Master of Science, The Ohio State University, 2023, Psychology

Background: Lung cancer is a product of inflammation and a dysfunctional immune system, and depression has similar dysregulation. Depression disproportionately affects lung cancer patients and has been shown to be significantly associated with systemic inflammation responses. Independently, systemic inflammation, depression, and the depressive symptom trajectory are predictive of non-small cell lung cancer (NSCLC) survival, but the impact of comorbid depressive symptoms with high inflammation at diagnosis on the depressive symptom trajectory is unknown. Studied is the depressive symptom trajectory of four baseline depressive symptom/inflammation profile groups (LoDep/LoInf, LoDep/HiInf, HiDep/LoInf, HiDep/HiInf), with the hypothesis that patients with high depression and high inflammation at baseline would show a uniquely different trajectory of depressive symptoms, one that is elevated compared to all other groups, including patients with high depression but low inflammation. Methods: Newly diagnosed stage-IV non-small cell lung cancer (NSCLC; N=182) patients were enrolled (ClinicalTrials.gov Identifier: NCT03199651). Clinical characteristics, cell count, and albumin data for inflammation biomarker calculation were abstracted from patient electronic medical records from first clinic visit or soon thereafter. Linear mixed models were used to test for differences in the depressive symptom trajectory from diagnosis through 8 months for each baseline depressive symptom/inflammation profile group. Results: Linear mixed models confirmed a significant interaction between Profile 4 (HiDep/HiInf) and time (F(24,945) = -.04, p = .001), indicating Profile 4 (HiDep/HiInf) membership at diagnosis was a significant predictor of the depressive symptom trajectory in both the simple model and the model adjusting for significant sociodemographic and clinical covariates. Tests of this interaction were insignificant for all other profiles, including Profile 3 (HiDep/LoInf). Conclu (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2020, Organizational Behavior

Affective climate constitutes the collective mood of organizational members. A positive affective climate has been viewed as a prerequisite of a healthy organization in which employees can achieve individual and collective goals, and is associated with greater individual loyalty to the organization and improved team performance, among other positive organizational outcomes. Leaders are the architects of the affective climate in teams, and through the process of mood contagion, the moods of leaders typically exert an outsized influence on the moods of those that they lead. Inflammation-associated mood deterioration (IAMD) has been demonstrated under experimental conditions, and has been linked to an increased incidence of mood disorder symptomatology. Across two studies, I use agent-based modeling to model affective climate, and its potential degradation over time via IAMD, as an emergent phenomenon that can be generated through the interaction of team members based on simple local rules. I simulate an organizational environment in which tasks and social interactions represent affective events, resulting in subsequent affective responses in the form of altered mood states via mood contagion. In Study 1, by employing parametric sensitivity analyses and the criterion of generative sufficiency, I found that increases in focal leader IAMD resulted in affective climate degradation over time. Increases in focal leader IAMD also resulted in climates that were more variable over time, and for which a more pronounced differential in follower moods also drove climate degradation. Increasing the number of teams within the simulated environment buffered against climate degradation and produced climates that were relatively more stable. In Study 2, non-linear patterns in affective climate were observed which reflected variations in distance between teams interacting with the effects of IAMD on the focal leader over time, resulting in non-linear degradations of climate. Findings f (open full item for complete abstract)

PhD, University of Cincinnati, 2020, Medicine: Molecular, Cellular and Biochemical Pharmacology

Acute and chronic inflammation are reflected by systemically greater abundance of proinflammatory cytokines and increased infiltration and activation of immune cells in various tissues. In particular, cardiac dysfunction is a common ailment associated with both acute and chronic inflammatory states. As a fundamental component of innate immunity, macrophages play critical roles in both initiating and resolving inflammation in the heart. In fact, macrophages are prominent cells that drive septic cardiomyopathy in animal models; and human monocytes/macrophages secrete more inflammatory cytokines in type 2 diabetic patients and positively correlate with atherosclerosis severity. Secreted and transmembrane protein 1 (Sectm1, also referred to as K12) is a type 1 transmembrane protein. The knowledge of Sectm1 function in human diseases is currently limited to its role as an alternative CD7 ligand to stimulate T cell proliferation. Whether Sectm1 plays a role in normal macrophage biology and inflammatory diseases has never been investigated. In this dissertation, we observed that mRNA levels of Sectm1a (mouse homolog of human Sectm1) was significantly increased in early time points (peak at 6 h), but reduced at later time points in LPS-treated bone marrow-derived macrophages (BMDMs) and spleen of wild-type (WT) mice injected with LPS. To determine the role of Sectm1a in macrophage activation and inflammation-induced cardiac injury, we generated a Sectm1a-knockout (KO) mouse model in which LPS-induced cardiac injury and mortality were greatly augmented. Further analysis revealed that inflammatory macrophages in hearts of KO-LPS mice was greatly accumulated, compared to WT-LPS controls. In accordance to the activated macrophage phenotype, lack of Sectm1a dramatically increased the production of inflammatory cytokines (TNFa, IL-6, and IL-1ß) and MCP-1 levels both in vitro (BMDMs) and in vivo (in serum and myocardium) after LPS challenge. Moreover, we detected significantly (open full item for complete abstract)

Master of Science, The Ohio State University, 2017, Human Ecology: Human Nutrition

Genetic, dietary and inflammatory factors contribute to the etiology of major mood disorders (MMD), thus impeding the identification of specific biomarkers to assist in diagnosis and treatment. We tested the association of vitamin D and inflammatory markers in 36 adolescents with bipolar disorder (BD) and major depressive disorder (MDD) forms of MMD and without MMD (non-mood control). We also assessed the overall level of inflammation using a cell-based reporter assay for nuclear factor-kappa B activation and measuring antibodies to oxidized LDL. We found that these factors were similar between non-mood and MMD youth. To identify potential biomarkers, we developed a screening immunoprecipitation-sequencing approach based on inflammatory brain glia maturation factor beta (GMFß). We discovered that a homologue of GMFß in human plasma is low molecular weight vitamin D binding protein (DBP-L). DBP-L was 8 times more abundant in plasma of BD compared to control participants. DBP-L is a product of enzymatic cleavage, transforming DBP into a macrophage-activating factor. DBP levels in participants' plasma were validated using western blot because mono- and polyclonal ELISA did not recognize DBP-L. We found significantly increased levels of total DBP and DBP-L in BD compared to control participants. The DBP responds early to cellular damage by scavenging structural proteins and activating inflammatory cells. Our data suggest DBP and DBP-L as marker candidates of BD warranting their validation in a larger cohort of adolescent and adult MMD patients.

Doctor of Philosophy in Regulatory Biology, Cleveland State University, 2014, College of Sciences and Health Professions

Inflammation is an obligatory attempt of the host immune system to protect the body against infection. However, unregulated synthesis of pro-inflammatory products can have detrimental effects. Though mechanisms which contribute to inflammation are well appreciated, those that resolve inflammation are poorly understood. Therefore, understanding the molecular basis of such pathways will provide an entirely novel approach to treat and prevent inflammatory diseases. Transcript-selective translational control can regulate the expression of a set of inflammatory genes. We have identified one such mechanism in a novel animal model which relies on the abrogation of ribosomal protein L13a-dependent translational silencing by creating macrophage-specific L13a-knockout mice where resolution of inflammation is severely compromised. We have used these knockout mice to study two different kinds of inflammation: LPS induced systemic inflammation and dextran sodium sulphate (DSS) induced experimental colitis. Upon LPS induced endotoxemia, these mice displayed high mortality rates and severe symptoms of inflammation such as infiltration of immune cells in the peritoneum and major organs leading to tissue destruction. These animals also exhibited high serum levels of TNF-a, blood urea nitrogen (BUN), aspartate aminotransferase (AST) and several other markers of inflammation. Macrophages from these knockouts showed unregulated synthesis of several chemokines (e.g., CXCL13, CCL22, CCL8 and CCR3) and increased polysomal abundance of these mRNAs due to the abrogation of their translational silencing. Upon DSS induced colitis, these knockout mice demonstrated higher susceptibility to colitis displaying reduced survival, significant weight loss, enhanced rectal bleeding and diarrhea. Histopathology analysis of tissue sections from the knockouts showed disruption of epithelial crypts in the colon with infiltration of macrophages in colon and spleen sections. Additionally, elevated levels of (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2013, Integrated Biomedical Science Graduate Program

Stress is commonly considered to be immunosuppressive, but in some diseases states, such as asthma or infection, stress can be immunoenhancing. This immunoenhancement has been associated with immune cell glucocorticoid resistance that renders the cells insensitive to the anti-inflammatory effects of glucocorticoids. A unique murine social disruption stress paradigm, SDR, can model the stress-induced glucocorticoid resistance and exacerbation of inflammation, which can be relevant to inflammatory diseases in humans. In the context of SDR, stress enhances inflammation and delays resolution in an Aspergillus fumigatus (Af) allergic airway inflammation model. In stressed and Af challenged mice, gene expression data suggested increased inflammation (IL-1ß, TNF-a, GM-CSF) with histological data supporting that the increase was due to infiltrating inflammatory cells. Furthermore, stress and Af challenge most prominently increased granulocytes in the lung compared to controls. Bone marrow chimeras demonstrated that the increase in immune cells was bone marrow-derived, and that stress induced myeloid progenitor cell egress and trafficking to lung. Closer examination of the granulocytic population identified many as neutrophilic populations. Using the antibodies to CD16 and CD49d, several distinct neutrophil populations were visualized including apoptotic, mature, activated, or immature neutrophils. Stress and Af challenge significantly increased the immature neutrophil population in both the lung and blood. In the clinic, it has been shown that a rapid release of immature neutrophils from the bone marrow can occur during times of stress and immune challenge. The consequences of this state of neutrophilia on disease are still being determined, but it is known these neutrophils have a higher capacity to induce inflammation and exacerbate patient symptoms. In a second study, we examined the consequences of Y1 receptor (Y1R), ß-adrenergic receptor (ßAR), and IL-1 receptor t (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2024, Pathology

Activation of Toll-like Receptors (TLRs) induces inflammation regulated by members of the nuclear factor kappaB (NF-κB) transcription factor family. NF-κB c-Rel, a subunit of NF-κB, is a key regulator of inflammatory signaling, and is critical in specific dendritic cell functions. Dendritic cells bridge the innate and adaptive immune response through the secretion of cytokines, sampling and presentation of antigens, and activation of naive T cells during immune response. In this work, we describe the role of c-Rel following TLR activation as an important regulator of dendritic cell function. We describe the TLR7/c-Rel signaling axis and its critical role in the expression of inflammatory cytokines needed for psoriasis pathogenesis. We found that TLR7 agonism, and not application of its vehicle compound isostearic acid, is the primary driver of the Aldara-induced psoriasis mouse model, thus elucidating important mechanisms behind disease models. Finally, we describe how the increase in O-GlcNAcylation, and the enhancement of c-Rel specific O-GlcNAcylation, during TLR4 signaling regulates dendritic cell activation. Together, this work expands on the fundamental understanding behind how c-Rel acts as a transcriptional regulator during TLR signaling, and the downstream consequences in disease propagation.

Doctor of Philosophy, The Ohio State University, 2024, Psychology

Background: Approximately one-third of depression cases feature clinically elevated inflammation. The Social Signal Transduction Theory of Depression outlines one pathway to inflammation-driven depressive symptoms. It posits that those who report more frequent social stress and who have heightened inflammatory responses to an acute laboratory social stressor will have the greatest depressive symptom increases over time. Aims: This series of studies tested the Social Signal Transduction Theory of Depression, and whether this pathway is specific to social stress. It also investigated whether omega-3 supplementation impedes this etiological pathway, especially among those who are socially stressed. Methods: To test the Social Signal Transduction Theory of Depression, 76 physically healthy adults and 79 breast cancer survivors completed a laboratory social stressor (a marital conflict or the Trier Social Stress Test, respectively), had their blood drawn to assess inflammatory responsivity, and reported their stress exposure at baseline and their depressive symptoms at baseline and follow-up (one month later or four and eight months later, respectively). To test omega-3's effect on inflammatory responses, 138 middle-aged, sedentary adults were randomized to 2.5 g/day of omega-3, 1.25 g/day of omega-3, or placebo for four months. Before and after supplementation, they completed the Trier Social Stress Test and repeatedly had their blood drawn to assess inflammatory responsivity. The final study features secondary analyses from the same randomized, controlled trial to examine whether omega-3 reduced self-reported depressive symptoms among those who reported more social stress. Results: In the first study, those who reported more frequent social stress, but not other types of stress, and had greater inflammatory responsivity at baseline had heightened depressive symptoms at follow-up. This effect was specific to social stress. In the second study, omega-3 iii supplemen (open full item for complete abstract)

Master of Science, The Ohio State University, 2024, Human Ecology: Human Nutrition

Current dietary guidelines recommend the consumption of 3-4 ounces of whole grains per day. However, evidence from controlled trials is equivocal whether meeting recommendations effectively manages cardiometabolic risk, especially glucose intolerance. Understanding the benefits of whole grains is important consistent with prediabetes afflicting 38% of US adults, which drives their risk for overt type 2 diabetes mellitus (T2DM) and premature mortality. The objective of this thesis was to investigate whole wheat-mediated changes in glucose tolerance, insulin, and inflammation in persons with and without a family history of diabetes (FHD). The hypothesis was that whole grain consumption would improve glucose tolerance and inflammation in persons with prediabetes, and that the effect would be greater in persons with no FHD. To test this, a randomized, controlled, crossover trial was conducted in persons with unmanaged prediabetes in which they received a fully prescribed eucaloric diet containing white bread (WHITE) or wheat bread (WHEAT; 4 daily slices) for 2 weeks. Plasma glucose, insulin, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured prior to and after each 2-week study arm. Postprandial glycemia and insulinemia were also assessed following an oral glucose tolerance test at the end of each study arm. Participants (n = 39) completed the trial with high-compliance to test bread consumption (99.7%) and adherence to the controlled diet (97.5% of prescribed iii diet) regardless of treatment arm. Fasting glucose and insulin were unaffected by WHEAT. However, postprandial glucose was lower (P = 0.03) and postprandial insulin tended to be higher (P = 0.06) in WHEAT. Only those with no FHD were observed to have improved glucose tolerance (P = 0.004) and a tendency for higher postprandial insulin (P = 0.10). Although insulinogenic index (IGI) and disposition index (DI) scores were unaffected by WHEAT in all participants (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Biomedical Sciences

Cancer patients experience debilitating physiological (e.g., gastrointestinal) and behavioral (e.g., cognitive decline) symptoms due to the cancer itself and subsequent cancer treatments. These symptoms are related to reduced quality of life and treatment delays and dose reductions, thereby increasing patient mortality. Inflammation and gut microbiome disruptions are both commonly hypothesized to play a role in these symptoms. Here, I investigate the extent to which breast cancer and chemotherapy independently and synergistically cause immune dysfunction, gut microbiome disruption, and physiological and behavioral symptoms. Chapter 2 characterizes a comprehensive breast cancer mouse model in terms of immune, neuroimaging, and behavioral effects. In this model, chemotherapy induced inflammation, neuroimaging alterations, and reduced locomotor activity. In chapter 3, I demonstrate that mammary tumors blunt microglial and behavioral responses to immune challenges in mice. This impairment of immune and behavioral responses is specific to a peripheral route of immune challenge administration, suggesting a non-brain-specific mechanism. Chapter 4 demonstrates that chemotherapy induces gut microbiome disruption, elevates circulating TNF-α, and induces cognitive decline in breast cancer patients. Furthermore, cognitive decline is related to decreases in microbial diversity but not elevated circulating cytokines. Finally, in chapter 5, I show that decreased gut microbial diversity prior to chemotherapy treatment predisposes breast cancer patients to chemotherapy-induced gut microbiome disruption and gastrointestinal symptoms. The findings of this work demonstrate that tumors lead to immune dysfunction and behavioral consequences in a preclinical model of breast cancer. Furthermore, this work delineates the roles of chemotherapy-induced gut microbiome disruption and inflammation in the development of cognitive decline and gastrointestinal symptoms in a population of breast can (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Human Ecology: Human Nutrition

Chemotherapy is a common cancer treatment that induces neuroinflammation and may contribute to cancer-related cognitive impairment (CRCI). A higher intake of Omega-3 polyunsaturated unsaturated fatty acids (PUFAs) may reduce inflammation. In our previous mouse model of chemotherapy, Eicosapentaenoic acid (EPA) and Docosahexaenoic Acid (DHA)-enriched diets were shown to reduce pro-inflammatory biomarkers in the cortex, including Interleukin-6 (IL-6) and Keratinocyte chemoattractant / growth-regulated oncogene (KC/GRO) in the context of a background diet low in fat (19% of kilocalories). Considering that the majority of breast cancer survivors are overweight or obese at the time of diagnosis and high-fat diets can promote the develoment of obesity, EPA and DHA in diets with different fat contents should be evaluated to determine effects on neuroinflammation and neurodegeneration. In addition, the association of blood levels of fatty acids with cognitive function and the underlying mechanisms of CRCI have not been well studied in breast cancer survivors. In addition to omega-3 PUFAs, omega-6 PUFAs are also important for inflammatory processes. Moreover, we have found omega-9 monounsaturated fatty acids (MUFAs) to rise in mice brain after chemotherapy treatment, potentially suggesting neurodegeneration. Therefore, this dissertation will focus on understanding the relationship of fatty acids in the diet and blood, including omega-3 and omega-6 PUFAs and omega-9 MUFAs, with neuroinflammation, neurodegeneration, and cognitive outcomes in a chemotherapy-treated mouse model and human breast cancer survivors. The first project of this dissertation evaluated whether a diet rich in long-chain omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid (EPA and DHA) could reduce neuroinflammation and neurodegeneration in a mouse model of chemotherapy. In this study, female C57BL/6 mice were randomized to high fat, high fat omega-3, or low-fat diet groups for 8 week (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Biomedical Sciences

The innate immune response to infection involves a complex series of signaling events, threat recognition molecules, and effector proteins that act together to eliminate pathogens. As part of the patrolling immune cells, monocytes are often the first responders to infection and are specifically equipped to recognize a diverse range of pathogens and quickly respond to threats. One of these mechanisms involves a series of proteins known as inflammasomes that are critical for producing an adequate immune response to fend off pathogen infection while simultaneously being regulated to prevent hyper inflammation and inflammatory diseases such as sepsis. Inflammasomes are multimeric complexes that become activated upon pathogen detection by an upstream sensor molecule that can be in response to both bacterial and viral infection. Once activated, a highly regulated signaling cascade occurs that results in the eventual enzymatic activation of the pore forming protein Gasdermin D (GSDMD). Once activated, GSDMD traffics to cellular membranes to form pores often leading to an inflammatory form of cell death known as pyroptosis. While cell death is necessary to maintain homeostasis and cell turnover, dysregulated cell death in the case of GSDMD induced pyroptosis can lead to severe inflammatory diseases such as sepsis and acute respiratory distress syndrome (ARDS). Despite significant advances in unraveling the mechanism of GSDMD activation and designing targeted therapeutics against inflammation, gaps in knowledge still persist as evident by the high mortality rate of sepsis and inflammatory disorders. As such, it is essential to improve our understanding about the signaling events leading to GSDMD activation, the impact of active GSDMD on inflammation and cell death, and the regulators involved with GSDMD activation. Our lab has recently discovered a novel avenue of GSDMD mediated cell injury through the release of monocyte derived exosomes (EVs) containing active GSDMD that a (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Psychology

Perceived discrimination is a psychosocial stressor defined as the experience of unfair treatment based on race, sex, religion, or other characteristics. Experiences of discrimination have been associated with negative physical and psychological health outcomes. Though less frequently studied, discrimination has also been linked to adverse cognitive outcomes. Discrimination is particularly important to study as chronic stress may accelerate preexisting vulnerabilities, thereby exacerbating negative health outcomes. The goal of this project is to clarify the role of discrimination in two important contexts: racial disparities in cognitive health and age-related cognitive decline. The current study will examine the association between discriminatory experiences and cognitive functioning in a sample of healthy adults from the Midlife in the United States (MIDUS) dataset. Moreover, I will leverage the comprehensive biological and psychological information available through MIDUS to explore the mediating impact of inflammatory markers, metabolic syndrome, and allostatic load, as well as the moderating impact of psychosocial factors on these relationships. I will test these relationships by pursuing three specific studies. Study 1 investigates whether perceived discrimination mediates the relationship between self-reported race and cognitive functioning. Study 2 describes the relationship between perceived discrimination and cognition across the lifespan. Additionally, this study will explore the role of moderating social factors on the relationship between discrimination and cognition. Study 3 then clarifies the role of health mediators in these relationships. The implications of these results are threefold. First, they will provide a more comprehensive understanding of the relationship among these factors; second, they will highlight who may be at increased risk for cognitive decline following experiences of discrimination; and third, these results may enable researcher (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2023, Neuroscience Graduate Studies Program

Sensorineural hearing loss (SNHL) is a common hearing health disorder caused by damage to cochlear sensory hair cells and neurons, which can occur during normal aging and from acoustic insults throughout the lifespan. Age-related hearing loss (ARHL) describes the form of SNHL that happens in aging patients with progressive loss of hearing perception. Noise-induced hearing loss (NIHL) occurs from noise damage and can happen at any age. Both ARHL and NIHL share similar features in cochlear tissue damages, including the loss of sensory hair cells, auditory neurons, and synapses in the cochlea. Further synaptopathy occurs in the cochlear nucleus (CN), which is where all arriving auditory information from the ear first enters the central nervous system. Acute and chronic cochlear inflammation are associated with worsening outcomes in SNHL. Resident innate immune cells modulate local inflammatory responses and are implicated in both the cochlea and the brain during SNHL. Tissue damage and age-related degeneration increase the activation of both cochlear macrophages and microglia in the brain. These activated immune cells release factors that recruit additional immune cells and alter tissues in ways that can contribute to the progression of pathology. Example signals potentially released by resident immune cells include complement factors, which are proteins also found in circulation that can accumulate in damaged or diseased tissues. This dissertation investigates the activation of innate immune cells, including cochlear macrophages and microglia during ARHL and NIHL, and whether the activation of complement pathways in the cochlea and CN may contribute to SNHL pathophysiology. CBA/CaJ mice were used as the animal model in this research, which were either aged in ambient noise environments to develop ARHL or exposed to various intensities of noise to cause NIHL. Hearing was assessed in all mice and tissues were collected to measure changes in the resident immune cells and (open full item for complete abstract)

MS, University of Cincinnati, 2023, Allied Health Sciences: Nutrition

Background/Purpose: Cancer survivors who undergo a blood and marrow transplant often report low quality of life along with a variety of symptoms, with fatigue being the symptom of most interest for this study. Evidence regarding inflammation and its relationship to fatigue has been accumulating in recent years. The ability of the diet to impact inflammation and therefore possibly fatigue is the main interest of this study. Antioxidants of interest in this study were mainly zinc, selenium, vitamin A, vitamin C, and vitamin E. This research aimed to investigate whether there was an association between a low versus high dietary antioxidant capacity and chronic fatigue and related symptoms in BMT survivors one year after transplant. Methods: This study was a secondary data analysis of a convergent design mixed methods study involving BMT survivors from the University of Cincinnati Medial Center (UCMC) and the Jewish Hospital-Mercy Health Blood and Marrow Transplantation programs entitled Factors Contributing to Symptoms of Survivors of Adults Blood and Marrow Transplant (SOS-A BMT) (PI Dr. Caroline F. Morrison, PhD, RN). Diet was assessed with the Diet History Questionnaire III, and antioxidant potential of the diet was assessed using Dietary Antioxidant Index (DAI) scores and Dietary Antioxidant Quality (DAQ). Diet quality was assessed by calculating Dietary Approaches to Stop Hypertension (DASH) scores and Healthy Eating Index (HEI) scores. These measures were compared to clinical indicators/symptoms using items from the Promis-29, FACT-BMT, and Memorial Symptom Assessment Scale (MSAS) questionnaires. Participants data was split into two groups (High) and (Low), at the median score for each measure. Population averages for each clinical indicator in both groups were obtained and analyzed for significance. Results: Participant's DAI scores had a mean of -1.43, indicating that on average, participants' diets did not have significant anti-inflammato (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2023, Psychology

Lung cancer is the most prevalent type of cancer and the leading cause of cancer mortality worldwide. The predominant histological subtype – non-small cell lung cancer (NSCLC) – is most frequently diagnosed in its advanced stage (Stage IV), when the cancer has metastasized beyond the lungs, is most symptomatic, and is least responsive to treatment. Patients with lung cancer experience a substantial psychological and physical symptom burden. However, these patients, especially those with advanced disease, have received minimal attention in psychosocial research over the years. Prior research was conducted in the era of cancer treatments using chemotherapy alone, which have since been replaced or enhanced by modern treatments utilizing immunotherapies and targeted therapies. It is critical that psychosocial interventions targeting depressive and anxiety symptoms are developed for patients with advanced lung cancer and implemented as part of an integrated treatment approach, in order to improve quality of life and overall survival. To address this need, this Phase IIa pilot examined the feasibility and effectiveness of A Biobehavioral/Cognitive (ABC) Treatment to improve psychological symptoms, physical symptoms, and systemic inflammation for patients (N=30 enrolled, 19 treated) with stage IV NSCLC and comorbid depression and/or anxiety. The intervention was found to be tolerable, acceptable, and mostly feasible for this patient population. Longitudinal mixed-effects modeling using three assessment time points (baseline, week 5, week 10) and including relevant covariates revealed that ABC patients experienced statistically and clinically significant reductions in depressive and anxiety symptoms, stability in physical symptoms and systemic inflammation, and an increase in perceived social support over the course of treatment. From baseline to follow-up, depressive and anxiety symptoms decreased from ‘moderate' to ‘minimal' severity. Exploratory analyses compared ABC gro (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2023, Pathology

Autoimmunity in type 1 diabetes is primarily caused by destruction of insulin producing pancreatic beta cells by cytotoxic T cells, in part due to dysfunctional T regulatory (Tregs) cells. This leads to hyperglycemia, which is a hallmark of diabetes. Adverse pathological effects of hyperglycemia include the increased posttranslational modification of cellular proteins at serine and threonine residues by the sugar N-acetylglucosamine, in a process termed O-GlcNAcylation. We found that the transcription factor nuclear factor kappaB (NF-κB) subunit c-Rel is a target for this pathologic O-GlcNAcylation at serine residue 350 in T lymphocytes. c-Rel is the major regulator of CD4+ and CD8+ T cell function and Treg development that controls autoimmunity and immunosuppression, respectively. Earlier, we found that c-Rel O-GlcNAcylation increases its transcriptional activity and the expression of pro-autoimmune cytokines in CD4+ T cells. However, the role c-Rel O-GlcNAcylation plays in Tregs and cytotoxic T cells remains elusive. Here, we describe dual mechanisms showing c-Rel O-GlcNAcylation acts as both a negative regulator in the transcription of forkhead box P3 (FOXP3) in Tregs while also a positive regulator of transcription of the cytotoxic genes, Fas Ligand (FasL) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), in cytotoxic T cells. To study more closely how O-GlcNAcylation is changing c-Rel-DNA binding, we have developed two tools – a site-specific monoclonal antibody for O-GlcNAcylated c-Rel and a peptidomimetic drug called OGC350 to block its transcriptional activity. Use of the S350 site-specific anti-O-GlcNAcylated c-Rel antibody has the potential to reveal the role of c-Rel O-GlcNAcylation in regulating T cell function in autoimmune diabetes, beyond the regulation of FOXP3 and cytotoxic genes, and can provide evidence of how OGC350 may further impact O-GlcNAc-sensitive transcription in T cells.

PhD, University of Cincinnati, 2023, Medicine: Cancer and Cell Biology

IRAKs are a family of related kinases that operate at the nexus of multiple inflammatory pathways implicated in myeloid malignancies. IRAK4 inhibitors have advanced into clinical trials for MDS and AML. Early data from these trials validate IRAK4 as a therapeutic target; however, the overall responses remain modest. Herein, we explored mechanisms of resistance to IRAK4-selective inhibitors in MDS/AML. Consistent with observations from clinical trials, inhibition or deletion of IRAK4 in MDS/AML cell lines and patient samples lines resulted in incomplete suppression of LSPCs and a corresponding activation of innate immune pathways. Given the evolutionary conserved redundancy of IRAK-dependent pathways, we examined the expression of IRAK paralogs. Deficiency or inhibition of IRAK4 in MDS/AML cells induced overexpression and activation of the IRAK4 paralog, IRAK1. To validate the compensation of IRAK1, we deleted IRAK1 in MDS/AML cells and found that concomitant suppression of IRAK1 led to a significant reduction of LSPC function in IRAK4-KO MDS/AML cells. Canonical IRAK signaling depends on recruitment of MyD88 and IRAK4 to activated receptors, which results in the subsequent recruitment and activation of IRAK1. Based on this canonical model, IRAK1 and IRAK4 are independently essential for signaling downstream of MyD88. However, MyD88-KO AML cells did not exhibit a functional defect but did retain sensitivity to deficiency of IRAK1 and IRAK4, indicating canonical MyD88-dependent signaling is not operational in MDS/AML. We next investigated gene expression programs dependent on IRAK1 and/or IRAK4, yet independent of MyD88. IRAK1/4 deletion correlated with dysregulation of transcriptional programs involved in stem cell maintenance and myeloid differentiation. The requirement for IRAK1/4 in preserving an undifferentiated LSPC state was corroborated by morphological and immunophenotypic assessment of IRAK1/4dKO MDS/AML cells. To delineate non-canonical sign (open full item for complete abstract)

PhD, University of Cincinnati, 2023, Medicine: Immunology

The unabated obesity pandemic drives increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD has enacted an enormous health and financial burden worldwide. Yet, therapies for this disease are lacking in part because etiology and progression of this disease are underdefined. Inflammation is a critical link between obesity and NAFLD. Moreover, inflammatory mediators and immune cells are invoked in the transition from benign steatosis to inflammatory non-alcoholic steatohepatitis (NASH). Hence, understanding mechanisms that regulate inflammation during obesity driven NAFLD may allow for development of novel therapeutics. In this dissertation, we focus on two factors that regulate immune cell inflammation and NAFLD progression, cellular metabolism and thermoneutral housing. Among the myriad immune cells, CD4+ T cells are garnering attention as key contributors to NAFLD progression. We show that exploitation of CD4+ T cell glutamine metabolism via exogenous glutamine supplementation negatively regulates their inflammatory capacity in obesity driven NAFLD. Indeed, CD4+ inhibition of glutaminolysis uniquely increased their inflammatory vigor, activation of IL-17 signaling axis and exacerbated hepatocellular damage. Notably, we show that hepatocellular IL-17RA expression was central to amplified hepatocellular damage and NAFLD. Although inflammation is essential to NAFLD pathogenesis, pre-clinical research is plagued by the lack of experimental models that recapitulate human disease. Here, we expand upon previous findings in demonstrating that augmented immune cell inflammatory vigor and exacerbated NAFLD prompted by thermoneutral housing (Tn) are conserved in multiple experimental models of NAFLD. Hence, addressing both metabolism and inflammation should be a two-pronged approached when investigation mechanisms of NAFLD pathogenesis. Notably, Tn housing modifies both in mice and should be utilized as a tool for interrogating cellular metabolic mechanisms (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2023, Nursing

Type 2 diabetes mellitus (T2DM) affects how the body processes glucose and uses insulin. As a result of improper glucose metabolism, people with T2DM may experience kidney disease, increased risks for macrovascular complications, heart attacks and strokes. Many people diagnosed with T2DM find it difficult cope with necessary lifestyle changes related to medication adherence, diet and overall self-management. The purpose of this secondary analysis was to explore the relationship of depressive symptoms and food security by race and gender in older adults with T2DM. Outcomes of c-reactive protein (CRP) and HbA1c were used to measure T2DM control. Results revealed a statistically significant difference in c-reactive protein by gender and a statistically significant difference in depressive symptoms by race and gender. There was also a statistically significant difference in food security by gender. Lastly, regression models revealed depressive symptoms influenced CRP. Future research should further explore factors that impact CRP and HbA1c in this population.