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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

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
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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

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
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Description
Bexarotene (Bex) is a FDA-approved drug used to treat cutaneous T-cell lymphoma (CTCL). It binds with high affinity to the retinoid-X-receptor (RXR), a nuclear receptor implicated in numerous biological pathways. Bex may have the potential to attenuate estrogenic activity by acting as an estrogen receptor alpha (ERα) signaling antagonist, and

Bexarotene (Bex) is a FDA-approved drug used to treat cutaneous T-cell lymphoma (CTCL). It binds with high affinity to the retinoid-X-receptor (RXR), a nuclear receptor implicated in numerous biological pathways. Bex may have the potential to attenuate estrogenic activity by acting as an estrogen receptor alpha (ERα) signaling antagonist, and can therefore be used to treat ERα-positive cancers, such as breast cancer. Using dual luciferase reporter assays, real-time qRT-PCR, and metabolic proliferation assays, the anti-estrogenic properties of Bex were ascertained. However, since Bex produces numerous contraindications, select novel RXR drug analogs were also evaluated. Results revealed that, in luciferase assays, Bex could significantly (P < 0.01) inhibit the transcriptional activity of ERα, so much so that it rivaled ER pan-antagonist ZK164015 in potency. Bex was also able to suppress the proliferation of two breast cancer cell models, MCF-7 and T-47D, and downregulate the expression of an estrogen receptor target gene (A-myb), which is responsible for cell proliferation. In addition, novel analogs A30, A33, A35, and A38 were evaluated as being more potent at inhibiting ERE-mediated transcription than Bex at lower concentrations. Analogs A34 and A35 were able to suppress MCF-7 cell proliferation to a degree comparable to that of Bex. Inhibition of T-47D cell proliferation, by contrast, was best achieved by analogs A34 and A36. For those with ERα – positive breast cancer who are refractory to current chemotherapeutics used to treat breast cancer, Bex and its analogs may prove to be useful alternative options.
ContributorsBains, Supreet (Author) / Jurutka, Peter (Thesis director) / Hackney Price, Jennifer (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
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Description

Forensic entomology is an important field of forensic science that utilizes insect evidence in criminal investigations. Blow flies (Diptera: Calliphoridae) are among the first colonizers of remains and are therefore frequently used in determining the minimum postmortem interval (mPMI). Blow fly development, however, is influenced by a variety of factors

Forensic entomology is an important field of forensic science that utilizes insect evidence in criminal investigations. Blow flies (Diptera: Calliphoridae) are among the first colonizers of remains and are therefore frequently used in determining the minimum postmortem interval (mPMI). Blow fly development, however, is influenced by a variety of factors including temperature and feeding substrate type. Unfortunately, dietary fat content remains an understudied factor on the development process, which is problematic given the relatively high rates of obesity in the United States. To study the effects of fat content on blow fly development we investigated the survivorship, adult weight and development of Lucilia sericata (Meigen; Diptera: Calliphoridae) and Phormia regina (Meigen; Diptera: Calliphoridae) on ground beef with a 10%, 20%, or 27% fat content. As fat content increased, survivorship decreased across both species with P. regina being significantly impacted. While P. regina adults were generally larger than L. sericata across all fat levels, only L. sericata demonstrated a significant (P < 0.05) difference in weight by sex. Average total development times for P. regina are comparable to averages published in other literature. Average total development times for L. sericata, however, were nearly 50 hours higher. These findings provide insight on the effect of fat content on blow fly development, a factor that should be considered when estimating a mPMI. By understanding how fat levels affect the survivorship and development of the species studied here, we can begin improving the practice of insect evidence analysis in casework.

ContributorsNoblesse, Andrew (Author) / Weidner, Lauren (Thesis director) / Parrott, Jonathan (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
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Description

Beginning in the early 1990s, nuclear forensic science is a relatively young field that focuses on “re-establishing the history of nuclear material of unknown origin” (Mayer, et al. 2010, p. 1). Specifically, investigators compare these unknown materials, pre-detonation in this case, based on their characteristics and process history (Mayer, et

Beginning in the early 1990s, nuclear forensic science is a relatively young field that focuses on “re-establishing the history of nuclear material of unknown origin” (Mayer, et al. 2010, p. 1). Specifically, investigators compare these unknown materials, pre-detonation in this case, based on their characteristics and process history (Mayer, et al. 2010, p. 1). In 2010, the Committee of Nuclear Forensics made ten recommendations on the procedures that could lead to improvement in investigation methods. In particular, this paper discusses Recommendation 6: “The nuclear forensics community should develop and adhere to standards and procedures that are rooted in the applicable underlying principles that have been recommended for modern forensic science, including calibration using reference standards; cross-comparison with other methods; inter-laboratory comparisons; and identification, propagation, and characterization of uncertainties'' (Committee of Nuclear Forensics, 2010, p. 11). The main objective of this paper is to compile a literature review to determine how this recommendation was followed, if at all, and produce a list of suggestions that could complement any effort towards the improvement of the field. Out of the methods recommended, that which has fostered the most growth has been cross-comparison. For example, the need for human supervision has decreased, which has decreased the need for human error (Reading, et al., 2017, p. 6013). However, areas that would benefit from development are increasing the number of disciplines in the field (Croudace, et al., 2016, p. 128). These conclusions provided the basis for improvements to other existing studies like DNA and fingerprinting.

ContributorsSarraf, Yasmine (Author) / Montero, Shirly (Thesis director) / Sellner, Erin (Committee member) / van Zalen, Ed (Committee member) / Barrett, The Honors College (Contributor) / School of Social and Behavioral Sciences (Contributor) / School of Mathematical and Natural Sciences (Contributor) / School of Complex Adaptive Systems (Contributor)
Created2021-12
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

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
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Description
The steroid hormone 20-hydroxyecdysone (20E) controls molting in arthropods. The timing of 20E production, and subsequent developmental transitions, is regulated by a variety of factors including nutrition and photoperiod. Environmental factors, such as temperature, play a critical role in regulation as well. The increasing prevalence of urban heat islands (UHI),

The steroid hormone 20-hydroxyecdysone (20E) controls molting in arthropods. The timing of 20E production, and subsequent developmental transitions, is regulated by a variety of factors including nutrition and photoperiod. Environmental factors, such as temperature, play a critical role in regulation as well. The increasing prevalence of urban heat islands (UHI), or areas with elevated temperature due to retained heat by built structures, in response to rapid urbanization has made it critical to understand how organisms respond to elevating global temperatures. Some arthropods, such as the Western black widow spider, Latrodectus hesperus, appear to thrive under UHI conditions, but the physiological mechanism underlying their success has not been explored. Recently, we have shown that L. hesperus, a troublesome urban pest, in fact responds to urban heat island conditions in Phoenix, AZ with delayed development, reduced body mass, and increased mortality. Here we look at the relationship between 20E levels and development in spiderlings reared under desert (27ᵒC), intermediate (30ᵒC), and urban (33ᵒC) temperatures, filling a noticeable gap in not only understanding ecdysteroids’ role in arachnid development but how incremental changes in environmental conditions affect the regulation of this process. Developmental progression and hemolymph 20E titers were recorded for several families of spiders collected from across the urban Phoenix area with data spanning from day 55 to 75 of development, focusing on the second developmental instar. We found that 33°C, but not 30°C, led to 1) a significantly higher production of 20E throughout development, 2) a reduced and delayed molt-inducing 20E peak, and 3) noticeable reductions in growth rate and mass. At 30°C, a variable response is seen in molt timing, without the negative impacts on size and mortality as seen at 33°C, suggesting that at UHI temperatures, the optimal developmental temperature threshold has been surpassed.
Created2019-05