Over time, tumor treatment resistance inadvertently develops when androgen de-privation therapy (ADT) is applied to metastasized prostate cancer (PCa). To combat tumor resistance, while reducing the harsh side effects of hormone therapy, the clinician may opt to cyclically alternates the patient’s treatment on and off. This method,known as intermittent ADT, is an alternative to continuous ADT that improves the patient’s quality of life while testosterone levels recover between cycles. In this paper,we explore the response of intermittent ADT to metastasized prostate cancer by employing a previously clinical data validated mathematical model to new clinical data from patients undergoing Abiraterone therapy. This cell quota model, a system of ordinary differential equations constructed using Droop’s nutrient limiting theory, assumes the tumor comprises of castration-sensitive (CS) and castration-resistant (CR)cancer sub-populations. The two sub-populations rely on varying levels of intracellular androgen for growth, death and transformation. Due to the complexity of the model,we carry out sensitivity analyses to study the effect of certain parameters on their outputs, and to increase the identifiability of each patient’s unique parameter set. The model’s forecasting results show consistent accuracy for patients with sufficient data,which means the model could give useful information in practice, especially to decide whether an additional round of treatment would be effective.

Efforts to treat prostate cancer have seen an uptick, as the world’s most commoncancer in men continues to have increasing global incidence. Clinically, metastatic
prostate cancer is most commonly treated with hormonal therapy. The idea behind
hormonal therapy is to reduce androgen production, which prostate cancer cells
require for growth. Recently, the exploration of the synergistic effects of the drugs
used in hormonal therapy has begun. The aim was to build off of these recent
advancements and further refine the synergistic drug model. The advancements I
implement come by addressing biological shortcomings and improving the model’s
internal mechanistic structure. The drug families being modeled, anti-androgens,
and gonadotropin-releasing hormone analogs, interact with androgen production in a
way that is not completely understood in the scientific community. Thus the models
representing the drugs show progress through their ability to capture their effect
on serum androgen. Prostate-specific antigen is the primary biomarker for prostate
cancer and is generally how population models on the subject are validated. Fitting
the model to clinical data and comparing it to other clinical models through the
ability to fit and forecast prostate-specific antigen and serum androgen is how this
improved model achieves validation. The improved model results further suggest that
the drugs’ dynamics should be considered in adaptive therapy for prostate cancer.

Cancer is a disease involving abnormal growth of cells. Its growth dynamics is perplexing. Mathematical modeling is a way to shed light on this progress and its medical treatments. This dissertation is to study cancer invasion in time and space using a mathematical approach. Chapter 1 presents a detailed review of literature on cancer modeling.

Chapter 2 focuses sorely on time where the escape of a generic cancer out of immune control is described by stochastic delayed differential equations (SDDEs). Without time delay and noise, this system demonstrates bistability. The effects of response time of the immune system and stochasticity in the tumor proliferation rate are studied by including delay and noise in the model. Stability, persistence and extinction of the tumor are analyzed. The result shows that both time delay and noise can induce the transition from low tumor burden equilibrium to high tumor equilibrium. The aforementioned work has been published (Han et al., 2019b).

In Chapter 3, Glioblastoma multiforme (GBM) is studied using a partial differential equation (PDE) model. GBM is an aggressive brain cancer with a grim prognosis. A mathematical model of GBM growth with explicit motility, birth, and death processes is proposed. A novel method is developed to approximate key characteristics of the wave profile, which can be compared with MRI data. Several test cases of MRI data of GBM patients are used to yield personalized parameterizations of the model. The aforementioned work has been published (Han et al., 2019a).

Chapter 4 presents an innovative way of forecasting spatial cancer invasion. Most mathematical models, including the ones described in previous chapters, are formulated based on strong assumptions, which are hard, if not impossible, to verify due to complexity of biological processes and lack of quality data. Instead, a nonparametric forecasting method using Gaussian processes is proposed. By exploiting the local nature of the spatio-temporal process, sparse (in terms of time) data is sufficient for forecasting. Desirable properties of Gaussian processes facilitate selection of the size of the local neighborhood and computationally efficient propagation of uncertainty. The method is tested on synthetic data and demonstrates promising results.

The analysis focuses on a two-population, three-dimensional model that attempts to accurately model the growth and diffusion of glioblastoma multiforme (GBM), a highly invasive brain cancer, throughout the brain. Analysis into the sensitivity of the model to

changes in the diffusion, growth, and death parameters was performed, in order to find a set of parameter values that accurately model observed tumor growth for a given patient. Additional changes were made to the diffusion parameters to account for the arrangement of nerve tracts in the brain, resulting in varying rates of diffusion. In general, small changes in the growth rates had a large impact on the outcome of the simulations, and for each patient there exists a set of parameters that allow the model to simulate a tumor that matches observed tumor growth in the patient over a period of two or three months. Furthermore, these results are more accurate with anisotropic diffusion, rather than isotropic diffusion. However, these parameters lead to inaccurate results for patients with tumors that undergo no observable growth over the given time interval. While it is possible to simulate long-term tumor growth, the simulation requires multiple comparisons to available MRI scans in order to find a set of parameters that provide an accurate prognosis.

This dissertation develops a second order accurate approximation to the magnetic resonance (MR) signal model used in the PARSE (Parameter Assessment by Retrieval from Single Encoding) method to recover information about the reciprocal of the spin-spin relaxation time function (R2*) and frequency offset function (w) in addition to the typical steady-state transverse magnetization (M) from single-shot magnetic resonance imaging (MRI) scans. Sparse regularization on an approximation to the edge map is used to solve the associated inverse problem. Several studies are carried out for both one- and two-dimensional test problems, including comparisons to the first order approximation method, as well as the first order approximation method with joint sparsity across multiple time windows enforced. The second order accurate model provides increased accuracy while reducing the amount of data required to reconstruct an image when compared to piecewise constant in time models. A key component of the proposed technique is the use of fast transforms for the forward evaluation. It is determined that the second order model is capable of providing accurate single-shot MRI reconstructions, but requires an adequate coverage of k-space to do so. Alternative data sampling schemes are investigated in an attempt to improve reconstruction with single-shot data, as current trajectories do not provide ideal k-space coverage for the proposed method.

The physics of waves control most of the world, in multiple forms, such as electromagnetic waves. Mathematicians and physicists have developed equations which describe the patterns in which waves evolve over time, while moving through space. Due to their partial differential form, solutions to these equations must be approximated. This study introduces a new numerical scheme to perform the approximation which is highly stable and computationally efficient. This numerical scheme is formulated with respect to Maxwell’s equations, employing spatial and temporal staggering to implement a fourth-order phase accuracy. It is then compared to the traditional Yee scheme and the Runge-Kutta 3 scheme in one-dimensional applications, revealing a similar accuracy to the Runge-Kutta 3 scheme while requiring less computations per time step. Simulations are then performed in the two-dimensional case. First, no boundary conditions are implemented, causing reflection at the edge of the spatial domain. Next, the simulation is conducted while employing absorbing boundary conditions, simulating wave propagation over an infinite spatial domain. These results are compared to the results of a large domain simulation, in which the wave propagation does not reach the boundaries. Comparing the simulations, it is concluded that the numerical scheme is stable and highly accurate when employing absorbing boundary conditions. Finally, the scheme is tested in two dimensions with wave propagation through nonlinear media, as opposed to the prior simulations which were performed as if in a vacuum. After performing spectral analysis on the resulting waves after a long-time domain simulation, the resulting angular frequencies match those expected from theory. Therefore, the scheme is concluded to be powerful in one-dimensional, two-dimensional, and nonlinear simulations, all while being computationally efficient.

I investigate two models interacting agent systems: the first is motivated by the flocking and swarming behaviors in biological systems, while the second models opinion formation in social networks. In each setting, I define natural notions of convergence (to a ``flock" and to a ``consensus'', respectively), and study the convergence properties of each in the limit as $t \rightarrow \infty$. Specifically, I provide sufficient conditions for the convergence of both of the models, and conduct numerical experiments to study the resulting solutions.

Two urban flows are analyzed, one concerned with pollutant transport in a Phoenix, Arizona neighborhood and the other with windshear detection at the Hong Kong International Airport (HKIA).

Lagrangian measures, identified with finite-time Lyapunov exponents, are first used to characterize transport patterns of inertial pollutant particles. Motivated by actual events the focus is on flows in realistic urban geometry. Both deterministic and stochastic transport patterns are identified, as inertial Lagrangian coherent structures. For the deterministic case, the organizing structures are well defined and are extracted at different hours of a day to reveal the variability of coherent patterns. For the stochastic case, a random displacement model for fluid particles is formulated, and used to derive the governing equations for inertial particles to examine the change in organizing structures due to ``zeroth-order'' random noise. It is found that, (1) the Langevin equation for inertial particles can be reduced to a random displacement model; (2) using random noise based on inhomogeneous turbulence, whose diffusivity is derived from $k$-$\epsilon$ models, major coherent structures survive to organize local flow patterns and weaker structures are smoothed out due to random motion.

A study of three-dimensional Lagrangian coherent structures (LCS) near HKIA is then presented and related to previous developments of two-dimensional (2D) LCS analyses in detecting windshear experienced by landing aircraft. The LCS are contrasted among three independent models and against 2D coherent Doppler light detection and ranging (LIDAR) data. Addition of the velocity information perpendicular to the lidar scanning cone helps solidify flow structures inferred from previous studies; contrast among models reveals the intramodel variability; and comparison with flight data evaluates the performance among models in terms of Lagrangian analyses. It is found that, while the three models and the LIDAR do recover similar features of the windshear experienced by a landing aircraft (along the landing trajectory), their Lagrangian signatures over the entire domain are quite different - a portion of each numerical model captures certain features resembling those LCS extracted from independent 2D LIDAR analyses based on observations. Overall, it was found that the Weather Research and Forecast (WRF) model provides the best agreement with the LIDAR data.

Finally, the three-dimensional variational (3DVAR) data assimilation scheme in WRF is used to incorporate the LIDAR line of sight velocity observations into the WRF model forecast at HKIA. Using two different days as test cases, it is found that the LIDAR data can be successfully and consistently assimilated into WRF. Using the updated model forecast LCS are extracted along the LIDAR scanning cone and compare to onboard flight data. It is found that the LCS generated from the updated WRF forecasts are generally better correlated with the windshear experienced by landing aircraft as compared to the LIDAR extracted LCS alone, which suggests that such a data assimilation scheme could be used for the prediction of windshear events.

Magnetic resonance imaging (MRI) data of metastatic brain cancer patients at the Barrow Neurological Institute sparked interest in the radiology department due to the possibility that tumor size distributions might mimic a power law or an exponential distribution. In order to consider the question regarding the growth trends of metastatic brain tumors, this thesis analyzes the volume measurements of the tumor sizes from the BNI data and attempts to explain such size distributions through mathematical models. More specifically, a basic stochastic cellular automaton model is used and has three-dimensional results that show similar size distributions of those of the BNI data. Results of the models are investigated using the likelihood ratio test suggesting that, when the tumor volumes are measured based on assuming tumor sphericity, the tumor size distributions significantly mimic the power law over an exponential distribution.

The tools developed for the use of investigating dynamical systems have provided critical understanding to a wide range of physical phenomena. Here these tools are used to gain further insight into scalar transport, and how it is affected by mixing. The aim of this research is to investigate the efficiency of several different partitioning methods which demarcate flow fields into dynamically distinct regions, and the correlation of finite-time statistics from the advection-diffusion equation to these regions.

For autonomous systems, invariant manifold theory can be used to separate the system into dynamically distinct regions. Despite there being no equivalent method for nonautonomous systems, a similar analysis can be done. Systems with general time dependencies must resort to using finite-time transport barriers for partitioning; these barriers are the edges of Lagrangian coherent structures (LCS), the analog to the stable and unstable manifolds of invariant manifold theory. Using the coherent structures of a flow to analyze the statistics of trapping, flight, and residence times, the signature of anomalous diffusion are obtained.

This research also investigates the use of linear models for approximating the elements of the covariance matrix of nonlinear flows, and then applying the covariance matrix approximation over coherent regions. The first and second-order moments can be used to fully describe an ensemble evolution in linear systems, however there is no direct method for nonlinear systems. The problem is only compounded by the fact that the moments for nonlinear flows typically don't have analytic representations, therefore direct numerical simulations would be needed to obtain the moments throughout the domain. To circumvent these many computations, the nonlinear system is approximated as many linear systems for which analytic expressions for the moments exist. The parameters introduced in the linear models are obtained locally from the nonlinear deformation tensor.