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Background: Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear.

Background: Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear. High levels of androgens have traditionally been viewed as driving abnormal proliferation leading to cancer, but it has also been suggested that low levels of androgen could induce selective pressure for abnormal cells. We formulate a mathematical model of androgen regulated prostate growth to study the effects of abnormal androgen levels on selection for pre-malignant phenotypes in early prostate cancer development.

Results: We find that cell turnover rate increases with decreasing androgen levels, which may increase the rate of mutation and malignant evolution. We model the evolution of a heterogeneous prostate cell population using a continuous state-transition model. Using this model we study selection for AR expression under different androgen levels and find that low androgen environments, caused either by low serum testosterone or by reduced 5α-reductase activity, select more strongly for elevated AR expression than do normal environments. High androgen actually slightly reduces selective pressure for AR upregulation. Moreover, our results suggest that an aberrant androgen environment may delay progression to a malignant phenotype, but result in a more dangerous cancer should one arise.

Conclusions: The model represents a useful initial framework for understanding the role of androgens in prostate cancer etiology, and it suggests that low androgen levels can increase selection for phenotypes resistant to hormonal therapy that may also be more aggressive. Moreover, clinical treatment with 5α-reductase inhibitors such as finasteride may increase the incidence of therapy resistant cancers.

ContributorsEikenberry, Steffen (Author) / Nagy, John D. (Author) / Kuang, Yang (Author) / College of Liberal Arts and Sciences (Contributor)
Created2010-04-20
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Background: Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration.

Background: Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.

Methods: A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.

Results: The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.

Conclusion: Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.

ContributorsEikenberry, Steffen (Author) / College of Liberal Arts and Sciences (Contributor)
Created2009-08-09
Description

Climate is a critical determinant of agricultural productivity, and the ability to accurately predict this productivity is necessary to provide guidance regarding food security and agricultural management. Previous predictions vary in approach due to the myriad of factors influencing agricultural productivity but generally suggest long-term declines in productivity and agricultural

Climate is a critical determinant of agricultural productivity, and the ability to accurately predict this productivity is necessary to provide guidance regarding food security and agricultural management. Previous predictions vary in approach due to the myriad of factors influencing agricultural productivity but generally suggest long-term declines in productivity and agricultural land suitability under climate change. In this paper, I relate predicted climate changes to yield for three major United States crops, namely corn, soybeans, and wheat, using a moderate emissions scenario. By adopting data-driven machine learning approaches, I used the following machine learning methods: random forest (RF), extreme gradient boosting (XGB), and artificial neural networks (ANN) to perform comparative analysis and ensemble methodology. I omitted the western US due to the region's susceptibility to water stress and the prevalence of artificial irrigation as a means to compensate for dry conditions. By considering only climate, the model's results suggest an ensemble mean decline in crop yield of 23.4\% for corn, 19.1\% for soybeans, and 7.8\% for wheat between the years of 2017 and 2100. These results emphasize potential negative impacts of climate change on the current agricultural industry as a result of shifting bio-climactic conditions.

ContributorsSwarup, Shray (Author) / Eikenberry, Steffen (Thesis director) / Mahalov, Alex (Committee member) / Barrett, The Honors College (Contributor) / Computer Science and Engineering Program (Contributor)
Created2023-05
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Anthropogenic climate change caused by increasing carbon emissions poses a threat to nearly every living organism. One consequence of these emissions is ocean acidification (OA). While OA has been shown to directly inhibit growth in calcifying animals, it might also have negative effects on other marine life. I conducted a

Anthropogenic climate change caused by increasing carbon emissions poses a threat to nearly every living organism. One consequence of these emissions is ocean acidification (OA). While OA has been shown to directly inhibit growth in calcifying animals, it might also have negative effects on other marine life. I conducted a systematic quantitative literature review on the effects of OA on fish behavior. The review consisted of 29 peer-reviewed, published journal articles. Most articles report some degree of negative impact of OA. Impacts include sensory impairment, erratic swimming patterns and attraction to predators. Many studies report insignificant impacts, thus continued research is needed to understand the consequences of human behavior and assist in mitigating our impact.
ContributorsKubiak, Allison Noelle (Co-author) / Kubiak, Allison (Co-author) / Gerber, Leah (Thesis director) / Eikenberry, Steffen (Committee member) / Kelman, Jonathan (Committee member) / School of Sustainability (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
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Description
Climate change is one of the most pressing issues affecting the world today. One of the impacts of climate change is on the transmission of mosquito-borne diseases (MBDs), such as West Nile Virus (WNV). Climate is known to influence vector and host demography as well as MBD transmission. This dissertation

Climate change is one of the most pressing issues affecting the world today. One of the impacts of climate change is on the transmission of mosquito-borne diseases (MBDs), such as West Nile Virus (WNV). Climate is known to influence vector and host demography as well as MBD transmission. This dissertation addresses the questions of how vector and host demography impact WNV dynamics, and how expected and likely climate change scenarios will affect demographic and epidemiological processes of WNV transmission. First, a data fusion method is developed that connects non-autonomous logistic model parameters to mosquito time series data. This method captures the inter-annual and intra-seasonal variation of mosquito populations within a geographical location. Next, a three-population WNV model between mosquito vectors, bird hosts, and human hosts with infection-age structure for the vector and bird host populations is introduced. A sensitivity analysis uncovers which parameters have the most influence on WNV outbreaks. Finally, the WNV model is extended to include the non-autonomous population model and temperature-dependent processes. Model parameterization using historical temperature and human WNV case data from the Greater Toronto Area (GTA) is conducted. Parameter fitting results are then used to analyze possible future WNV dynamics under two climate change scenarios. These results suggest that WNV risk for the GTA will substantially increase as temperature increases from climate change, even under the most conservative assumptions. This demonstrates the importance of ensuring that the warming of the planet is limited as much as possible.
ContributorsMancuso, Marina (Author) / Milner, Fabio A (Thesis advisor) / Kuang, Yang (Committee member) / Kostelich, Eric (Committee member) / Eikenberry, Steffen (Committee member) / Manore, Carrie (Committee member) / Arizona State University (Publisher)
Created2023