School of Biomedical Sciences

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    The Interaction Between Arterial Stiffness, Amplitude of Cerebral Blood Flow Oscillations, and Cerebral Tissue Oxygenation
    (2024-05) Hudson, Lindsey M.; Rickards, Caroline A.; Tune, Johnathan D.; Dick, Gregory M.
    Inducing 0.1 Hz (10-s cycle) oscillations in cerebral blood flow attenuates the reduction in cerebral tissue oxygenation during simulated hemorrhage in humans. Our laboratory has developed a potential therapeutic technique called pulsatile perfusion therapy (PPT) which induces 0.1 Hz oscillations in cerebral blood flow. It is unknown, however, how stiffness of the arteries influences the magnitude of cerebral blood flow oscillations, and/or the protection of cerebral tissue oxygenation. When 0.1 Hz oscillations are induced during simulated hemorrhage, we hypothesized that: 1) arterial stiffness of the internal carotid artery (ICA) and common carotid artery (CCA) would increase from rest; 2) the amplitude of 0.1 Hz oscillations in cerebral blood flow would be higher in individuals with stiffer arteries, and; 3) the reduction in cerebral tissue oxygenation would be smaller with higher amplitude of cerebral blood flow oscillations. Two studies using two different techniques of PPT were performed to investigate these hypotheses. Study 1: In a retrospective analysis, 8 healthy human participants (age: 30.1±7.6 y) underwent a 10-min hypovolemic oscillatory lower body negative pressure (OLBNP) protocol, where chamber pressure oscillated every 5-s between -30 mmHg and -90 mmHg (i.e., 0.1 Hz). ICA β-stiffness index was calculated from measurements of ICA diameter (via ultrasound imaging), and arterial pressure (via finger photoplethysmography). Middle cerebral artery velocity (MCAv) was measured using transcranial doppler ultrasound, and cerebral tissue oxygenation (ScO2) was measured with near infrared spectroscopy. Fast Fourier transformation was used to quantify oscillations in mean MCAv at ~0.1 Hz. While mean MCAv 0.1 Hz oscillations increased from baseline to OLBNP (N=8, 34.0±33.9 (cm/s)2 vs. 104.7±58.1 (cm/s)2, p=0.01), ICA β stiffness did not increase (N=5, 6.1±0.7 au vs. 8.2±2.7 au, p=0.21). There was no relationship between baseline ICA β-stiffness and the percent change in mean MCAv 0.1 Hz oscillations (N=5; r=0.44, p=0.46). ScO2 decreased from baseline to OLBNP (N=8, 66.5±2.9 % vs. 64.8±2.9 %, p=0.03), but there was also no relationship between the percent change in mean MCAv 0.1 Hz oscillations and the decrease in ScO2 (r=0.28, p=0.50). Study 2: In a prospective pilot study, 3 participants underwent a 10-min LBNP protocol to a chamber pressure of -60 mmHg, and hemodynamic oscillations were simultaneously induced with bilateral thigh cuffs inflating for 5-s to 230 mmHg then deflating for 5-s in a 10-s cycle (i.e., 0.1 Hz). β-stiffness index of the CCA was measured. In this pilot study, insufficient data were collected to perform statistics for each of the three aims, so descriptive results are presented. Adequate ultrasound measurements were made for assessment of CCA β- stiffness in two participants; in the control condition, CCA β-stiffness was 6.7 ± 2.4 au during baseline and increased to 7.4 ± 1.1 au during LBNP (N=2). With PPT, CCA β-stiffness was 6.6 ± 1.6 au during baseline and increased to 7.8 ± 2.2 au during LBNP (N=2). The amplitude of MCAv 0.1 Hz oscillations increased from 7.9 (cm/s)2 at baseline of the control condition to 179.8 (cm/s)2 (i.e., a ~23-fold increase) during LBNP. The amplitude of MCAv 0.1 Hz oscillations increased from 25.8 (cm/s)2 during baseline of PPT to 210.2 (cm/s)2 (~8-fold increase) during LBNP (N=1). ScO2 decreased from 75.0% to 71.3% during LBNP in the control condition, and from 73.4% to 71.6% in the PPT condition (N=1). Based on the results of Study 1, 0.1 Hz OLBNP does not increase ICA stiffness, and there is no relationship between ICA stiffness, amplitude of induced 0.1 Hz cerebral blood flow oscillations, and the reduction in cerebral tissue oxygenation during simulated hemorrhage. However, as this analysis was performed retrospectively, and arterial stiffness was not initially an outcome measure, there were limited data available for analysis. For Study 2, we were successfully able to induce 0.1 Hz oscillations in cerebral blood flow by combining LBNP with bilateral thigh cuff inflations. However, insufficient data were available to make definitive conclusions about the role of PPT on CCA β-stiffness, 0.1 Hz oscillations in cerebral blood flow, or the relationship in 0.1 Hz oscillations in cerebral blood flow and protection of cerebral tissue oxygenation. This study is currently ongoing, and additional data will provide further insight into these relationships.
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    New Insights into the Roles of Glutaredoxins in the Lens
    (2024-05) Zhang, Jinmin; Wu, Hongli; Ellis, Dorette Z.; Green, Kayla; Prokai-Tatrai, Katalin; Yan, Liang-Jun
    Glutaredoxins (Grxs) play a crucial role in reversing protein glutathionylation. Glutaredoxin 1 (Grx1) and Glutaredoxin 2 (Grx2) are two main members of Grxs. Our prior studies have demonstrated that the Grx1 and Grx2 double knockout (DKO) mice develop cataracts prematurely at three months of age, and they are more susceptible to UV radiation. Therefore, these findings have highlighted the importance of Grx1 and Grx2 in preserving the transparency of the lens. However, the precise mechanisms underlying the faster development of cataracts in response to simultaneous deletion of Grx1 and Grx2 remain unknown. Lens epithelial cells (LECs) are pivotal for preserving lens transparency and overall lens functionality. Consequently, a comprehensive understanding of the antioxidant defenses and cell repair mechanisms in LECs is vital for cataract prevention and treatment strategies. We hypothesized that the absence of Grx1 and Grx2 could alter LECs function, triggering cataractogenesis. To test the hypothesis, we isolated primary LECs from WT and DKO mice and conducted a range of in vitro experiments to assess the effects of Grxs deletion on the epithelial phenotype, cellular proliferation, apoptosis, and mitochondrial function in LECs. We also conducted histology analysis of lens tissues using hematoxylin and eosin (H&E) staining. Our results revealed that Grx1 and Grx2 deficiency altered epithelial phenotype, reduced proliferation rate, and aberrant cell cycle distribution of DKO LECs compared to WT LECs. The deficiency also induced cellular senescence in cultured DKO LECs, which is consistent with our H&E staining data showing that LECs in the lens tissue from DKO mouse had accelerated senescence. Additionally, DKO LECs displayed compromised mitochondrial function and a compensatory metabolic shift towards glycolysis, indicating an adaptive response to Grx deficiency. Importantly, we also found that the OHPy2N2 activated Grxs and prevented the lens from H2O2-induced lens opacification. In conclusion, the findings in this study indicate that Grxs are important in regulating the aging process in the lens. Compounds that can activate Grxs may be promising candidates for preventing cataracts.
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    Assessment of Digit Skin Temperatures Via Infrared Thermography Under Different Climatic Conditions
    (2024-05) Boettger, Chloe E.; Maddux, Scott D.; Cho, Elizabeth; Romero, Steven A.
    The responsiveness of the manual/pedal digits (i.e., finger/toes) to temperature changes makes them valuable indicators of thermoregulatory function. Further, while infrared thermography is used in many medical settings, its utility in assessing acute changes in digit skin temperatures remains poorly established. Accordingly, this research investigated the use of forward-looking infrared (FLIR) imaging as a methodological tool for analyzing digital skin temperatures across varying climatic conditions. A Teledyne FLIR E76 camera and associated FLIR Studio software were used to assess peripheral digit skin temperatures in a sample of 10 living human subjects (3 female, 7 male). Images of each hand and foot were captured every 5 minutes over a 45-minute period during exposure to four controlled climatic conditions in an environmental chamber. These experimental conditions included a control (22°C and 50% humidity), hot-humid (37°C and 85% humidity), hot-dry (44°C and 15% humidity), and cold-dry (5°C and 80% humidity) exposures. All images were taken at a perpendicular angle from the skin surface at a distance of 0.45 mm, as measured using the camera's laser-guided range finder function. Baseline images were similarly taken during a preliminary rest period prior to each experimental exposure. This resulted in a total of 2,200 images collected from the left hand and left foot of the 25 participants. Following theoretical expectations, preliminary findings indicate peripheral digit temperatures predictably decrease during the cold-dry exposure, while the hot-dry and hot-humid exposures induce increases in digit temperatures. These preliminary results suggest that infrared thermography likely provides an expedient mechanism for accurately assessing peripheral skin temperatures in humans under different climatic conditions. Infrared thermography may thus have valuable applications for assessing thermoregulatory function in both clinical and research settings.
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    Carvedilol, an alternative for lowering liver stiffness in patients with cirrhosis and portal hypertension
    (2024-05) Guriginjakunta, Niharika; Sankpal, Umesh; Heck, Amber J.
    Liver cirrhosis, often associated with portal hypertension, presents a significant health burden globally. Carvedilol, a non-selective beta-blocker, has emerged as a promising therapeutic option for managing portal hypertension in patients with liver cirrhosis. This retrospective analysis assessed the effect of Carvedilol treatment on patients with liver cirrhosis and clinically suspected portal hypertension, focusing on its effects on liver function parameters, non-invasive fibrosis scores, and liver stiffness measurements. A total of 130 patients from the Liver Center of Texas were included in this retrospective analysis, comprising 65 patients in the treatment group receiving Carvedilol and 65 patients in the control group. Statistical analyses, including t-tests, were conducted to assess the differences between groups. Carvedilol treatment led to significant improvements in liver function parameters, including a reduction in AST levels, indicative of improved liver function. Non-invasive fibrosis scores, such as FIB-4, AGILE 3, AGILE 4, and APRI, showed notable improvements after Carvedilol treatment in the treatment group, suggesting a reduction in liver fibrosis and improved prognosis. Liver stiffness measurements using eKpa and CAP scores demonstrated significant reductions after Carvedilol treatment within the treatment group, indicating improved liver stiffness. The study suggests that Carvedilol is effective in managing portal hypertension in patients with liver cirrhosis. Further research is needed to confirm these findings in larger cohorts and evaluate the long-term efficacy, and safety of Carvedilol treatment. Additionally, addressing disparities in liver disease diagnosis and treatment is crucial for improving outcomes and reducing the burden of liver-related morbidity and mortality.
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    Comparative Patient Outcome Analysis Between Two Radiation Therapies for Head and Neck Cancers
    (2023-05) Stein, Maggie J.; Ranjan, Amalendu P.; Basha, Riyaz; Neufeld, Sarah; Desai, Kajal
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    Isolation and characterization of a novel bacteriophage for Pseudomonas aeruginosa
    (2023-05) Serralta, John E.; Allen, Michael S.; Zhang, Yan; Hughes, Lee
    Pseudomonas aeruginosa is a frequent nosocomial pathogen with emergent strains that display increasing resistance to a wide range of antibiotics including carbapenems. The goal of our study was to isolate and characterize novel bacteriophages with lytic activity against multidrugresistant (MDR) strains of P. aeruginosa. Isolation of wastewater phages was achieved through a series of plaque assays on a control strain (P. aeruginosa BAA-31). The host range of phage isolates was evaluated in vitro with MDR strains from the CDC Antibiotic-Resistance Isolate Bank. To prepare and sequence a library of phage genomes, we used Illumina's TruSeq® Nano DNA Library Prep Kit and MiSeq® system with reagent kit v2. The Center for Phage Technology's Galaxy platform was used for genome processing and annotation. We report the isolation of the novel Pseudomonas phage Jes517. Host range screening revealed 12 of 55 tested strains (21.8%) were at least partially susceptible to Jes517 with 3 showing consistently strong growth reduction in its presence. The ten closest relatives of Jes517 are in the genus Bruynoghevirus with percent identities ranging from 88.7% to 92.8%. Jes517 has a linear dsDNA genome of 45,608 bp encoding 76 open reading frames (ORFs) including three tRNAs. No known integrases, toxins, or resistance factors were identified during gene annotation. Based on its strong growth suppression of MDR P. aeruginosa and predicted lack of virulence genes, phage Jes517 makes a compelling candidate for further investigation and possible therapy.
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    A Novel Scanning and Staining Methodology for Visualizing Skeletal and Soft Tissue Using Micro-CT
    (2023-05) Stalls, Javan A.; Menegaz, Rachel A.; Gonzales, Lauren A.; Lesciotto, Kate M.
    While there are many forms of radiological imaging that can be used to gather anatomical data from biological specimens, micro-computed tomography (micro-CT) imaging has been the standard for visualizing dense tissue, such as bone, with detailed resolution. However, this imaging modality is not well suited for soft tissues due to their decreased tissue density. This inability to distinguish between soft tissues in CT scans limits our ability to investigate bone-muscle interactions that are thought to stimulate and direct bone modeling during early postnatal development. The goal of this project was to develop a novel CT protocol that incorporates at least two new methods for visualizing soft tissue in CT imaging: iodine staining intended to capture muscle, and ruthenium red staining intended to capture cartilage. The ultimate goal is to enable the creation of an anatomical model that shows the development of both skeletal and soft tissue structures in the crania of neonatal mice from birth to weaning.
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    Impact of Endoscopic Vacuum-Assisted Closure on Quality of Life in Patients After Treatment of Gastrointestinal Leaks
    (2023-05) Rana, Rashmeen K.; Malaer, Joseph D.; Preskitt, John T.; Farmer, George
    Endoscopic Vacuum Assisted Wound Closure (EVAC) is an effective therapeutic option to treat Gastrointestinal (GI) leaks after the surgery. Prior to EVAC, conventional approaches to treat leaks included surgical intervention or endoscopic stents. Even though EVAC has been in use for more than a decade and has proven to be successful in treating GI leaks, the long-term quality of life impact of this treatment is uncertain. With the use of a short form (SF-36) survey, a validated questionnaire to assess both physical and mental health, the long-term impact of EVAC on the quality of life was evaluated. When assessing the long-term quality of life for patients who are at least 2 years out from their sentinel surgery, the EVAC group scored higher in all 8 quality of life domains with 4 domains reaching statistical significance as compared with conventional therapy group which received other treatments for leak management.
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    The Role of Mitochondrial Respiration in Müller Glia Survival and Function Under Normal and Glaucomatous Conditions In Vivo
    (2023-05) Nsiah, Nana Yaa; Inman, Denise M.; Stankowska, Dorota L.; Zode, Gulab S.; Yang, Shaohua
    Several markers of mitochondrial dysfunction have been observed in the retinas of glaucoma patients and experimental animal models. However, these studies have primarily focused on retinal neuron cells even though glial cells too contain significant amounts of mitochondria. Thus, little is known about how glial cell mitochondrial dysfunction contributes to glaucoma pathology. As the principal macroglial cells of the retina, Müller glia (MG) function is essential to maintaining homeostasis in the retina. However, very little is known about how MG generate energy to support their function in vivo. In this study, we address the role of mitochondrial respiration in MG using an inducible Cox10 knockout transgenic mouse model. Cox10 (protoheme IX farnesyltransferase) encodes a component of cytochrome c oxidase (COX), complex IV, of the electron transport chain. Cox10 deficient cells lack functional COX. Disruption of COX function in MG did not affect MG survival nor retinal structure but impaired visual function and upregulated glycolysis pathway protein expression in the retina. These data suggest that MG-specific mitochondrial respiration is essential for whole retinal energy metabolism and visual processing. Hypoxia-inducible factor 1α (HIF-1α) has been shown to be upregulated in the glaucomatous retina and optic nerve, yet its role in glaucoma pathogenesis remains unexplored. HIF-1α is a transcription factor that promotes glycolysis and metabolic adaptation during hypoxia. By blocking HIF-1α degradation through pharmacologic inhibition, we found that prolonged HIF- 1α stabilization led to retinal glycolysis and oxidative phosphorylation (OXPHOS) protein downregulation and AMP-activated protein kinase (AMPK) activation, indicating low energy status. These changes were accompanied by impaired retinal ganglion cell (RGC) function and glial cell activation. Taken together, these results demonstrate the essential role of MG-specific OXPHOS in the retina, as well as pointing to a role for HIF-1α in neurodegeneration in the retina.
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    MRI Detected EMVI Post-Neoadjuvant Therapy for Rectal Cancer: Retrospective Chart Review, Recurrence, and Clinical Implications
    (2023-05) Piña, Emerald M.; Mathew, Stephen O.; Malaer, Joseph D.; Preskitt, John T.
    There is limited and conflicting data on the value of EMVI status on post-neoadjuvant therapy MRI reports as a prognostic indicator. The study conducted was an IRB approved retrospective chart review to assess the relationship of EMVI status on post-neoadjuvant therapy MRI reports with recurrence and survival. Data collection was conducted on Baylor University Medical Center patients that were enrolled in a multi-disciplinary tumor board for rectal cancer from 2013 to 2021. Descriptive and statistical analysis was performed that showed statistically significant differences between EMVI status on post-neoadjuvant therapy MRI reports and age, recurrence, metastasis, survival probability, and tumor regression grade.
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    Hemodynamic Responses to Oscillatory Thigh Cuff Inflations
    (2023-05) McIntyre, Benjamin J.; Rickards, Caroline A.; Tune, Johnathan D.; Farmer, George
    Experimental generation of 0.1 Hz oscillations (~10-s cycle) in arterial pressure and cerebral blood flow (CBF) increases tolerance to simulated hemorrhage, and protects cerebral tissue oxygenation. In this study we evaluated a clinically applicable method of inducing 0.1 Hz oscillations in arterial pressure and CBF via repeated thigh cuff inflations. We also characterized the effect of common carotid artery (CCA) stiffness on the magnitude of cerebral blood flow oscillations, and evaluated the effects of intermittent thigh cuff inflation on several markers of cardiac function. We hypothesized that: 1) the amplitude of arterial pressure and CBF oscillations at 0.1 Hz would increase in response to repeated thigh cuff inflations at 0.1 Hz, 2) the magnitude of 0.1 Hz CBF oscillations would be positively correlated to the stiffness of the CCA, and 3) measurements of cardiac function would increase in response to thigh cuff induced oscillations of arterial pressure at 0.1 Hz. Thirteen healthy human participants were tested (6 male, 7 female; 27.1 ± 4.3 y). In response to 10-min of intermittent thigh cuff inflations at 0.1 Hz, the amplitude of 0.1 Hz oscillations increased for mean arterial pressure (MAP; 24.4 ± 20.1 mmHg2 vs. 932.0 ± 758.1 mmHg2; P<0.01) and middle cerebral artery velocity (MCAv; 17.5 ± 13.8 (cm/s)2 vs. 325.5 ± 279.9 (cm/s)2; P<0.01). There was also a large increase in MAP-MCAv coherence at 0.1 Hz (0.60 ± 0.24 a.u. vs. 0.90 ± 0.11 a.u.; P<0.01) during the oscillatory period compared to baseline. There was a moderate positive relationship between CCA stiffness and amplitude of MCAv power at 0.1 Hz during intermittent thigh cuff inflations (r=0.68, P=0.01), but not at rest (r=-0.08, P=0.80). When compared to baseline, no changes were observed during the oscillatory period for heart rate (P=0.47), stroke volume (P=0.87), cardiac output (P=0.55), MAP (P=0.20), or dP/dTmax (P=0.61). Future studies directly examining sympathetic nerve activity are needed to better elucidate the effects of induced 0.1 Hz hemodynamic oscillations on neural regulation of the cardiovascular system. In conclusion, we have shown that intermittent thigh cuff inflations can be used to increase hemodynamic variability at a target frequency, and therefore could be a therapy for treating tissue hypoperfusion following severe blood loss injuries.
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    Factors Influencing Parents' Decision to Use Complementary and Alternative (CAM) Therapies in Children with Chronic Conditions
    (2023-05) Munshi, Aliyah I.; Fulda, Kimberly; Franks, Susan; Schranz, Damon
    Introduction/Background: Complementary and Alternative Medicine, or CAM, therapies are defined as treatments, or therapies, outside of conventional medical practices, some of which have a basis outside of traditional Western practices and are often used in children with chronic conditions. Studies have found that patients, or caregivers of patients, do not always inform their doctors when they are using a CAM therapy, with this disconnect sometimes leading to interference in their treatment plan and possibly becoming a complicating factor. Therefore, it is important to understand the factors that influence a caregiver to use CAM therapies in order to bridge the gap in knowledge linking various factors to CAM therapy usage. Methods: Participants were recruited from the UNTHSC Health Pavilion Pediatrics and Family Medicine Clinics, as well as from various social media platforms. Data was collected through a survey questionnaire that 50 total eligible participants filled out. Participants answered questions regarding their CAM therapy usage, or their willingness to. They additionally answered questions about sociodemographic factors, their child's condition, and possible physician discussion of CAM therapies. Data was analyzed using descriptive statistics comparing CAM therapy usage to the variables mentioned previously. Results: Type of chronic condition was not associated with an increase in CAM therapy usage. 83.3% of participants whose child's condition was more severe reported having used CAM therapies while 76.9% of participants whose child's condition was less severe reported having used CAM therapies. Sociodemographic factors such as child race/ethnicity (p= 0.412), caregiver race/ethnicity (p=0.236), caregiver education level (p=0.180), caregiver marital status (p= 1.000), caregiver employment status (p=0.575), and reliable form of transportation (unable to perform test) were not associated with CAM therapy usage. Physician discussion of the following CAM therapies were associated with an increased usage, or willingness to use those CAM therapies: Botanical drugs/natural product drugs (p=0.032), breathing and relaxation techniques (0.009), dietary supplements (0.002), and psychotherapy (0.040). Conclusion: There was a trend possibly associating CAM therapy usage and severity; however, statistical tests were unable to be performed and prevented statistically backed conclusions to be made. Physician discussion of certain CAM therapies is associated with an increase in participants using those CAM therapies, or being willing to use them. Further studies with larger sample sizes gathered from more diverse recruitment sites are needed to better explore these relationships and possible factors that may influence a caregiver to use CAM therapies for their child with a chronic condition(s).
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    Effect of Vestibular Rehabilitaiton on Recovery Outcomes in Adolescents with Sports Related Concussions
    (2023-05) McCorkle, Megan J.; Romero, Steven A.
    Purpose: To examine the association between timing of vestibular rehabilitation initiation and recovery time in adolescents with sports related concussions. Hypothesis: Earlier intervention with vestibular rehabilitation following a sports related concussion will reduce recovery time Methods: This retrospective case-control study included patients 12-22 years old who were seeking treatment for a sports related concussion and received vestibular rehabilitation. Measures for clinical profiles, benign paroxysmal positional vertigo, and recovery time were analyzed. Results: The early intervention group (8-10 days) had a median recovery time that was 10 days less than the late intervention group (>10 days) despite similar treatment times with 46.15% of those with primary vestibular profile being designated as cleared ("Not Applicable") after vestibular rehabilitation. Of note, only 5.95% of the patients were diagnosed with benign paroxysmal positional vertigo. Conclusion: In adolescents with sports related concussion, earlier vestibular rehabilitation reduces recovery time.
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    Systematic Evaluation of Clinical Research Studies for Enhanced Strategic Decision-Making
    (2023-05) Haigh, Kristen; Mathew, Stephen O.; Acharya, Suchismita; Dennis, Vicki
    Clinical trials are expensive, highly complex projects that require the cooperation of numerous individuals on interdisciplinary teams to be successful. While larger organizations may have dedicated teams working to identify risks, monitor timeline milestones, and oversee budgets, smaller organizations and academic institutions must also engage in these essential practices to improve study execution and success. Implementing a protocol assessment at the outset of a project can capture feasibility and complexity attributes leading to enhanced strategic decision-making, communication, and project success.
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    Novel Role of Bone-Targeted Cabazitaxel Nanoparticles: Beyond the Classical Taxane Function in Metastatic Prostate Cancer Cells
    (2023-05) Lampe, Jana B.; Vishwanatha, Jamboor K.; Hsieh, Jer-Tsong; Gryczynski, Zygmunt
    Bone-metastatic prostate cancer symbolizes the beginning of the end-stage disease. Bone is the primary metastatic site for prostate cancer, a condition correlated to low five-year overall survival rates, extreme pain, and poor quality of life. We designed a cabazitaxel-loaded, poly (lactic-co-glycolic acid) (PLGA) nanoparticle using an emulsion-diffusion-evaporation technique. Bis (sulfosuccinimidyl) suberate (BS3) was non-covalently inserted into the nanoparticle as a linker for the conjugation of a bone-targeting moiety to the outside of the nanoparticle. I hypothesized that the nanoparticles would have the ability to inhibit the epithelial-to-mesenchymal transition (EMT), invasion, and migration in prostate cancer cells. Targeted, cabazitaxel-loaded nanoparticles attenuate the EMT marker, Vimentin, and lead to an increase in E-cadherin expression, which imparts epithelial characteristics to cells and inhibits cancer progression of advanced prostate cancer to distant sites. I observed the reduction of phosphorylated Src at tyrosine 416 along with increased expression of phosphorylated cofilin, cofilin at serine 3, which could affect migration and invasion pathways in cancer cells. Both increased expression of p-120 catenin and inhibition in IL-8 expression were seen in targeted, cabazitaxel-loaded nanoparticles. Overall, our data show that the targeted, cabazitaxel-loaded nanoparticles can act as a promising treatment for prostate cancer by inhibiting invasion, migration, and EMT in prostate cancer cells. Finally, I discuss an ongoing project that also targets bone metastatic PCa with a different strategy, a liposomal drug delivery system.
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    Interactive Influence of Climate and Energetics on Human Nasal Morphology
    (2023-05) Kelly, Alexa P.; Maddux, Scott D.; Menegaz, Rachel A.; Rosales, Armando; Yang, Shaohua
    For more than a century, studies have demonstrated strong statistical associations between climate and modern human nasal morphology, showing that populations indigenous to colder-drier environments exhibit relatively narrower nasal apertures, more projecting nasal bones, and taller/longer/narrower nasal cavities than those from warmer-humid environments. This ecogeographic patterning of nasal morphology has historically been attributed to pressures for intranasal air-conditioning (i.e., heat and moisture transfer) in different climatic conditions. However, recent studies suggest that energetic requirements also represent an important selection pressure on nasal morphology, with greater metabolic demands for oxygen intake necessitating larger nasal passages in order to respire more air with each breath. This theoretical precept has consequently been deemed the "respiratory-energetics hypothesis." Yet, despite substantial evidence that both climatic pressures and metabolic demands likely influence nasal anatomy, virtually no research has investigated the interaction and possible trade-offs of both factors on nasal size and shape. Thus, this dissertation has three objectives, 1) test the respiratory-energetics hypothesis in a mixed-sex sample from a circumscribed geographic locale (i.e., holding climate constant), 2) test the applicability of the respiratory-energetics hypothesis across ecogeographically diverse populations, and 3) investigate the influence of metabolic demands on ecogeographic variation in the nasal index. A total of 232 cranial computed tomography (CT) scans of modern human skeletons from a wide range of climatic regimes were employed in this study. Linear measurements and three-dimensional coordinate landmarks were collected from the nasal skeletons of each individual along with basal metabolic rate (BMR, kcal/day) estimates derived from associated postcranial elements. Multivariate analyses were then performed to complete each of the three objectives. This study found the basic tenets of the respiratory-energetics hypothesis to be supported both across and within modern human populations, with higher BMRs associated with larger nasal passages. Further, this study found that metabolically-mediated variation in passage size is predominantly driven by nasal passage heights and lengths, while breadths appear differentially constrained by climatic pressures.
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    Sigma-1 Receptors and and their Effects on Mice with rmTBI
    (2023-05) Kuo, Aaron, J.; Schreihofer, Derek A.; Sumien, Nathalie; Ortega, Sterling
    Repetitive mild traumatic brain (rmTBI) injury is common in contact sports, yet there are no specific treatments to mitigate the potential long-term detrimental effects of such injuries. Retrospective studies have observed athletes in contact sports such as American football, boxing, rugby, soccer, and martial arts have higher rates of Chronic Traumatic Encephalopathy (CTE), mood and behavior disturbance, motor and dementia-related diseases, and other neuropathological diseases. We propose that activation of S1R can mitigate detrimental behavioral and biochemical consequences of repetitive mild head injury in a mouse model. Sigma-1 receptors (S1R) are intracellular chaperone proteins that are involved in numerous cell processes. Among their diverse actions, activation of the S1R has been observed to reduce neurodegeneration in experimental models of stroke, Alzheimer's disease, Parkinson's disease and others. This wide range of effectiveness suggests that targeting S1R could also be beneficial for other neurological injuries including traumatic brain injury. In this short-term study of rmTBI in male mice, we observed only minor behavioral deficits 5 weeks after the last of 7 closed head injuries that may be mitigated by treatment with the prototypical S1R agonist PRE-084. However, PRE-084 itself had basal effects on cognition, making firm conclusions premature. Continued observation of these mice will help to determine whether there are additional long-term effects of the injury model
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    Impact of GLUT1 transporter knockout in optic nerve head astrocytes and retinal ganglion cells
    (2023-05) Gollamudi, Phani Sree Harsha; Inman, Denise M.; Clark, Abbot F.; Krishnamoorthy, Raghu R.
    Introduction: Astrocytes and RGC axons are the primary constituents of the optic nerve head, the initial site of neurodegeneration in glaucoma. This study was intended to understand the metabolic relationship between them. We hypothesized that reducing glucose transporter-1 (GLUT1) expression in astrocytes will increase the RGC-associated pathology after ocular hypertension (OHT). Methods: Mice carrying a GLUT1 gene flanked by loxP sites crossed with a mouse carrying the glial fibrillary acidic protein (GFAP) promoter directing a Cre-ERT2 fusion protein (GFAP-GLUT1") were used (n=30) and were divided into 4 groups: GLUT1-knockout+OHT (Tamox OHT), Control OHT, GLUT1-knockout+No OHT (Tamox), and Control+No OHT (Control naïve). Baseline and final intra-ocular pressure (IOP), pattern electroretinogram (PERG), and visual evoked potential (VEP) measurements were taken. OHT was induced via magnetic microbead injection. Retinas, optic nerves, and brains were collected for retinal ganglion cell (RGC) quantification, synapse analysis, biochemical assays, and protein analysis. Results: Statistically significant increases were noted in the IOP data between mice subjected to OHT and the No OHT groups. OHT led to statistically significant decreases in RGC number, regardless of GLUT1 status. Statistically significant decreases in PERG amplitude were noted in all groups subjected to OHT. GLUT1 knockout PERG amplitude was significantly lower than Control at the outset, suggesting a negative impact on retinal physiology from loss of the GLUT1 in astrocytes. Conclusion: Our data indicate glial metabolic homeostasis can impact retinal physiology, but GLUT1 knockout did not appear, on its own, to negatively impact RGC survival. Future studies will give us better understanding of other structural or functional compromise induced by loss of GLUT1 in astrocytes, including potential compensatory mechanisms that enabled astrocytes to meet their metabolic needs.
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    Does a Prior History Predict Prolonged Recovery Times from Sports-Related Concussion in Adolescents Seen In A Specialty Clinic?
    (2023-05) Elliott, William C.; Mathis, Keisa W.; Gwirtz, Patricia A.
    Purpose: The goal of our study was to examine the effect a prior history of concussion has on clinical recovery times for adolescent patients seen in a specialty clinic for sports related concussion (SRC). Additionally, concussion clinical profiles were compared in patients with a prior history of concussion and prolonged recovery to expand empirical evidence for the therapeutic use of these profiles in specialty clinics. Hypothesis: Patients with a prior history of concussion will have similar recovery times compared to patients with no prior history of concussion. Methods: A retrospective chart review was used to identify eligible patients for analysis (n=302). A non-inferiority analysis was used to assess if patients with a history of concussion had significantly non-inferior recovery times compared to patients with no history. Chi-square analysis was used to compare clinical profiles. Exploratory analysis conducted for a small cohort (n=12) of patients who were treated for two separate concussions using within-subjects design. Results: Recovery time in patients with a history was significantly noninferior to the recovery time of patients without a history (p = 0.01). There was no association of clinical profiles across groups. The exploratory analysis revealed a non-significant decrease in recovery time across injuries, but this analysis had low power due to small sample size. Conclusion: Recovery times do not significantly increase for patients with prior history of concussion seen at a specialty clinic.
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    Population-Specific mtDNA Indices of Mitochondrial Stress Associated with Alzheimer's Disease in Mexican Americans and Non-Hispanic Whites
    (2023-05) Gorham, Isabelle K.; Phillips, Nicole R.; Barber, Robert C.; Jones, Harlan P.
    Age is known to be the biggest risk factor for Alzheimer's disease (AD), and Mexican Americans (MAs) are the fastest-aging ethnic group in America. This puts MAs at a uniquely elevated risk for AD. This study aimed to identify ethnicity-specific markers for mitochondrial dysfunction associated with cognitive decline and detectable in peripheral blood cells (PBMCs). Specifically, copy numbers of mtDNA and nuclear DNA in PBMCs and blood plasma from non-Hispanic white and Mexican American participants were assessed by qPCR as potential markers of mitochondrial dysfunction and increased risk for cognitive decline. Evidence from these experiments shows that there are ethnicity-specific markers for this blood-based phenotype of mitochondrial dysfunction, which may also be indicative of an increased risk for cognitive decline and Alzheimer's disease.