Vaccination Generates Functional Progenitor Tumor-Specific CD8 T Cells and Long-Term Tumor Control

Immune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however, only a subset of patients with certain types of cancer achieve durable remission. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term Tumor immune reprogramming and arrest cancer progression. We developed a clinically relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiated in mice with early sporadic lesions as compared with late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, impact TST function and liver cancer progression. We found that in mice with early lesions, a subset of TST were PD1+ TCF1+ TOX− and could produce IFNγ while TST present in mice with late liver cancers were PD1+ TCF1lo/− TOX+ and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressing Listeria monocytogenes (LMTAG) blocked liver cancer development and led to a population of TST that were PD1-heterogeneous, TCF1+ TOX− and polyfunctional cytokine producers. Vaccine-elicited TCF1+TST could self-renew and differentiate, establishing them as progenitor TST. In contrast, ICB administration did not slow cancer progression or improve LMTAG vaccine efficacy. Our study shows that vaccination, but not ICB, generated a population of functional progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. For people at high risk of cancer progression, vaccination administered when a responsive progenitor TST population is present may be the optimal immunotherapy to induce long-lasting progression-free survival

‘More Autonomy, More Burnout:’ Healthcare Transition Experiences of College Students Living With Chronic Illness

Every year, an increasing number of college students are living with a chronic medical condition. While much scholarly attention has been paid to the unique structural, psychosocial, and financial difficulties young adults face when transitioning from pediatric to adult healthcare, little is known about the healthcare transition experiences of college students living with chronic illness, who are simultaneously transitioning healthcare systems and transitioning to university life. To begin addressing this gap in the literature, I conducted a review of the literature examining pediatric-to-adult healthcare transition for adolescents and young adults followed by a series of interviews with college students in Nashville, Tennessee living with a chronic medical condition beginning in childhood. The literature review summarizes the state of the literature in emerging adulthood, college student development, and healthcare transition-readiness for adolescents and young adults with chronic medical conditions. Through the series of twelve interviews, I present a new perspective on transitioning to college with a chronic illness. I argue that the individualization and social development unique to the university environment and the consolidation of resources through student support networks can protect against several psychosocial challenges related to healthcare transition. Still, however, the process of transitioning to the college space acts as a confounding structural barrier to healthcare transition, exacerbating documented barriers to medical care for young adults with chronic illness. Further, I suggest that this paradoxical effect gives rise to recommendations for both healthcare systems and universities to better prepare young adults with chronic medical conditions for the realities of adult care and university life

School Choice and Urban Socio-Spatial Boundaries

Expansive school choice programs are often implemented for the perceived ability for students to overcome geographic disparities in access to high-quality education, though it remains to be seen if these programs are in fact connecting communities that were separated through racial segregation and addressing the educational inequities associated with it. These initiatives take place in complex environments, and historical context makes it important to acknowledge how they impact the communities they serve. This study pairs census data with administrative data from a large urban school district in the southeastern United States to examine how the implementation of an expansive school choice program impacted geographic and demographic patterns in where students enroll. Findings indicate that affluent and marginalized areas of the city maintain school segregation even when students opt into choice schools, challenging assumptions about how school choice could impact broader community processes

The Means of Value Production: Translating Social Causes into Business Concerns

This dissertation examines the intersection of social movements and business, including the availability and use of business-based frames and tactics, the targeting of businesses by movement actors, and the participation of businesses in cause-based efforts. It primarily draws upon social movements literature, which is supplemented by management and organizational literature. The first, qualitative study analyzes why a pro-LGBTQ business-based framing tactic emerged in Mississippi. It draws upon documentary and interview data and uses narrative analysis in a theory-driven case study to identify the discursive opportunity structure and resonant frame that fostered the availability of a framing tactic for the campaign’s founders, supporters, and participants to enact in the midst of a closed political opportunity structure. The second, quantitative study analyzes why large firms are receptive to and aligned with the workplace equality movement. It models the relationship between corporate opportunity structures – internal firm characteristics and external firm contexts – and movement receptivity and alignment when all firms are targeted by the same persuasive movement tactic. The study finds that existing ideological and structured commitment to a related cause, attentiveness to meeting expectations, and predisposition to act on issues are all positive significant predictors of firms’ likelihood of receptivity to and alignment with the workplace equality movement. The results of both studies provide support for the malleability of meaning making; the dynamic interaction among movement contexts, targets, and tactics; the utility of persuasive tactics; and the potence of business as a site of social change. Ultimately, this dissertation explores how social causes are translated into issues that are viewed as meaningful and valuable within business

Autoeroticism, Solitude, and Christianity in Jane Eyre

Hiding, retreating, or fleeing from surveilling eyes and coercive religious discourse, Jane finds safety only within herself. Designating spaces for self-solace, rumination, and prayer, her absolute solitude is augmented by erotic and religious energies. These autoerotic and secluded moments, usually following some form of mistreatment, crippling confusion, or distress, help her to ultimately develop both self-possession and religious devotion. Mr. Brocklehurst, Helen Burns, St. John Rivers, and Edward Rochester offer various depictions of coercion and irreligion that reinforce Jane’s need for safe spaces and independence. This article partners with Eve Kosofsky Sedgwick’s “Jane Austen and the Masturbating Girl” to highlight the erotic and religious vitalities in spaces of complete inaccessibility: the alcove and corners of Jane’s childhood or the couches and bedchambers of her adulthood. She forces herself and her self to be utterly, rebelliously, out of reach—out of range of religious authority’s discipline and masculine control. In these common but private places, Jane’s Christian pilgrimage is punctuated by solitary gratification—her solitary communion—which unites religious-driven pleasure in attaining self-possession through a self-service akin to masturbation. Parson-less and self-motivated, Jane redefines the nineteenth-century Christian woman

Molecular Mechanisms Underlying Plasticity to Photoperiod in the Suprachiasmatic Nucleus

*Portion of abstract previously published in Cox et al., 2024. Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel candidate genes for molecular mechanisms of photoperiod plasticity, we performed RNAseq and preliminary DNA methylation analysis on whole SCN dissected from mice raised in Long (LD 16:8) and Short (LD 8:16) photoperiods. Further, DNA methylation analysis was conducted in SCN slice culture incubated with DNA methyltransferase inhibitors RG108 and SGI-1027. RNAseq detected fewer rhythmic genes in Long photoperiod, and in general the timing of gene expression rhythms was advanced 4-6 hours. However, a few genes showed significant delays, including Gem. There were significant changes in the expression clock-associated gene Timeless and in SCN genes related to light responses, neuropeptides, GABA, ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genes Prokr2 and Cck, as well as convergent regulation of the expression of three SCN light response genes, Dusp4, Rasd1, and Gem. Transcriptional modulation of Dusp4 and Rasd1, and phase regulation of Gem, are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation of Prokr2 and Cck may critically support SCN neural network reconfiguration during photoperiodic entrainment. Overall, the RNAseq findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity. DNA methylation analysis via sodium bisulfite pyrosequencing of Rasd1 found a significant difference in methylation at the 3’ enhancer region of the gene between photoperiods at the projected time of lights off. In SCN slice culture at baseline (no light stimulus) in the presence of DNA methyltransferase inhibitors, no differences in DNA methylation were detected via sodium bisulfite pyrosequencing in regulatory regions in the core clock genes Bmal1, Per1, and Nr1d1 or in the light-signaling gene Rasd1. Overall, the results of the DNA methylation analyses are preliminary but agree with the results from the RNAseq study in that no changes in expression are observed in the core clock genes, whereas Rasd1 is significantly differentially expressed between photoperiods

Falling in "Another Country"

In his novel, Another Country, James Baldwin abruptly breaks his reader’s expectations when his protagonist, Rufus Scott, commits suicide by jumping from the George Washington Bridge only eighty pages into the novel. This paper seeks to understand Rufus’s jump by analyzing him through the broader context of loneliness and its relation to physics. Drawing on Baldwin’s essays, as well as Simone Weil’s Gravity and Grace, and affect theorists like Sienne Ngai and Eugenie Brinkema, this paper examines loneliness as an explicitly fundamental concept for Baldwin, and the ways in which affect correlates to physics to determine character actions before they happen. Starting with a close reading of Rufus’s jump, I look at how Rufus’s loneliness is affectively constructed before moving to Simone Weil’s Gravity and Grace to look at other instances of metaphysical gravity, and then look to Baldwin’s invocation of physical touch, in particular, the embrace, as the only remedy for loneliness

Leveraging the Gel-to-Sol Transition of Physically Crosslinked Thermoresponsive Polymer Hydrogels to Enable Reactions Induced by Lowering Temperature

Much work has been done on the use of heating to trigger reactions via the temperature-dependent removal of a barrier or constraint separating reagents. Far less work, however, has been done on the use of cooling to achieve a similar goal. Numerous applications, such as those involving components or materials susceptible to persistent low temperatures and cases in which energy for heating is not available would benefit from this inverse approach. Hence, in this study we explore whether physically crosslinked hydrogels can be reliably used as thermoresponsive constraints that allow reagents to react only upon cooling. We achieve this by loading reagents into adjacent blocks of thermoresponsive hydrogel and showing that these reagents can only react with each other after the temperature of the hydrogel falls below its lower critical solution temperature (LCST). Above the LCST, the reagents remain sequestered in separate gels and no reaction occurs; this “OFF” state is stable for extended periods. When the system is allowed to cool, the hydrogels liquify and flow into each other, allowing mixing of the embedded reagents (“ON” state). We tune the hydrogels’ LCSTs using NaCl, quantify the NaCl’s tuning effect using rheometry, and determine that reactions are triggered reproducibly at temperatures similar to the tuned LCSTs. We also demonstrate generalizability of the concept by exploring situations involving radically different reaction types. This concept therefore constitutes a new approach to autonomous material behavior based on cooling

Principles of Provision: Understanding Occupational Enactment and Provider Activism in Substance-Use Treatment for Pregnant People

As reproductive politics have grown increasingly volatile, the prosecution of pregnant people for their behavior during pregnancy has become a growing issue. Healthcare providers often operate as mandatory reporters in these situations, complicating their role as medical professionals. In this study, I utilize a Millsian framework to explore the ways in which biography, social structure, and history impact the entrance of mission-driven providers into pregnancy care for people with substance use issues, and the degree to which these providers engage in forms of advocacy when working within institutional and policy constraints. First, I outline the biographical pathways preceding their entrance into their profession. Next, I examine how they navigate their current occupational landscape and the ways in which competing patient logics complicate patient care. Finally, I explore the degree to which these providers seek to advance health equity and social justice by engaging in occupational activism within the workplace in spite of institutional and policy constraints. I find that, overall, these individuals operate as mission-driven professionals in the healthcare field and seek to deliver high-quality care that centers patient rehabilitation rather than punishment. This research is one step in uncovering the micro-level interactions that result in population-level health inequalities in reproductive health

On Some Basic Problems of Riesz Kernels in Potential Theory

This dissertation contains discussions of three open problem areas in Potential Theory involving the Riesz kernels. In the first discussion, we consider the k-nearest neighbor logarithmic energies. We will establish first- and second-order asymptotics of the energies as the number of particles goes to infinity on any Jordan measurable set. The second discussion involves continuous energies with external fields. We will investigate a particular case of dimension reduction phenomena where the support of the equilibrium measure becomes a single sphere. For the third discussion, we study polarization problems or Chebyshev problems under the effect of external fields for Riesz-like kernels. In particular, we try to find a connection between discrete and continuous polarizations with external fields by establishing a minimum principle