Oscillatory dynamics in a model of vascular tumour growth -- implications for chemotherapy

Background\ud \ud Investigations of solid tumours suggest that vessel occlusion may occur when increased pressure from the tumour mass is exerted on the vessel walls. Since immature vessels are frequently found in tumours and may be particularly sensitive, such occlusion may impair tumour blood flow and have a negative impact on therapeutic outcome. In order to study the effects that occlusion may have on tumour growth patterns and therapeutic response, in this paper we develop and investigate a continuum model of vascular tumour growth.\ud Results\ud \ud By analysing a spatially uniform submodel, we identify regions of parameter space in which the combination of tumour cell proliferation and vessel occlusion give rise to sustained temporal oscillations in the tumour cell population and in the vessel density. Alternatively, if the vessels are assumed to be less prone to collapse, stable steady state solutions are observed. When spatial effects are considered, the pattern of tumour invasion depends on the dynamics of the spatially uniform submodel. If the submodel predicts a stable steady state, then steady travelling waves are observed in the full model, and the system evolves to the same stable steady state behind the invading front. When the submodel yields oscillatory behaviour, the full model produces periodic travelling waves. The stability of the waves (which can be predicted by approximating the system as one of λ-ω type) dictates whether the waves develop into regular or irregular spatio-temporal oscillations. Simulations of chemotherapy reveal that treatment outcome depends crucially on the underlying tumour growth dynamics. In particular, if the dynamics are oscillatory, then therapeutic efficacy is difficult to assess since the fluctuations in the size of the tumour cell population are enhanced, compared to untreated controls.\ud Conclusions\ud \ud We have developed a mathematical model of vascular tumour growth formulated as a system of partial differential equations (PDEs). Employing a combination of numerical and analytical techniques, we demonstrate how the spatio-temporal dynamics of the untreated tumour may influence its response to chemotherapy.\ud Reviewers\ud \ud This manuscript was reviewed by Professor Zvia Agur and Professor Marek Kimmel

Towards a solution of the closure problem for convective atmospheric boundary-layer turbulence

We consider the closure problem for turbulence in the dry convective atmospheric boundary layer (CBL). Transport in the CBL is carried by small scale eddies near the surface and large plumes in the well mixed middle part up to the inversion that separates the CBL from the stably stratified air above. An analytically tractable model based on a multivariate Delta-PDF approach is developed. It is an extension of the model of Gryanik and Hartmann [1] (GH02) that additionally includes a term for background turbulence. Thus an exact solution is derived and all higher order moments (HOMs) are explained by second order moments, correlation coefficients and the skewness. The solution provides a proof of the extended universality hypothesis of GH02 which is the refinement of the Millionshchikov hypothesis (quasi- normality of FOM). This refined hypothesis states that CBL turbulence can be considered as result of a linear interpolation between the Gaussian and the very skewed turbulence regimes. Although the extended universality hypothesis was confirmed by results of field measurements, LES and DNS simulations (see e.g. [2-4]), several questions remained unexplained. These are now answered by the new model including the reasons of the universality of the functional form of the HOMs, the significant scatter of the values of the coefficients and the source of the magic of the linear interpolation. Finally, the closures 61 predicted by the model are tested against measurements and LES data. Some of the other issues of CBL turbulence, e.g. familiar kurtosis-skewness relationships and relation of area coverage parameters of plumes (so called filling factors) with HOM will be discussed also

A floer homology approach to traveling waves in reaction-diffusion equations on cylinders

Traveling waves form a prominent feature in the dynamics of scalar reaction-diffusion equations on unbounded cylinders. The traveling waves can be identified with the bounded solutions of the (Formula Prtsented) Ω ⊂ R d is a bounded domain, Δ is the Laplacian on Ω, and B denotes Dirichlet, Neumann, or periodic boundary data. We develop a new homological invariant for the dynamics of the bounded solutions of the above elliptic PDE. Restrictions on the nonlinearity f are kept to a minimum; for instance, any nonlinearity exhibiting polynomial growth in u can be considered. In particular, the set of bounded solutions of the traveling wave PDE may not be uniformly bounded. Despite this, the homology is invariant under lower order (but not necessarily small) perturbations of the nonlinearity f, thus making the homology amenable for computation. Using the new invariant we derive lower bounds on the number of bounded solutions of our PDE, thus obtaining existence and multiplicity results for traveling wave solutions of reaction-diffusion equations on unbounded cylinders

Cubic autocatalysis in a reaction-diffusion annulus: semi-analytical solutions

Semi-analytical solutions for cubic autocatalytic reactions are considered in a circularly symmetric reaction-diffusion annulus. The Galerkin method is used to approximate the spatial structure of the reactant and autocatalyst concentrations. Ordinary differential equations are then obtained as an approximation to the governing partial differential equations and analyzed to obtain semi-analytical results for this novel geometry. Singularity theory is used to determine the regions of parameter space in which the different types of steady-state diagram occur. The region of parameter space, in which Hopf bifurcations can occur, is found using a degenerate Hopf bifurcation analysis. A novel feature of this geometry is the effect, of varying the width of the annulus, on the static and dynamic multiplicity. The results show that for a thicker annulus, Hopf bifurcations and multiple steady-state solutions occur in a larger portion of parameter space. The usefulness and accuracy of the semi-analytical results are confirmed by comparison with numerical solutions of the governing partial differential equations

ANALYSIS OF TWO CLASSES OF CROSS DIFFUSION SYSTEMS

A mathematical and numerical analysis has been carried out for two cross diffusion systems arising in applied mathematics. The first system appears in modelling the movement of two interacting cell populations whose kinetics are of competition type. The second system models axial segregation of a mixture of two different granular materials in a long rotating drum. A fully practical piecewise linear finite element approximation for each system is proposed and studied. With the aid of a fixed point theorem, existence of the fully discrete solutions is shown. By using entropy-type inequalities and compactness arguments, the convergence of the approximation of each system is proved and hence existence of a global weak solution is obtained. Providing further regularity of the solution of the axial segregation model, some uniqueness results and error estimates are established. The long time behaviour of both systems is investigated and estimates between the weak solutions and the mean integrals of the corresponding initial data are derived. Finally, a practical algorithm for computing the numerical solutions of each system is described and some numerical experiments are performed to illustrate and verify the theoretical results

Phase reduction of stochastic biochemical oscillators

A common method for analyzing the effects of molecular noise in chemical reaction networks is to approximate the underlying chemical master equation by a Fokker--Planck equation and to study the statistics of the associated chemical Langevin equation. This so-called system-size expansion involves performing a perturbation expansion with respect to a small dimensionless parameter \epsilon = \Omega - 1 , where \Omega characterizes the system size. For example, \Omega could be the mean number of proteins produced by a gene regulatory network. In the deterministic limit \Omega \rightarrow \infty , the chemical reaction network evolves according to a system of ordinary differential equations based on classical mass action kinetics. In this paper we develop a phase reduction method for chemical reaction networks that support a stable limit cycle in the deterministic limit. We present a variational principle for the phase reduction, yielding an exact analytic expression for the resulting phase dynamics. We demonstrate that this decomposition is accurate over timescales that are exponential in the system size \Omega . This contrasts with the phase equation obtained under the system-size expansion, which is only accurate up to times O(\Omega ). In particular, we show that for a constant C, the probability that the system leaves an O(\zeta ) neighborhood of the limit cycle before time T scales as T exp( - C\Omega b\zeta 2 ), where b is the rate of attraction to the limit cycle. We illustrate our analysis using the example of a chemical Brusselator