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#### Fachbereich / Organisatorische Einheit

SDE-driven modeling of phenotypically heterogeneous tumors: The influence of cancer cell stemness
(2018)

We deduce cell population models describing the evolution of a tumor (possibly interacting with its
environment of healthy cells) with the aid of differential equations. Thereby, different subpopulations
of cancer cells allow accounting for the tumor heterogeneity. In our settings these include cancer
stem cells known to be less sensitive to treatment and differentiated cancer cells having a higher
sensitivity towards chemo- and radiotherapy. Our approach relies on stochastic differential equations
in order to account for randomness in the system, arising e.g., by the therapy-induced decreasing
number of clonogens, which renders a pure deterministic model arguable. The equations are deduced
relying on transition probabilities characterizing innovations of the two cancer cell subpopulations,
and similarly extended to also account for the evolution of normal tissue. Several therapy approaches
are introduced and compared by way of tumor control probability (TCP) and uncomplicated tumor
control probability (UTCP). A PDE approach allows to assess the evolution of tumor and normal
tissue with respect to time and to cell population densities which can vary continuously in a given set
of states. Analytical approximations of solutions to the obtained PDE system are provided as well.

Multifacility location problems arise in many real world applications. Often, the facilities can only be placed in feasible regions such as development or industrial areas. In this paper we show the existence of a finite dominating set (FDS) for the planar multifacility location problem with polyhedral gauges as distance functions, and polyhedral feasible regions, if the interacting facilities form a tree. As application we show how to solve the planar 2-hub location problem in polynomial time. This approach will yield an ε-approximation for the euclidean norm case polynomial in the input data and 1/ε.

In this article a new numerical solver for simulations of district heating networks is presented. The numerical method applies the local time stepping introduced in [11] to networks of linear advection equations. In combination with the high order approach of [4] an accurate and very efficient scheme is developed. In several numerical test cases the advantages for simulations of district heating networks are shown.

We continue in this paper the study of k-adaptable robust solutions for combinatorial optimization problems with bounded uncertainty sets. In this concept not a single solution needs to be chosen to hedge against the uncertainty. Instead one is allowed to choose a set of k different solutions from which one can be chosen after the uncertain scenario has been revealed. We first show how the problem can be decomposed into polynomially many subproblems if k is fixed. In the remaining part of the paper we consider the special case where k=2, i.e., one is allowed to choose two different solutions to hedge against the uncertainty. We decompose this problem into so called coordination problems. The study of these coordination problems turns out to be interesting on its own. We prove positive results for the unconstrained combinatorial optimization problem, the matroid maximization problem, the selection problem, and the shortest path problem on series parallel graphs. The shortest path problem on general graphs turns out to be NP-complete. Further, we present for minimization problems how to transform approximation algorithms for the coordination problem to approximation algorithms for the original problem. We study the knapsack problem to show that this relation does not hold for maximization problems in general. We present a PTAS for the corresponding coordination problem and prove that the 2-adaptable knapsack problem is not at all approximable.

This paper presents a case study of duty rostering for physicians at a department of orthopedics and trauma surgery. We provide a detailed description of the rostering problem faced and present an integer programming model that has been used in practice for creating duty rosters at the department for more than a year. Using real world data, we compare the model output to a manually generated roster as used previously by the department and analyze the quality of the rosters generated by the model over a longer time span. Moreover, we demonstrate how unforeseen events such as absences of scheduled physicians are handled.

We extend the standard concept of robust optimization by the introduction of an alternative solution. In contrast to the classic concept, one is allowed to chose two solutions from which the best can be picked after the uncertain scenario has been revealed. We focus in this paper on the resulting robust problem for combinatorial problems with bounded uncertainty sets. We present a reformulation of the robust problem which decomposes it into polynomially many subproblems. In each subproblem one needs to find two solutions which are connected by a cost function which penalizes if the same element is part of both solutions. Using this reformulation, we show how the robust problem can be solved efficiently for the unconstrained combinatorial problem, the selection problem, and the minimum spanning tree problem. The robust problem corresponding to the shortest path problem turns out to be NP-complete on general graphs. However, for series-parallel graphs, the robust shortest path problem can be solved efficiently. Further, we show how approximation algorithms for the subproblem can be used to compute approximate solutions for the original problem.

We propose a multiscale model for tumor cell migration in a tissue network. The system of equations involves a structured population model for the tumor cell density, which besides time and
position depends on a further variable characterizing the cellular state with respect to the amount
of receptors bound to soluble and insoluble ligands. Moreover, this equation features pH-taxis and
adhesion, along with an integral term describing proliferation conditioned by receptor binding. The
interaction of tumor cells with their surroundings calls for two more equations for the evolution of
tissue fibers and acidity (expressed via concentration of extracellular protons), respectively. The
resulting ODE-PDE system is highly nonlinear. We prove the global existence of a solution and
perform numerical simulations to illustrate its behavior, paying particular attention to the influence
of the supplementary structure and of the adhesion.

We propose and analyze a multiscale model for acid-mediated tumor invasion
accounting for stochastic effects on the subcellular level.
The setting involves a PDE of reaction-diffusion-taxis type describing the evolution of the tumor cell density,
the movement being directed towards pH gradients in the local microenvironment,
which is coupled to a PDE-SDE system characterizing the
dynamics of extracellular and intracellular proton concentrations, respectively.
The global well-posedness of the model is shown and
numerical simulations are performed in order to illustrate the solution behavior.

This work presents a framework for the computation of complex geometries containing intersections of multiple patches with Reissner-Mindlin shell elements. The main objective is to provide an isogeometric finite element implementation which neither requires drilling rotation stabilization, nor user interaction to quantify the number of rotational degrees of freedom for every node. For this purpose, the following set of methods is presented. Control points with corresponding physical location are assigned to one common node for the finite element solution. A nodal basis system in every control point is defined, which ensures an exact interpolation of the director vector throughout the whole domain. A distinction criterion for the automatic quantification of rotational degrees of freedom for every node is presented. An isogeometric Reissner-Mindlin shell formulation is enhanced to handle geometries with kinks and allowing for arbitrary intersections of patches. The parametrization of adjacent patches along the interface has to be conforming. The shell formulation is derived from the continuum theory and uses a rotational update scheme for the current director vector. The nonlinear kinematic allows the computation of large deformations and large rotations. Two concepts for the description of rotations are presented. The first one uses an interpolation which is commonly used in standard Lagrange-based shell element formulations. The second scheme uses a more elaborate concept proposed by the authors in prior work, which increases the accuracy for arbitrary curved geometries. Numerical examples show the high accuracy and robustness of both concepts. The applicability of the proposed framework is demonstrated.

An isogeometric Reissner-Mindlin shell derived from the continuum theory is presented. The geometry is described by NURBS surfaces. The kinematic description of the employed shell theory requires the interpolation of the director vector and of a local basis system. Hence, the definition of nodal basis systems at the control points is necessary for the proposed formulation. The control points are in general not located on the shell reference surface and thus, several choices for the nodal values are possible. The proposed new method uses the higher continuity of the geometrical description to calculate nodal basis system and director vectors which lead to geometrical exact interpolated values thereof. Thus, the initial director vector coincides with the normal vector even for the coarsest mesh. In addition to that a more accurate interpolation of the current director and its variation is proposed. Instead of the interpolation of nodal director vectors the new approach interpolates nodal rotations. Account is taken for the discrepancy between interpolated basis systems and the individual nodal basis systems with an additional transformation. The exact evaluation of the initial director vector along with the interpolation of the nodal rotations lead to a shell formulation which yields precise results even for coarse meshes. The convergence behavior is shown to be correct for k-refinement allowing the use of coarse meshes with high orders of NURBS basis functions. This is potentially advantageous for applications with high numerical effort per integration point. The geometrically nonlinear formulation accounts for large rotations. The consistent tangent matrix is derived. Various standard benchmark examples show the superior accuracy of the presented shell formulation. A new benchmark designed to test the convergence behavior for free form surfaces is presented. Despite the higher numerical effort per integration point the improved accuracy yields considerable savings in computation cost for a predefined error bound.