Matching Items (10)
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- All Subjects: Cancer
- Creators: Blattman, Joseph
- Member of: Barrett, The Honors College Thesis/Creative Project Collection
- Resource Type: Text
Description
Adaptive therapy utilizes competitive interactions between resistant and sensitive cells by keeping some sensitive cells to control tumor burden with the aim of increasing overall survival and time to progression. The use of adaptive therapy to treat breast cancer, ovarian cancer, and pancreatic cancer in preclinical models has shown significant results in controlling tumor growth. The purpose of this thesis is to draft a protocol to study adaptive therapy in a preclinical model of breast cancer on MCF7, estrogen receptor-positive, cells that have evolved resistance to fulvestrant and palbociclib (MCF7 R). In this study, we used two protocols: drug dose adjustment and intermittent therapy. The MCF7 R cell lines were injected into the mammary fat pads of 11-month-old NOD/SCID gamma (NSG) mice (18 mice) which were then treated with gemcitabine.<br/>The results of this experiment did not provide complete information because of the short-term treatments. In addition, we saw an increase in the tumor size of a few of the treated mice, which could be due to the metabolism of the drug at that age, or because of the difference in injection times. Therefore, these adaptive therapy protocols on hormone-refractory breast cancer cell lines will be repeated on young, 6-week old mice by injecting the cell lines at the same time for all mice, which helps the results to be more consistent and accurate.
ContributorsConti, Aviona (Author) / Maley, Carlo (Thesis director) / Blattman, Joseph (Committee member) / Seyedi, Sareh (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Glioblastoma multiforme (GBM) is an aggressive malignant brain tumor with a median prognosis of 14 months. Human hairless protein (HR) is a 130 kDa nuclear transcription factor that plays a critical role in skin and hair function but was found to be highly expressed in neural tissue as well. The expression of HR in GBM tumor cells is significantly decreased compared to the normal brain tissue and low levels of HR expression is associated with shortened patient survival. We have recently reported that HR is a DNA binding phosphoprotein, which binds to p53 protein and p53 responsive element (p53RE) in vitro and in intact cells. We hypothesized that HR can regulate p53 downstream target genes, and consequently affects cellular function and activity. To test the hypothesis, we overexpressed HR in normal human embryonic kidney HEK293 and GBM U87MG cell lines and characterized these cells by analyzing p53 target gene expression, viability, cell-cycle arrest, and apoptosis. The results revealed that the overexpressed HR not only regulates p53-mediated target gene expression, but also significantly inhibit cell viability, induced early apoptosis, and G2/M cell cycle arrest in U87MG cells, compared to mock groups. Translating the knowledge gained from this research on the connections between HR and GBM could aid in identifying novel therapies to circumvent GBM progression or improve clinical outcome.
ContributorsBrook, Lemlem Addis (Author) / Blattman, Joseph (Thesis director) / Hsieh, Jui-Cheng (Committee member) / Goldstein, Elliott (Committee member) / Harrington Bioengineering Program (Contributor) / School of Social Transformation (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Since Metastatic Osteosarcoma is unresponsive to most of the current standards of care currently available, and yields a survival rate of 20%, it is pertinent that novel approaches to treating it be undertaken in scientific research. Past studies in our lab have used a The Immune Blockade Therapy, utilizing α-CTLA-4 and α-PD-L1 to treat mice with metastatic osteosarcoma; this resulted in 60% of mice achieving disease-free survival and protective immunity against metastatic osteosarcoma. 12 We originally wanted to see if the survival rate could be boosted by pairing the immune blockade therapy with another current, standard of care, radiation. We had found that there were certain, key features to experimental design that had to be maintained and explored further in order to raise survival rates, ultimately with the goal of reestablishing the 60% survival rate seen in mice treated with the immune blockade therapy. Our results show that mice with mature immune systems, which develop by 6-8 weeks, should be used in experiments testing an immune blockade, or other forms of immunotherapy, as they are capable of properly responding to treatment. Treatment as early as one day after should be maintained in future experiments looking at the immune blockade therapy for the treatment of metastatic osteosarcoma in mice. The immune blockade therapy, using α-PD-L1 and α-CTLA-4, seems to work synergistically with radiation, a current standard of care. The combination of these therapies could potentially boost the 60% survival rate, as previously seen in mice treated with α-PD-L1 and α-CTLA-4, to a higher percent by means of reducing tumor burden and prolonging length of life in metastatic osteosarcoma.
ContributorsLabban, Nicole (Author) / Blattman, Joseph (Thesis director) / Appel, Nicole (Committee member) / Barrett, The Honors College (Contributor)
Created2017-05
Description
PD-L1 blockade has shown recent success in cancer therapy and cancer vaccine regimens. One approach for anti-PD-L1 antibodies has been their application as adjuvants for cancer vaccines. Given the disadvantages of such antibodies, including long half-life and adverse events related to their use, a novel strategy using synbodies in place of antibodies can be tested. Synbodies offer a variety of advantages, including shorter half-life, smaller size, and cheaper cost. Peptides that could bind PD-L1 were identified via peptide arrays and used to construct synbodies. These synbodies were tested with inhibition ELISA assays, SPR, and pull down assays. Additional flow cytometry analysis was done to determine the binding specificity of the synbodies to PD-L1 and the ability of those synbodies to inhibit the PD-L1/PD-1 interaction. Although analysis of permeabilized cells expressing PD-L1 indicated that the synbodies could successfully bind PD-L1, those results were not replicated in non-permeabilized cells. Further assays suggested that the binding of the synbodies was non-specific. Other tests were done to see if the synbodies could inhibit the PD-1/PD-L1 interaction. This assay did not yield any conclusive results and further experimentation is needed to determine the efficacy of the synbodies in inhibiting this interaction.
ContributorsMujahed, Tala (Author) / Johnston, Stephen (Thesis director) / Blattman, Joseph (Committee member) / Diehnelt, Chris (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The p53 gene functions as a tumor suppressor that inhibits proliferation, regulates apoptosis, DNA repair, and normal cell cycle arrest. Mutation of the p53 gene is linked to be prevalent in 50% of all human cancers. In this paper, we are exploring triple negative breast cancer and the effects of simvastatin on tumor growth and survival. Simvastatin is a drug that is primarily used to treat high cholesterol and heart disease. Simvastatin is unique because it is able to inhibit protein prenylation through regulation of the mevalonate pathway. This makes it a potential targeted drug for therapy against p53 mutant cancer. The mechanism behind this is hypothesized to be correlated to aberrant activation of the Ras pathway. The Ras subfamily functions to transcriptionally regulate cell growth and survival, and will therefore allow for a tumor to thrive if the pathway is continually and abnormally activated. The Ras protein has to be prenylated in order for activation of this pathway to occur, making statin drug treatment a viable option as a cancer treatment. This is because it acts as a regulator of the mevalonate pathway which is upstream of protein prenylation. It is thus vital to understand these pathways at both the gene and protein level in different p53 mutants to further understand if simvastatin is indeed a drug with anti-cancer properties and can be used to target cancers with p53 mutation. The goal of this project is to study the biochemistry behind the mutation of p53's sensitivity to statin. With this information we can create a possible signature for those who could benefit from Simvastatin drug treatment as a possible targeted treatment for p53 mutant cancers.
ContributorsGrewal, Harneet (Co-author) / Loo, Yi Jia Valerie (Co-author) / Anderson, Karen (Thesis director) / Blattman, Joseph (Committee member) / Ferdosi, Shayesteh (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
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.
ContributorsBalsley, Cassandra Sierra (Author) / Maley, Carlo (Thesis director) / Wynne, Clive (Committee member) / Tollis, Marc (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
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.
ContributorsKnowles, Madelyn Ann (Author) / Kwan, Virginia S. Y. (Thesis director) / Presson, Clark (Committee member) / Salamone, Damien (Committee member) / Department of Psychology (Contributor) / School of Human Evolution and Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
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.
ContributorsO'Neill, Liam Martin (Author) / Sweazea, Karen (Thesis director) / Angadi, Siddhartha (Committee member) / Dickinson, Jared (Committee member) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
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
ContributorsEsposito, Sydney Maria (Author) / Martinez, AirÃÂn (Thesis director) / Hruschka, Daniel (Committee member) / School of Human Evolution and Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
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.
ContributorsBergamaschi, Julia (Author) / Kibler, Karen (Thesis director) / Jacobs, Bertram (Committee member) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05