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DIRECTED ENZYME PRODRUG THERAPY: THE SYNTHESIS OF A Β-GLUCURONIDE LINKER AND ITS COUPLING WITH Z-IODOCOMBSTATIN

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…

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

Providing Evidence-Based Resources Regarding Complementary and Alternative Medicine Options for the Management of Chemotherapy Side Effects: Creation of a Third-Party Website for NCI-Designated Cancer Centers

Description

Chemotherapy refers to the use of chemical agents to inhibit or stop the growth of rapidly dividing cancer cells. There are many side effects of systemic chemotherapy, which are caused because the drug not only kills cancer cells but healthy cells as well (American Cancer Society, 2017). Common side effects…

Chemotherapy refers to the use of chemical agents to inhibit or stop the growth of rapidly dividing cancer cells. There are many side effects of systemic chemotherapy, which are caused because the drug not only kills cancer cells but healthy cells as well (American Cancer Society, 2017). Common side effects include fatigue, hair loss, bruising/ bleeding, infection, anemia, nausea and vomiting, appetite changes, constipation, diarrhea, oral sores, nerve and muscle pain, dry skin and color change, kidney dysfunction, weight loss, cognitive difficulties, mood changes, sexual dysfunction, and fertility problems (American Cancer Society, 2017). Research shows that complementary and alternative medicine (CAM) may help relieve some of the side effects of chemotherapy. Examples of CAM include herbal medicine, dietary supplements, acupuncture, yoga, Tai Chi, massage, electromagnetic therapy, meditation, biofeedback, music, dance, and guided imagery (Johns Hopkins Medicine, 2017). The aim of this creative project was to design a third-party website to provide information to patients undergoing chemotherapy and their family members regarding the use of CAM for the treatment of chemotherapy-induced side effects. Rationale for this project stemmed from a preliminary research step. We analyzed and coded for presence or absence of CAM-specific information on the websites of 20 National Cancer Institute-designated comprehensive cancer centers across the United States. Fifty percent of websites were double-coded. Inter-rater reliabilities (kappa values) for coding of the presence or absence of specific CAM therapies ranged from 0.38 for acupuncture to 1.00 for exercise and yoga, expressive arts, and herbs (mean kappa = 0.75). Fourteen of the 20 websites mentioned meditation or mindfulness; 13 mentioned nutrition; 12 mentioned acupuncture; 11 mentioned exercise or yoga; 11 mentioned massage; 8 mentioned expressive arts; and 3 mentioned herbs. Frequencies for presence of either a description of the specific CAM therapy or an explanation of how the therapy works were lower. We then conducted a literature review using PUBMED to find peer-reviewed research on the efficacy of the previously described seven CAM therapies. The literature search focused on systematic reviews and meta-analyses published within the past 10 years. Based on the literature obtained, we created summaries of the scientific evidence for each CAM therapy. This information is now provided on our third-party website in tabular form with summative statements. The website describes in lay language: chemotherapy, chemotherapy side effects, CAM, seven specific CAM therapies, and evidence for the efficacy or lack thereof of each. Per the American Nurses Association (2015), it is our responsibility to advocate for our patients through education and holistic treatment. The role of the nurse is to educate the patient about treatment options; however, it is not within the nurse's scope of practice to prescribe a treatment. As such, this website should not be viewed as a prescription for CAM therapies, but instead as a user-friendly and easily accessible resource for informed decision-making regarding the adjunctive use of CAM therapies.

ContributorsNichols, Abrianna (Co-author) / Varosky, Maxwell (Co-author) / Langer, Shelby (Thesis director) / Morris, Brenda (Committee member) / Arizona State University. College of Nursing & Healthcare Innovation (Contributor) / Sanford School of Social and Family Dynamics (Contributor) / Barrett, The Honors College (Contributor)

Created2017-12

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

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…

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

Use of the Multiple Myeloma Immunosignature for the Synthesis of Synbody Therapeutic Treatment

Description

Currently, treatment for multiple myeloma (MM), a hematological cancer, is limited to post-symptomatic chemotherapy combined with other pharmaceuticals and steroids. Even so, the immuno-depressing cancer can continue to proliferate, leading to a median survival period of two to five years. B cells in the bone marrow are responsible for generating…

Currently, treatment for multiple myeloma (MM), a hematological cancer, is limited to post-symptomatic chemotherapy combined with other pharmaceuticals and steroids. Even so, the immuno-depressing cancer can continue to proliferate, leading to a median survival period of two to five years. B cells in the bone marrow are responsible for generating antigen-specific antibodies, but in MM the B cells express mutated, non-specific monoclonal antibodies. Therefore, it is hypothesized that antibody-based assay and therapy may be feasible for detecting and treating the disease. In this project, 330k peptide microarrays were used to ascertain the binding affinity of sera antibodies for MM patients with random sequence peptides; these results were then contrasted with normal donor assays to determine the "immunosignatures" for MM. From this data, high-binding peptides with target-specificity (high fluorescent intensity for one patient, low in all other patients and normal donors) were selected for two MM patients. These peptides were narrowed down to two lists of five (10 total peptides) to analyze in a synthetic antibody study. The rationale behind this originates from the idea that antibodies present specific binding sites on either of their branches, thus relating high binding peptides from the arrays to potential binding targets of the monoclonal antibodies. Furthermore, these peptides may be synthesized on a synthetic antibody scaffold with the potential to induce targeted delivery of radioactive or chemotherapeutic molecular tags to only myelomic B cells. If successful, this would provide a novel alternative to current treatments that is less invasive, has fewer side effects, more specifically targets the cause of MM, and reliably diagnoses the cancer in the presymptomatic stage.

ContributorsBerry, Jameson (Co-author) / Buelt, Allison (Co-author) / Johnston, Stephen (Thesis director) / Diehnelt, Chris (Committee member) / School of Molecular Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Division of Teacher Preparation (Contributor) / Barrett, The Honors College (Contributor)

Created2016-05

Preclinical assessment of Wee1 inhibitor AZD1775 and DNA damaging agents in the chemotherapeutic treatment of esophageal adenocarcinoma with mutated TP53

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…

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

Walker Norris

Description

Extreme heat is the deadliest weather and climate-related hazard in the United States, and the threat it poses to urban residents is rising. City planners increasingly recognize these risks and are taking action to mitigate them. However, the COVID-19 pandemic has disrupted many plans. Building on a…

Extreme heat is the deadliest weather and climate-related hazard in the United States, and the threat it poses to urban residents is rising. City planners increasingly recognize these risks and are taking action to mitigate them. However, the COVID-19 pandemic has disrupted many plans. Building on a previous survey which queried city planners from across the United States about how concerned they were about extreme heat, and their heat management efforts. This thesis examines how these perceptions and efforts have changed in the face of the COVID-19 pandemic. In general, it was found that public spaces which would typically have been used to shelter individuals from extreme heat conditions were closed to mitigate close-contact and to encourage social distancing. Furthermore, priorities were changed as the presence of the virus became commonplace, with plans being altered, delayed, or shelved to diverge more time and effort towards the crisis at hand. Working environments and conditions also changed, which in several cases led to technological shortcomings, resulting in further delays. Finally, most planners had attained a surface-level understanding of which socio-economic groups were most impacted by both COVID-19 and extreme heat, in congruence with the current literature written on the topic. Generally, it appears that planners feel that the impact of COVID-19 on heat planning efforts has been limited.

ContributorsNorris, Walker Yale (Author) / Meerow, Sara (Thesis director) / Keith, Ladd (Committee member) / Dean, W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)

Created2021-05

The Making of a COVID-19 Lab: A Business Exploration

Description

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts…

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts and aspects. The business agility of the lab and it’s quickness to innovation has allowed the lab to enjoy great success. Looking into the future, the laboratory has a promising future and will need to answer many questions to remain the premier COVID-19 testing institution in Arizona.

ContributorsQian, Michael (Co-author) / Cosgrove, Samuel (Co-author) / English, Corinne (Co-author) / Agee, Claire (Co-author) / Mattson, Kyle (Co-author) / Compton, Carolyn (Thesis director) / Schneller, Eugene (Committee member) / School of Accountancy (Contributor) / Department of Finance (Contributor) / Department of Information Systems (Contributor) / Barrett, The Honors College (Contributor)

Created2021-05

The Making of a COVID-19 Lab: A Business Exploration

Description

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts…

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts and aspects. The business agility of the lab and it’s quickness to innovation has allowed the lab to enjoy great success. Looking into the future, the laboratory has a promising future and will need to answer many questions to remain the premier COVID-19 testing institution in Arizona.

ContributorsEnglish, Corinne (Co-author) / Cosgrove, Samuel (Co-author) / Mattson, Kyle (Co-author) / Agee, Claire (Co-author) / Qian, Michael (Co-author) / Compton, Carolyn (Thesis director) / Schneller, Eugene (Committee member) / Department of Information Systems (Contributor) / Department of Supply Chain Management (Contributor) / Dean, W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)

Created2021-05

The Making of a COVID-19 Lab: A Business Exploration

Description

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts…

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts and aspects. The business agility of the lab and it’s quickness to innovation has allowed the lab to enjoy great success. Looking into the future, the laboratory has a promising future and will need to answer many questions to remain the premier COVID-19 testing institution in Arizona.

ContributorsAgee, Claire (Co-author) / English, Corinne (Co-author) / Mattson, Kyle (Co-author) / Qian, Michael (Co-author) / Cosgrove, Samuel (Co-author) / Compton, Carolyn (Thesis director) / Schneller, Eugene (Committee member) / Department of Finance (Contributor) / Department of Supply Chain Management (Contributor) / Barrett, The Honors College (Contributor)

Created2021-05

The Making of a COVID-19 Lab: A Business Exploration

Description

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts…

For our project, we explored the growth of the ASU BioDesign Clinical Testing Laboratory (ABCTL) from a standard university research lab to a COVID-19 testing facility through a business lens. The lab has pioneered the saliva-test in the Western United States. This thesis analyzes the laboratory from various business concepts and aspects. The business agility of the lab and it’s quickness to innovation has allowed the lab to enjoy great success. Looking into the future, the laboratory has a promising future and will need to answer many questions to remain the premier COVID-19 testing institution in Arizona.

ContributorsMattson, Kyle (Co-author) / Agee, Claire (Co-author) / English, Corinne (Co-author) / Cosgrove, Samuel (Co-author) / Compton, Carolyn (Thesis director) / Schneller, Eugene (Committee member) / Department of Marketing (Contributor) / Department of Supply Chain Management (Contributor) / Barrett, The Honors College (Contributor)

Created2021-05

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