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The Ethical Use of Mice in Demonstrating Viral Cancer Treatment Using Vaccinia

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Laboratory animals represent an invaluable, yet controversial, resource in the field of biomedical research. Animal research has been behind many influential discoveries in the field of emerging therapeutics. They provide the link between the theory of the lab bench and

Laboratory animals represent an invaluable, yet controversial, resource in the field of biomedical research. Animal research has been behind many influential discoveries in the field of emerging therapeutics. They provide the link between the theory of the lab bench and the functional application of medicine to influence human health. The use of animals in research is a consideration which must be heavily weighed, and the implementation must be carried out at a very high standard in order to retain research integrity and responsibility. We are in the process of conducting an experiment using laboratory mice to demonstrate cancer treatment using vaccinia (VACV) mutants as a possible oncolytic therapy for certain strains of melanoma. VACV is a double-stranded DNA poxvirus with a large and easily altered genome. This virus contains many genes dedicated to immune evasion, but has shown sensitivity to cell death by necroptosis in mouse studies (5). We have identified the absence of the kinase RIP3 which is vital in the necroptosis pathway as a potential target for oncolytic therapy using VACV mutants in specific strains of melanoma. Multiple groups of SCID Beige mice were inoculated with different melanoma cell lines and observed for tumor growth. Upon reaching 1 cm3 in volume, tumors were injected with either VACV- Δ83N, VACV- Δ54N, or PBS, and observed for regression. It was hypothesized that melanoma tumors that are RIP3-/- such as the MDA5 cell line will show regression, but melanoma tumors that are RIP3-positive and capable of necroptosis, such as the 2427 cell line, will resist viral replication and continue to proliferate. Our results so far tentatively support this hypothesis, but the data collection is ongoing. Strict and specific protocols with regard to the ethical and responsible use of mice have been implemented and upheld throughout the experiment. Animals are closely monitored, and if their quality of life becomes too poor to justify their continued use in the experiment, they are humanely euthanized, even at the expense of valuable data. The importance of commitment to a high ethical standard is pervasive throughout our work. Animals represent an invaluable contribution to research, and it is important to maintain high standards and transparency with regard to their use. Education and engagement in critical discussions about the use and care of animals in the laboratory contribute to the overall merit and legitimacy of biomedical research in the public and professional eye as a whole, and give legitimacy to the continued use of animals as models to advance science and health.

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2018-05

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Does an extended washout period of six weeks following the end of chronic stress continue the benefits on spatial learning and memory?

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Chronic stress often leads to cognitive deficits, especially within the spatial memory domain mediated by the hippocampus. When chronic stress ends and a no-stress period ensues (i.e., washout, WO), spatial ability improves, which can be better than non-stressed controls (CON).

Chronic stress often leads to cognitive deficits, especially within the spatial memory domain mediated by the hippocampus. When chronic stress ends and a no-stress period ensues (i.e., washout, WO), spatial ability improves, which can be better than non-stressed controls (CON). The WO period is often the same duration as the chronic stress paradigm. Given the potential benefit of a post-stress WO period on cognition, it is important to investigate whether this potential benefit of a post-stress WO period has long-lasting effects. In this project, chronic restraint (6hr/d/21d) in Sprague-Dawley rats was used, as it is the minimum duration necessary to observe spatial memory deficits. Two durations of post-stress WO were used following the end of chronic restraint, 3 weeks (STR-WO3) and 6 weeks (STR-WO6). Immediately after chronic stress (STR-IMM) or the WO periods, rats were tested on various cognitive tests. We corroborated past studies that chronic stress impaired spatial memory (STR-IMM vs CON). Interestingly, STR-WO3 and STR-WO6 failed to demonstrate improved spatial memory on a radial arm water maze task, performing similarly as STR-IMM. Performance outcomes were unlikely from differences in anxiety or motivation because rats from all conditions performed similarly on an open field task and on a simple object recognition paradigm, respectively. However, performance on object placement was unusual in that very few rats explored, suggesting some degree of anxiety or fear in all groups. One possible interpretation of the unusual results of the 3 week washout group may be attributed to the different spatial memory tasks used across studies or external factors from the study. Further exploration of these other factors led to the conclusion that they did not play a role and the STR-WO3 RAWM data were anomalous to other studies. This suggests that a washout period following chronic stress may not be fully understood.

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2017-05

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The Effect of Inbreeding and Life History Traits on the Risk of Cancer Mortality in Dogs

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Due to artificial selection, dogs have high levels of phenotypic diversity, yet, there appears to be low genetic diversity within individual breeds. Through their domestication from wolves, dogs have gone through a series of population bottlenecks, which has resulted in

Due to artificial selection, dogs have high levels of phenotypic diversity, yet, there appears to be low genetic diversity within individual breeds. Through their domestication from wolves, dogs have gone through a series of population bottlenecks, which has resulted in a reduction in genetic diversity, with a large amount of linkage disequilibrium and the persistence of deleterious mutations. This has led to an increased susceptibility to a multitude of diseases, including cancer. To study the effects of artificial selection and life history characteristics on the risk of cancer mortality, we collected cancer mortality data from four studies as well as the percent of heterozygosity, body size, lifespan and breed group for 201 dog breeds. We also collected specific types of cancer breeds were susceptible to and compared the dog cancer mortality patterns to the patterns observed in other mammals. We found a relationship between cancer mortality rate and heterozygosity, body size, lifespan as well as breed group. Higher levels of heterozygosity were also associated with longer lifespan. These results indicate larger breeds, such as Irish Water Spaniels, Flat-coated Retrievers and Bernese Mountain Dogs, are more susceptible to cancer, with lower heterozygosity and lifespan. These breeds are also more susceptible to sarcomas, as opposed to carcinomas in smaller breeds, such as Miniature Pinschers, Chihuahuas, and Pekingese. Other mammals show that larger and long-lived animals have decreased cancer mortality, however, within dog breeds, the opposite relationship is observed. These relationships could be due to the trade-off between cellular maintenance and growing fast and large, with higher expression of growth factors, such as IGF-1. This study further demonstrates the relationships between cancer mortality, heterozygosity, and life history traits and exhibits dogs as an important model organism for understanding the relationship between genetics and health.

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2017-12

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Fighting the War on Cancer: Effects of War Frame, Loss-Gain Prime and Patient Gender on Treatment Decision

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This purpose of this thesis study was to examine variables of the "War on Cancer" frame, loss-gain prime, and patient gender on treatment decision for advanced cancer patients. A total of 291 participants (141 females) participated in an online survey

This purpose of this thesis study was to examine variables of the "War on Cancer" frame, loss-gain prime, and patient gender on treatment decision for advanced cancer patients. A total of 291 participants (141 females) participated in an online survey experiment and were randomly assigned to one of eight possible conditions, each of which were comprised of a combination of one of two levels for three total independent variables: war frame ("War on Cancer" frame or neutral frame), loss-gain prime (loss prime or gain prime), and patient gender (female or male). Each of the three variables were operationalized to determine whether or not the exposure to the war on cancer paradigm, loss-frame language, or male patient gender would increase the likelihood of a participant choosing a more aggressive cancer treatment. Participants read a patient scenario and were asked to respond to questions related to motivating factors. Participants were then asked to report preference for one of two treatment decisions. Participants were then asked to provide brief demographic information in addition to responding to questions about military history, war attitudes, and cancer history. The aforementioned manipulations sought to determine whether exposure to various factors would make a substantive difference in final treatment decision. Contrary to the predicted results, participants in the war frame condition (M = 3.85, SD = 1.48) were more likely to choose the pursuit of palliative care (as opposed to aggressive treatment) than participants in the neutral frame condition (M = 3.54, SD = 1.23). Ultimately, these significant findings suggest that there is practical information to be gained from treatment presentation manipulations. By arming healthcare providers with a more pointed understanding of the nuances of treatment presentation, we can hope to empower patients, their loved ones, and healthcare providers entrenched in the world of cancer treatment.

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2016-05

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The Integration of Complementary and Alternative Medicine (CAM) into Western Biomedical Oncology Treatment

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Through a standpoint feminist perspective (Harding 2009) I conducted a situational analysis (Clarke, 2015) that examined academic literature and cancer support discussion boards (DBs) to identify how Western biomedicine, specifically oncology, can integrate complementary and alternative medicine (CAM) to improve

Through a standpoint feminist perspective (Harding 2009) I conducted a situational analysis (Clarke, 2015) that examined academic literature and cancer support discussion boards (DBs) to identify how Western biomedicine, specifically oncology, can integrate complementary and alternative medicine (CAM) to improve cancer treatment in children. The aims of this project were: 1) to identify the CAM treatments that are being used to alleviate the side effects from oncological treatments and/or treat pediatric cancers; 2) to compare the subjective experience of CAM to Western biomedicine of cancer patients who leave comments on Group Loop, Cancer Compass and Cancer Forums, which are online support groups (N=20). I used grounded theory and situational mapping to analyze discussion threads. The participants identified using the following CAM treatments: herbs, imagery, prayer, stinging nettle, meditation, mind-body therapies and supplements. The participants turned to CAM treatments when their cancer was late-stage or terminal, often as an integrative and not exclusively to treat their cancer. CAM was more "effective" than biomedical oncology treatment at improving their overall quality of life and functionality. We found that youth on discussion boards did not discuss CAM treatments like the adult participants, but all participants visited these sites for support and verification of their cancer treatments. My main integration recommendation is to combine mind-body CAM therapies with biomedical treatment. This project fills the gap in literature that ignores the ideas of vulnerable populations by providing the experiences of adult and pediatric cancer patients, and that of their families. It is applicable to areas of the social studies of medicine, patient care, and families suffering from cancer. KEYWORDS: Cancer; Complementary and Alternative Medicine; Situational Analysis; Standpoint Feminism

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2016-12

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High-Intensity Exercise Preconditioning Prevents Downregulation of eNOS Expression in the Aorta Following Doxorubicin Treatment

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The anthracycline drug Doxorubicin (DOX) is a highly effective treatment for breast cancer, but its clinical utility is limited by dose-dependent cardiovascular toxicity. The toxic effects are partly attributed to DOX-induced generation of reactive oxygen species, which may impair nitric

The anthracycline drug Doxorubicin (DOX) is a highly effective treatment for breast cancer, but its clinical utility is limited by dose-dependent cardiovascular toxicity. The toxic effects are partly attributed to DOX-induced generation of reactive oxygen species, which may impair nitric oxide-mediated vasodilation. Exercise training activates antioxidant defense mechanisms and is thus hypothesized to counteract oxidative stress when initiated prior to DOX administration. Adult 8-week old, ovariectomized female Sprague-Dawley rats were divided into 4 groups: sedentary + vehicle (Sed+Veh); Sed+DOX; exercise + veh (Ex+Veh); and Ex+DOX. Rats in the exercise groups were preconditioned with high intensity interval training consisting of 4x4 minute bouts of exercise at 85-95% of VO2peak separated by 2 minutes of active recovery performed 5 days per week. Exercise was implemented one week prior to the first injection and continued throughout the study. Animals received either DOX (4mg/kg) or veh (saline) intraperitoneal injections bi-weekly for a cumulative dose of 12 mg/kg per animal. Five days following the final injection, animals were anesthetized with isoflurane, decapitated and aortas and perivascular adipose tissue (PVAT) were removed for western blot analyses. No significant differences in aortic protein expression were detected for inducible nitric oxide synthase (iNOS) or the upstream activator of endothelial nitric oxide synthase (eNOS), Akt, across groups (p>0.05), whereas eNOS protein expression was significantly downregulated in Sed+DOX (p=0.003). In contrast, eNOS expression was not altered in Ex+DOX treated animals. Protein expression of iNOS in PVAT was upregulated with exercise in the DOX-treated groups (p=0.039). These findings suggest that exercise preconditioning may help mitigate vascular effects of DOX by preventing downregulation of eNOS in the aorta.

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2016-12