Addressing the Hippo in the Room: Investigating the Mechanism of YAP/TAZ as a Treatment Target in Clear Cell Renal Cell Carcinoma

Ph.D.Clear Cell Renal Cell Carcinoma (ccRCC) is the most common subtype of kidney neoplasms characterized by a near universal inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein. Targeted therapies that inhibit the unfettered transcriptional signaling of Hypoxia-inducible Factor 2ɑ (HIF2ɑ) transcription factor and its downstream pro-angiogenic effectors, consequential to VHL loss, has undoubtedly improved patient survival. Despite these improvements, a substantial fraction of patients with advanced ccRCC experience upfront or acquired resistance to presently available treatment options, warranting the investigation into adjunct therapies capable of improving efficacy and response duration to existing treatments. Assessing tumor copy number alteration, methylation, and expression data from large ccRCC patient cohorts, we demonstrate that dysregulation of the Hippo tumor suppressor pathway occurs commonly in ccRCC, correlates with increased YAP/TAZ target gene expression, and is associated with worse overall survival in treatment naïve patients. In addition, we showed that high YAP/TAZ gene signature is associated with poor treatment response to therapies that target HIF2ɑ-VEGF signaling. In vivo efficacy studies with a first-in-class TEAD palmitoylation inhibitor or YAP/TAZ-targeted shRNAs showed both forms of YAP/TAZ silencing substantially delays the development of acquired resistance to a clinical HIF2ɑ inhibitor in a ccRCC xenograft model sensitive to HIF2ɑ inhibition. Moreover, the TEAD inhibitor also exhibited profound single agent anti-tumor efficacy in a patient-derived ccRCC xenograft model of upfront resistance to HIF2ɑ-targeted treatments. By combining ATAC-seq, BRB-seq and Cut&Tag analysis, we assessed the chromatin binding and gene regulation of YAP and HIF2ɑ, and unveiled that these two proteins are co-recruited to AP-1 sites through interactions with the AP-1 transcription factors. YAP/TAZ, HIF2ɑ and JUN are dependent on each other to maintain their expression, and function cooperatively to promote the expression of highly expressed transcription factors and other important oncogenes. Our findings not only revealed the therapeutic potentials of adjunct YAP/TAZ-based therapies in the treatment of advanced ccRCC, but also revealed novel mechanistic insights into the dynamic interactions among YAP, HIF2ɑ and AP-1 proteins that could be further exploited to improve treatment for ccRCC

Budgeting the Blaze: An Analysis of the Relationship Between Prescribed Burns and Wildfire Suppression Costs

M.P.P.Federal wildland firefighting agencies spend billions each year to contain and manage wildfires. These costs have grown exponentially as wildfire seasons have grown more severe. Unfortunately, climate scientists anticipate that the frequency and scope of these disasters will continue to grow over the next several decades as temperatures increase. It is crucial to understand how fuel reduction strategies can mitigate these effects. This thesis paper draws upon wildfire incident data from the National Geographic Area Coordination Center (GACCC) and prescribed fire data from the US Forest Service to examine the impact of prescribed burns in previous years on reducing wildfire suppression costs. This relationship analysis occurs on a county-level basis across the continental United States. Additionally, the wildfire data covers the years 2020 through 2023, and the prescribed fire data covers the years 2015 through 2023. This leaves 2,243 observations of counties that experienced wildfires and 3779 county observations that were treated with a prescribed burn. By evaluating the economic effects of prescribed burns by year on future wildfire suppression costs, this paper seeks to add to the existing literature on mitigation and serve as a reference for better financial management of the growing wildfire crisis

Environmental Woes and Their Economic Echoes

Ph.D.This dissertation is a compilation of three essays on the economic consequences of environmental shocks.In the first chapter, No Point Crying over Spilled Oil: Impact of Crude Oil Spills on Out-Migration in Nigeria, I study adaptation measures adopted by households in the face of land pollution shocks, namely crude oil spills. I use a staggered difference-in-differences framework to find that exposure to crude oil spills increases the likelihood of out-migration. A sub-group analysis helps me investigate the causal mechanism driving my results. I find that oil spills are linked to migration only for those who resided in households that practiced agriculture at baseline. They report fewer hours worked in cultivation and weak evidence suggests that rural household members migrate to urban areas as a consequence of oil spill exposures, indicating a substitution away from their farms. Reported short-term migration responses to oil spill exposure are often marriage-related, while longer-term migrations are reportedly driven by work and education pursuits, predominantly among female members. Thus, persistent exposure to land pollution shocks can prompt agriculture-dependent households to resort to out-migration as a coping strategy.The second chapter, High Temperature and Learning Outcomes: Evidence from Ethiopia, ---co-authored with Kibrom Tafere and A. Patrick Behrer--- investigates the impact of high temperatures on the test scores of students in high-stakes examinations in Ethiopia. We rely on quasi-random variation in daily temperature during the year preceding an exam for identification. Our results indicate that an additional day with maximum temperature exceeding 33°C leads to a significant decrease in students' total test scores by 0.009 standard deviations. We also find meaningful heterogeneity in effects based on the gender of students. Specifically, female students' exam scores appear to be less influenced by high temperatures, implying that climate change has differential impacts by gender. Additionally, we find that students from schools located in hotter regions can better cope with higher temperatures as compared to their counterparts from cooler regions. We posit this as suggestive evidence of heat acclimatization since Ethiopian schools have negligible adoption of cooling technologies.In the third chapter, Agriculture Production Potential of Groundwater Irrigation in Sub-Saharan Africa, ---co-authored with Ifeanyi N. Edochie, Aparajita Goyal, and Andrew Dabalen--- we investigate the potential of the vast under-utilized groundwater reserves available in Sub-Saharan African countries to increase agricultural production and resilience. By combining a novel groundwater aquifer database with geo-spatial agriculture productivity data, we simulate the gains from expanding groundwater access-- ensuring access is kept within sustainable limits-- on agriculture productivity and production and find substantial gains. This analysis is particularly relevant against the backdrop of climate change and the impending disruption to rain-fed agriculture

Youth Mainstreaming in Small Arms and Light Weapons Control

This essay examines the critical issue of youth exclusion and its impact on global peace and security, focusing on the inordinate effects of armed violence on youth and the challenges hindering their integration into decision-making spheres. Despite being disproportionately affected by armed violence, youth find themselves marginalized in discussions that directly impact their lives and futures. Through an exploration of grassroots initiatives and governmental actions, the essay highlights the importance of youth mainstreaming in small arms control efforts. It proposes recommendations for research, funding, and inclusion measures to ensure meaningful youth participation in policymaking and implementation processes. Hence, the essay underscores the necessity of incorporating youth perspectives and leadership in small arms and light weapons control initiatives to foster sustainable peace and security worldwide

Random Utilities and How to Find Them

Ph.D.In this dissertation, I study the random utility model. The random utility model is an extension of the classic paradigm of economics which assumes that decision makers choose according to some underlying preference. The random utility model extends this paradigm by allowing for heterogeneity across either a population of decision makers or across time for the same decision maker. This heterogeneity is modeled as there being a distribution over preferences inducing a distribution over choices. In Chapter 1, I study when an analyst is able to recover the underlying distribution over preferences from choice data. I provide fully characteristic conditions under which we are able to recover the underlying distribution over preferences. In Chapter 2, I readdress the problem of testing the random utility model. While axiomatic tests of the random utility model have been known, only recently has a hypothesis test for the random utility model been developed which can be applied to real data. However, this hypothesis test is not computationally feasible in many reasonable applications. I provide an alternative hypothesis test, applicable to real data, that offers large computational improvements over the current standard methodology. In Chapter 3, I study the random utility model in a dynamic setting where a decision maker's past choices can impact their preference today. First, I broach the problem of aggregation. In general, if a decision maker's preference depends on their history of choices, the time average of their choices does not coincide with the random utility model. I provide characteristic conditions for when the random utility model is an accurate model of time aggregated choice. Second, I develop a test for this type of dynamic random utility when we have time disaggregated but population level data. I provide a fully characteristic axiomatic test as well as a hypothesis test for history dependent random utility for this type of data

The Repeating Book: In Search of the Creole Text in the Caribbean

Ph.D.In my dissertation, I argue that Caribbean thought and literature exhibit exceptional characteristics that make them unique, sharing features that make them what I call the “creole text.” Orlando Fals Borda’s Historia Doble de la Costa (1979-86) and Antonio Benítez Rojo's La Isla que se Repite (1989) guide my analysis. Historia Doble de la Costa is a much lesser-known book, it is a tetralogy that navigates between a poetic and a historicist discourse which, for lack of a better term, can be described as a social history whose structure duplicates its pages as if it contained two books, one of them a history from below, with parallel texts on facing pages. Historia Doble de la Costa also repeats itself because each of its four volumes repeat elements of the others to narrate the histories of the different subregional islets of the Colombian Caribbean. Through drawing on Benitez Rojo idea of “repetition”, I show that this repetition characterizes textual creolity in general, such as in C.L.R. James's The Black Jacobins (1938), Fernando Ortiz's Contrapunteo Cubano del Tabaco y el Azúcar (1940), Lydia Cabrera's El Monte (1954), George Lamming's The Pleasures of the Exile (1960), Édouard Glissant's Le Discours Antillais (1981), Manuel Zapata Olivella's Changó, el Gran Putas (1983), among others. I maintain that the creole text is cannibalistic in the sense that it is a textual assemblage that combines different fields of knowledge, approaches, intellectual traditions, formats and writing styles in an undisciplined manner. This anthropophagous attitude constitutes an artistic amalgam, unclassifiable, with a tendency towards excessiveness and the baroque, generating polyphony. In this way, the creole text opens up, including not only the oral record and myth, but also narrating the agency of subjects previously considered passive objects, in particular, the historical experience of the African diaspora

Regulation of Steroid Hormone Biosynthesis by Thymic Epithelial Cells

Ph.D.Selective processes early in T cell development ensure that most thymocytes expressing αβ T cell antigen receptors (TCRs) are eliminated, and only self-restricted and self-tolerant cells join the peripheral T cell repertoire. Glucocorticoids produced by thymic epithelial cells (TECs) promote the survival of such thymocytes to increase the breadth and efficacy of the repertoire. There are two TEC subsets, cortical (cTECs) and medullary (mTECs), each contributing to selection at different developmental stages. The exact source and regulation of thymic-derived glucocorticoid production are not fully understood, and their precise identification will help determine whether they enhance positive selection or antagonize negative selection. It was hypothesized that glucocorticoids are synthesized by cTECs, with the potential to influence both stages of selection. To test this, a transgenic reporter mouse was utilized in which endogenous Cyp11b1, the final and essential enzyme in de novo glucocorticoid biosynthesis, was fused with fluorescent mScarlet. Cyp11b1mScarlet was detected in a lineage of mTECs that express the transcription factor Aire, which is known to drive promiscuous expression of tissue-restricted antigens (TRAs) involved in negative selection and the establishment of peripheral immune tolerance. In Aire-knockout mice, detection of Cyp11b1mScarlet, transcripts encoding enzymes required for the de novo pathway, and ex-vivo glucocorticoid synthesis were significantly reduced, supporting Aire’s role in regulating glucocorticoid biosynthesis. This presents a novel yet paradoxical role for Aire in promoting both positive and negative thymocyte selection, the combined effect serving to enlarge the pool of self-restricted yet self-tolerant T cells. This also supports a new function for Aire in coordinating the expression of genes involved in an entire biosynthetic pathway whose secondary products have known paracrine functions. To this end, Aire was found to drive de novo sex steroid biosynthesis, supporting a broader role for Aire in shaping the thymic microenvironment and paving the way for future investigations

Trauma-Informed Practices for Teaching and Learning

Trauma-informed pedagogy is a strategic pedagogical approach that prioritizes emotional resilience and inclusivity across academic environments. While it is a well-established paradigm in K-12 education, these pedagogical practices are not as well described in higher education. In this session, workshop participants will reflect on well-established trauma-informed principles, and through vignette based discussions, participants will collaboratively develop strategies to apply in their own educational contexts

Impact of an Open Access Scheduling System on No-Show Rates in an Urban Federally Qualified Health Center

D.N.P.No-show medical appointments lead to health disparities and threaten the financial survival of Federally Qualified Health Centers (FQHCs). Open access scheduling eliminates long lead times, a common reason for no-show visits. Preventive health screenings and chronic disease management were drastically reduced during the COVID-19 pandemic, requiring innovative methods to increase access to care. The purpose of this quality improvement (QI) project was to measure the impact of an open access scheduling system on no-show rates in an urban FQHC. A pre-post observational design compared two days per week of no-show data for a span of 10 weeks between two family medicine physicians’ schedules. No-show data from the pre-intervention group (N = 175) was collected from October 17, 2022–December 20, 2022 and compared to no-show data from the open access post-intervention group (N = 82) collected from October 16, 2023–December 19, 2023. No-show rates were significantly lower in the open access post-intervention group (3.5%) compared to the traditional pre-intervention group (36%),