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Development of Next Generation Inhibitors to Disrupt C-terminal Binding Protein\u27s Oncogenic Effects
No full textMany of the most aggressive solid tumor cancers such as breast, ovarian, pancreatic, and colon cancers rely on C-terminal Binding Proteins (CtBPs) for growth and metastasis. CtBP is a transcriptional coregulator that links chromatin remodeling proteins with DNA-bound transcription factors for multiple genes. CtBP overexpression in tumor cells is oncogenic, turning on known oncogenes (e.g., MDR1 and Tiam1) and turning off tumor-suppressor genes (e.g., Bik, PTEN, BRCA1, and E-cadherin). The knockout of CtBP in a mouse xenograft model prevents tumor growth and metastasis, demonstrating its relevance as a therapeutic target. Our lab has developed a long-term program to develop small molecules that inhibit the transcriptional coregulator activity of CtBP to develop new cancer therapeutics. Previous generation CtBP inhibitors, HIPP and JW-43 respectively, have demonstrated the ability to reverse CtBP-mediated oncogenic activity and induce cell death in multiple cancer cell lines and in vivo mouse models. The optimization of HIPP to the more potent JW-43 by modification of the aryl system suggests a promising direction for additional investigations of structure-activity relationships (SAR). To probe the SAR for the naphthyl ring system, three virtual libraries of analogues were designed in sequence based on the structure of JW-43 and the molecular interactions in the CtBP-HIPP co-crystal structure (4U6Q). The libraries of virtual analogues were docked in GOLD and AutoDock Vina and scored with their respective scoring functions. A total of ten high scoring compounds were synthesized and tested in cell viability assays in multiple ovarian cancer cell lines. All analogues performed better than previous CtBP inhibitors, but the NAS-2-133 analogue performed the best, with a single-digit micromolar GI50 in OVCAR4 (GI50 = 3.9 mM) and OVCAR8 (GI50 = 5.4 mM). The mechanism of cell death for NAS-2-133 was found to be apoptosis, and it showed ~10-fold selectivity for ovarian cancer cell line (OVCAR4) over healthy cells (FT-282). In a xenograft mouse model, both NAS-2-133 and NAS-2-134 analogues decreased tumor volume and weight without compromising overall mouse weight over the course of five weeks. This structure-activity relationship study has yielded our most potent and selective CtBP inhibitors to date. These next-generation CtBP inhibitors show genuine potential in becoming a new tumor-selective targeted therapy for ovarian cancer
Junior Recital, Andrew Joseph, euphonium and John Rose, trumpet, video
Get PDFJunior Recital, videoAndrew Joseph, euphoniumJohn Rose, trumpetDaniel Stipe, pianoMonday, April 28, 2025 at 5:00 p.m.Recital HallJames W. Black Music Center1015 Grove Avenue | Richmond, VirginiaThe presentation of this junior recital will fulfill in part the requirements for the Bachelor of Music degree in Performance. Andrew Joseph studies euphonium with Dr. Ross Walter. John Rose studies trumpet with Samuel Huss
The Fantasyscape Quotidian: On Life in Other Worlds
No full textThis dissertation explores how high fantasy, single-player, East Asian role-playing videogames represent and simulate the experience of everyday life in imagined worlds. Through close and too-close readings, I argue that there is value in exploring in depth the way these worlds are crafted for the insight they give into the materially lived experiences of everyday life encountered by humanity. From a vantage that alternates between and occasionally melds optimism and pessimism, futurity and defeatism, criticality and naivete, these games are envisioned to offer the revolutionary potential of utopian dreams, the ameliorative potential of critical modes of survival, and the liberatory potential of pure escapism. This ideological and analytical work simultaneously connects the disparate fields of game studies, speculative fiction, and critical theory of the everyday to work towards integrating not only these areas, but to provide a working example of the value of doing so towards understanding the culture and mediascape of the mid-2020s in which the non-mimetic, the ludic, and the relatable increasingly dominate
A Higher Education Response to Exploitation on Campus
No full textIntroduction: Sex trafficking of college students is severely understudied, despite evidence that other forms of sexual victimization disproportionately impact college students. The lack of formal recognition of trafficking in higher education is a barrier to policy creation and the provision of sustainable resources for victims of this crime. This study helps address this critical barrier to progress by providing a deeper understanding of sexual exploitation and trafficking on college campuses that can provide needed guidance for higher education in identifying and responding to sex trafficking of students on college campuses.
Purpose: Because this is a vastly understudied population, the purpose of this project is to provide institutions of higher education with insights into how and why sexual exploitation is occurring among college students and evidence-based tools to address exploitation as it occurs within this unique setting.
Methods: This study utilized an explanatory sequential mixed method design to survey undergraduates at a large, urban, public university in the Southeast. Questions were added to an existing campus wide survey to assess the prevalence of exploitation, intimate partner violence, and sugar dating on campus. Participants who reported these experiences and agreed to be contacted for follow-up studies were invited to a one-on-one semi-structured interview.
Results: 6% of undergraduates reported having participated in arrangement relationships while at VCU, while 5.5% had experiences that met the definition of sex trafficking. 150 participants endorsed a Gender-Based Violence/Harassment item since enrollment in college and met the eligibility requirement for the interview portion of the study. Out of these, 33% of survey respondents had experiences that met the definition of sex trafficking before the age of 18, and 16% of respondents had experienced this since enrolling at college. Interview participants described coercive experiences in their relationships, as well as their knowledge and perception of sugar dating relationships. Additionally, they discussed how financial pressures in college led some to try exchanging photos and camming for money.
Conclusion: College students would benefit from learning signs of intimate partner violence, having additional sex education in college, as well as online safety tips. Guaranteed campus housing would protect the most financially vulnerable students
The Bitch and the Boogeyman: Violence Against Women and Gendered Morality in American Slasher Films
Get PDFThis research examines the relationships between on-screen depictions of violence in American slasher horror films and depictions of gendered morality of victims. Slashers are a subgenre of horror film that arose out of the exploitation cinema movement of the 1970s that are characterized primarily by the presence of one or more human killers inflicting violence on a group of protagonists, typically through the use of bladed weapons. Data collected comes from a comprehensive set of thirty-six American slasher films that received a wide theatrical release, with exemptions for films whose primary genre is not slasher and only selecting three films per franchise. The unit of analysis is the character, coded for gender, participation in sexual activity, substance use, social attitudes, and violence received. Analysis reveals there is a significant correlation between the sex of the victim, level of violence received, and the rate of death. Specific traits considered generally to be “punishable” in the context of the films, such as substance use or bullying, tend to receive similar levels of violence for men and women, with the exception of promiscuity. Female promiscuity has a strong positive correlation with rate of death that is not present for male victims
Investigating Mitochondrial Stress Response Mechanisms in Aging
Get PDFMitochondrial dysfunction is widely recognized as a key contributor to aging and age-related diseases. The concept of mitohormesis suggests that low levels of ROS can activate stress-responsive transcription factors, promoting adaptive mechanisms that enhance longevity. We hypothesized that changes in protein abundance under conditions of mild mitochondrial stress reflect an adaptive response, and that commonly altered proteins across diverse genetic backgrounds of mitochondrial stress can help identify key regulators of stress resilience and aging. Our study identified conserved mitochondrial stress response pathways and highlighted candidate regulators for further investigation. These regulators appear to impair mitochondrial energy production by downregulating ATP synthesis and components of the electron transport chain. In turn, cells compensate by activating alternative metabolic pathways, modulating transcriptional programs, and initiating stress response mechanisms. Phenotypic analysis revealed specific genes whose overexpression enhanced cellular stress resilience and overexpression of proteins commonly altered in mitochondrial genome maintenance mutants generally extended chronological lifespan. These findings support our hypothesis that protein abundance changes under mild mitochondrial stress reflect an adaptive, pro-survival response
Wander, Wonder: beyond the window
Get PDFThis thesis explores how small, site-specific interventions can reframe everyday spaces through acts of observation, walking, and placement. In response to the increasing detachment from physical environments caused by digitized, image-saturated culture, this research asks how gentle gestures might restore presence and embodied perception in overlooked urban sites.
Drawing on the notion of the flâneur and grounded in theories by Peter Zumthor, Rebecca Solnit, and others, walking is employed as a form of spatial inquiry—a way of thinking through movement, of seeing through slowness. Along a recurring route between home and studio, three underappreciated sites were identified and engaged through a series of minimal interventions using soft, humble materials such as wood, yarn, and cable ties.
Inspired by the unexpected discovery of three stones in one site, three objects were fabricated in identical scale using different materials, echoing the original forms while allowing new interpretations to emerge. These objects were placed and re-placed across multiple contexts, prompting subtle shifts in meaning, presence, and interaction. The act of placing becomes a quiet method of engagement—an invitation rather than an instruction—leaving space for others to notice, respond, or simply pass by.
Through this process, the thesis proposes a design sensibility that values slowness, impermanence, and care. It suggests that through close attention to everyday things, designers can create meaningful spatial experiences that reconnect us to our surroundings—one gesture at a time
PROBLEM GAMBLING HELPLINE USE AND HELP-SEEKING
No full textThis study investigated problem gambling help-seeking behavior and helpline use guided by the Biopsychosocial Model of Addiction. Gambling disorder is recognized as the first non-substance-related use disorder, with problem gambling classified as a subtype. Utilizing a quantitative retrospective methodology, this research analyzed data from a helpline collected between 2018 and 2023. The population using the problem gambling helpline is predominantly male and older than 46, gambling type shifted toward skills games, though casino gambling remained popular. Age and employment type presented with the strongest association to sustained engagement. The relationship of initial contact duration on subsequent help-seeking engagement and self-reported changes in gambling behavior was found to be null. Examining these variables addresses gaps in current research and lays the path for continued problem gambling help-seeking research. Implications for future research, health policy, and impacts for stakeholders will be discussed
Preferred Habitat for Coastal Shrub Establishment Across a Barrier Island Landscape
No full textBarrier islands occur along the Eastern Coast of North America and buffer mainland coasts from major oceanic storms. Landscape characteristics and vegetation profiles of these islands are constantly changing in response to varying environmental drivers, especially salinity, shoreline erosion and accretion. Relationships between shrubs and other native flora can affect the island landscapes and resiliencies against storms. Hog island is a barrier island along the Eastern Shore of Virginia and is within the Virginia Coast Reserve NSF funded Long-Term Ecological Research (VCR/LTER) site. As such, Hog Island has a well-documented history of changes in landscapes and ecosystems. Northern and southern portions of Hog Island differ, with the northern part, low elevation marsh and grassy swales transition to shrub thickets while the southern portion has been primarily grassland habitat. Over the last 20 years, shrubs, Morella cerifera and Baccharis halimifolia, have been encroaching towards the southern part of the island. These species are dispersed by birds and wind, respectively, and mostly in a random fashion. This study is quantifying the spatial variations in environmental variables for Hog Island to both characterize habitat where seedlings and smaller shrubs currently exist. These variables include distance to shoreline, elevation, depth to groundwater, soil salinity, and vegetation profiles of each area. Where shrubs are currently established, location in relation to the ocean and dunes was an important factor in the success of shrub seedling survival. As shrubs encroach into the southern grasslands and densities increase, that region may shift to a community dominated by woody species, potentially leading to changes in landscape structure. The knowledge gained 8 from this study will be used by scientists at the VCR/LTER to help understand the long term effects of shrub encroachment on barrier islands
