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Tigit And Gdf-15 As Biomarkers And Targets In Renal Cell Carcinoma Resistant To Immune Checkpoint Inhibitors, Oscar Norberto Perales

Yale Medicine Thesis Digital Library

Immune checkpoint inhibitors have become the standard of care treatment for local and systemic clear cell renal cell carcinoma (RCC). However, a subset of patients fail these therapies due to the development of disease refractory to such treatments. Therefore, it is imperative that we study the potential mechanisms of resistance to immune checkpoint inhibition within the tumor microenvironment. Likewise, establishing biomarkers indicative of treatment resistance may benefit clinicians and patients when it comes to the initial selection of treatment. Moreover, biomarkers of resistance might also serve as potential drug targets. In this study we analyzed expression of TIGIT and GDF-15, …

Cutaneous Fungal Infections In The United States: A Cross-Sectional Analysis Of National Surveys, Sarah Lee Spaulding

Yale Medicine Thesis Digital Library

Superficial cutaneous fungal infections (SCFIs), caused by yeasts, dermatophytes, and nondermatophyte molds, are prevalent skin conditions with substantial economic and quality-of-life implications. This study aimed to evaluate trends in the prevalence of SCFIs in the United States between 2005 and 2016, using data from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS).We performed a cross-sectional analysis of outpatient visits with SCFIs diagnoses, identified through the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification (ICD-9-CM and ICD-10-CM). Diagnoses included conditions such as tinea unguium, tinea pedis, and candidiasis of the skin …

Prognostic Factors In Active Surveillance Of Low-Risk Prostate Cancer: A Future Of Tailored Surveillance, Vinaik Mootha Sundaresan

Yale Medicine Thesis Digital Library

PROGNOSTIC FACTORS IN ACTIVE SURVEILLANCE OF LOW-RISK PROSTATE CANCER: A FUTURE OF TAILORED SURVEILLANCE.

Vinaik M. Sundaresan and Michael S. Leapman. Department of Urology, Yale University, School of Medicine, New Haven, CT.

As most Prostate Imaging Reporting and Data System (PI-RADS) 5 lesions on MRI harbor Gleason grade (GG) group ≥2 disease on biopsy, optimal management of patients with imaging-biopsy discordance remains unclear. To estimate grade misclassification, we evaluated the incidence of Gleason upgrading among patients with GG1 disease in the setting of a PI-RADS 5 lesion.

We conducted a single-institution retrospective analysis to identify patients with GG1 prostate cancer …

The Use Of Biologic Agents In Cutaneous Immune-Related Adverse Events Due To Immune Checkpoint Inhibitors, Kailyn Valido

Yale Medicine Thesis Digital Library

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape in the field of oncology due to their effective antineoplastic properties for various cancers. Though revolutionary in cancer treatment, their use is limited by various immune-related adverse events (irAE). Cutaneous immune-related adverse events (cirAE) are the most common type of irAE and encompass a spectrum of dermatological manifestations. These include lichenoid reactions, psoriasiform eruptions, eczematous dermatitis, immunobullous disorders, granulomatous reactions, pruritus (with or without a primary eruption), vitiligo, and severe cutaneous adverse reactions such as Stevens–Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

The standard approach in …

Changes In Healthcare Coverage And Access To Eyecare Among Low-Income Adults After Medicaid Expansion, Elliott Vanderford

Yale Medicine Thesis Digital Library

Introduction: Access to quality eyecare is important for early diagnosis and prevention of vision loss. Understanding the role of Medicaid expansion (as a result of the Affordable Care Act) in improving eye health outcomes has the potential to guide health policy and address disparities in vision care in the United States. Here, we investigate the impact of Medicaid expansion on access to eyecare among low-income adults across the United States.

Methods: Survey data was extracted from the National Health Interview Survey (NHIS) for the years 2010 through 2018 for adults aged 18-64 years with a family income less than 125% …

Macrophage Migration Inhibitory Factor And D-Dopachrome Tautomerase As Biomarkers And Key Modulators Of Tumor Progression In Head And Neck Cancer And Melanoma, Caroline Naomi Valdez

Yale Medicine Thesis Digital Library

Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) are pro-inflammatory cytokines implicated in tumor progression across multiple cancers. Both MIF and DDT act through canonical CD74 and non-canonical CXCR2/4/7 signaling pathways, which contribute to immune suppression and tumor progression. Elevated MIF levels are associated with metastasis and poor prognosis in HNC and contribute to immune checkpoint inhibitor (ICI) resistance in melanoma. DDT’s role in cancer is not well understood. This study aims to evaluate the expression and therapeutic potential of MIF and DDT inhibition, focusing on their ability to modulate immune responses and improve survival outcomes as …

Bipolar Disorder Among Individuals With Atopic Dermatitis: A Case-Control Study In The All Of Us Research Program, Mitchel Wride

Yale Medicine Thesis Digital Library

Background: Atopic dermatitis has been associated with psychiatric comorbidities.Objectives: To characterize the association between atopic dermatitis and bipolar disorder with a case-control study of the NIH All of Us Research Program. Methods: Utilizing Systemized Nomenclature of Medicine diagnostic codes, we identified cases of atopic dermatitis. Four age, sex, and race/ethnicity matched controls were found for each case using propensity score matching. After controlling for age, sex, race/ethnicity, income, smoking status, and depression, the relationship between atopic dermatitis and bipolar disorder was evaluated using logistic regression. Results: We identified 13,431 atopic dermatitis cases with 53,724 matched controls. Participants with atopic dermatitis …

Evidence-Based Optimization Of Healthcare Utilization And Supportive Care For Patients With Acute Myeloid Leukemia, Cameron Joseph Hunter

Yale Medicine Thesis Digital Library

Acute myeloid leukemia (AML) care underwent a paradigm shift in 2017 with the development of a number of targeted therapies and less-intensive treatments. This changed expectations for survival and treatment course, particularly for those who are inappropriate candidates for intensive therapy due to frailty, comorbidities or disease-specific features. This period has also seen an evolution of healthcare system models that ultimately deliver sub-specialty care for patients with AML, including the rise of the academic center-affiliated community practices that may care for patients with this uncommon and high-stakes disease. These novel therapies and healthcare models also beget a lack of standardization …

Culture-Free Whole Genome Sequencing Of Mycobacterium Tuberculosis From Clinical Specimens, Chaney Christine Kalinich

Yale Medicine Thesis Digital Library

Tuberculosis (TB) is a leading cause of infection-related mortality worldwide, causing an estimated 1.13 million deaths in 2022. The majority of infections can be successfully treated with antibiotics, but the prevalence of drug-resistant TB and a lack of rapid and cost-effective drug susceptibility tests for many key antibiotics is a significant barrier to treatment. Whole-genome sequencing of Mycobacterium tuberculosis can be used for drug susceptibility testing and can provide valuable insight into transmission patterns. However, M. tuberculosis is slow to grow, meaning traditional sequencing methods which require culture can take many weeks to return results, greatly limiting the potential clinical …

Yale Medicine Magazine December 2025, Issue 175, Yale University. School Of Medicine

Yale Medicine Magazine - alumni bulletin and magazine

This is the December 2025 issue of Yale Medicine Magazine, issue 175. Prepared in cooperation with the alumni and development offices at the School of Medicine. Earlier volumes are called Yale School of Medicine alumni bulletins, dating from v.1 (1953) through v.13 (1965) and Yale Medicine: alumni bulletin of the School of Medicine, v.1 (1965) through v. 52, no.1. (Autumn 2017).

Improving Equity In Atherosclerotic Cardiovascular Disease Risk, Jordan Levandoski

Yale School of Nursing Digital Theses

The current use of racial categorization in Atherosclerotic Cardiovascular Disease (ASCVD) risk, limits assessment of confounders beyond cholesterol. The Life’s Essential Eight (LE8) categories of healthy diet, sleep, physical activity, smoking, body mass index, hypertension, total cholesterol, and blood glucose could reduce two million ASCVD events per year. The documentation of Z codes 55 – 65 describe social drivers of health (SDH) like housing, economics, and social systems which complicate care. Development of the ASCVD risk assessment and management protocol (ASCVD-RAMP) assessed ASCVD risk without race modification in patients aged 45 – 75 and improved health equity by pairing SDH …

Implementing A Patient-Centered Pediatric Obesity Protocol In A Population With Social And Environmental Risk Factors, Carolyn Walsh

Yale School of Nursing Digital Theses

Children and adolescents exposed to adverse childhood experiences (ACEs) and negative social determinants of health (SDoH) have an increased risk of developing pediatric obesity. The American Academy of Pediatrics Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity (2023) recommends assessing these factors in children with obesity. At a School-Based Health Center (SBHC), the standard of care for pediatric obesity did not include ACEs and SDoH screening, highlighting a gap in practice. This Doctor of Nursing Practice project developed, implemented, and evaluated a patient-centered pediatric obesity protocol incorporating ACEs, SDoH screening, and referrals to patient-centered …

Chromatin Architecture And Dynamics In Native Folding States, Tianyu Yuan

Yale Graduate School of Arts and Sciences Dissertations

The central question in chromatin architecture and dynamics is how meter-long DNA strands are organized within a micrometer-sized nucleus while maintaining regulation of all genomic activities. While some organizational principles have been identified and validated through both theoretical models and experiments, controversies between alternative mechanisms persist,continually refining and enriching our understanding of chromatin architecture and dynamics. At the intermediate length scale, chromatin architecture is characterized by topologically associating domains (TADs), revealed through experimental Hi-C contact maps. This organization can be explained and modeled using loop extrusion factor (LEF) models, which rely on the correlation between TAD boundaries and the genomic …

Chk2 Sustains Mitotic Plk1 Activity To Promote Proper Chromosome Segregation, Elizabeth Maureen Black

Yale Graduate School of Arts and Sciences Dissertations

Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate mitotic PLK1 remain poorly understood. Here, I identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome …

Intestinal Mast Cell Control Of Behavioral And Oral Anaphylactic Responses, Nathaniel Dale Bachtel

Yale Graduate School of Arts and Sciences Dissertations

Organisms are challenged on a day-to-day basis with the decision of what, when and how much of a given food source to eat. These fundamental decisions require sensory mechanisms that evaluate the relative quantities of desired nutrients and harmful toxins present in each food source and integration of these factors with the current organismal state. In mammals, this sensing is accomplished by a diverse array of cells types, including epithelial cells, neurons, and immune cells which communicate the value of ingested food with the brain. Moreover, the immune system can store memory of past harm a given food source was …

Regulation Of Pre-Mrna Processing Through Nascent Rna Folding, Leonard Schaerfen

Yale Graduate School of Arts and Sciences Dissertations

RNA sequence determines the formation of intramolecular base pairs. Together with tertiary contacts, base pairs define every RNA's structure, or fold. The catalytic, regulatory, or coding potential of an RNA strongly depends on its folding pattern. Because base pairing occurs much faster than RNA synthesis (transcription) in cells, early structural states can govern RNA processing events and dictate the formation of functional conformations. These co-transcriptional structural states remained largely unknown. To address this gap, I developed CoSTseq, a chemical probing and enrichment method to measure nascent RNA base pairing upon exit from RNA polymerases (Pols) transcriptome-wide in living Saccharomyces cerevisiae …

Renewing Cells, Enduring Genes, And Metabolic Decline In Murine Liver Aging, John T. Gonzalez

Yale Graduate School of Arts and Sciences Dissertations

Aging is associated with physiological and molecular decline and a concurrent increase in dysfunction, chronic disease, and mortality. Despite the fact that aging is the greatest risk factor for many chronic diseases, fundamental aging research has historically lagged behind disease-specific research. This deterioration and it's repercussions has different manifestations in different organs. This dissertation focuses on dynamics of mouse aging with a focus on the liver. The liver's diverse functions are integral to many homeostatic processes, including maintaining metabolic balance, detoxifying harmful substances, supporting immune defense, and regulating blood and endocrine systems. Its impairment can lead to significant health issues. …

Liquid-Liquid Phase Separation Of Cellular Prion Protein And Its Biological Implications, Yangyi Liu

Yale Graduate School of Arts and Sciences Dissertations

Liquid-liquid phase separation (LLPS) of macromolecules allows for a variety of cellular functions such as signal transduction and regulation of gene expression and is implicated in neurodegeneration. Cellular prion protein (PrPC) as the central player in prion and Alzheimer’s diseases has been previously discovered to undergo LLPS, while its molecular underpinnings and physiological functions remain unclear.

This thesis delves into the complexity of PrPC LLPS, characterizes its biophysical properties, and initiates a connection between PrPC LLPS and its physiological functions. In Chapter 2, site-specific interactions of PrPC that drive LLPS are identified, highlighting the importance of interactions between the N-terminal …

Characterizing The Photochemistry And Photophysics Of Benzoylbenzoate And Formylbenzoate Anions Using Cryogenic Ion Spectroscopy, Olivia Caroline Moss

Yale Graduate School of Arts and Sciences Dissertations

Marine chromophoric dissolved organic matter (mCDOM) is a large and complex class of material predominantly found at the air-water interface in bodies of water. While it is known to generate radicals and unwanted byproducts, such as HONO· and ·OH, the mechanism of formation for these products currently is unknown. In this dissertation, a bottom-up approach is utilized to investigate possible reaction pathways by scaling down to small-molecule models of mCDOM. Namely, this dissertation investigates the photochemistry and photophysics of benzoylbenzoates (BBA¯). Analysis of the UV spectrum of the deprotonated species reveals two dominant processes upon photoexcitation of 4BBA¯, tag loss …

Ole Rna Is A Component Of A Large Particle That Promotes Bacterial Growth Under Diverse Stresses, Seth Eugene Lyon

Yale Graduate School of Arts and Sciences Dissertations

Prior to the 1980s, RNA macromolecules were largely viewed as a transient carrier of the genetic code used for protein synthesis, with little chemical versatility beyond Watson-Crick-Franklin base-pairing. The discovery of catalytic RNAs in 1982, however, upended this view and established that RNA was a chemically capable biopolymer. Since then, several classes of RNA with functions independent from protein synthesis have been discovered in all domains of life. Excluding those that have functions relevant to protein translation, noncoding RNAs that are large (> 200 nt) and have a conserved, complex structure are rare in bacteria. However, as more bacteria were …

Molecular Mechanism Of Vibrio Cholerae Biofilm Adhesion, Xin Huang

Yale Graduate School of Arts and Sciences Dissertations

Bacterial biofilms are surface-attached communities of bacterial cells enclosed in an extracellular matrix formed on environmental surfaces and host tissues. Biofilm formation represents a common strategy in facilitating host colonization and infection by human pathogens, and the polymeric matrix provides a mechanism for drug and host immune resistance by acting as a barrier around biofilm-dwelling cells. Bacteria often express multiple adhesive proteins (adhesins), but it is often unclear whether adhesins have specialized or redundant roles. Here, we combine mutagenesis, biochemistry, single-cell imaging, and bioinformatics to show how Vibrio cholerae, the causal agent of pandemic cholera, uses two biofilm-specific adhesins …

Disruption Of The Rhogef Trio In Neurodevelopmental Disorders Leads To Impairments In Multiple Domains Of Function, Amanda Jeng

Yale Graduate School of Arts and Sciences Dissertations

Neurodevelopmental disorders (NDDs) affect the normal development and function of the brain, and include disorders such as autism spectrum disorder, intellectual disability, schizophrenia, bipolar disorder, and epilepsy. While these are diagnostically distinct disorders, NDDs share considerable comorbidities and present with overlapping symptoms. In addition, the risk genes for NDDs overlap significantly, further suggesting shared underlying pathology of these disorders. Mutations in the gene TRIO are enriched in individuals with neurodevelopmental disorders. TRIO encodes a large multidomain protein with two guanine nucleotide exchange factor domains for the Rho family of small GTPases and a putative kinase domain, as well as multiple …

Investigating Tlr-Mediated Cytokine Synergy In Macrophages, Erick Salvador Rocha

Yale Graduate School of Arts and Sciences Dissertations

Cytokine dysregulation during microbial infections can dangerously increase the severity of associated diseases. Non-additive responses to simultaneous activation of toll-like receptor (TLR) signaling pathways are one potential contributor. Here we explored mechanisms underlying the TLR2/MyD88 and TLR3/TRIF-mediated responses in macrophages for canonical pro-inflammatory and antiviral targets including TNF, IL-6, IL-12p40, IFN-β and CXCL10. We found that all targets exhibited characteristic levels of synergistic cytokine activation that varied with TLR-ligand concentration and exposure time. These trends were conserved when the TLR3-ligand polyI:C (PIC) was combined with either of the TLR2-mediated pathogens S. aureus or L. pneumophila. Using pharmacological inhibitors, genetic …

Decoding Heterogeneity In Human Aging: Omic Biomarkers Of Age-Related Disorders, Yaroslav Markov

Yale Graduate School of Arts and Sciences Dissertations

Biological aging unfolds along multiple heterogeneous trajectories shaped by both acquired molecular drift and inherited genetic variation. This dissertation investigates two complementary axes of aging heterogeneity: (1) stochastic, individually acquired epigenomic deviations; and (2) genotype-defined risk exemplified by the APOEε4 allele, the strongest genetic determinant of late-onset Alzheimer’s disease (AD).

1) Stochastic Epigenetic Mutation Detection

We developed SEMdetectR, a robust R-based pipeline for identifying and quantifying stochastic epigenetic mutations (SEMs) -- rare, outlier CpG methylation events that accumulate idiosyncratically with age. Using technical replicates from three independent cohorts, we uncovered previous methodological flaws undermining SEM reliability and trained a machine …

Biomedical Privacy And Security: Histology Image Vulnerabilities And Blockchain Solutions, Eric Ni

Yale Graduate School of Arts and Sciences Dissertations

Biomedical research increasingly relies on vast datasets, such as genomic sequences, electronic health records, and histology images, to advance scientific knowledge and clinical applications. However, the sensitive nature of biomedical data poses significant privacy risks, particularly with emerging capabilities of artificial intelligence and machine learning technologies. This dissertation addresses two central challenges in biomedical data privacy and security: quantifying privacy risks associated with histology images and developing innovative blockchain-based methods to ensure secure data storage and sharing.

The first part of this work investigates the vulnerability of histology images—commonly perceived as safe for public sharing—to privacy breaches. Utilizing advanced computational …

Discovery Of Plant Secondary Metabolism Through Computational And Synthetic Biology Technologies, Shenqi Wang

Yale Graduate School of Arts and Sciences Dissertations

Plants have evolved to produce a myriad of secondary metabolites, which have been a rich source of small molecules with numerous applications in modern medicine. However, many therapeutic small molecules still rely on plant sources for their production and confront various challenges such as low purification efficiency, slow growth of plants, and the scarcity of species. Advances in synthetic biology have created alternative opportunities to overcome these challenges by producing valuable plant natural products through heterologous expression of the biosynthetic pathways in microorganisms. However, the biosynthetic pathways of many plant natural products remain poorly understood due to inaccurate gene annotations …

Structural And Functional Analysis Of Translation Inhibition By Betacoronavirus Non-Structural Protein 1, Michael Brandon Vetick

Yale Graduate School of Arts and Sciences Dissertations

humans: SARS-CoV, SARS-CoV-2, and MERS-CoV. Key to their viral lifecycle is Non-structural protein 1 (Nsp1), an essential pathogenicity factor that potently restricts the cell’s antiviral response. Despite poor protein sequence conservation of Nsp1 between evolutionarily distant β-CoVs, these proteins have proven to be highly conserved both functionally and structurally. Nsp1 functions by inhibiting host gene expression through contacts made with two mRNA ribonucleoprotein (mRNP) complexes: the initiating ribosome and the Nxf1/Nxt1 mRNA nuclear export complex. It is believed that two Nsp1 functions occur on the ribosome: Nsp1 is able to coordinate cleavage of the host mRNA and Nsp1 is able …

Navigating The Neighborhood: Community, Identity, And Gentrification In Crown Heights, Brooklyn, Kayla Karyl Thomas

Yale Graduate School of Arts and Sciences Dissertations

Crown Heights, Brooklyn, New York. This dissertation is a multi-method community study focusing on 21st century gentrification, concurrent socio-political changes, and their relationship to the ways residents understand and negotiate routine interpersonal relationships. The empirical core of the dissertation consists of three distinct yet interrelated papers on the social landscape of the contemporary Crown Heights neighborhood. These papers detail a range of approaches that residents adopt to better understand their own experiences of discrimination, gentrification, and efforts at reconstructing community and responding to change. Complemented by a chapter on the history of a single ‘representative’ Crown Heights apartment building, its …

Majority Dynamics On Random Graphs With Almost Balanced Initial Settings: The Power Of Few, Hoang Bao Linh Tran

Yale Graduate School of Arts and Sciences Dissertations

A community of n people participate in a parliamentary election with two major parties. Every person initially supports one side, and with each day, changes their opinion to match the majority among their friends. This process, commonly known as Majority Dynamics in literature, and similar processes, have been studied in many different contexts, including Statistical Physics, Computer Science, Economics and Ecology, as discussed in the influential survey by Mossel and Tamuz (2014).

Tran and Vu (2019) considered the process on a Erdös-Rényi G(n, p) random graph and discovered the "Power of Few" phenomenon: Starting from a …

Psychosocial Correlates Of Hiv Prevention, Care, And Well-Being Among Older Women Aging With Hiv, Thi Vu

Yale Graduate School of Arts and Sciences Dissertations

Background: Approximately 54% of the nearly 1.1 million people living with diagnosed HIV in the United States are aged 50 and older. From 2015 to 2019, diagnoses among women ages 55 years and older increased by 7% while diagnoses among other age groups decreased. In 2019, women made up 19% of all HIV diagnoses. Despite advances in HIV science and education, there is still a dearth of research focused on the growing population of older women with HIV. Durvasula’s Contextualized Model for HIV/AIDS Care and Prevention for Older Women highlights that older women with HIV face different barriers to care, …