Medicine and Health Sciences Commons^™

Stimuli Responsive Nanoparticle For Cancer Targeted Therapy, Huacheng He

Theses and Dissertations

Nanoparticle is the particle with a size in the range from several nanometers to hundreds of nanometers. It has been extensively used for cancer diagnosis and therapy. However, it is still a great challenge to fabricate nanoparticles with spatiotemporally controllable delivery of anticancer drugs to tumors and with high therapeutic efficacy. This thesis mainly focuses on the development of stimuli responsive nanoparticles for cancer targeted therapy. These nanoparticles either response to internal stimuli such as pH and redox potential or external stimuli like temperature and light could effectively target tumors and control the release of anticancer drugs there to improve …

Evaluation Of Vaccination Policies Among Outpatient Oncology Clinics In Utah: A Pilot Study, Sarah Louise Stocksdale

Theses and Dissertations

Background: In Utah, all major hospital facilities have employee vaccination policies. However, the presence of health care worker vaccination policies in the Utah outpatient oncology setting was unknown. Objectives: The objectives were to identify Utah oncology outpatient employee vaccination policies and to identify what consequences, if any, were present for unvaccinated employees. Methods: This was a cross-sectional, descriptive study design in which clinic managers from outpatient oncology clinics in Utah were asked, via questionnaire, to describe the clinic's employee vaccination policy and the consequences for refusing the policy. Findings: Most vaccination policies applied to employees primarily assigned to work in …

Dual Pi3k/Mtor Inhibition With Bez235 Augments The Therapeutic Efficacy Of Doxorubicin In Cancer Without Influencing Cardiac Function, David E. Durrant

Theses and Dissertations

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. …

Synthesis, Surface Functionalization, And Biological Testing Of Iron Oxide Nanoparticles For Development As A Cancer Therapeutic, Stanley E. Gilliland Iii

Theses and Dissertations

Iron oxide nanoparticles are highly researched for their use in biomedical applications such as drug delivery, diagnosis, and therapy. The inherent biodegradable and biocompatible nanoparticle properties make them highly advantageous in nanomedicine. The magnetic properties of iron oxide nanoparticles make them promising candidates for magnetic fluid hyperthermia applications. Designing an efficient iron oxide nanoparticle for hyperthermia requires synthetic, surface functionalization, stability, and biological investigations. This research focused on the following three areas: optimizing synthesis conditions for maximum radiofrequency induced magnetic hyperthermia, designing a simple and modifiable surface functionalization method for specific or broad biological stability, and in vitro and in …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Design And Development Of A Novel Class Of Cell Cycle Cdk Inhibitors Targeting The Cyclin Binding Groove Utilizing The Replace Strategy, Padmavathy Nandha Premnath

Theses and Dissertations

Inhibition of CDK2 activity in G1 and S phases of the cell cycle can promote selective apoptosis of cancer cells through the E2F1 pathway. Currently available CDK inhibitors target the ATP binding pocket and result in lack of specificity for the cell cycle vs. the transcriptional CDKs. It has been shown that a peptide HAKRRLIF derived from the tumor suppressor p21 binds to the cyclin binding groove (CBG) and selectively inhibits cell cycle CDKs (CDK2/Cyclin A, CDK2/Cyclin E and CDK4/Cyclin D). The CBG is unique to cell cycle CDKs hence targeting this site avoids the inhibition of transcriptional CDKs can …

Role Of Chronic Inflammation On Liver Function During Cachexia Progression In The ApcMin/+ Mouse Model, Aditi Narsale

Theses and Dissertations

Cachexia is a multifactorial syndrome that manifests during the advanced stage of chronic diseases and is characterized by a progressive loss of body mass sustained by underlying inflammation. The ApcMin/+ mouse is an established model of cachexia that exhibits a gradual loss of body mass correlating with increasing tumor burden and plasma IL – 6 levels. Moreover it also mimics other secondary characteristics observed in cachectic patients like splenomegaly, elevated plasma endotoxin levels, gut barrier dysfunction, hypogonadism and an overall hypermetabolic state. Liver controls the energy metabolism in the body by regulating glucose and lipid metabolism, glycogen storage, filtration of …

Role Of Micro Rna 148/152 Family In Cancer Progression, Anusha Chaparala

Theses and Dissertations

Micro RNA are small single stranded RNA that regulate the expression of various genes. MiRNA guide the mRNA disintegrating RISC complex to the complimentary sequence in the target mRNA. Each micro RNA has multiple targets and can play a different biological role depending on the population of targets at the particular stage of the cell or a physiological state. Several miRNA show elevated or decreased levels of expression in various cancers because of their role in tumor initiation and progression. MiRNA belonging to mir148/152 family are examples of such MicroRNA. This family includes miR148a, miR148b and miR152. MiR148a and miR152 …

Stress Management For Cancer Survivors Using A Technologically Adapted Psychosocial Intervention: A Randomized Trial Determining The Effect Of Expressive Writing On Psychoneuroimmunology Based Outcomes, Utkarsh B. Subnis

Theses and Dissertations

Patients with cancer transitioning from completing their final cancer treatments to survivorship are particularly at risk for experiencing psychosocial stress, and the Institute of Medicine (IOM) has referred to these cancer patients as “lost in transition.” In this study, patients with cancer in their transition phase after completing their final radiation treatment were defined as cancer survivors (CS). CS must deal with chronic stressors such as the fear of cancer recurrence as well as the resumption of their roles in their family and work lives. Chronic stress impacts the nervous system and increases secretion of stress hormones (e.g. cortisol) from …

The Role Of Nitric Oxide Dysregulation In Tumor Maintenance, Christopher Rabender

Theses and Dissertations

The inflammatory nature of the tumor microenvironment provides a cytokine and chemokine rich proliferative environment. Much of the responsibility of this environment is due to the production of Reactive Oxygen Species (ROS). These studies examined the proliferative rich tumor environment from a new perspective of Nitric Oxide Synthase (NOS) dysregulation. NOS’s have the ability to become uncoupled and generate superoxide in lieu of nitric oxide (NO). A requirement of NOS for the production of NO is the cofactor tetrahydrobiopterin (BH4) and when it is missing NOS becomes uncoupled and turns into a peroxynitrite synthase. Here I demonstrate that NOS is …

Role Of Nucleosome Remodeling Factor (Nurf) In Tumorigenesis Using A Breast Cancer Mouse Model, Aiman Alhazmi

Theses and Dissertations

Understanding the impact of epigenetic mechanisms on tumorigenesis is essential, as epigenetic alterations are associated with tumor initiation and progression. Because epigenetic changes are reversible, they are potential targets for cancer therapy. Nucleosome Remodeling Factor (NURF) is a chromatin-remodeling complex that regulates gene expression by changing nucleosome positioning along the DNA sequence. Previous studies have shown a role for NURF in embryonic development as well as regulating genes involved in tumor progression. In this work we investigated the impact of eliminating NURF function in tumorigenesis in vivo. BALB/c mice challenged with syngeneic 67NR breast cancer cell lines, injected into the …

The Use Of Targeted Charge-Reversal Nanoparticles (Tcrns) To Investigate Nuclear Delivery Of Fluorescent Agents To Cancer Cells: Implications For Novel Prostate And Breast Cancer Therapy, Mario Dance

Theses and Dissertations

Nanotechnology has recently emerged as a strong contributor toward research efforts to develop targeted systems of drug delivery in cancer therapy. Our work investigates the therapeutic potential of Targeted Charge-Reversal Nanoparticles (TCRNs), a novel nanoparticle with in vitro evidence of nuclear drug delivery. Using M12 prostate cancer cells, MDA-MB-231 breast cancer cells, and modified derivatives of these cell lines, we investigated the ability of Folic Acid-tagged TCRNs to deliver Nile Red and Dimethyl Indole Redfluorescent (DiR) fluorescent dyes to the nucleus of cells using confocal microscopy and in vivo biphontonic imaging using Xenogen® Technology. Confocal imaging with the SCP28 derivative …

Oncology Nurses' Impact Scores For Obstacles And Supportive Behaviors At The End Of Life, Joan M. Collett

Theses and Dissertations

Introduction: Oncology nurses provide end-of-life (EOL) care to their patients daily. Oncology nurses' perceptions regarding how to provide quality care to dying patients could be an important addition to the ongoing research on quality EOL care. The purpose of this study was to determine the impact of specific obstacle and supportive behaviors in EOL care as perceived by hospital-based oncology nurses. This study extended the work of Beckstrand, Moore, Callister, and Bond (2009).

Methods: A 69-item questionnaire adapted from previous studies (Beckstrand & Kirchhoff, 2005; Beckstrand, Smith, Heaston, & Bond, 2008) was sent to 1,000 nurses who were members of …

Heat Shock Proteins As Novel Cancer Therapeutics: Targeting The Hallmarks Of Cancer, Chao Li

Theses and Dissertations

Molecular chaperones, commonly known as heat shock proteins (HSPs), are essential for mammalian cells to maintain homeostasis, and HSPs function by inducing an ATPase-coupled structural change, followed by interactions with diverse co-chaperones and over 200 client proteins implicated in many critical signaling networks. These highly expressed HSPs participate in the onset and progression of several human diseases including cancer, and their connection with tumorigenesis has facilitated research and clinical trials related to targeting HSPs as a novel anti-tumor therapy. The predominant mechanism of chaperone inhibition is through either disruption of the HSP association with client protein or an altered binding …

Antifolate Modulators Of Amp-Activated Protein Kinase Signaling As Cancer Therapeutics, Scott Rothbart

Theses and Dissertations

Since its discovery, it was appreciated that the antifolate pemetrexed had multiple targets within folate metabolism. This laboratory was instrumental in showing that pemetrexed elicited its primary action as a thymidylate synthase inhibitor. Unusual for an antifolate, pemetrexed showed significant clinical activity against malignant pleural mesothelioma and non-small cell lung cancer. Accordingly, the FDA recently issued first-line approvals for pemetrexed in these diseases, leading us to question whether the effects of pemetrexed on other folate-dependent targets could explain this atypical clinical activity of the drug. Studies in this dissertation showed that in addition to thymidylate synthase inhibition, pemetrexed was also …

Cell Death And Sustained Senescence Arrest In Colon Carcinoma And Melanoma Tumor Cells In Response To The Novel Microtubule Poison, Jg-03-14, Jonathan Biggers

Theses and Dissertations

Previous studies from this and other laboratories have shown that the novel microtubule poison, JG-03-14, which binds to the colchicine binding site of tubulin, has the capacity to promote both autophagy and apoptosis in breast tumor cells, as well as interfering with endothelial cell function and potentially disrupting tumor vasculature. The current work was designed to investigate the interaction between JG-03-14 and cell culture models of colon carcinoma and melanoma, specifically HCT116 human colon carcinoma cells and B16F10 murine melanoma cells. In both cases, JG-03-14 promoted death in the bulk of the treated population. FACS analysis, DAPI and TUNEL staining …

Nursing Home Organizational Characteristics And Utilization Of Cancer-Related Medical Services, Chun-Chieh Lin

Theses and Dissertations

Cancer is the second leading cause of death in the U.S and is more common among the elderly. Since frailty and other age related conditions put the elderly at risk for nursing home care, nursing homes may be the site of care and death for many elderly cancer patients. However, there is a large gap in knowledge concerning cancer treatment of elderly nursing home residents. Since residents rely heavily on their nursing facilities, nursing homes might influence them in their treatment decisions. After controlling for resident and nursing home market characteristics, this study applies Andersen’s Behavioral Model to examine whether …

Use Of Oral Chemotherapeutic Medications In Non-Traditional Ambulatory Settings, Sameer Arora

Theses and Dissertations

Background: Cancer is the second leading cause of death in economically developed countries. The use and availability of oral treatment for cancer has increased dramatically in the past 10 years. Few studies have described the use of oral chemotherapy in non-traditional ambulatory settings by health care professionals across different specialties. Objective: The purpose of this study is to describe the usage of oral chemotherapeutic medications in ambulatory settings. Methods: Cross sectional study of 2007 NAMCS Survey analysis involving 21,761 subjects aged 18 years and above with cancer who participated in the 2007 National Ambulatory Medical Survey (NAMCS). Main Outcome Measure: …

Transcriptional, Epigenetic, And Signal Events In Antifolate Therapeutics, Alexandra Racanelli

Theses and Dissertations

A targeted approach to the development of antifolate therapies has been sought for many years. Central to the success of such development is an understanding of the molecular mechanisms dictating the sensitivity of cells to antifolates and the fundamental differences of these processes between normal and neoplastic phenotypes. This dissertation addressed transcriptional mechanisms and cell-signaling events responsible for the efficacy of antifolate therapies. Transcriptional processes and cell signaling pathways are often aberrant in neoplastic tissues, providing a potential point of distinction between a normal and neoplastic cellular state. Folylpolyglutamate synthetase (FPGS) catalyzes the formation of poly-γ-glutamate derivatives of folates and …

Therapeutic Drugs In Cancer And Resistance., Aditi Pandya Martin

Theses and Dissertations

We investigated the mechanism of toxicity and resistance development of small molecule tyrosine kinase inhibitor lapatinib in HCT 116 colon cancer cells. Lapatinib mediated cell death in HCT 116 cells was caspase independent and involved cytosolic release of apoptosis inducing factor. Treatment of HCT 116 cells with 10µM Lapatinib lead to the outgrowth of lapatinib resistant HCT 116 cells. Our studies show that alterations in the expression and activation of Bcl-2 family proteins allow lapatinib resistant HCT 116 cells to resist cytotoxic effects of lapatinib as well as of other commonly used chemotherapeutic agents. In hepatoma and pancreatic cancer cells, …

The Relationship Between Perceived Personal Risk Of Getting Prostate Cancer And Prostate-Specific Antigen (Psa) Screening, Yeatoe G. Mcintosh

Theses and Dissertations

Abstract Title: The Relationship between Perceived Personal Risk of getting Prostate cancer and Prostate-Specific Antigen (PSA) Screening Yeatoe G. McIntosh, MPH Candidate Advisor: Emmanuel Anum, MBChB, MPH, PHD Preceptor: Emmanuel Anum, MBChB, MPH, PHD Background: Prostate cancer is one of the most common cancer diagnoses in the United States. The American Cancer Society estimates that in 2008 28,660 deaths would be attributed to prostate cancer, projecting it to be the leading cause of cancer deaths in U.S. men. Despite the potential threat this cancer presents to men and the potential for improved disease outcomes from early detection, guidelines for screening …

Nucleoplasmic And Cytoplasmic Degradation Of Telomerase: Implications Toward Telomerase-Based Cancer Therapy, Binh Nguyen

Theses and Dissertations

Telomerase is a ribonucleoprotein that is reactivated in cancer cells to allow for continuous cellular division and indefinite growth. With telomerase being expressed in more than 85% of all cancer, it is imperative that we understand how to selectively inactivate and degrade this unique DNA polymerase. In doing so, we can specifically target tumor cells to erode their telomeres so that they will undergo apoptosis or senescence. Through this research, we have learned that telomerase can be degraded in the nucleoplasm by Hsp90 chaperone inhibition and in the cytoplasm by the dominant negative mutant, D712A V713I. These findings should guide …

A Critical Review Of Telomerase Biology And Model Systems For The Study Of Telomerase, Jeremy Charles Aisenberg

Theses and Dissertations

The study of telomere and telomerase biology holds substantial promise in uncovering the molecular process of aging and the treatment of cancers. Studies have shown that telomere shortening is directly linked to cellular aging and that telomerase expression is found in over 85% of human cancers, including 95% of all advanced malignancies. Development of effective model systems to elucidate the molecular mechanisms underlying the role of telomeres and telomerase in the processes aging and cancer is of particular importance. While inbred strains of mice have provided a wealth of information for a variety of pathways and diseases, the mouse model …

Dual Regulation Of Telomerase Activity By Hsf1 And Its Role In Prostate Cancer Progression, Keith Douglas Ostergaard Jensen

Theses and Dissertations

It has been shown that the key components of the hsp90 chaperone complex, including hsp90, p23, hsp70, hsp40, and HOP (p60), associate with telomerase; however, their specific roles in telomerase function and tumor progression have not yet been defined. HSF1, the primary mammalian heat shock protein transcription factor, may affect telomerase activity and transformation by regulating the expression of several hsp90 chaperone complex proteins in response to stress as well as regulating the transcription of hTERT, the protein subunit of telomerase.In our in vitro model of prostate cancer progression, as cells progress from immortal but non-tumorigenic (P69) to tumorigenic (M2182) …

The Effect Of Silencing The Wilms' Tumor 1 Gene On The Radiation Sensitivity Of Glioblastoma Cells, Dana C. Chan

Theses and Dissertations

Glioblastomas are among the most devastating of human cancers with a median survival of only 9-12 months. This type of brain tumor is incurable, largely due its remarkable proliferative capacity and resistance to current treatments. High levels of the Wilms' Tumor 1 (WTI) gene have been identified in glioblastomas, suggesting an oncogenic function. Moreover, known WT1 target genes have been implicated in resistance to radiation. To determine the role of WT1 in radiation resistance, two glioblastoma cell lines expressing WT1 were treated with siRNAs to silence this gene. Confirmation of WT1 knockdown was achieved through real-time PCR and Western blot. …