Matching Items (6)
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- All Subjects: Tumors
- Creators: Kuang, Yang
- Status: Published
Description
In a 2004 paper, John Nagy raised the possibility of the existence of a hypertumor \emph{i.e.}, a focus of aggressively reproducing parenchyma cells that invade part or all of a tumor. His model used a system of nonlinear ordinary differential equations to find a suitable set of conditions for which these hypertumors exist. Here that model is expanded by transforming it into a system of nonlinear partial differential equations with diffusion, advection, and a free boundary condition to represent a radially symmetric tumor growth. Two strains of parenchymal cells are incorporated; one forming almost the entirety of the tumor while the much more aggressive strain
appears in a smaller region inside of the tumor. Simulations show that if the aggressive strain focuses its efforts on proliferating and does not contribute to angiogenesis signaling when in a hypoxic state, a hypertumor will form. More importantly, this resultant aggressive tumor is paradoxically prone to extinction and hypothesize is the cause of necrosis in many vascularized tumors.
appears in a smaller region inside of the tumor. Simulations show that if the aggressive strain focuses its efforts on proliferating and does not contribute to angiogenesis signaling when in a hypoxic state, a hypertumor will form. More importantly, this resultant aggressive tumor is paradoxically prone to extinction and hypothesize is the cause of necrosis in many vascularized tumors.
ContributorsAlvarez, Roberto L (Author) / Milner, Fabio A (Thesis advisor) / Nagy, John D. (Committee member) / Kuang, Yang (Committee member) / Thieme, Horst (Committee member) / Mahalov, Alex (Committee member) / Smith, Hal (Committee member) / Arizona State University (Publisher)
Created2014
Description
The phycologist, M. R. Droop, studied vitamin B12 limitation in the flagellate Monochrysis lutheri and concluded that its specific growth rate depended on the concentration of the vitamin within the cell; i.e. the cell quota of the vitamin B12. The Droop model provides a mathematical expression to link growth rate to the intracellular concentration of a limiting nutrient. Although the Droop model has been an important modeling tool in ecology, it has only recently been applied to study cancer biology. Cancer cells live in an ecological setting, interacting and competing with normal and other cancerous cells for nutrients and space, and evolving and adapting to their environment. Here, the Droop equation is used to model three cancers.
First, prostate cancer is modeled, where androgen is considered the limiting nutrient since most tumors depend on androgen for proliferation and survival. The model's accuracy for predicting the biomarker for patients on intermittent androgen deprivation therapy is tested by comparing the simulation results to clinical data as well as to an existing simpler model. The results suggest that a simpler model may be more beneficial for a predictive use, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting.
Next, two chronic myeloid leukemia models are compared that consider Imatinib treatment, a drug that inhibits the constitutively active tyrosine kinase BCR-ABL. Both models describe the competition of leukemic and normal cells, however the first model also describes intracellular dynamics by considering BCR-ABL as the limiting nutrient. Using clinical data, the differences in estimated parameters between the models and the capacity for each model to predict drug resistance are analyzed.
Last, a simple model is presented that considers ovarian tumor growth and tumor induced angiogenesis, subject to on and off anti-angiogenesis treatment. In this environment, the cell quota represents the intracellular concentration of necessary nutrients provided through blood supply. Mathematical analysis of the model is presented and model simulation results are compared to pre-clinical data. This simple model is able to fit both on- and off-treatment data using the same biologically relevant parameters.
First, prostate cancer is modeled, where androgen is considered the limiting nutrient since most tumors depend on androgen for proliferation and survival. The model's accuracy for predicting the biomarker for patients on intermittent androgen deprivation therapy is tested by comparing the simulation results to clinical data as well as to an existing simpler model. The results suggest that a simpler model may be more beneficial for a predictive use, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting.
Next, two chronic myeloid leukemia models are compared that consider Imatinib treatment, a drug that inhibits the constitutively active tyrosine kinase BCR-ABL. Both models describe the competition of leukemic and normal cells, however the first model also describes intracellular dynamics by considering BCR-ABL as the limiting nutrient. Using clinical data, the differences in estimated parameters between the models and the capacity for each model to predict drug resistance are analyzed.
Last, a simple model is presented that considers ovarian tumor growth and tumor induced angiogenesis, subject to on and off anti-angiogenesis treatment. In this environment, the cell quota represents the intracellular concentration of necessary nutrients provided through blood supply. Mathematical analysis of the model is presented and model simulation results are compared to pre-clinical data. This simple model is able to fit both on- and off-treatment data using the same biologically relevant parameters.
ContributorsEverett, Rebecca Anne (Author) / Kuang, Yang (Thesis advisor) / Nagy, John (Committee member) / Milner, Fabio (Committee member) / Crook, Sharon (Committee member) / Jackiewicz, Zdzislaw (Committee member) / Arizona State University (Publisher)
Created2015
Description
In 1968, phycologist M.R. Droop published his famous discovery on the functional relationship between growth rate and internal nutrient status of algae in chemostat culture. The simple notion that growth is directly dependent on intracellular nutrient concentration is useful for understanding the dynamics in many ecological systems. The cell quota in particular lends itself to ecological stoichiometry, which is a powerful framework for mathematical ecology. Three models are developed based on the cell quota principal in order to demonstrate its applications beyond chemostat culture.
First, a data-driven model is derived for neutral lipid synthesis in green microalgae with respect to nitrogen limitation. This model synthesizes several established frameworks in phycology and ecological stoichiometry. The model demonstrates how the cell quota is a useful abstraction for understanding the metabolic shift to neutral lipid production that is observed in certain oleaginous species.
Next a producer-grazer model is developed based on the cell quota model and nutrient recycling. The model incorporates a novel feedback loop to account for animal toxicity due to accumulation of nitrogen waste. The model exhibits rich, complex dynamics which leave several open mathematical questions.
Lastly, disease dynamics in vivo are in many ways analogous to those of an ecosystem, giving natural extensions of the cell quota concept to disease modeling. Prostate cancer can be modeled within this framework, with androgen the limiting nutrient and the prostate and cancer cells as competing species. Here the cell quota model provides a useful abstraction for the dependence of cellular proliferation and apoptosis on androgen and the androgen receptor. Androgen ablation therapy is often used for patients in biochemical recurrence or late-stage disease progression and is in general initially effective. However, for many patients the cancer eventually develops resistance months to years after treatment begins. Understanding how and predicting when hormone therapy facilitates evolution of resistant phenotypes has immediate implications for treatment. Cell quota models for prostate cancer can be useful tools for this purpose and motivate applications to other diseases.
First, a data-driven model is derived for neutral lipid synthesis in green microalgae with respect to nitrogen limitation. This model synthesizes several established frameworks in phycology and ecological stoichiometry. The model demonstrates how the cell quota is a useful abstraction for understanding the metabolic shift to neutral lipid production that is observed in certain oleaginous species.
Next a producer-grazer model is developed based on the cell quota model and nutrient recycling. The model incorporates a novel feedback loop to account for animal toxicity due to accumulation of nitrogen waste. The model exhibits rich, complex dynamics which leave several open mathematical questions.
Lastly, disease dynamics in vivo are in many ways analogous to those of an ecosystem, giving natural extensions of the cell quota concept to disease modeling. Prostate cancer can be modeled within this framework, with androgen the limiting nutrient and the prostate and cancer cells as competing species. Here the cell quota model provides a useful abstraction for the dependence of cellular proliferation and apoptosis on androgen and the androgen receptor. Androgen ablation therapy is often used for patients in biochemical recurrence or late-stage disease progression and is in general initially effective. However, for many patients the cancer eventually develops resistance months to years after treatment begins. Understanding how and predicting when hormone therapy facilitates evolution of resistant phenotypes has immediate implications for treatment. Cell quota models for prostate cancer can be useful tools for this purpose and motivate applications to other diseases.
ContributorsPacker, Aaron (Author) / Kuang, Yang (Thesis advisor) / Nagy, John (Committee member) / Smith, Hal (Committee member) / Kostelich, Eric (Committee member) / Kang, Yun (Committee member) / Arizona State University (Publisher)
Created2014
Description
The role of climate change, as measured in terms of changes in the climatology of geophysical variables (such as temperature and rainfall), on the global distribution and burden of vector-borne diseases (VBDs) remains a subject of considerable debate. This dissertation attempts to contribute to this debate via the use of mathematical (compartmental) modeling and statistical data analysis. In particular, the objective is to find suitable values and/or ranges of the climate variables considered (typically temperature and rainfall) for maximum vector abundance and consequently, maximum transmission intensity of the disease(s) they cause.
Motivated by the fact that understanding the dynamics of disease vector is crucial to understanding the transmission and control of the VBDs they cause, a novel weather-driven deterministic model for the population biology of the mosquito is formulated and rigorously analyzed. Numerical simulations, using relevant weather and entomological data for Anopheles mosquito (the vector for malaria), show that maximum mosquito abundance occurs when temperature and rainfall values lie in the range [20-25]C and [105-115] mm, respectively.
The Anopheles mosquito ecology model is extended to incorporate human dynamics. The resulting weather-driven malaria transmission model, which includes many of the key aspects of malaria (such as disease transmission by asymptomatically-infectious humans, and enhanced malaria immunity due to repeated exposure), was rigorously analyzed. The model which also incorporates the effect of diurnal temperature range (DTR) on malaria transmission dynamics shows that increasing DTR shifts the peak temperature value for malaria transmission from 29C (when DTR is 0C) to about 25C (when DTR is 15C).
Finally, the malaria model is adapted and used to study the transmission dynamics of chikungunya, dengue and Zika, three diseases co-circulating in the Americas caused by the same vector (Aedes aegypti). The resulting model, which is fitted using data from Mexico, is used to assess a few hypotheses (such as those associated with the possible impact the newly-released dengue vaccine will have on Zika) and the impact of variability in climate variables on the dynamics of the three diseases. Suitable temperature and rainfall ranges for the maximum transmission intensity of the three diseases are obtained.
Motivated by the fact that understanding the dynamics of disease vector is crucial to understanding the transmission and control of the VBDs they cause, a novel weather-driven deterministic model for the population biology of the mosquito is formulated and rigorously analyzed. Numerical simulations, using relevant weather and entomological data for Anopheles mosquito (the vector for malaria), show that maximum mosquito abundance occurs when temperature and rainfall values lie in the range [20-25]C and [105-115] mm, respectively.
The Anopheles mosquito ecology model is extended to incorporate human dynamics. The resulting weather-driven malaria transmission model, which includes many of the key aspects of malaria (such as disease transmission by asymptomatically-infectious humans, and enhanced malaria immunity due to repeated exposure), was rigorously analyzed. The model which also incorporates the effect of diurnal temperature range (DTR) on malaria transmission dynamics shows that increasing DTR shifts the peak temperature value for malaria transmission from 29C (when DTR is 0C) to about 25C (when DTR is 15C).
Finally, the malaria model is adapted and used to study the transmission dynamics of chikungunya, dengue and Zika, three diseases co-circulating in the Americas caused by the same vector (Aedes aegypti). The resulting model, which is fitted using data from Mexico, is used to assess a few hypotheses (such as those associated with the possible impact the newly-released dengue vaccine will have on Zika) and the impact of variability in climate variables on the dynamics of the three diseases. Suitable temperature and rainfall ranges for the maximum transmission intensity of the three diseases are obtained.
ContributorsOkuneye, Kamaldeen O (Author) / Gumel, Abba B (Thesis advisor) / Kuang, Yang (Committee member) / Smith, Hal (Committee member) / Thieme, Horst (Committee member) / Nagy, John (Committee member) / Arizona State University (Publisher)
Created2018
Description
Cancer is a major health problem in the world today and is expected to become an even larger one in the future. Although cancer therapy has improved for many cancers in the last several decades, there is much room for further improvement. Mathematical modeling has the advantage of being able to test many theoretical therapies without having to perform clinical trials and experiments. Mathematical oncology will continue to be an important tool in the future regarding cancer therapies and management.
This dissertation is structured as a growing tumor. Chapters 2 and 3 consider spheroid models. These models are adept at describing 'early-time' tumors, before the tumor needs to co-opt blood vessels to continue sustained growth. I consider two partial differential equation (PDE) models for spheroid growth of glioblastoma. I compare these models to in vitro experimental data for glioblastoma tumor cell lines and other proposed models. Further, I investigate the conditions under which traveling wave solutions exist and confirm numerically.
As a tumor grows, it can no longer be approximated by a spheroid, and it becomes necessary to use in vivo data and more sophisticated modeling to model the growth and diffusion. In Chapter 4, I explore experimental data and computational models for describing growth and diffusion of glioblastoma in murine brains. I discuss not only how the data was obtained, but how the 3D brain geometry is created from Magnetic Resonance (MR) images. A 3D finite-difference code is used to model tumor growth using a basic reaction-diffusion equation. I formulate and test hypotheses as to why there are large differences between the final tumor sizes between the mice.
Once a tumor has reached a detectable size, it is diagnosed, and treatment begins. Chapter 5 considers modeling the treatment of prostate cancer. I consider a joint model with hormonal therapy as well as immunotherapy. I consider a timing study to determine whether changing the vaccine timing has any effect on the outcome of the patient. In addition, I perform basic analysis on the six-dimensional ordinary differential equation (ODE). I also consider the limiting case, and perform a full global analysis.
This dissertation is structured as a growing tumor. Chapters 2 and 3 consider spheroid models. These models are adept at describing 'early-time' tumors, before the tumor needs to co-opt blood vessels to continue sustained growth. I consider two partial differential equation (PDE) models for spheroid growth of glioblastoma. I compare these models to in vitro experimental data for glioblastoma tumor cell lines and other proposed models. Further, I investigate the conditions under which traveling wave solutions exist and confirm numerically.
As a tumor grows, it can no longer be approximated by a spheroid, and it becomes necessary to use in vivo data and more sophisticated modeling to model the growth and diffusion. In Chapter 4, I explore experimental data and computational models for describing growth and diffusion of glioblastoma in murine brains. I discuss not only how the data was obtained, but how the 3D brain geometry is created from Magnetic Resonance (MR) images. A 3D finite-difference code is used to model tumor growth using a basic reaction-diffusion equation. I formulate and test hypotheses as to why there are large differences between the final tumor sizes between the mice.
Once a tumor has reached a detectable size, it is diagnosed, and treatment begins. Chapter 5 considers modeling the treatment of prostate cancer. I consider a joint model with hormonal therapy as well as immunotherapy. I consider a timing study to determine whether changing the vaccine timing has any effect on the outcome of the patient. In addition, I perform basic analysis on the six-dimensional ordinary differential equation (ODE). I also consider the limiting case, and perform a full global analysis.
ContributorsRutter, Erica Marie (Author) / Kuang, Yang (Thesis advisor) / Kostelich, Eric J (Thesis advisor) / Frakes, David (Committee member) / Gardner, Carl (Committee member) / Jackiewicz, Zdzislaw (Committee member) / Arizona State University (Publisher)
Created2016
Description
Hundreds of thousands of people die annually from malaria; a protozoan of the genus Plasmodium is responsible for this mortality. The Plasmodium parasite undergoes several life stages within the mosquito vector, the transition between which require passage across the lumen of the mosquito midgut. It has been observed that in about 15% of parasites that develop ookinetes in the mosquito abdomen, sporozoites never develop in the salivary glands, indicating that passage across the midgut lumen is a significant barrier in parasite development (Gamage-Mendis et al., 1993). We aim to investigate a possible correlation between passage through the midgut lumen and drug-resistance trends in Plasmodium falciparum parasites. This study contains a total of 1024 Anopheles mosquitoes: 187 Anopheles gambiae and 837 Anopheles funestus samples collected in high malaria transmission areas of Mozambique between March and June of 2016. Sanger sequencing will be used to determine the prevalence of known resistance alleles for anti-malarial drugs: chloroquine resistance transporter (pfcrt), multidrug resistance (pfmdr1) gene, dihydropteroate synthase (pfdhps) and dihydrofolate reductase (pfdhfr). We compare prevalence of resistance between abdomen and head/thorax in order to determine whether drug resistant parasites are disproportionately hindered during their passage through the midgut lumen. A statistically significant difference between resistance alleles in the two studied body sections supports the efficacy of new anti-malarial gene surveillance strategies in areas of high malaria transmission.
ContributorsPhillips, Keeley Isabella (Author) / Huijben, Silvie (Thesis director) / Gile, Gillian (Committee member) / Young, Steven (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05