PhD, University of Cincinnati, 2017, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

Background: In 2009, after reviewing 32 case reports describing severe liver injury, the FDA issued a warning on the use of orlistat. The objective is to assess the association between the use of orlistat and the risk of acute liver injury. Methods: Both retrospective cohort and self-controlled case series (SCCS) studies were conducted by using Truven MarketScan® Commercial Claims data (2003-2004). For cohort study, patients prescribed at least one prescription of orilistat, sibutramine or phentermine were included. A propensity score matching was used to balance the baseline characteristics between two groups. Kaplan-Meier curves were conducted to compare the rates of acute liver injury events between the orlistat group and the sibutramine/phentermine group. COX proportional hazard regression was performed to estimate the effect of risk factors on acute liver injury. For SCCS study, patients prescribed at least one prescription of orlistat and experienced an acute liver injury during the study period were included. Conditional Poisson regression model was used to calculate the incidence rate ratios comparing the risk of acute liver injury during periods of orlistat exposure with periods of no exposure. Results: For cohort study, a total of 13,792 patients were identified. The Kaplan-Meier curves showed acute liver injury rates were 3.30% in the orlistat group and 2.77% in the comparison group (P-value: 0.0143). The result of COX proportional hazard regression showed patients in the orlistat group were more likely to have acute liver injury events than patients in the sibutramine/phentermine group (Hazard Ratio (HR), 1.376; 95% confidence interval (CI): 1.064-1.780; P-value=0.0151). In addition, elderly patients (HR, 1.020; 95% CI: 1.005-1.036; P-value=0.0083), patients with type 2 diabetes (HR, 1.518; 95% CI: 1.142-2.017; P-value=0.0040), hyperlipidemia (HR, 1.498; 95% CI: 1.142-1.965; P-value=0.0035), and patients took hepatotoxic drugs in the washout period or (open full item for complete abstract)

Committee: Jianfei Guo Ph.D. (Committee Chair); Teresa Cavanaugh Pharm.D. (Committee Member); Pamela Heaton Ph.D. (Committee Member); Christina Kelton Ph.D. (Committee Member); Tianying Wu M.D. (Committee Member) Subjects: Pharmaceuticals

Master of Science, The Ohio State University, 2010, Mechanical Engineering

Research has shown that abdominal injuries account for approximately 3-5% of all injuries that occur during motor vehicle collisions. However these injuries, especially to the solid organs of the abdomen like the liver, represent a much higher percentage of life threatening injuries. Research has suggested that in blunt liver trauma the mechanism of injury is linked to the rapid increase in internal pressure. Previous work also has shown a correlation between vascular pressure and liver injury in human surrogates and in pressurized ex vivo human and porcine livers when subjected to blunt impacts. The objective of this work is to further investigate the relationship between pressure and liver injury using full-body post-mortem human surrogates (PMHS) subjected to lateral and oblique impacts with boundary conditions more representative of motor vehicle collisions. Specifically, the goals of this research were to (1) correct and re-analyze previous experimental work done by Sparks et al (2007) and Gustafson (2009); (2) continue work by Gustafson and complete an additional four rigid impacts to PMHS (for a total of n=10); (3) determine if a correlation exists between several pressure-related variables and liver injury from PMHS data and ex vivo work performed by Sparks et al; (4) compare the results to previously proposed biomechanical predictors of abdominal injury. For the combined PHMS study, each PMHS was instrumented with pressure sensors in the abdominal vessels, these included: the abdominal aorta, the hepatic veins, and the inferior vena cava. The subjects' abdominal vessels were pressurized to physiological pressures using saline. Using a pneumatic ram, all subjects were impacted at approximately 7.0 m/s at the estimated level of the liver. Autopsies were conducted on each subject following the impacts to determine the severity of injury to the PMHS and data from the pressure sensors were used to develop injury risk functions correlating pressure to the docume (open full item for complete abstract)

Committee: John Bolte, IV Ph. D (Advisor); Rebecca Dupaix Ph. D (Committee Member) Subjects: Biomechanics; Mechanical Engineering

Doctor of Philosophy in Clinical-Bioanalytical Chemistry, Cleveland State University, 2023, College of Sciences and Health Professions

Throughout my doctoral research, I have focused on three projects examining the role of RNase L, in liver and kidney diseases. In the first project, we explored the involvement of RNase L in the development of nonalcoholic fatty liver disease (NAFLD). We induced NAFLD in RNase L wild type (WT) and knockout (KO) mice using a high-fat, high-cholesterol diet (HFHCD) and assessed their progression to nonalcoholic steatohepatitis (NASH). Surprisingly, RNase L WT mice exhibited more severe NASH, characterized by macro-vesicular steatosis, hepatocyte ballooning degeneration, inflammation, and fibrosis. Further analyses revealed that RNase L contributes to the expression of some key genes associated with lipid metabolism, inflammation, and fibrosis signaling. The findings suggest that targeting RNase L expression and activity may represent a novel therapeutic approach for NAFLD intervention and treatment. In the second project, we investigated the role of RNase L in kidney function and acute kidney injury (AKI) recovery. AKI is a prevalent clinical disorder with substantial morbidity and mortality, posing a significant healthcare burden. In the experiments, AKI was induced in RNase L WT and KO mice with folic acid (FA), and the renal function, histological structure, and recovery were evaluated. Our findings demonstrated that RNase L deficiency attenuated kidney damage caused by FA and promoted renal recovery from AKI through reducing systemic inflammation. Mechanistically, the lack of RNase L increased the activation of the EGFR/AKT signaling and suppressed apoptosis in the kidney after FA exposure. In the third project, we studied the potential relationship between RNase L and kidney aging in mice. Aged RNase L WT and KO mice were evaluated for physical and renal changes, with the KO mice demonstrating signs that are associated with slower kidney aging. To determine how RNase L is involved in kidney function and renal diseases, we performed immunoprecipitat (open full item for complete abstract)

Committee: Aimin Zhou (Advisor); David Anderson (Committee Member); Michael Kalafatis (Committee Member); Bin Su (Committee Member); Aaron Severson (Committee Member) Subjects: Biochemistry; Biology; Biomedical Research; Experiments; Medicine; Molecular Biology; Pathology; Physiology

Master of Science, The Ohio State University, 2009, Mechanical Engineering

Research has shown that abdominal injuries account for 3‐5% of injuries from motor vehicle crashes. However, abdominal injuries, especially to the solid organs of the abdomen such as the liver, represent a higher proportion of serious injuries. Previous work has shown a correlation between vascular pressure and liver injury in human surrogates and in pressurized ex vivo human and porcine livers when subjected to blunt impact. The objectives of this work are to further investigate the relationship between pressure and liver njury using post‐mortem human surrogates. Specifically, the goals were to (1) conduct rigid impacts on PMHS (n=6) withre‐pressurized abdominal vascular systems and measure vascular pressure; (2) determine if a correlation exists between measured vascular pressure and liver injury; (3) compare the results with previously proposed biomechanical predictors of abdominal injury. For the study, each PMHS was instrumented with pressure sensors in the abdominal vessels, including the abdominal aorta, the hepatic veins, and the inferior vena cava. The subject's abdominal vessels were pressurized to physiological pressures using saline. For lateral impacts, the impact was applied to the right side of the subject. For oblique impacts, the impact was applied on the right side at 30 degrees anterior of lateral. The impact face was 30 cm by 15 cm. The lower edge of the impactor was aligned with the lowest rib at the mid‐axillary line, typically rib eleven. The injuries observed to the liver were similar to those documented in the Crash Injury Research Engineering Network (CIREN) trauma database and included three livers with superficial lacerations to the capsule and one liver injury with a serious burst injury. Using binary logistic regression to predict the injury risk, various pressure related variables had statistically significant relationships to injury including peak change in pressure (Pmax), peak rate of change of pressure (Pdotmax) as well as Pmax*Pd (open full item for complete abstract)

Committee: John Bolte IV PhD (Advisor); Rebecca Dupaix PhD (Committee Member) Subjects: Mechanical Engineering

Doctor of Philosophy, The Ohio State University, 2007, Biomedical Engineering

Research suggests that in certain types of blunt liver trauma the mechanism of injury is linked to rapid increases in internal pressure within the liver. The objectives of this study were (1) to characterize the relationship between impact-induced pressures and blunt liver injury in an ex vivo organ experimental model; (2) to compare human liver intra-parenchymal pressure and vascular pressure with other biomechanical variables as predictors of liver injury risk; (3) to investigate the feasibility of measuring liver vascular pressure in impacts to pressurized full body post-mortem human subjects (PMHS); and (4) to develop a constitutive model of the mechanical behavior of human liver tissue in blunt impact loading. Test specimens included 19 ex vivo porcine livers, 14 ex vivo human livers, and 2 full body PMHS. Specimens were perfused with normal saline solution at physiological pressures, and a drop tower applied blunt impact at varying energies. Impact-induced pressures were measured by transducers in the hepatic veins and parenchyma (caudate lobe) of ex vivo specimens. Binary logistic regression demonstrated that tissue pressure measured in the parenchyma was the best indicator of serious liver injury risk (p = .002, Pseudo R-square = .78). A peak tissue pressure of 48 kPa was correlated to 50% risk of serious (AIS ≥ 3) liver injury. A burst injury mechanism directly related to hydrostatic pressure is postulated for the ex vivo liver loaded dynamically in a drop test experiment. A constitutive model previously developed for finite strain behavior of amorphous polymers was adapted to model liver stress-strain behavior observed in the ex vivo human liver impacts. The model includes six material properties and captures three features of liver stress-strain behavior in impact loading: (1) a relatively stiff initial modulus; (2) a rate-dependent yield or rollover to viscous “flow” behavior; and (3) strain hardening at large strains. Results of this research could be a (open full item for complete abstract)

Committee: Alan Litsky (Advisor) Subjects:

Doctor of Philosophy, Case Western Reserve University, 2013, Biomedical Engineering

Uncontrolled hemorrhage comprises 60-70% of trauma-associated mortality in the absence of other lethal conditions (e.g. damage to central nervous or cardiac system). Immediate intervention is critical to improving chances of survival. While there are several products to control bleeding for external wounds including pressure dressings, tourniquets or topical hemostatic agents there are few, if any, effective treatments that can be administered in the field to help staunch internal bleeding. Intravenous hemostatic nanoparticles that augment blood clotting when administered after trauma have been previously shown to half bleeding times in a femoral artery injury model in rats. The aims of the present study were to: 1) Determine their efficacy in a lethal hemorrhagic liver injury model, 2) determine the impact of targeting ligand concentration on hemostasis, and 3) test them in a clinically relevant porcine model of hemorrhage. Nanoparticle administration (GRGDS-NP1, 40 mg/kg) after lethal liver resection in the rat increased 1-hour survival to 80% compared to 40-47% in controls. Targeting ligand conjugation was then increased 100-fold (GRGDS-NP100), and a dosing study performed. GRGDS-NP100 hemostatic nanoparticles (2.5 mg/kg) were efficacious at doses 8-fold lower than GRGDS-NP1, and increased 1-hour survival to 92%. In vitro analysis using rotational thromboelastometry (ROTEM) confirmed the increased dose-sensitivity of GRGDS-NP100 and laid the foundation for methods to determine optimal ligand concentration parameters. Hemostatic nanoparticles were then tested in a clinically relevant porcine liver injury model, which elucidated an unexpected adverse reaction, comprised of a massive hemorrhagic response. A naive (uninjured) porcine model was then employed. These experiments revealed an adverse reaction consistent with complement activation related pseudoallergy (CARPA), which could be mediated by tuning nanoparticles' zeta potential. Neutralizing the nanopa (open full item for complete abstract)

Committee: Erin Lavik Sc.D. (Committee Chair); Jeffrey Ustin M.D. (Committee Member); Horst von Recum Ph.D. (Committee Member); Robert Miller Ph.D. (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Medicine