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Modeling Spatial Competition and Adaptive Therapy Protocols in Three-Dimensional Vascularized Tumors
Description
In contrast to traditional chemotherapy for cancer which fails to address tumor heterogeneity, raises patients’ levels of toxicity, and selects for drug-resistant cells, adaptive therapy applies ideas from cancer ecology in employing low-dose drugs to encourage competition between cancerous cells, reducing toxicity and potentially prolonging disease progression. Despite promising results in some clinical trials, optimizing adaptive therapy routines involves navigating a vast space of combina- torial possibilities, including the number of drugs, drug holiday duration, and drug dosages. Computational models can serve as precursors to efficiently explore this space, narrowing the scope of possibilities for in-vivo and in-vitro experiments which are time-consuming, expensive, and specific to tumor types. Among the existing modeling techniques, agent-based models are particularly suited for studying the spatial inter- actions critical to successful adaptive therapy. In this thesis, I introduce CancerSim, a three-dimensional agent-based model fully implemented in C++ that is designed to simulate tumorigenesis, angiogenesis, drug resistance, and resource competition within a tissue. Additionally, the model is equipped to assess the effectiveness of various adaptive therapy regimens. The thesis provides detailed insights into the biological motivation and calibration of different model parameters. Lastly, I propose a series of research questions and experiments for adaptive therapy that CancerSim can address in the pursuit of advancing cancer treatment strategies.
ContributorsShah, Sanjana Saurin (Author) / Daymude, Joshua J (Thesis advisor) / Forrest, Stephanie (Committee member) / Maley, Carlo C (Committee member) / Arizona State University (Publisher)
Created2023
Description
Speciation, or the process by which one population diverges into multiple populations that can no longer interbreed with each other, has brought about the incredible diversity of life. Mechanisms underlying this process can be more visible in the early stages of the speciation process. The mechanisms that restrict gene flow in highly mobile species with no absolute barriers to dispersal, especially marine species, are understudied. Similarly, human impacts are reshaping ecosystems globally, and we are only just beginning to understand the implications of these rapid changes on evolutionary processes. In this dissertation, I investigate patterns of speciation and evolution in two avian clades: a genus of widespread tropical seabirds (boobies, genus Sula), and two congeneric passerine species in an urban environment (cardinals, genus Cardinalis). First, I explore the prevalence of gene flow across land barriers within species and between sympatric species in boobies. I found widespread evidence of gene flow over all land barriers and between 3 species pairs. Next, I compared the effects of urbanization on the spatial distributions of two cardinal species, pyrrhuloxia (Cardinalis sinuatus) and northern cardinals (Cardinalis cardinalis), in Tucson, Arizona. I found that urbanization has different effects on the spatial distributions of two closely related species that share a similar environmental niche, and I identified environmental variables that might be driving this difference. Then I tested for effects of urbanization on color and size traits of these two cardinal species. In both of these species, urbanization has altered traits involved in signaling, heat tolerance, foraging, and maneuverability. Finally, I tested for evidence of selection on the urban populations of both cardinal species and found evidence of both parallel selection and introgression between the species, as well as selection on different genes in each species. The functions of the genes that experienced positive selection suggest that light at night, energetics, and air pollution may have acted as strong selective pressures on these species in the past. Overall, my dissertation emphasizes the role of introgression in the speciation process, identifies environmental stressors faced by wildlife in urban environments, and characterizes their evolutionary responses to those stressors.
ContributorsJackson, Daniel Nelson (Author) / McGraw, Kevin J (Thesis advisor) / Amdam, Gro (Committee member) / Sweazea, Karen (Committee member) / Taylor, Scott (Committee member) / Arizona State University (Publisher)
Created2023
Description
Riparian ecosystems comprise less than 2% of the landscape in the arid western U.S. yet provide habitat and resources to over half of arid-land wildlife species, including a broad diversity of anurans (frogs and toads). I surveyed anurans using passive acoustic monitoring to capture spring advertisement calls in wilderness area tributaries of the Verde River, Arizona, USA. In the spring and summer of 2021 and 2022, 13-29 autonomous recording units (ARUs) were deployed along perennial, intermittent, and ephemeral reaches across eight headwater streams. I characterized stream reaches based on the percent of pool, riffle, run, and side channel habitat within 100 meters of each ARU. I quantified substrate, discharge at 95% exceedance probability, flow width, and canopy cover at each site. To relate anuran occupancy and relative habitat use to environmental and hydrological variables, I evaluated acoustic data using single-species occupancy and Royle-Nichols and N-mixture (relative habitat use) models. Four species were detected in this study: canyon treefrog (Hyla arenicolor), red-spotted toad (Anaxyrus punctatus), Woodhouse’s toad (Anaxyrus woodhousii), and non-native American bullfrog (Lithobates catesbeianus), with canyon treefrog being the most ubiquitous species observed. Occupancy of canyon treefrog was greater at perennial and intermittent sites compared to ephemeral sites, and presence of pool was the most important driver of canyon treefrog occupancy and relative habitat use. Notably, this study did not detect several species with historical records in the middle Verde River watershed, including Arizona toad (Anaxyrus microscaphus) and Northern leopard frog (Lithobates pipiens). Given climate change-related flow declines and intensifying demands for water in the Southwest, maintaining stream flows that provide consistent and suitable hydroregimes for anuran breeding and larval development is of increasing importance. Determining habitat use and flow regimes necessary to support anuran populations can aid in prioritization of conservation actions related to water management and predict how changes in water availability may impact stream-breeding anurans.
ContributorsHuck, Margaret (Author) / Bateman, Heather L (Thesis advisor) / Albuquerque, Fabio S (Thesis advisor) / Lewis, Jesse S (Committee member) / Arizona State University (Publisher)
Created2023
Description
Hydration status serves as an essential pillar of human health. Adequate hydration reduces cardiovascular strain, improves the body's ability to thermoregulate, stabilizes mood, and may reduce the risk of physiologic diseases like that of diabetes and urolithiasis. While many studies have shown the importance of adequate fluid intake on hydration status, very few have investigated the influence of dietary food moisture on hydration status. This study collected daily food diaries, daily fluid diaries, and spot urine samples over a 24hr period from 694 participants in Northwest Arkansas participating in the HYBISKUS study. Fluid and food diaries were logged in NDSR and analyzed using JMP while combined spot urine samples were analyzed using a freezing point depression osmometer to retrieve 24hr urine osmolality. Urine osmolality data was extracted from 24hr urine samples and used as the hydration status biomarker for study participants. The average contributions of water from fluids and foods in participants was 79.3 ±9.6% and 20.7 ±9.5% respectively. This study found that dietary food moisture has a significant effect on hydration status in adults with no specific macronutrient groups take precedence over any others in regard to dietary food moisture contributions. These results suggest that there are legitmate reasons to consider dietary food moisture intake when water intake recommendations are made for adults attempting to optimize health or prepare for physical exercise.
ContributorsKleinschmidt, Hunter (Author) / Kavouras, Stavros SK (Thesis advisor) / Sweazea, Karen KS (Committee member) / Katsanos, Christos CK (Committee member) / Arizona State University (Publisher)
Created2019
Description
Mast cells, components of the immune system, promote allergic symptoms such as itching, sneezing, and increased intestinal motility. Although mast cells have a detrimental role in allergies, they might have unrecognized physiological functions. Indeed, mast cells have been reported to protect against lethal envenomation. I hypothesized that mast cells have a protective role in the defense against toxins. Because toxin-induced diarrheal diseases are one of the top five causes of mortality in children worldwide (induced by cholera toxin, for example), I tested the role of mast cells in sensing relevant dietary toxins. My goals were to a) establish an in vitro model of mast cell activation using foodborne toxins and b) determine the mast cell transcriptional programs induced by these toxins. To establish the in vitro model, I generated mast cells from murine bone marrow precursors and cultured them in mast cell-specific media for 5 weeks. Mature mast cells were then stimulated with toxins from phylogenetically distinct origins. I found that, surprisingly, no toxin was able to induce significant cell death, even after 24h of culturing, suggesting that mast cells are resistant to the toxic effects of these compounds. To assess mast cell activation, I quantified the levels of TNF-α 6h after toxin exposure. None of the toxins were able to induce TNF-α production by mast cells, suggesting that toxins might not induce inflammation in mast cells. However, I found that mast cells induced expression of activation-related transcripts like Il1b, Tpsab1, Alox5, Egr1, Tnfa and Hdc in response to cholera toxin, when compared with controls. Mast cells stimulated with retrorsine induced the expression of Tph1, Alox5, Il1b and Hdc. Deoxynivalenol induced Ltc4, Il6, Tpsab1, Tnfa, Hdc, and Alox5 while okadaic acid induced Il6, Tnfa, Tph1, Alox5, Egr1, Il1b and Hdc expression. Aconitine only induced Il6, Hdc, and Tpsab1. Lastly, Ochratoxin A induced expression of Il1b, Il6, Tpsab1, Egr1 and Hdc. Altogether, these results suggest that mast cells directly sense and respond to food toxins, which was unknown. How exactly mast cells contribute to toxin defenses will be crucial to investigate as they impact both toxin-induced and inflammatory diseases.
ContributorsGalarza, Mayka (Author) / Borges Florsheim, Esther (Thesis advisor) / Lucas, Alexandra (Committee member) / Mana, Miyeko (Committee member) / Arizona State University (Publisher)
Created2023
Description
Obesity increases the risk for colorectal cancer. In mice, a pro-obesity high-fat-diet (HFD) leads to an intestinal phenotype characterized by enhanced proliferation, numbers, function and tumor-initiating capacity of stem cells, the cell-of-origin for many intestinal cancers. This phenotype is driven by a lipid metabolism program facilitated by an intrinsic Peroxisome Proliferator-Activated Receptor/Fatty Acid Oxidation (PPAR/FAO) axis that senses and utilizes cellular lipids. However, the microbiome is a known regulator of lipid metabolism in the gut, but little is understood about how the gut commensals affect access to the lipids and alter stem cell function. Here, we use the long term HFD-fed mouse model to analyze the phenotypic changes in the intestinal stem cells (ISCs) after depletion of the gut microbiota. We find that the loss of the gut microbiome after four weeks of antibiotic treatment imposes significant changes in ISC function leading to reduced HFD ISC regenerative potential. These results indicate that the gut microbiome plays a crucial role in the lipid metabolic process which regulates and maintains the HFD ISC phenotype, and further suggests that the gut microbiome may augment the diet-induced tumor initiating capacity by altering the stem cell function.
ContributorsSantos Molina, Pablo (Author) / Mana, Miyeko (Thesis director) / Whisner, Corrie (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / Historical, Philosophical & Religious Studies, Sch (Contributor)
Created2022-05
Description
Evolutionary theory provides a rich framework for understanding cancer dynamics across scales of biological organization. The field of cancer evolution has largely been divided into two domains, comparative oncology - the study of cancer across the tree of life, and tumor evolution. This work provides a theoretical framework to unify these subfields with the intent that an understanding of the evolutionary dynamics driving cancer risk at one scale can inform the understanding of the dynamics on another scale. The evolution of multicellular life and the unique vulnerabilities in the cellular mechanisms that underpin it explain the ubiquity of cancer prevalence across the tree of life. The breakdown in cellular cooperation and communication that were required for multicellular life define the hallmarks of cancer. As divergent life histories drove speciation events, it similarly drove divergences in fundamental cancer risk across species. An understanding of the impact that species’ life history theory has on the underlying network of multicellular cooperation and somatic evolution allows for robust predictions on cross-species cancer risk. A large-scale veterinary cancer database is utilized to validate many of the predictions on cancer risk made from life history evolution. Changing scales to the cellular level, it lays predictions on the fate of somatic mutations and the fitness benefits they confer to neoplastic cells compared to their healthy counterparts. The cancer hallmarks, far more than just a way to unify the many seemingly unique pathologies defined as cancer, is a powerful toolset to understand how specific mutations may change the fitness of somatic cells throughout carcinogenesis and tumor progression. Alongside highlighting the significant advances in evolutionary approaches to cancer across scales, this work provides a lucid confirmation that an understanding of both scales provides the most complete portrait of evolutionary cancer dynamics.
ContributorsCompton, Zachary Taylor (Author) / Maley, Carlo C. (Thesis advisor) / Aktipis, Athena (Committee member) / Buetow, Kenneth (Committee member) / Nedelcu, Aurora (Committee member) / Compton, Carolyn (Committee member) / Arizona State University (Publisher)
Created2023
Description
Decay of plant litter represents an enormous pathway for carbon (C) into the atmosphere but our understanding of the mechanisms driving this process is particularly limited in drylands. While microbes are a dominant driver of litter decay in most ecosystems, their significance in drylands is not well understood and abiotic drivers such as photodegradation are commonly perceived to be more important. I assessed the significance of microbes to the decay of plant litter in the Sonoran Desert. I found that the variation in decay among 16 leaf litter types was correlated with microbial respiration rates (i.e. CO2 emission) from litter, and rates were strongly correlated with water-vapor sorption rates of litter. Water-vapor sorption during high-humidity periods activates microbes and subsequent respiration appears to be a significant decay mechanism. I also found that exposure to sunlight accelerated litter decay (i.e. photodegradation) and enhanced subsequent respiration rates of litter. The abundance of bacteria (but not fungi) on the surface of litter exposed to sunlight was strongly correlated with respiration rates, as well as litter decay, implying that exposure to sunlight facilitated activity of surface bacteria which were responsible for faster decay. I also assessed the response of respiration to temperature and moisture content (MC) of litter, as well as the relationship between relative humidity and MC. There was a peak in respiration rates between 35-40oC, and, unexpectedly, rates increased from 55 to 70oC with the highest peak at 70oC, suggesting the presence of thermophilic microbes or heat-tolerant enzymes. Respiration rates increased exponentially with MC, and MC was strongly correlated with relative humidity. I used these relationships, along with litter microclimate and C loss data to estimate the contribution of this pathway to litter C loss over 34 months. Respiration was responsible for 24% of the total C lost from litter – this represents a substantial pathway for C loss, over twice as large as the combination of thermal and photochemical abiotic emission. My findings elucidate two mechanisms that explain why microbial drivers were more significant than commonly assumed: activation of microbes via water-vapor sorption and high respiration rates at high temperatures.
ContributorsTomes, Alexander (Author) / Day, Thomas (Thesis advisor) / Garcia-Pichel, Ferran (Committee member) / Ball, Becky (Committee member) / Hall, Sharon (Committee member) / Roberson, Robert (Committee member) / Arizona State University (Publisher)
Created2020
Description
The desire to start a family is something millions of people around the globe strive to achieve. However, many factors such as the societal changes in family planning due to increasing maternal age, use of birth control, and ever-changing lifestyles have increased the number of infertility cases seen in the United States each year. Infertility can manifest as a prolonged inability to conceive, or inability to carry a pregnancy full-term. Modern advancements in the field of reproductive medicine have begun to promote the use of Assisted Reproductive Technologies (ART) to circumvent reduced fertility in both men and women. Implementation of techniques such as In Vitro Fertilization, Intracytoplasmic Sperm Injection, and Pre-Implantation Genetic Testing have allowed many couples to conceive. There is continual effort being made towards developing more effective and personalized fertility treatments. This often begins in the form of animal research—a fundamental step in biomedical research. This dissertation examines infertility as a medical condition through the characterization of normal reproductive anatomy and physiology in the introductory overview of reproduction. Specific pathologies of male and female-factor infertility are described, which necessitates the use of ARTs. The various forms of ARTs currently utilized in a clinical setting are addressed including history, preparations, and protocols for each technology. To promote continual advancement of the field, both animal studies and human trials provide fundamental stepping-stones towards the execution of new techniques and protocols. Examples of research conducted for the betterment of human reproductive medicine are explored, including an animal study conducted in mice exploring the role of tyramine in ovulation. With the development and implementation of new technologies and protocols in the field, this also unearths ethical dilemmas that further complicate the addition of new technologies in the field. Combining an extensive review in assisted reproduction, research and clinical fieldwork, this study investigates the history and development of novel research conducted in reproductive medicine and explores the broader implications of new technologies in the field.
ContributorsPeck, Shelbi Marie (Author) / Baluch, Debra P (Thesis advisor) / Maienschein, Jane (Thesis advisor) / Sweazea, Karen (Committee member) / Ellison, Karin (Committee member) / Arizona State University (Publisher)
Created2021
Description
Eusocial insect colonies have often been imagined as “superorganisms” exhibiting tight homeostasis at the colony level. However, colonies lack the tight spatial and organizational integration that many multicellular, unitary organisms exhibit. Precise regulation requires rapid feedback, which is often not possible when nestmates are distributed across space, making decisions asynchronously. Thus, one should expect poorer regulation in superorganisms than unitary organisms.Here, I investigate aspects of regulation in collective foraging behaviors that involve both slow and rapid feedback processes. In Chapter 2, I examine a tightly coupled system with near-instantaneous signaling: teams of weaver ants cooperating to transport massive prey items back to their nest. I discover that over an extreme range of scenarios—even up vertical surfaces—the efficiency per transporter remains constant. My results suggest that weaver ant colonies are maximizing their total intake rate by regulating the allocation of transporters among loads. This is an exception that “proves the rule;” the ant teams are recapitulating the physical integration of unitary organisms.
Next, I focus on a process with greater informational constraints, with loose temporal and spatial integration. In Chapter 3, I measure the ability of solitarily foraging Ectatomma ruidum colonies to balance their collection of protein and carbohydrates given different nutritional environments. Previous research has found that ant species can precisely collect a near-constant ratio between these two macronutrients, but I discover these studies were using flawed statistical approaches. By developing a quantitative measure of regulatory effect size, I show that colonies of E. ruidum are relatively insensitive to small differences in food source nutritional content, contrary to previously published claims.
In Chapter 4, I design an automated, micro-RFID ant tracking system to investigate how the foraging behavior of individuals integrates into colony-level nutrient collection. I discover that spatial fidelity to food resources, not individual specialization on particular nutrient types, best predicts individual forager behavior. These findings contradict previously published experiments that did not use rigorous quantitative measures of specialization and confounded the effects of task type and resource location.
ContributorsBurchill, Andrew Taylor (Author) / Pavlic, Theodore P (Thesis advisor) / Pratt, Stephen C (Thesis advisor) / Hölldobler, Bert (Committee member) / Cease, Arianne (Committee member) / Berman, Spring (Committee member) / Arizona State University (Publisher)
Created2022