM-13-RES cells with AC220 lead to loss of the FLT3 wild-type allele and the duplication of the FLT3-ITD-D835Y allele. Our FLT3-Aurora kinase inhibitor, CCT137690, successfully inhibited growth of FLT3-ITD-D835Y cells in vitro and in vivo, suggesting that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML.

Model reduction for nonlinear aerodynamics and aeroelasticity using a Discrete Empirical Interpolation Method

A novel surrogate model is proposed in lieu of Computational Fluid Dynamics (CFD) solvers, for fast nonlinear aerodynamic and aeroelastic modeling. A nonlinear function is identified on selected interpolation points by
a discrete empirical interpolation method (DEIM). The flow field is then reconstructed using a least square approximation of the flow modes extracted
by proper orthogonal decomposition (POD). The aeroelastic reduce order
model (ROM) is completed by introducing a nonlinear mapping function
between displacements and the DEIM points. The proposed model is investigated to predict the aerodynamic forces due to forced motions using
a N ACA 0012 airfoil undergoing a prescribed pitching oscillation. To investigate aeroelastic problems at transonic conditions, a pitch/plunge airfoil
and a cropped delta wing aeroelastic models are built using linear structural models. The presence of shock-waves triggers the appearance of limit
cycle oscillations (LCO), which the model is able to predict. For all cases
tested, the new ROM shows the ability to replicate the nonlinear aerodynamic forces, structural displacements and reconstruct the complete flow
field with sufficient accuracy at a fraction of the cost of full order CFD
model.

Monitoring and model updating of an FRP pedestrian truss bridge

This paper presents the results of a real bridge field experiment, carried out on a fiber reinforced polymer (FRP) pedestrian truss bridge of which nodes are reinforced with stainless steel plates. The aim of this paper is to identify the dynamic parameters of this bridge by using both conventional techniques and a model updating algorithm. In the field experiment, the bridge was instrumented with accelerometers at a number of locations on the bridge deck, recording both vertical and transverse vibrations. It was excited via jump tests at particular locations along its span and the resulting acceleration signals are used to identify dynamic parameters, such as the bridge mode shape, natural frequency and damping constant. Pedestrianinduced vibrations are also measured and utilized to identify dynamic parameters of the bridge. For a complete analysis of the bridge, a numerical model of the FRP bridge is created whose properties are calibrated utilizing a model updating algorithm. Comparable frequencies and mode shapes to those from the experiment were obtained by the FE models considering the reinforcement by increasing elastic modulus at every node of the bridge by stainless steel plate. Moreover, considering boundary conditions at both ends as fixed in the model resulted in modal properties comparable/similar to those from the experiment. This study also demonstrated that the effect of reinforcement and boundary conditions must be properly considered in an FE model to analyze real behavior of the FRP bridge.

Model reduction for nonlinear aeroelasticity using the Discrete Empirical Interpolation Method

A novel surrogate model is proposed in lieu of computational fluid dynamic (CFD) code for fast nonlinear aerodynamic modeling. First, a nonlinear function is identified on selected interpolation points defined by discrete empirical interpolation method (DEIM). The flow field is then reconstructed by a least square approximation of flow modes extracted by proper orthogonal decomposition (POD). The proposed model is applied in the prediction of limit cycle oscillation for a plunge/pitch airfoil and a delta wing with linear structural model, results are validate against a time accurate CFD-FEM code. The results show the model is able to replicate the aerodynamic forces and flow fields with sufficient accuracy while requiring a fraction of CFD cost.