Doctor of Philosophy, Case Western Reserve University, 2024, Clinical Translational Science

Ascending aortic dissection is a surgical emergency involving the proximal aorta with an incidence of between 5 and 30 cases per million persons per year and an estimated mortality of 20% within 24 hours. Worryingly, mortality after dissection increases 1–2% per hour following symptom onset. Aortic dissection is closely associated with aortic aneurysm and thus, action to reduce the prevalence of aortic dissection has been primarily directed at improving the management of ascending aortic aneurysms. The morbidity and mortality associated with ascending aortopathy are direct results of the biomechanical dysfunction and failure of aortic tissue. Understanding the complex mechanical behavior of aortic tissue and the influence of microstructural components on its behavior may provide novel insights to better predict ascending aortic dissection and improve clinical decision making surrounding aortopathy. Proteoglycans are an important part of the extracellular matrix of the aorta, whose function is balancing tensile forces within tissue. Aggrecan, a proteoglycan, previously believed to be confined to cartilage tissue, has been identified in massive amounts in diseased aortic tissue. Although beneficial in normal quantities, excess accumulation of proteoglycans, such as aggrecan, may be associated with aortopathy and biomechanical dysfunction. The underlying hypothesis of this dissertation is that increased proteoglycan deposition is correlated with aortopathy-associated biomechanical dysfunction. Using a prospective translation study I demonstrate that: i) aggrecan is a sensitive biomarker of ascending aortopathy and elevated preoperative blood levels are independently associated with aortic disease, ii) blood aggrecan concentration is correlated with aortopathy-associated biomechanical dysfunction, assessed using ex vivo biomechanical testing methods corresponding with aortic dissection, and iii) increased proteoglycan deposition resulting i (open full item for complete abstract)

Committee: Eugene Blackstone (Committee Chair); Suneel Apte (Committee Member); Robb Colbrunn (Committee Member); Eric Roselli (Advisor) Subjects: Anatomy and Physiology; Biomechanics; Biomedical Engineering; Biostatistics; Medicine; Surgery

Doctor of Philosophy, The Ohio State University, 2023, Comparative Biomedical Sciences

Urinary tract infections (UTIs), including cystitis and pyelonephritis, are one of the most common infections across species. Approximately 80% of these infections are caused by uropathogenic Escherichia coli (UPEC). The host's innate immune response is paramount in the defense against UPEC and is initiated by urinary tract epithelial cells with subsequent recruitment of leukocytes. Despite a robust immune response, UPEC can persist in the urinary tract, can cause recurrent infections, and can be resistant to antibiotic therapy. There is a growing and imminent risk for antibiotic resistant UTIs, thus necessitating investigations into alternative therapeutic options. One possibility is utilizing mechanisms to enhance existing host innate immune defenses; however, our understanding of innate immunity against UPEC, especially in the kidney, is limited. In this work, we aimed to characterize the host immune response to UPEC in cell culture and in various important mouse models of UTI to identify potential targets for augmenting host defense against UPEC. The first portion of this thesis investigates the in vitro pathogenesis of UPEC in one of the host's most important UTI renal defenders, the kidney collecting duct intercalated cell. Previous work from our lab and others have shown that intercalated cells are required for protection against UPEC due to direct binding to these cells, their role in immune cell recruitment, and secretion of bactericidal antimicrobial peptides. We found that upon UPEC infection, intercalated cells activate multiple innate immune pathways including those associated with pattern recognition receptor (PRR) signaling. We identified that nucleotide oligomerization domain (NOD) 2 and Toll-like receptor (TLR) 4 are two intercalated cell PRRs that, upon initial activation, can protect against subsequent UPEC infection. Additionally, NOD2 activation induces upregulation of multiple innate immune pathway genes along with genes associated with vari (open full item for complete abstract)

Committee: John David Spencer (Advisor); Kara Corps (Committee Member); Rachel Cianciolo (Committee Member); Brian Becknell (Committee Member); Sheryl Justice (Advisor) Subjects: Biology; Immunology; Microbiology; Molecular Biology; Pathology

Doctor of Philosophy, The Ohio State University, 2021, Comparative and Veterinary Medicine

Staphylococci are commensal organisms and important pathogenic bacteria in humans and other animal species. Staphylococcus aureus and Staphylococcus pseudintermedius are the most clinically relevant staphylococci causing skin infections in humans and dogs, respectively. Staphylococci produce various virulence factors that modulate the host immune system and play critical roles in disease pathogenesis. While recurrent infection by staphylococcus is common, the protective mechanisms against this pathogen remain poorly understood. Currently, effective vaccines preventing staphylococcal infections are not yet available in both species. The failures of high-profile vaccines in human clinical trials further highlight the urgent need to better understand protective immunity against staphylococcal infections. The first chapter focuses on a comparative review of bacterial virulence, host-pathogen interaction, and clinical trial outcomes in humans and dogs with staphylococcal skin infections. We describe the striking similarities between Staphylococcus aureus and S. pseudintermedius in their respective hosts with regards to bacterial virulence, mechanism of immune evasion, clinical manifestation of disease, and host immune response. The second chapter investigates the mechanism by which anti-α-hemolysin antibody protects against S. aureus-induced dermonecrosis in a mouse model. We report early pathological correlates predicting protection against dermonecrosis, which include early abscess formation with compartmentalization of bacteria and attenuation of vascular damage. We also demonstrate that antibody-mediated protection is dependent on toxin neutralization, rather than enhanced opsonophagocytic killing by neutrophils or reduced toxin-mediated cytolysis of neutrophils. Therefore, early synergism between antibody-mediated toxin neutralization and tissue-specific neutrophilic inflammation confer protection against dermonecrosis during S. aureus skin infection. The (open full item for complete abstract)

Committee: Christopher Montgomery (Advisor); Lauren Bakaletz (Advisor); Ryan Jennings (Committee Member); Partida-Sanchez Santiago (Committee Member) Subjects: Biomedical Research

PhD, University of Cincinnati, 2018, Engineering and Applied Science: Mechanical Engineering

High-intensity focused ultrasound (HIFU) has gained increasing popularity as a non-invasive therapeutic procedure to treat solid tumors. However, collateral damage and long sonication times occurring during HIFU ablation procedures limit clinical advancement. In this research, an investigation to determine whether the use of magnetic nano-particles (mNPs) or gold nano-particles (gNPs) could reduce the power required to ablate tissue or, for the same power, reduce the duration of the procedure was performed using invasive and non-invasive modalities. Phantoms containing embedded thermocouples (TCs) and physiologically acceptable concentrations (phi) of mNPs (0%, 0.0047%, and 0.047%) and gNPs (0.0625%, and 0.125%) were sonicated at acoustic powers of 5.2 W, 9.2 W, and 14.5 W, for 30 seconds. It was found that with the 0.047% mNP phi, the power required to obtain a lesion volume of 13 mm^3 could be halved. When the phi of gNPs was doubled from 0.0625% to 0.125%, the temperature rise increased by 80% for a power of 5.2 W. Subsequently, a study was conducted to assess the utility of using gNPs during HIFU procedures, using non-invasive modality in phantoms and in-vivo mouse tumors. Tumors were grown using melanoma tumor cells (B16/F10) subcutaneously on the right flanks of mice (C57Bl/6). Histopathology study was conducted using a cleaved caspase 3 antibody and Hematoxylin and Eosin staining after removing the tumors from the mice. For an acoustic power of 10 W, the maximum temperature rise increased by 32% and 43% for gNPs phi of 0.0625% and 0.125%, respectively, when compared to the 0% gNPs phi in phantoms. For the power of 15 W, in phantoms, a lesion volume of 0 mm^3, 44.5+/-7 mm^3, and 63.4+/-32 mm^3 was calculated for the gNPs phi of 0%, 0.0625%, and 0.125%, respectively. In tumors, for an acoustic power of 30 W, end-of-sonication temperature rises of 25.4+/-3.8 deg C (0% gNP), 33.6+/-0.1 deg C (0.0625% gNP), and 42.2+/-4.6 deg C (0.125% gNP) were measured. Usin (open full item for complete abstract)

Committee: Rupak Banerjee Ph.D (Committee Chair); Michael Kazmierczak Ph.D. (Committee Member); Jay Kim Ph.D. (Committee Member); Matthew Myers Ph.D. (Committee Member) Subjects: Mechanical Engineering

Master of Science, The Ohio State University, 2017, Public Health

Multi-model data integration has large scope in cancer research, in diagnosis, therapy and prognosis. The integration and analysis of different data types as one has wide impact in personalized medicine too. In papillary thyroid cancer, the most common but least aggressive type of thyroid cancer, the integration of histopathology features to gene expression profiles, survival data and tumor stage information can help improve prognosis of the condition. The study indicated that certain nuclear features extracted from slides are significantly associated with several genes. To be noted was the fact that many features related most significantly with genes involved in immune responses and general immunity.

Committee: Kevin Coombes (Committee Member); Kun Huang (Advisor); Courtney Hebert (Committee Member); Susan Olivo-Marston (Committee Member) Subjects: Bioinformatics; Public Health

Doctor of Philosophy, The Ohio State University, 2017, Veterinary Biosciences

Any breakdown of epidermal barrier function leaves the host susceptible to infection. The innate immune system is tasked with the ability to clear these infections and provide an environment that can progress through the remaining stages of wound healing. There is a growing population of both immune competent and immunocompromised individuals that develop non-healing soft tissue injuries. Consistent identification of opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus in chronic wounds has focused our attention on these bacterial species. Specifically, these opportunistic pathogens often exist as sessile, aggregated communities within these wounds and are profoundly resistant to exogenous and host derived antimicrobials. Therefore, we hypothesized that P. aeruginosa and S. aureus are able to subvert the innate immune system leading to persistent inflammation and delayed wound healing. The first part of this thesis investigates the host response to P. aeruginosa and S. aureus in a chronic porcine burn wound model. Previous work in our lab, established this model in collaboration with Drs. Shahwati Roy and Chandan Sen and other members of the Ohio State University's Comprehensive Wound Center. In the establishment of this wound it was apparent that although epidermal wound healing was achieved after poly-microbial infection, there remained incompetence of the barrier function. Mono-species infections with P. aeruginosa and S. aureus or co-infections with both of these species had previously not been conducted in a chronic wound model using a clinically relevant species. We discovered that bacterial infection results in a host response unique to the infective bacterial species and additive pathologic effects were expressed when present together. Specifically, we were able to identify mono-species infection induced responses by the epidermis that recapitulate defining features of chronic wounds in humans. Ultimately, this work generated a stan (open full item for complete abstract)

Committee: Daniel Wozniak (Advisor); Paul Stromberg (Committee Member); Luanne Hall-Stoodley (Committee Member); Sashwati Roy (Committee Member) Subjects: Microbiology; Veterinary Services

PHD, Kent State University, 2016, College of Arts and Sciences / School of Biomedical Sciences

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating, neurodegenerative disease characterized by a diverse clinical course and varying patterns of disease progression. It affects millions of individuals worldwide and is responsible for the majority of non-traumatic disability in young adults. Abnormal magnetic resonance imaging (MRI) signals in cerebral white matter (WM) are detected in MS patients, and these demyelinating white matter lesions (WML) are considered to be the pathological hallmark of MS, and are often observed macroscopically in postmortem brains. However, gray matter (GM) demyelination also occurs in MS brains and can exceed the amount of WM demyelination, but it can be detected only by immunohistochemical analysis. GM demyelination in the absence of WML has not yet been studied. The goal of this thesis was to determine the pathogenesis of cortical demyelination in MS patients with few cerebral WML (referred to as myelocortical MS) and the specificity of MRI in detecting the underlying MS WM pathology. Despite postmortem MRIs predictive of extensive cerebral WML burden, myelocortical MS patients had an unusually low number of macroscopic WML; however, significant cortical and spinal cord demyelination, axonal pathology in MRI WM abnormalities and significant brain atrophy. These data suggest that a substantial amount of cortical demyelination can occur independently of WML and that MRI is not specific for detection of MS cerebral WM demyelination. However, MRI is effective at detecting axonal swelling, edema and gliosis. Furthermore, this study supports the concept that MS may be a neurodegenerative disease with a secondary aberrant immune response.

Committee: Bruce Trapp PhD (Advisor); Jennifer McDonough PhD (Committee Member); Robert Dorman PhD (Committee Member); Mary Ann Raghanti PhD (Committee Member); Marilyn Norconk PhD (Committee Member) Subjects: Biomedical Research

MS, University of Cincinnati, 2014, Engineering and Applied Science: Computer Science

Glioblastoma is a form of malignant brain tumor in humans involving glial or non-neuronal cells. The state-of-the-art diagnosis of Glioblastoma is predominantly based on subjective opinion of trained pathologists. However, with the availability of large-scale databases of Glioblastoma histopathology images, it is now possible, in principle, to objectively study and classify this class of tumors via image analysis and pattern recognition techniques. The objective of this work is to develop a quantitative framework for the analysis of Glioblastoma. The first, fundamental step in this process is the identification of histological structures in these images, that is, segmenting the constituent nuclei in the tissue. The work presents a two-step process of iterative thresholding and cleaving (ITC) to identify aforementioned structures. This improves significantly over standard color-based cell segmentation techniques in identifying cellular structures, giving 91.8% precision and 94.7% recall. Furthermore, using various architectural features obtained from each image, it ensures that the identification of regions important for the diagnosis process is distinctly clearer using the ITC approach than with standard approaches such as the Otsu method and adaptive thresholding.

Committee: Anca Ralescu Ph.D. (Committee Chair); Fred Annexstein Ph.D. (Committee Member); Bruce Aronow Ph.D. (Committee Member) Subjects: Computer Science

Master of Science, The Ohio State University, 2014, Comparative and Veterinary Medicine

Medial coronoid disease (MCD), a component of canine elbow dysplasia, is the most common cause of thoracic limb lameness in juvenile medium- to large-breed dogs. The goal of this study is to describe the magnetic resonance imaging (MRI), arthroscopic and histopathological changes in dogs with medial coronoid disease and to identify potential relationships between these findings. Twenty-five diseased medial coronoid processes (MCP) were collected from 19 dogs with a confirmed diagnosis of medial coronoid disease that underwent surgical management with subtotal coronoid ostectomy. A reference group of normal MCPs was harvested from 9 dogs that were euthanatized for reasons unrelated to elbow disease. MCP specimens were evaluated by magnetic resonance imaging (MRI) using a novel grading scheme (all dogs), arthroscopy using a modified Outerbridge scheme (affected dogs only) and histopathology (all dogs). The common histopathologic findings were subchondral microfractures, subchondral microfractures continuous with cartilaginous fissures, moderate to severe hypercellularity of the marrow space, trabecular bone necrosis and articular cartilage degeneration. The severity of cartilage disease in the MCP was moderate to severe in most of the specimens, even in cases with minimal arthroscopic pathology. Three distinct patterns of bone marrow lesion (BML) were identified adjacent to the MCP, but there was no correlation between BML pattern and either histopathological or arthroscopic findings. There was moderate correlation between modified Outerbridge scores and MRI scores. No correlation was identified between the histopathological changes and either MRI or arthroscopic scores. There was no significant correlation between the clinical scores and histopathological changes. Ongoing improvements in the resolution of noninvasive imaging techniques will likely improve description and understanding of the MCP disease in dogs.

Committee: Matthew Allen (Advisor); Noel Fitzpatrick (Committee Member); Tod Drost (Committee Member); Duncan Russell (Committee Member) Subjects: Scientific Imaging; Surgery; Veterinary Services

Doctor of Philosophy, The Ohio State University, 2012, Electrical and Computer Engineering

The use of computers in medical image analysis has seen tremendous growth following the development of imaging technologies that can capture image data in-vivo as well as ex-vivo. While the field of radiology has adopted computer aided image analysis in research as well as clinical settings, the use of similar techniques in histopathology is still in a nascent stage. The current gold standard in diagnosis involves labor-intensive tasks such as cell counting and quantification for disease diagnosis and characterization. This process can be subjective and affected by human factors suach as reader bias and fatigue. Computer based tools such as digital image analysis have the potential to help alleviate some of these problems while also offering insights that may not be readily apparent when viewing glass slides under an optical microscope. Commercially available high-resolution slide scanners now make it possible to obtain images of whole slides scanned at 40x microscope resolution. Additionally, advanced tools for scanning tissue images at 100x resolution are also available. Such scanning tools have led to a large amount of research focused on the development of image analysis techniques for histopathological images. While the availability of high-resolution image data presents innumerable research opportunities, it also leads to several challenges that must be addressed. This dissertation explores some of the challenges associated with computer-aided analysis of histopathological images. Specifically, we develop a number of tools for Follicular Lymphoma and Lupus. We aim to develop algorithms for detection of salient features in tissue biopsies of follicular lymphoma tumors. We analyze the algorithms from a computational point of view and develop techniques for processing whole slide images efficiently using high performance computing resources. In the application of image analysis for Lupus, we analyze mouse renal biopsies for characterizing the distribution of in (open full item for complete abstract)

Committee: Ashok Krishnamurthy PhD (Advisor); Bradley Clymer PhD (Committee Member); Kimerly Powell PhD (Committee Member) Subjects: Electrical Engineering; Information Systems; Medical Imaging

Doctor of Philosophy, The Ohio State University, 2010, Electrical and Computer Engineering

The recent developments in whole-slide digital scanners have spurred a revolution in imaging technology for histopathology. While these commercially available, high-throughput whole-slide scanners address data acquisition issues, the amount of data provided by them currently far exceeds the rate at which they can be analyzed efficiently. More importantly, the qualitative microscopic visual inspection of tissue slides by human readers (e.g., pathologists) is often subject to significant inter- and intra-reader variations. Using computerized image analysis, it is possible to extract more objective and precise quantitative diagnostic clues that will help improving the current evaluation of histopathological data. The main goal of this dissertation is to understand and address the challenges associated with the development of image analysis techniques for the computer-aided interpretation of high-resolution histopathology imagery. We aim to design algorithms for key image analysis tasks such as robust and adaptive segmentation of cytological components for higher level processing, construction of biologically relevant and computationally tractable features and their mathematical representations in order to differentiate distinct tissue subtypes, detection of prognostically significant tissue structures, and spatial alignment of tissue sections prepared with different stains in order to incorporate complementary information. We demonstrate the effectiveness of the proposed approaches on three important histopathology applications: analysis of whole-slide tissue sections for neuroblastoma prognosis, automated grading of follicular lymphoma and quantitative characterization of muscle fiber subtypes from serial transverse skeletal muscle tissue samples. For computer-aided analysis of whole-slide neuroblastoma tissue sections, we develop a comprehensive, multi-resolution image analysis framework including the establishment of multi-resolution image hierarchy, image segmentat (open full item for complete abstract)

Committee: Umit V. Catalyurek PhD (Advisor); Metin N. Gurcan PhD (Committee Member); Bradley D. Clymer PhD (Committee Member); Ashok Krishnamurthy PhD (Committee Member) Subjects: Bioinformatics; Computer Science; Electrical Engineering; Pathology