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

Cancer remains one of the most significant challenges in modern medicine, with global incidence steadily rising. In 2022, the American Cancer Society reported 20 million new cancer cases and 9.7 million cancer-related deaths worldwide, a number predicted to reach 35 million by 2050. Initiatives like the Cancer Moonshot program, launched by President Joe Biden in 2016, have spurred collaborations and innovations in cancer research. Understanding cancer biology and developing effective therapeutic interventions are imperative in combating this complex disease. Over decades, significant progress has been made in revealing the molecular mechanisms underlying cancer development, leading to diverse therapeutic options. From traditional approaches like surgery and chemotherapy to novel immunotherapies and targeted therapies, the therapies against cancer have expanded. However, therapy resistance and adverse effects persist, necessitating ongoing research and innovation. Surgery offers a curative option for localized solid tumors, while chemotherapy disrupts cancer cell proliferation. Chemotherapy, often paired with radiation therapy, is standard care for some cancers despite associated adverse effects. Immunotherapy, leveraging the body's immune system, and targeted therapies, selectively targeting molecular anomalies, have transformed cancer care. Yet, tumor heterogeneity and microenvironment composition pose challenges, highlighting the need for continued research. Monoclonal antibodies (mAbs) and immune checkpoint inhibitors have provided targeted treatment options with reduced systemic toxicity. mAbs disrupt key signaling pathways essential for tumor growth and survival, while immune checkpoint inhibitors "release the breaks" of the immune system. Despite success, only a fraction of patients experience clinical benefit, emphasizing the need for predictive biomarkers and understanding the tumor microenvironment's role. The tumor microenvironment (TME) comprises of ca (open full item for complete abstract)

Committee: William Carson III (Advisor) Subjects: Biology; Immunology; Oncology

Doctor of Philosophy, The Ohio State University, 2023, Molecular, Cellular and Developmental Biology

Malignant Peripheral Nerve Sheath Tumor (MPNST) is an aggressive subtype of soft tissue sarcoma characterized by poor prognosis, limited response to traditional chemotherapy, and high rates of post-surgical recurrence. Immune-based therapies have emerged as a promising avenue for tumor treatment due to their ability to induce durable and safe clinical responses. Unleashing T cell responses is crucial for engaging the immune system and generating targeted long-lasting therapeutic effect. To address the pressing need for novel therapeutic strategies, we have developed two immune-based approaches aimed at harnessing the antitumor potential of T cells and enhancing their efficacy against MPNST. Firstly, we engineered a chlorotoxin bispecific T cell engager, designed to target MPNST cells through chlorotoxin and redirect T cells via CD3 (Chapter 2). Co-culturing the chlorotoxin bispecific T cell engager with the human MPNST-derived cell line S426TY and peripheral blood mononuclear cells led to a substantial reduction in tumor cell viability and activation of T cells. These results indicate that the chlorotoxin bispecific T cell engager effectively directed the cytotoxic activity of T cells towards MPNST cells. Secondly, we investigated the therapeutic utility of combining T-VEC oncolytic viroimmunotherapy with myelolytic treatments (Trabectedin or Pexidartinib) in murine models (Chapter 3). Our study demonstrated that this rational combination significantly improved survival in weakly-immunogenic mouse models with varying levels of immunogenicity. Notably, the enhanced efficacy of the combination of T-VEC and Trabectedin was attributed to enhanced antitumor T cell response. In summary, our findings provide compelling evidence for the potential of myelolytic viroimmunotherapy and chlorotoxin bispecific T cell engagers as effective therapeutic approaches against MPNST. These results underscore the significance of investigating T cell-based strategies for the treatment of M (open full item for complete abstract)

Committee: Timothy Cripe (Advisor) Subjects: Oncology; Therapy

PhD, University of Cincinnati, 2021, Engineering and Applied Science: Materials Science

Glass topological phases and melt dynamics of especially dry and homogeneous binary AsxS100-x melts/glasses are studied in Raman scattering, Modulated-DSC and volumetric experiments. In the S-rich glasses (12% < x < 23%), unambiguous and direct evidence for the elusive 537 cm-1 stretch vibrational mode of the Quasi-Tetrahedral (QT), S=As(S1/2)3, local structure is observed in Fourier Transform-Raman (FT-Raman) scattering once the melts homogenized and the glasses cycled through Tg+10°C for an extended period. The enthalpy of relaxation at Tg, ?Hnr(x), fragility index, m(x), Molar volumes Vm(x) – each display three distinct regime of variation. Specifically, ?Hnr(x) shows an abrupt square-well like variation (Reversibility window), and m(x) shows a Gaussian like global minimum (Fragility window) whereas Vm(x) shows a Gaussian-like local minimum (Volumetric window) in the isostatically rigid phase (22.5% < x < 28.5%). At low x (< 20%) in the Flexible phase, glasses are segregated with a S8-rich nanophase that decouples from the As-S glassy backbone. At medium x (22.5% < x < 28.5%) glassy backbones form an isostatically rigid phase displaying a vanishing ?Hnr(x) term, and compacted structures with corresponding melts being super-strong (m < 20). At high x (28.5% < x < 40%) in the Stressed-Rigid phase, glasses possess an increasing ?Hnr(x) term, and melts become increasingly fragile, with m(x) > 20 as x increases. Taken together, these results demonstrate that super-strong melts yield isostatically rigid glasses, while fragile glasses form either Flexible or Stressed-Rigid upon cooling. The onset of the rigidity transition near = 2.22 instead of the usual value of = 2.40, is identified with the presence of QT local units in addition to pyramidal As(S1/2)3 local units in the glassy backbone, and with a small but finite fraction of polymeric Sn chains being decoupled from the backbone.

Committee: Punit Boolchand Ph.D. (Committee Chair); Marc Cahay Ph.D. (Committee Member); Jude Iroh Ph.D. (Committee Member); Vijay Vasudevan Ph.D. (Committee Member) Subjects: Materials Science

Master of Science, The Ohio State University, 2021, Anatomy

Head and neck squamous cell carcinoma presents itself as a public health crisis, being the tenth most diagnosed form of cancer in the United States. Alcohol and tobacco use are among the greatest risk factors for development of oral cancer, and with their decreasing use as a result of public awareness campaigns, rates of oral cancer were on the decline. However, human papillomavirus is a more recent known cause of oral cancer and cases of virally induced oral cancer are on the rise. With surgical intervention being the primary treatment option for oral cancer, targets for immunomodulatory therapies are being actively sought. Macrophage migration inhibitory factor (MIF) is a pleiotropic, pro-inflammatory cytokine that has been linked to a worse prognosis in many cancers, including some early research that would suggest the same for oral cancer, however the role that MIF plays in the context of oral cancer remains unclear. Using a murine, orthotopic head and neck cancer model in mice sufficient or deficient for MIF, our group has begun to elucidate the function of this protein within the tumor microenvironment, with a focus on its interaction with pro-tumoral myeloid derived suppressor cells (MDSC). Interestingly, we have found that MIF deficient mice have increased tumor growth and burden compared to their wild-type counterparts. Flow cytometric analysis of immune populations within the primary tumor site revealed increased accumulations of immunosuppressive M2 macrophages and MDSC in MIF deficient mice. Suppression iii assays further demonstrate that MDSC taken from MIF deficient mice have enhanced T cell suppressive function compared to MIF sufficient MDSCs. Mechanistically, we show that upregulation of Pdl1, Arg1, S100a8, S100a9 and Ptgs2 as well as increased lymphocyte expression of PD-1 all play a role in mediating this immunosuppression. While MIF antagonist drugs are being actively pursued in the treatment of oral canc (open full item for complete abstract)

Committee: Steve Oghumu PhD (Advisor); James Cray PhD (Advisor); Kirk McHugh PhD (Committee Member) Subjects: Anatomy and Physiology

PhD, University of Cincinnati, 2019, Medicine: Molecular Genetics, Biochemistry, and Microbiology

Abstract Approximately 328,030 new cases of digestive tract cancers were reported in 2019 and about 165,460 of those individuals are predicted to die. Additionally, 136 billion dollars are spent on gastric diseases every year, more than the money spent on cardiac diseases or mental illness. Research in this area is of grave need due to not only the high mortality rate of gastric diseases, but also the fiscal burden these diseases put on the United States. Thus far appropriate models to study the microenvironment of gastric diseases are lacking. Cell lines are clonal and therefore incapable of representing the complexity of digestive organs. This work illustrates the ability of organoids to recapitulate digestive organ physiology in vitro. Unlike cell lines organoids have multiple cell types found in the organ of origin and can be derived from human tissue. These organoids are physiologically relevant as they are able to function as the organ of origin. Organoids derived from the fundus or the corpus of the stomach are able to secrete acid when stimulated with histamine, organoids derived from a cancerous pancreas are able to secrete cytokines and growth factors that have been characterized as being secreted from cancerous pancreases in vivo. Further organoids can be infected with bacteria and co-cultured with autologous immune cells in order to investigate disease progression and the immune response to these diseases. Helicobacter pylori infection occurs on the apical side of the stomach. In the antrum infection predominately causes ulcers, whereas in the corpus infection can cause gastric cancer. In order to study the development of gastric cancer, organoids derived from the corpus were microinjected with Helicobacter pylori in order to mimic the apical infection that occurs in a human stomach. Immune cells of both a myeloid and lymphoid lineage can be added to the cultures to create a full picture of the gastric cancer microenvironment. CD8+ T cell induced a (open full item for complete abstract)

Committee: Yana Zavros Ph.D. (Committee Chair); Syed Ahmad Ph.D. (Committee Member); Anil Menon Ph.D. (Committee Member); Peter Stambrook Ph.D. (Committee Member); James Wells Ph.D. (Committee Member) Subjects: Molecular Biology

MS, University of Cincinnati, 2011, Engineering and Applied Science: Electrical Engineering

We introduce a Raman profiling method to track heterogeneity of melts over days as starting materials are reacted and batch compositions homogenize. Results on 2 gram sized dry GexSe100-x melts, reacted at 950°C, show that they homogenize on a scale of 10 microns after 168 hours in a process that has two steps. In the first step, elements of local structure evolve, followed by extended range structures forming as the Ge/Se stoichiometry across a batch composition equalizes by a slow diffusive process with a Diffusion constant, D = 2 x 10-6 cm2/sec. Such homogenization is precursive to self-organization. We have synthesized 21 glass compositions spanning the range, 10% < x < 33.33%, and have examined their thermal, optical and mechanical behavior in modulated DSC, Dispersive Raman scattering and Molar volume experiments respectively. These data, on glasses of unprecedented homogeneity, reveal sharply defined rigidity transition near xc (1) = 19.5(5)% and stress transition near xc(2) = 26.0(5)%, with optical elastic power-laws in the Intermediate Phase (IP: 19.5% < x < 26.0%) of p1 = 1.10(10), and in the Stressed rigid phase (x > 31.5%) of p2 = 1.50(3). The variation of non-reversing enthalpy, ΔHnr(x), at Tg is found to display three regimes, a global minimum (~0) in the IP, and an increase outside the IP, but with sharply defined walls at xc (1) and xc(2), the two elastic thresholds deduced from optical measurements. Variation of Molar volumes, Vm(x), also displays three regimes of behavior with a global minimum in the IP and an increase outside that phase. The ΔHnr term ages over weeks outside the IP glass compositions but not inside the IP. The variation of glass transition temperature, Tg(x) in the 10% < x < 33.33% range is well described by a polynomial. A sharp cusp in ΔHnr(x) term is observed near x = 31.5(5)% , and it coincides with a maximum in the slope of Tg with x, features that we identify with the first appearance of Ge-Ge bonds with increasing x, and de (open full item for complete abstract)

Committee: Punit Boolchand PhD (Committee Chair); Bernard Goodman PhD (Committee Member); Darl McDaniel PhD (Committee Member); Marc Cahay PhD (Committee Member); Altan Ferendeci PhD (Committee Member) Subjects: Condensation

MS, University of Cincinnati, 2007, Engineering : Electrical Engineering

Knowledge on elastic phase transitions is the key to understanding the basic structure and properties of network glass systems. Generally, one can classify the inorganic glasses into three distinct phases, flexible-intermediate-stressed rigid, based on coordinates of the Lagrangian bonding constrains per atom, nc. Optimally constrained networks are characterized as nc =3, and labeled as Intermediate Phase. Those having nc < 3 are structurally flexible and those with nc > 3 are stressed-rigid in nature. In Potassium Germante glasses, an Intermediate Phase is observed in these glasses in the composition range 4% < x < 9%, where glasses transitions become thermally reversing. Trends of glass transition temperature (Tg), specific heat jump (ΔCp) and non-reversing enthalpy at Tg, ΔHnr , are recorded. Raman and IR spectroscopies are applied on present glasses and an optical elasticity power-law is deduced in the intermediate phase. From electrical conductivity measurement two conclusions are derived: first, conductivity jumps concur near x = 4% and x = 9% at the elastic phase boundaries; second, conductivity increase as a power-law in flexible glasses(x > 9%). Molar volume show a minimum when glasses enter the flexible phase. Present thermal, optical, electrical and mechanical experiments suggest that the Germanate Anomaly a result of the Intermediate Phase. However, connections to theory and fine structure in local and medium ranges are open to discussion.

Committee: Dr. Punit Boolchand (Advisor) Subjects:

Master of Science, The Ohio State University, 2012, Veterinary Clinical Sciences

For a majority of the past century, cytotoxic chemotherapy has served as the basis for the treatment of cancer, both in humans as well as in domestic animals. While the strategy of using drugs designed primarily to kill rapidly growing neoplastic cells achieved some initial successes, time has proven that this strategy is not sufficient to maintain long-term remissions or cures for most patients. Immunotherapeutic approaches to cancer treatment, such as cancer vaccines, showed initial success in preclinical studies but generally failed to demonstrate the expected clinical activity in patients when evaluated in clinical trials. The shortcomings of such cancer immunotherapies are believed to primarily involve inadequate recruitment of the cellular components of the immune system by the vaccine allowing for poor tumor recognition and subsequent tumor progression and metastasis. One of the pivotal cell types that has been shown to limit the efficacy of these therapies is a cell of bone marrow origin termed a myeloid derived suppressor cells (MDSCs). MDSCs are immature myeloid cells of bone marrow origin that are increased in both cancer bearing mice and humans and distinguished by their co-expression of CD11b and GR-1. Their primary mechanism of action is inhibition of the innate and adaptive T lymphocyte responses. To date these cells have not been described in the dog. The primary limiting factor preventing the identification of these cells in the dog has been a lack of analogous murine, human and canine antibodies. Using commercially available canine antibodies, CD11b and CADO48A, peripheral blood myeloid cells from forty healthy control dogs and forty untreated, tumor-bearing dogs were compared for the differential expression of myeloid cells. Using this technique, a population of CD11blow/CADO48Alow cells was found to be up-regulated in tumor bearing dogs, potentially representing a canine MDSC phenotype. The identification of MDSCs in the canine represents another (open full item for complete abstract)

Committee: Tracey Papenfuss DVM,PhD (Advisor); William Kisseberth DVM, PhD (Advisor); Cheryl London DVM, PhD (Committee Member) Subjects: Veterinary Services

Doctor of Philosophy, The Ohio State University, 2011, Integrated Biomedical Science Graduate Program

A class of immune suppressor cells termed myeloid-derived suppressor cells (MDSC) is known to be elevated in many solid tumor settings. MDSC are a heterogenous population of early myeloid cells that expand from the bone marrow during tumor progression and have the ability to inhibit both innate and adaptive immunity. Previous work from our laboratory and others indicated that patients with cancer exhibited reduced activation of signaling pathways when stimulated with Type I and II IFN as compared to normal donors. This reduced immune response could be a barrier to successful clinical outcomes, since ability to respond to IFN is known to be important for anti-tumor immunity and efficacy of immune-based therapies. We hypothesized that MDSC could inhibit an immune response to the growing tumor by reducing the ability of immune cells to respond to IFN stimulation. C26 tumor bearing mice had significantly elevated levels of GR1+/CD11b+ MDSC as compared to control mice, and splenocytes from these mice exhibited reduced phosphorylation of STAT1 in response to Type I and II IFN. Depletion of MDSC in C26 bearing mice restored splenocyte IFN responsiveness. Spleens from C26 tumor bearing animals displayed elevated levels of iNOS and nitric oxide (NO), which was associated with increased levels of nitration on STAT1. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. Finally, splenocytes from tumor-bearing iNOS knockout mice exhibited a significantly elevated IFN-response as compared to WT tumor-bearing mice. This demonstrated a novel mechanism of MDSC inhibition and created a direct link between increased nitric oxide and reduced IFN responsiveness. We further investigated an association between pro-inflammatory cytokines, subsets of MDSC, and reduced IFN responsiveness in patients with GI cancer. Plasma IL-6 was correlated with CD33+HLADR CD15+ MDSC, while IL 10 correlated with CD33+HLADR-CD15- MDSC. The percentage of multiple (open full item for complete abstract)

Committee: William Carson MD (Advisor); Brian Kaspar PhD (Committee Member); Cheryl London DVM, PhD (Committee Member); Tatiana Oberyszyn PhD (Committee Member) Subjects: Biomedical Research

Doctor of Philosophy, The Ohio State University, 2009, Integrated Biomedical Sciences

Breast cancer is the second leading malignancy in women behind only non-melanoma skin cancer. Likewise, it is the second leading cause of cancer-specific female mortality behind only lung cancer. Breast tumor interleukin-6 (IL-6) expression increases with tumor grade, and elevated serum IL-6 levels are associated with poor breast cancer patient survival. However, the mechanisms driving these clinical anomalies are currently undefined. Whereas IL-6 is better known as an inflammatory cytokine which mediates hematopoiesis and lymphocyte activation, it is becoming increasingly appreciated as a mediator of cancer progression. Our previous studies demonstrated that IL-6 is necessary for breast, bone, and lung fibroblast-induced breast cancer cell growth enhancement and furthermore, showed that IL-6 alone is a potent growth factor for breast cancer cells. Thus, we set out to further characterize the molecular consequences of IL-6 signaling in breast cancer, focusing on those associated with poor clinical outcome.In Chapter 2, we highlight IL-6 as one of only few factors capable of inducing a carcinoma-associated epithelial-mesenchymal transition (EMT) phenotype. Such EMT phenotypes correlate with decreased breast cancer patient survival. In particular, we demonstrated E-cadherin repression among multiple estrogen receptor-alpha (ERα)-positive human breast cancer cell lines following IL-6 exposure. Ectopic IL-6 expressing MCF-7 cells (MCF-7IL-6) exhibited a gene expression profile and phenotype consistent with EMT including down-regulated E-cadherin and aberrant induction of N-cadherin, Vimentin, Twist, and Snail. Furthermore, ectopic autocrine IL-6 signaling promoted breast cancer cell invasiveness. Intriguingly, Twist, a transcriptional repressor of E-cadherin, was shown to promote IL-6 production and constitutive STAT3 phophorylation. Ectopic IL-6 expression maintained an EMT phenotype in an orthotopic xenograft model, which exhibited increased tumor cell proliferative i (open full item for complete abstract)

Committee: Tatiana Oberyszyn PhD (Advisor); Xue-Feng Bai MD, PhD (Committee Member); Traci Wilgus PhD (Committee Member); Lisa Yee MD (Committee Member) Subjects: Biomedical Research; Immunology; Molecular Biology; Oncology

Master of Science in Chemical Engineering, Cleveland State University, 2010, Fenn College of Engineering

With the recent increase in awareness on the environmental impact of industrial coating processes, chromate-based coating processes have been elevated to the rank of the technologies targeted by the EPA for rapid replacement by environmentally friendly processes. Therefore, there is a clear need for advances in coating technologies to identify alternative industrial practices. This thesis characterizes a process developed at Cleveland State University as an alternative deposition technique to generate uniform coatings onto solid substrates. A kinetic analysis to extract scale up parameters involved in the reaction kinetics leading to high-performance coatings is demonstrated in this research. The work consists of thermal characterization of deposition experiments using Modulated Differential Scanning Calorimeter (MDSC), complemented with preliminary finite-element-modeling (FEM) of fluid flow and transport phenomena in the vicinity of the deposition assembly. MDSC is capable of using linear and modulated heating rates. Modulation over imposes a sinusoidal heating profile to a linear heating rate. Therefore, modulation combines two conventional DSC experiments into one. Modulation provides the ability to differentiate reversibility from irreversibility in transitions. This study intends to study both the advantages and disadvantages of the modulation compared to conventional DSC in the analysis of thin film deposition. A protocol to analyze deposition reaction kinetics using a conventional DSC was formulated in this research. While modulation was unable to produce results that could be compared to the conventional DSC, further in-depth studies need to be completed. This research outlines the experimental procedure to analyze deposition reactions via conventional DSC, and a kinetic analysis procedure to extract reaction kinetics is demonstrated. This research successfully demonstrated that the deposition mechanism can be characterized via DSC experiments. Further st (open full item for complete abstract)

Committee: Jorge Gatica PhD (Committee Chair); Dhananjai Shah PhD (Committee Member); Orhan Talu PhD (Committee Member) Subjects: Chemical Engineering