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- Creators: Jurutka, Peter
- Creators: School of Social and Behavioral Sciences
- 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
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
Description
Factors affecting juror decision-making have been studied extensively to determine what drives juror's decisions (Skorinko, Laurent, Bountress, Nyein, and Kuckuck, 2014). In utero androgen exposure measured using the 4D:2D ratio has been studied to understand how the amount of in utero androgen individuals are exposed to affects their personality and emotional development (Manning et. al., 2010; Kempe and Heffernan, 2011; Hampson, Ellis and Tenk, 2008; Fink, Manning and Neave, 2004; Knickmeyer, Baron-Cohen, Raggatt, Taylor and Hackett, 2006; Knickmeyer and Baron-Cohen, 2006; Wakabayashi and Nakazawa, 2010). Using 106 undergraduate students, the current study sought to understand how the 4D:2D ratio affects juror decision-making in civil cases by having participants assign a proportion of liability to a defendant. Participants reviewed jury instructions, as well as three case vignettes. One of these case vignettes was removed due to a description error that led almost all of the participants to find the plaintiff at fault. This study had three different experimental groups where age of the plaintiff was counterbalanced to control age as a factor in the amount of liability assigned. It was hypothesized that a higher 4D:2D ratio would result in lower defendant liability. Here we show that there was a significantly lower proportion of defendant liability assigned by the high 4D:2D ratio group as compared to the low 4D:2D ratio group; t(210) = 2.89, p < 0.01, d = 0.36. Interestingly, despite the difference between the group means, variability was such that the 4D:2D ratio was not predictive of the proportion of defendant liability assigned for experimental conditions.
ContributorsAnderson, Kayla Jo (Author) / Holloway, Steven (Thesis director) / Salerno, Jessica (Committee member) / Van Etten, Kathy (Committee member) / School of Social and Behavioral Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Stress, empathy, and emotion regulation are factors that can greatly shape an individual's behavior, thoughts, and physiology. The degree to which an individual experiences stress, demonstrates empathy, or is able to regulate emotions can influence his or her ability to establish strong social bonds. The current study investigated the relationships among stress, empathy, and emotion regulation and considered gender differences in these relationships. I hypothesized that higher levels of current stress would be associated with lower levels of empathy and greater difficulties with emotion regulation, and that empathy and emotion regulation would be positively related. Supporting these hypotheses, the following relationships were found: (a) negative correlation between stress and empathy, (b) positive correlation between stress and emotion regulation difficulties, and (c) negative correlation between empathy and emotion regulation difficulties. Results also revealed that greater perceived stress was associated with less empathy in women, but it was unrelated to empathy in men. On the other hand, stress was associated with greater emotion regulation difficulties in both men and women, indicating that either gender may experience a greater disturbance in their emotional response within a social situation when under the influence of stress. Empathy and emotion regulation are positively correlated in both genders, which might suggest that high emotion regulation may allow for appropriate empathy responses within a given social context.
ContributorsHanna, Rand Maria (Author) / Roberts, Nicole (Thesis director) / Burleson, Mary (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor) / School of Social and Behavioral Sciences (Contributor)
Created2016-12
Description
Fetal androgen exposure and childhood experiences are believed to contribute to the development and organization of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, which are responsible for the regulation and release of stress and sex hormones, respectively. Evidence suggests the HPA and HPG axes can couple in response to childhood adversity, and that hormonal dysregulation contributes to psychopathological disorders such as anxiety and depression. Recent research also suggests self-compassion interventions could reduce PTSD symptoms, and that the experience of childhood trauma is related to increased empathy. Still, little is known regarding the impact of fetal androgen exposure on PTSD susceptibility and the relationships between self-compassion, compassion for others, and empathy. The current study aims to determine whether fetal androgen exposure mitigates PTSD susceptibility, and to clarify the relationships between empathy, compassion for others, self-compassion, and PTSD symptoms. A sample of 208 adults completed an online survey designed to measure fetal androgen exposure, childhood maltreatment, self-compassion, compassion for others, empathy, and PTSD symptoms. Findings show a significant difference in PTSD symptoms between individuals in high and low fetal androgen exposure groups, and significant correlations were discovered between empathy and compassion for others, empathy and self-compassion, but not compassion for others and self-compassion. Future studies could explore the extent to which fetal androgen exposure influences PTSD symptom susceptibility and the clinical implications therein.
ContributorsMoore, Robin Ann (Author) / Holloway, Steven (Thesis director) / Lewis, Stephen (Committee member) / Nanez, Jose (Committee member) / School of Public Affairs (Contributor) / School of Social and Behavioral Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
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 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