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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

Medicolegal forensic entomology is the study of insects to aid with legal investigations (Gemmellaro, 2017). Insect evidence can be used to provide information such as the post-mortem interval (PMI). Blow flies are especially useful as these insects are primary colonizers, quickly arriving at a corpse (Malainey & Anderson, 2020). The

Medicolegal forensic entomology is the study of insects to aid with legal investigations (Gemmellaro, 2017). Insect evidence can be used to provide information such as the post-mortem interval (PMI). Blow flies are especially useful as these insects are primary colonizers, quickly arriving at a corpse (Malainey & Anderson, 2020). The age of blow flies found at a scene is used to calculate the PMI. Blow fly age can be estimated using weather data as these insects are poikilothermic (Okpara, 2018). Morphological analysis also can be used to estimate age; however, it is more difficult with pupal samples as the pupae exterior does not change significantly as development progresses (Bala & Sharma, 2016). Gene regulation analysis can estimate the age of samples. MicroRNAs are short noncoding RNA that regulate gene expression (Cannell et al., 2008). Here, we aim to catalog miRNAs expressed during the development of three forensically relevant blow fly species preserved in several storage conditions. Results demonstrated that various miRNA sequences were differentially expressed across pupation. Expression of miR92b increased during mid pupation, aga-miR-92b expression increased during early pupation, and bantam, miR957, and dana-bantam-RA expression increased during late pupation. These results suggest that microRNA can be used to estimate the age of pupal samples as miRNA expression changes throughout pupation. Future work could develop a statistical model to accurately determine age using miRNA expression patterns.

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

In this experiment, the viability of gunshot residue (GSR) was examined. This was done through the very rarely researched intersection of forensic firearms analysis and forensic entomology. The question being resolved is if GSR can reliably be detected from secondary evidence transfer of GSR laden carrion onto flies and their

In this experiment, the viability of gunshot residue (GSR) was examined. This was done through the very rarely researched intersection of forensic firearms analysis and forensic entomology. The question being resolved is if GSR can reliably be detected from secondary evidence transfer of GSR laden carrion onto flies and their larvae. While it is know that secondary and tertiary GSR evidence can be transferred by way of handshakes, no such research has been conducted on flies or their pupae. Findings indicated varying levels of detection of GSR on evidence. GSR could reliably be detected on fly bodies and their legs, but not on their pupae. This research is significant as it provides previously unknown information on this line of research and provides the groundwork for further research on this topic in the future.

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

The field of forensic science has been growing and changing with improvements in DNA analysis. One field affected is forensic entomology, which is exploring many ways in which DNA can increase the application of insects in forensic science. One application being explored is the use of insects as a source

The field of forensic science has been growing and changing with improvements in DNA analysis. One field affected is forensic entomology, which is exploring many ways in which DNA can increase the application of insects in forensic science. One application being explored is the use of insects as a source of human DNA in a criminal investigation. Using flies as a source of foreign DNA can also be utilized in ecological research to conduct surveys on the various species present in different environments. This experiment intends to determine if flies can act as a viable source of alternate DNA. This will be accomplished by an ecological survey of DNA extracted from flies. DNA extractions were performed on flies gathered from parts of the greater Phoenix area. The DNA was then amplified with primers targeting different animal species and examined to observe what animals the flies had come in contact with. Several samples had contamination due to human error and were not able to be evaluated. One DNA extraction out of fifteen yielded pig DNA, indicating flies can be used as a source of DNA. Future experiments should use different animal primers and amplify sections of DNA that can determine the different species consumed by flies. Further research into flies as a DNA source can increase the amount of information available to forensic scientists as well as improve ecologist’s observation of an environment’s biodiversity.

ContributorsRiccomini, Brianna (Author) / Parrott, Jonathan (Thesis director) / Marshall, Pamela (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2023-05
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
Forensic entomology is the use of insects in legal investigations, and relies heavily upon calculating the time of colonization (TOC) of insects on remains using temperature-dependent growth rates. If a body is exposed to temperatures that exceed an insect’s critical limit, TOC calculations could be severely affected. The determination of

Forensic entomology is the use of insects in legal investigations, and relies heavily upon calculating the time of colonization (TOC) of insects on remains using temperature-dependent growth rates. If a body is exposed to temperatures that exceed an insect’s critical limit, TOC calculations could be severely affected. The determination of critical thermal limits of forensically-relevant insects is crucial, as their presence or absence could alter the overall postmortem interval (PMI) calculation. This study focuses on the larvae of Phormia regina (Meigen) (Diptera: Calliphoridae), a forensically relevant blow fly common across North America. Three populations were examined (Arizona, Colorado, and New Jersey), and five day old larvae were exposed to one of two temperatures, 39℃ or 45℃, for five hours. Across all colonies, the survival rate was lower at 45℃ than 39℃, in both larval and emerged adult stages. The Arizona colony experienced a harsher drop in survival rates at 45℃ than either the Colorado or New Jersey colonies. This research suggests that the range of 39℃ - 45℃ approaches the critical thermal limit for P. regina, but does not yet exhibit a near or complete failure of survivorship that a critical temperature would cause at this duration of time. However, there is opportunity for further studies to examine this critical temperature by investigating other temperatures within the 39℃ - 45℃ range and at longer durations of time in these temperatures.
ContributorsMcNeil, Tara (Author) / Weidner, Lauren (Thesis director) / Meeds, Andrew (Committee member) / Barrett, The Honors College (Contributor) / School of Humanities, Arts, and Cultural Studies (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2022-05
Description
Previous literature in forensic entomology usually features blow fly research, making literature on forensically relevant beetles hard to find. Although some species of dermestid beetles have been well-studied in regions like Hawaii or the eastern portion of the United States, there has been little forensically focused research regarding dermestid beetles

Previous literature in forensic entomology usually features blow fly research, making literature on forensically relevant beetles hard to find. Although some species of dermestid beetles have been well-studied in regions like Hawaii or the eastern portion of the United States, there has been little forensically focused research regarding dermestid beetles found in the southwestern United States. We were able to report the presence of three species of forensically relevant dermestid beetles on carrion studied in Phoenix, Arizona as well as their relative abundance and wild sex ratios in the spring and summer seasons. Understanding the species of dermestid beetles found in Arizona will aid researchers in determining what beetle species are most important. Knowing the natural sex ratios of commonly found dermestid beetles will be invaluable for optimizing dermestid beetle colony performance for researchers breeding dermestid beetles. The detection of specific species of dermestid beetles will help determine which species of beetles need to be studied first.
ContributorsCromer, Barry (Author) / Weidner, Lauren (Thesis director) / Meeds, Andrew (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2023-12