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Indiana University-Purdue University Indianapolis (IUPUI) / Enteric viruses are infectious human pathogens that initiate infection in the gastrointestinal tract. They follow a fecal-oral route of transmission and are spread by contamination of food, water, or contact between individuals. Furthermore, enteric viruses also cause significant morbidity, mortality, and economic burdens yearly. Coxsackievirus (CV) is commonly isolated among enteric viruses and is an etiological agent of hand, foot, and mouth disease, hemorrhagic conjunctivitis, and myocarditis. The virus predominantly infects infants and young children and accounts for 11% of the fatality rate in neonates. Despite CV’s impact on human health, there are no treatments or vaccines for CV infections. Using a mouse model to study a key CV, Coxsackievirus B3 (CVB3), our laboratory has found two critical factors that impact CVB3 replication and pathogenesis. First, we have demonstrated that intestinal bacteria enhance intestinal CVB3 replication. We found that certain specific bacteria (Salmonella enterica) and its cell wall components, like lipopolysaccharides (LPS), enhanced CVB3 stability and infectivity in vitro. Additionally, we found that particular constituents of LPS are required for stability to occur. These data suggest that specific bacteria may be integral in maintaining CVB3 infectivity in the intestine. Besides virus-microbiome interaction, CVB3 is also impacted by sex hormones. Using castrated mice models, we observed a sex bias to CVB3 infection, with male mice succumbing to CVB3-induced disease at an increased rate compared to female mice. Our data suggest that testosterone, a predominant male sex hormone, enhanced CVB3 intestinal replication and viral dissemination to organs in male and female mice, but lethality only in male mice. Moreover, testosterone also affected the immune response by reducing the activation of the CD8+ T cells. CD8+ T cells are required to clear the viral infection and are integral in vaccine development. In contrast, we found an enhanced CD8+ T cell response in female mice to CVB3 infection, suggesting a sex-dependent T cell response that may underlie the sex bias in disease. Overall, these data represent an essential advancement in the CV field and will help develop future therapeutics and aid in vaccine design to limit CV infections.

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<p>Atherosclerosis is a multi-factorial disease and is the major cause of death in the western world. Numerous risk factors, including hyperlipidemia, obesity, diabetes, smoking, hypertension, and family history increase the risk of atherosclerosis and death from cardiovascular disease (CVD). Clinical and epidemiological studies have now shown that hyperhomocysteinemia (HHcy) is an independent risk factor for CVD. Further, we and others have demonstrated that HHcy accelerates atherosclerosis in apolipoprotein Edeficient ( apoff1-) mice. Although several studies have reported that homocysteineinduced endoplasmic reticulum (ER) stress causes growth arrest and programmed cell death (PCD) in cultured vascular endothelial cells, the cellular factors responsible for this effect and their relevance to atherosclerosis have not been completely elucidated.</p><p>Previously, we have demonstrated that homocysteine induces the expression of Tcell death associated gene 51 (TDAG51), a member of the pleckstrin homology-related domain family, in cultured human vascular endothelial cells. Transient overexpression of TDAG51 elicited significant changes in cell morphology, decreased cell adhesion and promoted detachment-mediated PCD. In support of these in vitro findings, TDAG51 expression was increased and correlated with PCD in the atherosclerotic lesions from apoff1-mice fed hyperhomocysteinemic diets, compared to mice fed control diet. To investigate the in vivo significance of TDAG51 on atherosclerotic lesion development and progression, knockout mice deficient in both TDAG51 and apoE genes were generated. Our findings show that TDAG51-1-/apoff1-double knockout (DKO) mice fed control chow diet have significantly reduced atherosclerotic lesion size, compared to ageand sex-matched apoff1-control mice. Atheroprotective function of TDAG51 deficiency may be explained in part by the observation that there is a significant upregulation of peroxisome proliferator-activated receptor y (PPAR-y) in TDAG51-deficient (TDAG51 _1_) cells including mouse embryonic fibroblasts (MEFs), compared to control wildtype MEFs. Given that PPAR-y has both atheroprotective and anti-inflammatory properties, TDAG51 may represent a unique negative regulator of PPAR-y and its downstream gene targets. Taken together, my findings demonstrate that TDAG51 is a novel cellular mediator involved in the development and progression of atherosclerosis.</p><p>In addition to its anti-atherogenic properties, I have demonstrated that TDAG5 l _1_ MEFs have increased migratory properties following monolayer disruption or in response to chemotaxis on fibronectin-coated Boyden chambers, compared to wildtype control MEFs. Although TDAG51-induced cell migration could potentially affect atherosclerotic lesion development, our recent observations suggest that TDAG51 may also have a role in wound healing. Our studies have shown that dorsal skin wounds within TDAG5 l _ 1_ mice healed slowly, compared to those in control mice through a mechanism involving impaired myofibroblast differentiation. Since the underlying mechanisms of wound healing and fibrosis are similar, it is conceivable that TDAG51 may have role in fibrosis.</p><p>In summary, this thesis provides novel evidence that TDAG5 l is involved in the pathogenesis of atherosclerosis and wound healing. Furthermore, TDAG51 may represent a novel therapeutic target for attenuating atherosclerotic lesion development, thereby reducing the risk of cardiovascular disease and its complications.</p> / Thesis / Doctor of Philosophy (PhD)

INTRODUCTION: Multiple Myeloma (MM) is a plasma cell malignancy that causes improper production of immunoglobulins and elevated levels of monoclonal protein. Resulting morbidity is a conglomeration of symptoms due to organ failure, lytic bone disease, and hematological insufficiencies. The American Cancer Society estimates more than 35,000 patients will be diagnosed with multiple myeloma in the United States in 2023. Current therapeutic regimen hinge on the idea of myeloma as a chronic disease that cannot be entirely cured and toxic chemotherapies with long-term treatment cycles are the standard of care. The need for a one-time therapy that is both safe and efficacious and with potentially curative action has led to the development of anti-BCMA CAR T-cell infusions. The overwhelming success of this novel therapy in MM has been demonstrated in clinical trials, but the need for data surrounding the long-term toxicities post-CAR T-cell treatment in a real-world population of MM patients still exists. Common expected adverse events that have been identified in clinical trials include cytokine release syndrome, neurotoxic events, hematological toxicities, and infections associated with immunosuppression. This study was formed to elucidate the long-term adverse events associated with anti-BCMA CAR T-cell therapy in a real-world patient population. METHODS: A total of 54 patients who received a CAR T-cell infusion for their relapsed and refractory multiple myeloma were studied in a retrospective analysis at Dana-Farber Cancer Institute. Data were collected prior, during, and after infusion to gauge treatment performance and toxic side effects. Analyses of collected data, including complete blood counts, serum protein electrophoresis, fluorescence in-situ hybridization (FISH) data from bone marrow biopsy, and imaging were performed. RESULTS: Patients were followed for a mean average of 165 days (range 29-462) post-infusion. Patients either received CiltaCel (n = 7) or IdeCel (n = 47). Grade 3 or greater cytopenia occurred in 48% of patients at some point following infusion and the median time to first onset was 30 days (10-189). Forty-six patients (85%) achieved a partial response or better as their best response to therapy. During inpatient infusion, 76% of patients experienced grade 1 or 2 cytokine release syndrome (CRS) and 8% experienced grade 1 or 2 immune effector cell-associated neurotoxicity syndrome (ICANS). A total of 12 patients (22%) developed infections after infusion with respiratory infections being the most frequent (17%). Nine patients were also evaluated on a closer scale for their experience with prolonged cytopenia, but no significant commonalities were found. DISCUSSION: The analysis of this study found this patient population to have a considerably less frequent incidence of high grade cytopenia as compared to clinical trial data. However, 92% of patients developed grade 1-3 anemia and 77% developed any grade thrombocytopenia, both figures are greater than those presented in the KarMMa-2 clinical trial study for ide-cel. Patients who developed severe cytopenia were able to recover absolute neutrophil counts (ANC) over the course of their follow-up appointments which is an important aspect in the prevention and avoidance of serious infection. This same recovery was not observed in platelet or hemoglobin counts. Additionally, 15 patients were reported to still have high-grade cytopenia at 30—60-days post infusion, but this number drops to only 5 patients for the 60—90-day timeframe, this steep drop is indicative of an early onset of severe cytopenia that may not carry on as the patient progresses further from their infusion date. Compared to the KarMMa-2 study which reported an infection incidence of 69%, observations from this current study suggest this real-world patient population remained healthier after infusion in terms of infection with only 23% of patients developing post-infusion infection. Instances of CRS and ICANS were comparable to data evaluated in clinical trials. Finally, treatment responses did not significantly differ between the population of patients who developed grade 3 or greater cytopenia and those patients who did not. More data is required to determine the risk-benefit profile of early intervention with CAR T-cell therapy as directly compared to the current standard of care. This study is an encouraging insight into the performance of real-world RRMM patients that should assure patients and clinicians of the safety and uncompromising efficacy of anti-BCMA therapy as a treatment option for multiple myeloma.

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