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- All Subjects: Bexarotene
- Status: Published
Description
Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.
ContributorsYang, Joanna (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Hibler, Elizabeth (Committee member) / Barrett, The Honors College (Contributor)
Created2012-05
Description
Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.
ContributorsSeto, David Hua (Author) / Marshall, Pamela (Thesis director) / Wagner, Carl (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor) / School of Social and Behavioral Sciences (Contributor)
Created2015-05
Description
Women and people of color are some of the most underrepresented groups in the STEM field (science, technology, engineering, and mathematics). The purpose of this study was to uncover the barriers that undergraduate Hispanic women, as well as other women of color, face while pursuing an education in a STEM-related major at Arizona State University (ASU). In-depth interviews were conducted with 13 adult participants to dig deeper into the experiences of each woman and analyze how race and class overlap in each of the women's experiences. The concept of intersectionality was used to highlight various barriers such as perceptions of working versus middle-class students, the experience of being a first-generation college student, diversity campus-wide and in the classroom, effects of stereotyping, and impacts of mentorships. All women, no matter their gender, race, or socioeconomic status, faced struggles with stereotyping, marginalization, and isolation. Women in STEM majors at ASU performed better when provided with positive mentorships and grew aspirations to become a professional in the STEM field when encouraged and guided by someone who helped them build their scientific identities. Working-class women suffered from severe stress related to finances, family support, employment, and stereotyping. Reforming the culture of STEM fields in higher education will allow women to achieve success, further build their scientific identities, and increase the rate of women graduating with STEM degrees.
ContributorsValdivia, Lilianna Alina (Author) / Kim, Linda (Thesis director) / Camacho, Erika (Committee member) / School of Mathematical and Natural Sciences (Contributor) / School of Social and Behavioral Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Child abuse is a hard topic to talk about, and even harder to diagnose without proper training. Though there is a list of general characteristics that child abuse victim's exhibit, it could be difficult to diagnose because everyone reacts to maltreatment differently. Teachers are required by law to report any case where they believe a child is in an abusive environment. Unfortunately, teachers are given the tools to report the abuse, but they lack the knowledge of what to look for. The results are two fold; one is there is an overflow of false reporting, and two, the children who do not having obvious symptoms go unnoticed. This project aims to bridge the gap between these two extremes. It will lower the frequency of false reporting while increasing the chance that a child in need will be helped. The best way to achieve this is through education. The purpose of the study is to create an informational manual for teachers at the kindergarten and elementary level on how to identify child abuse and neglect victims. It will outline the behavioral and physical symptoms of physical abuse, sexual abuse, emotional abuse, and neglect. It will also highlight the importance of realizing that not all maltreatment victims react the same to abuse. It will then follow into advice on how to approach the situation and what questions to ask. The primary form of research was primary observation by volunteering at the Mesa Child Crisis Center (with IRB approval). Interviews were conducted with Child Crisis Center workers, child behavioral psychologists, and Special Victims Unit detectives. The goal of this research is to help teachers better identify children that are at risk of abuse
eglect, and to understand the theory behind their behavior. In the end, teachers will be more informed on the topic so they can better help their students and create a safe environment for them, and be more confident in reporting.
eglect, and to understand the theory behind their behavior. In the end, teachers will be more informed on the topic so they can better help their students and create a safe environment for them, and be more confident in reporting.
ContributorsBaker, Karen Colette (Author) / Kobojek, Kimberly (Thesis director) / Broberg, Gregory (Committee member) / Kelley, Michael (Committee member) / School of Criminology and Criminal Justice (Contributor) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2015-12
Description
Scientific literacy is a critical part of the education of high school students. Students can demonstrate literacy in science by being able to read and write scientific reports as well as recognize and discuss how science affects daily lives. However, many teachers are not familiar with the topic and do not have the resources necessary to implement it into their classrooms. This project attempts to create a website that compiles information from many sources to one concise location that is simple for teachers to use. The goal of the website is to provide teachers with a resource that they can access and use quickly despite their busy schedules. The information provided is easily translatable into a classroom, and examples of lessons as well as links to resources are provided. Considerations of difficulties such as the need to prepare students for standardized tests as well as limited budgets were brought into consideration when choosing the concepts suggested for teachers. Aspects of scientific literacy addressed are: project based learning, virtual labs, apprenticeship programs, and peer mediated learning strategies. The project also addresses how demographics that are represented at lower levels in science can be aided. These groups include female students, minorities, and students with High Functioning Autism (HFA). The website portion of the project is accompanied by a paper that summarizes the research findings as well as the personal reaction of the author and how her teaching has been affected by the study. Upon completion of the project the website will be shared with school districts across Phoenix to provide teachers with access to the resources compiled in it.
ContributorsBlome, Rebecca Ellen (Author) / Marshall, Pamela (Thesis director) / Hart, Juliet (Committee member) / Division of Teacher Preparation (Contributor) / Barrett, The Honors College (Contributor)
Created2015-12
Description
The ever-increasing importance of cancer and neurodegenerative diseases continues to grow as populations across the world are affected by death and aging. The vitamin A (RXR) and vitamin D (VDR) receptor pathways offer promising potential to aid in treatment of cancer and Alzheimer’s disease. This thesis discusses the potential application of novel analogs of Bexarotene (RXR agonist), MeTC7 (a new potent VDR antagonist), and vitamin D as possible therapeutics for cancer and Alzheimer’s disease.
ContributorsHong, Jennifer (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2023-05
Description
Bexarotene is a Food and Drug administration (FDA)-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL). However, bexarotene therapy causes significant side effects like hyperlipidemia and hypothyroidism due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. More recently bexarotene has shown promise to reverse neurodegeneration, improve cognition and decrease levels of amyloid- β in transgenic mice expressing familial Alzheimer’s disease (AD) mutations. Bexarotene is a high affinity ligand for the retinoid X receptor (RXR) that heterodimerizes with the liver- X- receptors (LXR) and with peroxisome proliferator-activated receptor-gamma (PPARϒ) to control cholesterol efflux, inflammation, and transcriptionally upregulates the production of apolipoprotein (ApoE) in the brain. Enhanced ApoE expression may promote clearance of soluble Aβ peptides from the brain and reduce Aβ plaques, thus resolving both amyloid pathology and cognitive deficits. The present study assessed the potential of bexarotene and a group of 62 novel rexinoids to bind and activate RXR using a series of biological assays and screening methods, including: 1) a mammalian two-hybrid system (M2H) and an 2) Retinoid X Receptor response element (RXRE)-mediated reporter assays in cultured human cells. Moreover, Liver X Receptor response element (LXRE)-mediated luciferase assays were performed to analyze the ability of the novel analogs to activate LXRE - directed transcription, and to induce ApoE messenger ribonucleic acid (mRNA) in U87 glial cells. Furthermore, the most potent analogs were analyzed via quantitative polymerase chain reaction (qPCR) to determine efficacy in modulating expression of two critical tumor suppressor genes, activating transcription factor 3 (ATF3) and early growth response 3 (EGR3). Results from these multiple assays indicate that the panel of RXR ligands contains compounds with a range of activities, with some analogs capable of binding to RXR with higher affinity than others, and in some cases upregulating ApoE expression to a greater extent than bexarotene. The data suggests that minor modifications to the bexarotene core chemical structure may yield novel analogs possessing an equal or greater capacity to activate RXR and may be useful as therapeutic agents against CTCL and Alzheimer’s disease.
ContributorsReshi, Sabeeha Mushtaq (Author) / Jurutka, Peter (Thesis advisor) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Arizona State University (Publisher)
Created2023