Matching Items (5)
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- All Subjects: Chemotherapy
- All Subjects: community engagement
- Creators: College of Letters and Sciences
- Creators: Dickinson, Jared
- Member of: Barrett, The Honors College Thesis/Creative Project Collection
Description
The purpose of this project is to explore the benefit of using prodrugs in chemotherapy, as well as to explain the concept of angiogenesis and the importance of this process to tumor development. Angiogenesis is the formation of new blood capillaries that are necessary for the survival of a tumor, as a tumor cannot grow larger than 1-2 mm3 without developing its own blood supply. Vascular disrupting agents, such as iodocombstatin, a derivative of combretastatin, can be used to effectively cut off the blood supply to a growing neoplasm, effectively inhibiting the supply of oxygen and nutrients needed for cell division Thus, VDAs have a very important implication in terms of the future of chemotherapy. A prodrug, defined as an agent that is inactive in the body until metabolized to yield the drug itself, was synthesized by combining iodocombstatin with a β-glucuronide linker. The prodrug is theoretically hydrolyzed in the body to afford the active drug by β-glucuronidase, an enzyme that is produced five times as much by cancer cells as by normal cells. This effectively creates a “magic-bullet” form of chemotherapy, known as Direct Enzyme Prodrug Therapy (DEPT).
ContributorsClark, Caroline Marie (Author) / Pettit, George Robert (Thesis director) / Melody, Noeleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2015-05
Description
Looking into the school community cohesion and how refugee youth integrate into schools is important when addressing refugee resettlement issues at large. It is important that school community identity (SCI) formation for refugee high school youth is understood in order to develop school programs that can better assist integration process of refugee families. Looking at high school refugee youth from Arizona a model was created that better displays the specifics this study found when dealing with this population. Unlike non-refugee high school youth, refugee youth do not develop school community cohesion through voice, resonance, or empowerment like other studies have shown. This study shows that they must first develop a SCI before they can have a strong school community presence. School community identity is an important first step that facilitates sense of school community. Two focus groups were down at the Somali American United Council, and from these two groups four common themes surfaced: faculty support, emotional security, cultural understanding, and partnership/collaboration. Using these themes a refugee school identity model was created to represent the data collected. The participants in the focus group often told stories and used phrases that indicated a lack of identity in their school, and no claims to a need of a voice within their school community was mentioned. This indicates that refugee students need an identity within their school community before they will express a need for voice or influence.
ContributorsReiswig, Clinton Gene (Author) / Klimek, Barbara (Thesis director) / Zayas, Luis (Committee member) / Sambe, Pape (Committee member) / Barrett, The Honors College (Contributor) / College of Letters and Sciences (Contributor) / School of Public Affairs (Contributor) / School of Social Work (Contributor)
Created2015-05
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
Background: Esophageal adenocarcinoma (EAC) is one of the only malignancies whose incidence is rising in the United States. Current multidrug treatment for EAC has considerable toxic side effects that necessitate the development of less toxic, more specific target drugs. Recent large scale genomic analysis reveals that TP53 is the most frequently inactivated gene in EAC. One of the primary functions of TP53 and its gene product, the tumor suppressor p53, is in regulation of DNA repair in response to DNA damage. Inactivation of TP53 results in loss of the G1/S cell cycle checkpoint, and dependence on the G2/M checkpoint for DNA repair. Activity of cyclin-dependent kinase 1 (CDK1) is necessary for cells to exit the G2/M checkpoint and enter mitosis. Phosphorylation of CDK1 by the wee1 kinase inhibits CDK1 in response to DNA damage, allowing cells to maintain G2 arrest and repair the damaged DNA. Active in normal cells, wee1 kinase is critical in cancer cells to promote DNA repair and cell survival in response to DNA damage, particularly from commonly used DNA damaging therapies. AZD1775 is a small molecule inhibitor of wee1 kinase, currently under investigation in clinical trials. AZD1775 differentially targets cancer cells by blocking wee1 mediated inhibition of CDK1 and consequently preventing G2/M arrest in response to DNA damage. Combination of AZD1775 with DNA damaging agents is thought to push cancer cells with damaged DNA through to mitosis and initiate apoptosis instead of G2/M arrest and DNA repair. Based upon the incidence of TP53 mutation in EAC, we hypothesize that treatment with a DNA damaging agent in combination with AZD1775 will be as effective at eliciting DNA damage and cell death as the more toxic current standard of care, which is comprised of treatment with cisplatin, docetaxel, and radiation. Methods: p53 mutant EAC cell lines were dosed with cisplatin, AZD1775, and the combination of cisplatin and AZD1775, and then assayed for viability. Nude mice were implanted with p53 mutant patient derived xenograft esophageal adenocarcinoma tumors and randomized for treatment with AZD1775 alone, cisplatin and AZD1775, radiation and AZD1775, cisplatin, docetaxel, and radiation or vehicle (control). Tumor volume was measured over the five week treatment course. Results: In vitro and in vivo assays reveal a potent synergistic effect between AZD1775 and DNA damaging agents that is as efficacious as the standard of care therapy. The difference in AZD1775 sensitivity among TP53 mutant EAC cell lines indicates that TP53 alone may not be an adequate biomarker to assess for AZD1775- mediated toxicity.
ContributorsBlomquist, Mylan (Author) / Maley, Carlo (Thesis director) / Inge, Landon (Committee member) / Oberle, Eric (Committee member) / College of Letters and Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Estimates indicate that in the United States 1 in 8 women will develop breast cancer in their lifetime. Improved cancer screenings, early detection, and targeted treatments have increased breast cancer survival rates. However, breast cancer patients treated with chemotherapy are at an increased risk for cardiovascular disease, functional impairments, and loss of cardiorespiratory fitness. These negative outcomes have implications for early morbidity and mortality. The purpose of this thesis was to test the hypothesis that high-intensity exercise preconditioning (exercise commenced prior to initiating chemotherapy and continued throughout treatment cycles) preserves health-related outcomes in breast cancer patients treated with anthracycline-containing chemotherapy. Here, we present a subset of preliminary data from an ongoing trial (NCT02842658) that is focused on VO2peak and skeletal muscle outcomes from the first 10 participants that have enrolled in the trial. Breast cancer patients (N=10; 50 ± 11 y; 168 ± 4 cm; 92 ± 37 kg; 32.3 ± 12.3 kg/m2) scheduled to receive anthracycline-containing chemotherapy were randomly assigned to one of two interventions: 1) exercise preconditioning, (3 days per week of supervised exercise throughout treatment) or 2) standard of care (attention-control). Pre-testing occurred 1-2 week prior to chemotherapy. The interventions were initiated 1 week prior to chemotherapy and continued throughout anthracycline treatment. Post-testing occurred 3-7 days following the last anthracycline treatment. VO2peak (L/min) was reduced by 16% in the control group (P < 0.05), whereas VO2peak was preserved in the exercise preconditioning group. Trends for greater preservation and/or improvement in the exercise preconditioning group were also observed for lean body mass and peak heart rate. Hand grip strength was not changed in either group (P > 0.05). Both groups demonstrated an increase in ultrasound-derived echogenicity measures of the vastus lateralis (P < 0.05), indicating changes in the composition of the skeletal muscle during treatment. These preliminary data highlight that exercise preconditioning may serve as a strategy to preserve cardiorespiratory fitness and perhaps lean mass during anthracycline treatment of breast cancer. There remains a need for larger, definitive clinical trials to identify strategies to prevent the array of chemotherapy-induced toxicities that are observed in breast cancer patients treated with anthracyclines.
ContributorsCasey, Kathleen (Author) / Angadi, Siddhartha (Thesis director) / Gaesser, Glenn (Committee member) / Dickinson, Jared (Committee member) / College of Health Solutions (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05