The use of Design of Experiments for steady-state and transient inverse melanoma detection problems

Melanoma is one of the most fatal skin cancers; for this reason, there is a need for the development of new safe, non-invasive and efficient diagnostic techniques. Dynamic thermography is showing to be a promising technique for the early detection of skin cancers. Therefore, this paper investigates two different inverse bioheat problems using steady-state and transient skin temperature measurements. Both problems are investigated numerically to estimate how accurate blood perfusion rate, metabolic heat generation, diameter and thickness of the tumour can be estimated simultaneously under exact and noisy measurement data, based on a complex numerical model describing multilayer tissue. The inverse problems have been tested using different melanoma size, Clark II and Clark IV. The Design of Experiments (DOE) technique has been used to solve and analyse the inverse problems. A substantial number of numerical model evaluations, totalling 2,306,486 simulations, had to be undertaken as part of the full factorial DOE. The results show that it is always possible to obtain tumour parameters using exact static or dynamic measurement data. However, for noisy temperature data, the use of a dynamic approach showed an advantage over the steady-state one, which failed because of the very small temperature differences between the healthy skin and the tumour. The dynamic thermography can retrieve blood perfusion rate, thickness and diameter of the tumour as well as the metabolic heat generation despite the low sensitivity for low and high levels of measurement error; however, to detect melanoma lesions at an early stage, the measurement and model errors should be kept as low as possible

The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response

The DNA damage response (DDR) and epithelial-to-mesenchymal transition (EMT) are two crucial cellular programs in cancer biology. While the DDR orchestrates cell cycle progression, DNA repair and cell death, EMT promotes invasiveness, cellular plasticity and intratumor heterogeneity. Therapeutic targeting of EMT transcription factors, such as ZEB1, remains challenging, but tumor-promoting DDR alterations elicit specific vulnerabilities. Using multi-omics, inhibitors and high-content microscopy, we discover a chemoresistant ZEB1 high expressing sub-population (ZEB1hi) with co-rewired cell cycle progression and proficient DDR across tumor entities. ZEB1 stimulates accelerated S-phase entry via CDK6, inflicting endogenous DNA replication stress. However, DDR buildups involving constitutive MRE11-dependent fork resection allow homeostatic cycling and enrichment of ZEB1hi cells during TGFβ-induced EMT and chemotherapy. Thus, ZEB1 promotes G1/S transition to launch a progressive DDR benefitting stress tolerance, which concurrently manifests a targetable vulnerability in chemoresistant ZEB1hi cells. Our study thus highlights the translationally relevant intercept of the DDR and EMT

Numerical simulation of particle movement in cellular flows under the influence of magnetic forces

A numerical model of particle motion in fluid flow under the influence of hydrodynamic and magnetic forces is presented. The Lagrangian particle tracking algorithm was developed being capable of simulating dilute suspensions of particles in viscous flows where gravity, buoyancy, drag, pressure gradient, added mass and magnetophoretic forces are taken into account. The method is used to study the behaviour of magnetite particles in a periodic cellular flow field under the influence of a magnetic field produced by electric wires placed in cell centres. For such a flow field it is known that particles in steady state merge into individual trajectories. The influence of the magnetic field on the particle trajectories is examined and an exponential model for the time evolution of the fraction of adhered particles to the electric wires is proposed. Three particle Stokes number values are considered: 0.01, 0.1 and 1. The existence of a critical magnetic pressure coefficient was found, at which all particles end up to be adhered to the wires. The critical magnetic pressure coefficient was found to be proportional to the Stokes number. For sub-critical magnetic pressure coefficient, the particle trajectories are significantly altered by the magnetic field, both in their shape and in their number. Furthermore, in the sub-critical regime, the minimal distance of particles to the cell centres is larger for particles with smaller Stokes numbers

3D lid driven cavity flow by mixed boundary and finite element method

A numerical algorithm for the solution of the velocity-vorticity formulation of Navier-Stokes equations is presented. This formulation results in splitting of fluid flow into its kinematic and kinetic aspect. The Boundary Element Method (BEM) used for the solution of flow kinematics results in an implicit calculation of vorticity values at the boundary, whereas all transport equations are solved using Finite Element Method (FEM). The combination of both numerical techniques is proposed in order to increase the accuracy of computation of boundary vorticities, a weak point for a majority of numerical methods when dealing with velocity-vorticity formulation. Since the application of BEM results in fully populated system matrices, also the flow kinematics computation is done by combining BEM and FEM, the latter for computation of internal velocities, keeping the CPU time and computer storage requirements at the level close to Finite Element Method. To speed up the computation process and to distribute storage of integrals over several processors the algebraic parallelization of kinematics was performed. Lid driven flow in a cubic cavity was computed to show the robustness and versatility of the proposed numerical formulation. Results for Reynolds number value Re=100 and Re=1000 show good agreement with benchmark results

Effects of controlled nucleation on freeze-drying lactose and mannitol aqueous solutions

The lyophilization of lactose and mannitol aqueous solutions was investigated with an emphasis on analyzing the effects of controlled nucleation, temperature of nucleation, and pore size distribution on the freeze-drying process. The experimental procedure involved the depressurization technique of controlled nucleation, in-vial temperature measurements as well as measurements of the chamber pressure, which allowed the analysis of the product batch, loaded in the laboratory lyophilizator. The average pore enlargement was 93 and 58% with the incorporation of the controlled nucleation step in the lyophilization of 6 wt% lactose and 6 wt% mannitol solutions, respectively. Consequently, the primary drying times were lowered from 450 to 500 min in both cases. The pore sizes were determined to be as important as the solid material itself in the scope of the sublimation rates. Namely, the average equivalent diameter of the pores was larger in the dried mannitol cake compared to the lactose cake. However, despite the higher porosity of the dried mannitol cake, the end of the sublimation in the primary drying step was observed approximately 500 min earlier during the lyophilization of the lactose solution with the same initial concentration as the mannitol solution in a comparable freeze-drying protocol. In addition, an increase in mannitol concentration from 3 to 12 wt% was found to substantially extend the time required for the sublimation phase of the lyophilization

Lyophilization model of mannitol water solution in a laboratory scale lyophilizer

The paper reports on the development of a numerical model for the simulation of a lyophilization process in a vial. Experimental analysis is presented of lyophilization dynamics inside a single vial in a laboratory scale lyophilizer. The problems of lyophilization modelling of a mannitol water solution are covered in detail. The effects of the small scale of the laboratory device with respect to a correct definition of boundary conditions for the numerical simulations are described, especially the effect of the comparatively high temperatures of the chamber walls. In the numerical model, a 1D vial approximation of the governing equations of heat and mass transport with moving front between the frozen and porous part of the cake is used and solved in a time stepping nonlinear iteration procedure. A water vapour diffusion model, implemented in the mass conservation equations, based on the Knudsen model of diffusivities, is applied and linked to the typical pore size of the porous cake. A front tracking scheme with moving computational grid is applied, and a dedicated sub-model of surface layer ice sublimation is introduced, based on the one-sided vapour diffusion model. The comparison of the numerical and the experimental results show that the developed numerical model is able to capture the transition points from primary to secondary drying very accurately, with accompanying accurate capturing of the temperature levels inside of the drying material

Numerical and experimental modeling of lyophilization of lactose and mannitol water solutions in vials

The paper reports on the development of a numerical model for the simulation of a lyophilization process in a vial. Lactose and mannitol-water mixtures are used as the working media. Experimental analysis of the lyophilization dynamics inside a single vial in a laboratory scale lyophilizer is reported, with the main focus on the primary drying phase. In order to assess the primary drying kinetics, the temperature distribution along the vertical axis of the samples is measured. In the numerical model, a one-dimensional (1D) vial approximation is used, and governing equations of the heat and water vapor transport with moving front between the frozen and the porous part of the filling are solved by a finite difference method in a time stepping nonlinear iteration procedure. A dedicated mapping of heat transfer boundary conditions, derived for the axisymmetric vial case, is applied for the case of the 1D vial geometry approximation. The main difference in the drying of lactose and mannitol solutions lies in the fact that the lactose shows undercooling effects during the primary drying phase, which is not the case for the mannitol solution. This effect is a consequence of shrinking behavior of the lactose porous cake, leading to a loss of contact with the vial side and hence to a decrease in the overall heat input to the vial. In order to account for the shrinking process in the numerical model, a linear approximation of the decrease of the heat transfer from the vial side wall during the simulation is introduced. The comparison of the numerical and experimental results shows that the developed numerical model is able to accurately capture the movement of the sublimation front, dividing the frozen from the porous part of the filling, at typical locations inside the vial, accompanied also by an accurate capturing of the temperature levels inside the drying material, with the derived numerical model also able to reproduce the temperature drop during the primary drying of the lactose solution

Numerical and experimental modeling of lyophilization of lactose and mannitol water solitions in vials

The paper reports on the development of a numerical model for the simulation of a liofilization process in a vial. The lactose and mannitol-water mixtures are used as the working medium in the vial. Experimental analysis of lyofilization dynamics inside a single vial and multiple vials in a laboratory scale lyofilizer is reported, with the main focus on the primary drying phase. The key parameter measured is the temperature distribution inside the main axis of the vial filling. In the numerical model, a 1D vial approximation is used, and governing equations of heat and water vapor transport with moving front between the frozen and the porous part of the filling are solved by a dedicated finited difference method in a time stepping nonlinear iteration procedure. The comparison of numerical and experimental results show, that the developed numerical model is able to accurately capture the transition points from primary to secondary drying, accompanied by accurate capturing of the temperature levels inside the drying material. The main difference in drying of lactose and mannitol solutions lies in the fact, that the lactose shows undercooling effects during the primary drying phase, which is not the case for the mannitol solution. This effect is a consequence of shrinking behavior of lacose porous matrix, loosing contact with vial side and hence decreasing the overall heat input to the vial. The derived numerical model is able to accurately reproduce drying kinetics of mannitol, whereas for drying of lactose an upgrade of the model to axysimmetric geometry would be needed.Papers presented at the 13th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Portoroz, Slovenia on 17-19 July 2017 .International centre for heat and mass transfer.American society of thermal and fluids engineers