Translational Medical Research Commons^™

Absolute Quantification Of Tc-99m Activity Distributions Using A Planar Molecular Breast Imaging Commercial System, Benjamin P. Lopez

Dissertations and Theses (Open Access)

Molecular breast imaging (MBI) uses two dedicated-breast semiconductor detectors to visualize the preferential uptake of technetium-99m-sestamibi (^99mTc-sestamibi) by breast cancer cells relative to surrounding benign breast tissues. Clinically, MBI is used primarily as a supplementary tool to standard-of-care mammography because of its improved detection of breast cancers, especially in women with mammographically-dense breasts. Because of a lack of image corrections, MBI applications are currently limited to qualitative evaluations of relative pixel intensities between image regions with suspected lesions and normal tissue.

The objective of this dissertation was to use Monte Carlo simulations to better characterize the MBI imaging …

Bhlhe40: Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery Salmon, Avery J. Salmon

Dissertations and Theses (Open Access)

Advancements in immunotherapy treatments have become essential in the treatment of various cancers, such as those with high tumor burden like melanoma(Brahmer et al., 2012; Hodi et al., 2010). Immunotherapy, specifically immune checkpoint therapy (ICT) provides antagonist effect on specific immune checkpoints to control effector T cell functions(Pardoll, 2012). This therapy allows for the modulation of anti-tumor responses through the use of monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1 that block the receptors from binding with their ligands, thus allowing for CD4⁺ and CD8⁺ T cell priming and activation(Wei et al., 2017). However, the required epigenetic and transcriptional …

Cell-Free Dna Sequencing In Multiple Myeloma, Russell Irwin

Dissertations and Theses (Open Access)

Multiple myeloma (MM) is an incurable plasma cell dyscrasia. Recent advances in MM therapy, including CAR-T therapy, have increased survival and shown the value of assessing treatment response with great sensitivity, both in acute and long-term settings. Cell-free DNA, DNA fragments which are released into circulation as a part of normal cellular turnover, is a useful and dynamic biomarker in cancer patients due to the presence of circulating tumor DNA (ctDNA), which is readily identified using next generation sequencing. Here we report the analytical sensitivity, applicability, consistency, and prognostic ability of M5Seq, a novel hybrid capture panel designed for MM …

Prognostic Serum Biomarkers In Cancer Patients With Covid-19: A Systematic Review, Te-An Lee, Shih-Han Wang, Chun-Tse Kuo, Chia-Wei Li, Louise D Mccullough, Dhimiter Bello, Yun-Ju Lai

Faculty, Staff and Student Publications

Purpose: Cancer patients with COVID-19 likely express biomarker changes in circulation. However, the biomarkers used in SARS-CoV-2 infected cancer patients for COVID-19 severity and prognosis are largely unclear. Therefore, this systematic review aims to determine what biomarkers were measured in cancer patients with COVID-19 and their prognostic utility.

Methods: A systematic literature review in PubMed, Embase, and Scopus was performed on June 16th, 2021. The search keywords coronavirus, neoplasm, biomarkers, and disease progression were used to filter out 17 eligible studies, which were then carefully evaluated.

Results: A total of 4,168 patients, 16 types of cancer, and 60 biomarkers were …

Neoadjuvant Immunotherapy Across Cancers: Meeting Report From The Immunotherapy Bridge-December 1st–2nd, 2021, Elizabeth M Burton, Rodabe N Amaria, Tina Cascone, Myriam Chalabi, Neil D Gross, Elizabeth A Mittendorf, Richard A Scolyer, Padmanee Sharma, Paolo A Ascierto

Faculty, Staff and Student Publications

After the success of immunotherapy in the treatment of advanced metastatic cancer, further evaluation in earlier settings, including high-risk, surgically-resectable disease is underway. Potential benefits of a neoadjuvant immunotherapeutic approach include presurgical tumor shrinkage, reduced surgical morbidity, early eradication of micrometastases and prevention of distant disease, and greater antigen-specific T cell response. For some cancers, pathologic response has been established as a surrogate measure for long-term outcomes, therefore offering the ability for early and objective assessment of treatment efficacy and the potential to inform and personalize adjuvant treatment clinical decision-making. Leveraging the neoadjuvant treatment setting offers the ability to deeply …

Adipose-Derived Stromal Vascular Fraction Therapy Improves Age-Related Adrenergic Mediated Microvascular Dysfunction And Increases Revascularization Potential Following Injury., Gabrielle Brown

Electronic Theses and Dissertations

The role of the microcirculation is to balance blood flow and oxygen delivery to meet local metabolic and oxygen demands. With advancing age, the health of the endothelium declines leading to improper augmentation of the microcirculation; decreasing vasoreactivity and angiogenic potential which can further increase the risk of ischemia. The multiple contributing factors that drive the decline in endothelial health with age make traditional pharmacological interventions challenging whereas cell-based therapies can exert multifactorial gains. Adipose-derived stromal vascular fraction (SVF) is an emerging therapeutic for its easily accessible, autologous, anti-inflammatory, and angiogenic properties. It is a heterogenous population comprised of leukocyte …

Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis, Blake Mcalpin

Dissertations and Theses (Open Access)

One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test …

Spatial Transcriptomics Of Dorsal Root Ganglia Identifies Molecular Signatures Of Human Nociceptors, Diana Tavares-Ferreira, Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Vivekanand Jeevakumar, Ishwarya Sankaranarayanan, Anna M Cervantes, Jeffrey C Reese, Alexander Chamessian, Bryan A Copits, Patrick M Dougherty, Robert W Gereau, Michael D Burton, Gregory Dussor, Theodore J Price

Faculty, Staff and Student Publications

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG …

Impact Of Pooling Samples On Analytic Sensitivity Of A Real-Time Reverse Transcriptase Pcr Assay For Sars Cov-2, Subathra Marimuthu, Stephen P. Furmanek, Holly Aliesky, Leslie A. Wolf

The University of Louisville Journal of Respiratory Infections

During the COVID-19 pandemic, laboratories experienced periods of shortages for certain critical materials required to meet the high demand for SARS-CoV-2 testing. The U.S. Food & Drug Administration provided a template for molecular diagnostic testing, including guidance for a specimen pooling process in order to evaluate performance of the SARS-CoV-2 nucleic acid amplification assay. This study aimed to evaluate the testing of pooled specimens consisting of four nasopharyngeal swab specimens using the Luminex ARIES^® nucleic acid amplification platform. Results indicated that there was a loss of analytic sensitivity with pooled nasopharyngeal swab samples, demonstrating that this approach should be …

Activation Of Crtc2/Creb1 In Skeletal Muscle Enhances Weight Loss During Intermittent Fasting, Nelson E Bruno, Jerome C Nwachukwu, David C Hughes, Sathish Srinivasan, Richard Hawkins, David Sturgill, Gordon L Hager, Stephen Hurst, Shey-Shing Sheu, Sue C Bodine, Michael D Conkright, Kendall W Nettles

Department of Medicine Faculty Papers

The Creb-Regulated Transcriptional Coactivator (Crtc) family of transcriptional coregulators drive Creb1-mediated transcription effects on metabolism in many tissues, but the in vivo effects of Crtc2/Creb1 transcription on skeletal muscle metabolism are not known. Skeletal muscle-specific overexpression of Crtc2 (Crtc2 mice) induced greater mitochondrial activity, metabolic flux capacity for both carbohydrates and fats, improved glucose tolerance and insulin sensitivity, and increased oxidative capacity, supported by upregulation of key metabolic genes. Crtc2 overexpression led to greater weight loss during alternate day fasting (ADF), selective loss of fat rather than lean mass, maintenance of higher energy expenditure during the fast and reduced binge-eating …

Does Hiv Status Confer A Higher Risk Of Acquiring Covid-19? Using Clinical Decision Science To Combat Patients’ Anxiety, Camilo Guzman

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using

del Amo J, Polo R, Moreno S, et al. “Incidence and Severity of COVID-19 in HIV-Positive Persons Receiving Antiretroviral Therapy.” Annals of Internal Medicine. 2020;173(7):536-541. doi.org/10.7326/m20-3689

for a patient with HIV and concerns about COVID-19 for immunocompromised individuals.

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Physiology Faculty Publications

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

RESULTS: Single-cell …

Modulation Of Glucose Homeostasis By Nucleotide P2y2 Receptor And Biological Sex, Hailee Anne Marino

Graduate Theses/Dissertations

Recent insights into the pathological role of Nucleotide P2Y₂ receptor suggest P2Y₂R involvement in high fat diet-induced obesity and potentiates insulin resistance. However, these recent insights do not demonstrate how P2Y₂R modulates glucose homeostasis under physiological conditions. Further, it remains unknown how sex biological factors influence P2Y₂R receptor signaling in the regulation of glucose homeostasis. The research objective for the present study is to elucidate the novel roles of P2Y₂ in fasting blood glucose and glucose tolerance (basal insulin sensitivity) under resting conditions in males and females. We expected that under physiological …

Modulating Immunometabolism To Improve The Activity Of Car-Nk Cells Targeting Cd70 In Renal Cell Carcinoma, Hind Rafei

Dissertations and Theses (Open Access)

Despite the approval of several therapies for metastatic clear cell renal cell carcinoma (ccRCC), disease resistance and relapse are common, and therapies with novel mechanisms of action are urgently needed. Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable responses in hematologic malignancies, but many obstacles hinder success in solid tumors including the paucity of highly specific targets and the hostility of the tumor microenvironment (TME). Moreover, the limitations of generating an autologous cell product, such as cost of manufacture, and the challenges of toxicity with CAR-T cells highlight the need to develop new cell therapy products that are at …

Post-Acute Sequelae Of Covid-19 (Pasc): Association With Inflammation And Autoimmunity, Raghava S. Ambadapoodi, Fnu Deepti, Javaria Anwer Mbbs, Rafael Fernandez-Botran

The University of Louisville Journal of Respiratory Infections

It has become increasingly evident that a high percentage of patients that recover from acute COVID-19 infection continue to suffer from a variety of persistent symptoms even months after viral clearance, the most common ones being fatigue, dyspnea, anosmia, dysgeusia, cognitive dysfunction, and psychological problems, including anxiety and depression. This syndrome, known as Post-acute sequelae of COVID-19 (PASC), can severely affect the life quality and represents an important health care concern. The exact causes for the symptoms observed in patients with PASC remain to be adequately characterized, but are likely to be associated with multiple factors, including residual disease and/or …

Development Of Vaccines And Antivirals Against Zika Virus, Aryamav Pattnaik

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

The re-emergence of Zika virus (ZIKV), an arbovirus, poses a major global human health concern because of its ability to cause congenital abnormalities and neurological diseases. While many candidate vaccines and antiviral drugs are in the developmental pipeline, none have been approved for use against ZIKV infection. This dissertation describes the characterization of one vaccine and two antiviral drug candidates against ZIKV infection. A bacterial ferritin-based nanoparticle vaccine, termed zDIII-F, is designed to display multiple copies of ZIKV E protein domain III on its surface. These stable nanoparticles are shown to induce robust antibody-mediated protection against lethal ZIKV infection in …

An Update On The Hiv Dna Vaccine Strategy, Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Mudit Tyagi

Center for Translational Medicine Faculty Papers

In 2020, the global prevalence of human immunodeficiency virus (HIV) infection was estimated to be 38 million, and a total of 690,000 people died from acquired immunodeficiency syndrome (AIDS)–related complications. Notably, around 12.6 million people living with HIIV/AIDS did not have access to life-saving treatment. The advent of the highly active antiretroviral therapy (HAART) in the mid-1990s remarkably enhanced the life expectancy of people living with HIV/AIDS as a result of improved immune functions. However, HAART has several drawbacks, especially when it is not used properly, including a high risk for the development of drug resistance, as well as undesirable …

Non-Selective Primary Human Tumor Cell Line Generation From Surgical Resections To Be Paired With Flash Frozen And Paraffin Embedded Tissue: Advancements In Democratizing Translational Research Materials To Rural Institutions, Jennifer Hawkins, Rebecca Russell, Logan M. Lawrence, Amrita Valluri, Jessica Wellman, Krista Denning

Marshall Journal of Medicine

Translational cancer research relies on the availability of human patient tissue demonstrating the specific disease process under investigation. Biobanks of human tissue have historically been and remain to date the primary access point for cancer research samples. Biorepositories routinely supply researchers with varying sample types for use in biomedical studies; most commonly formalin-fixed and paraffin-embedded (FFPE) tissue, or fresh snap-frozen tissue. In conjunction with preserved tissue samples, viable tumor cell lines derived from patient tissue have emerged to be a new gold standard in cancer research particularly in drug discovery and functional prognostic assays. Tissue banks providing these samples are …

Streptococcus Anginosus Lung Infection And Empyema: A Case Report And Review Of The Literature, Nishita Tripathi, Kuldeep Ghosh, Anupama Raghuram

The University of Louisville Journal of Respiratory Infections

Streptococcus milleri group (SMG) also referred to as the Streptococcus anginosus group. These are Gram-positive, variable hemolysis, catalase negative, microaerophilic, non-motile facultative anaerobes which have been known to cause abscesses in humans. We report a case of empyema caused by Streptococcus anginosus in a patient with an unresolved pneumonia for over a month. In early October 2018, the patient presented to an emergency room with the complaints of shortness of air, productive cough, chills, subjective fever and weight loss for 4 weeks. A chest X-ray revealed a left lower lobe pneumonia. He was treated with 250 mg of azithromycin for …

Pvn Activity In Cardiac Sympathetic Afferent Reflex (Csar) Control And Cardiovascular Function, Shane H. Boomer

Honors Thesis

Regulation of blood pressure is essential in bodily health. Hypertension and hypotension can be associated with varying diseases that could potentiate further disease. From this, understanding the mechanisms that regulate blood pressure is important within medicine. In my study, I will be focusing on a cardiovascular reflex that is less well understood, the cardiac sympathetic afferent reflex (CSAR). In particular, this work will examine sex differences in this reflex in overall function and in the involvement of an area of the brain called the paraventricular nucleus (PVN). We will test the hypothesis that there will be a significant difference between …

H1n1 Influenza Virus (Swine Flu): A Comprehensive Insight Into Escalating Catch-22 Scenarios, Muhammad Shahzaib, Ehsan Ul Haq

The University of Louisville Journal of Respiratory Infections

Introduction: Viruses have always been a major cause of various disastrous pandemics in mankind’s history. H1N1 became a threat when its original strain was first discovered back in the swine flu pandemic of 2009. It became highly catastrophic on a large scale because none of the therapeutic interventions and methodologies that were already present at the time were effective against the virus.

Methods: A vast amount of literature and research is available regarding H1N1 influenza from different reputable sources online. The data were gathered with the contrasting and relative situations of 1918 and 2009 pandemics in mind. The overall extracted …

Development Of A Method Using Retrograde Neuronal Tracers To Neuroanatomically Characterize Respiratory Neural Circuitry, Samantha Thomas, Angelo Lepore

Phase 1

Introduction:

Loss of respiratory function is one of the leading causes of death following spinal cord injury (SCI). Existing studies have demonstrated that pre-phrenic interneurons (PPIN’s) can be recruited into the phrenic motor neuron (PhMN) pathway following cervical SCI and may contribute to respiratory recovery, but there is still a lack of information detailing the nature of these changes and the extent they may improve diaphragm function. This project aims to validate a method of utilizing neuronal tracers to further characterize the intact respiratory circuitry.

Methods:

This study was carried out using a rat model. A fluorophore-conjugated retrograde neuronal …

A Comparison Of Exhaustive And Non-Lattice-Based Methods For Auditing Hierarchical Relations In Gene Ontology, Rashmie Abeysinghe, Fengbo Zheng, Licong Cui

Faculty, Staff and Student Publications

Uncovering and fixing errors in biomedical terminologies is essential so that they provide accurate knowledge to downstream applications that rely on them. Non-lattice-based methods have been applied to identify various kinds of inconsistencies in different biomedical terminologies. In previous work, we have introduced two inference-based approaches that were applied in an exhaustive manner to audit hierarchical relations in the Gene Ontology: (1) Lexical-based inference framework, and (2) Subsumption-based sub-term inference framework. However, it is unclear how effective these exhaustive approaches perform compared with their corresponding non-lattice-based approaches. Therefore, in this paper, we implement the non-lattice versions of these two exhaustive …

Role Of P53 Deficient Clonogenic Endothelial Cells In The Pathogenesis Of Pulmonary Hypertension, Aneel Roy Bhagwani

Theses and Dissertations

Pulmonary Artery Hypertension (PAH) is a progressive disorder of the small vessels of the pulmonary vasculature. It is characterized by occlusive vascular remodeling leading to right heart failure and ultimately death. PAH pathogenesis involves a multifactorial etiology leading to formation of occlusive lesions in small (preacinary) pulmonary arteries. These lesions contain hyper-proliferative, apoptosis resistant endothelial cells (ECs), smooth muscle cells and fibroblasts. ECs play a major role in the development of PAH. These ECs in vascular lesions are primitive and express progenitor cell markers, including CD117 (c-kit).

We have isolated clonally expanded, c-kit+ ECs from the lungs of Green Fluorescent …

Comparison Of Circulating Tumour Dna And Extracellular Vesicle Dna By Low-Pass Whole-Genome Sequencing Reveals Molecular Drivers Of Disease In A Breast Cancer Patient, Olivia Ruhen, Bob Mirzai, Michael E. Clark, Bella Nguyen, Carlos Salomon, Wendy Erber, Katie Meehan

Research outputs 2014 to 2021

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. There is increasing recognition of circulating tumour DNA (ctDNA) as a non-invasive alternative to tumour tissue for the molecular characterisation and monitoring of disease. Recent evidence suggests that cancer-associated changes can also be detected in the DNA contained within extracellular vesicles (EVs). As yet, there has been limited investigation into the relationship between EV DNA and ctDNA, and no studies have examined the EV DNA of breast cancer patients. The aim of this study was to use low-pass whole-genome sequencing to identify copy number variants (CNVs) in serial samples of both …

Great Expectations: Phosph(On)Ate Prodrugs In Drug Design—Opportunities And Limitations, Victoria Yan

Dissertations and Theses (Open Access)

Phosphate and phosphonates are chemical moieties with historical precedence in anticancer and antiviral nucleotide analogues. Synchronous to modern efforts identifying novel therapeutic targets in cancer, such chemical moieties are being investigated in the design of novel inhibitors with antineoplastic potential. A central challenge to the delivery of phosph(on)ate-containing drugs is their anionic character at physiological pH, which portends poor membrane permeability. This limitation has been successfully overcome through the use of prodrugs. When attached to the phosph(on)ate moiety, prodrugs mask the negative charge and easily enable cell permeability. Upon cellular entry, the promoieties are enzymatically or environmentally cleaved to unveil …

Clinical Approach To A Request For Phentermine-Topiramate In A Young Woman With A History Of High-Risk Eating Behavior, Erin Spencer

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report appraising Safer DL, Adler S, Dalai SS, et al. A randomized, placebo-controlled crossover trial of phentermine-topiramate ER in patients with binge-eating disorder and bulimia nervosa. Int J Eat Disord. 2019;(September):1-12. https://doi.org/10.1002/eat.23192 to inform the clinical decision of whether or not to prescribe phentermine-topiramate to an overweight 27-year-old woman who endorses risky eating behaviors.

Cyclosporine Shows Benefit As Compared To Methotrexate For Treatment Of Pediatric Atopic Dermatitis Refractory To Topical Medications When Rapidity Of Clinical Response Is Of Key Importance To The Patient, Connor R. Buechler, Steven Daveluy Md

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report appraising El-Khalawany MA, Hassan H, Shaaban D, Ghonaim N, Eassa B. Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: a multicenter experience from Egypt. European Journal of Pediatrics. 2012;172(3):351-356. https://doi.org10.1007/s00431-012-1893-3 for a pediatric patient with severe atopic dermatitis.

The Role Of Rapid Diagnostic Point Of Care Igg/Igm Antibody Tests In The Diagnosis Of Sars-Cov-2 Infection, Nishita Tripathi, Daniya Sheikh, Dawn Balcom

The University of Louisville Journal of Respiratory Infections

Background: Current testing of symptomatic patients for SARS-CoV-2 involves the use of nucleic acid amplification tests, also known as genetic, RNA, or polymerase chain reaction (PCR), to detect viral RNA. The initial use of point of care (POC) antibody tests, also known as serological tests, in the management of SARS-CoV-2 infection was limited. In this review, we determine the significance of POC antibody serological tests and explore their possible role in the diagnosis and management of patients infected with the SARS-CoV-2 virus.

Methods: A literature search was conducted in Google Scholar, PubMed, and Embase, supplemented by searching the Centers for …

Opioid Dependency And Its Effects On Alcohol Consumption, Emily V. Flores

Psychology and Counseling Theses

Previous research has found dualistic effects on alcohol consumption with low doses of buprenorphine increasing alcohol and higher doses of buprenorphine reducing alcohol consumption in rats (Ciccocioppo et al., 2006). Other existing research on naloxone treatment and alcohol consumption in opioid use has demonstrated that alcohol consumption decreases after naloxone treatment in rats (Hyytia & Sinclair, 1993). Yet, no research has been conducted on either rats or humans on the effects of buprenorphine and naloxone medication combined. The effects of opioid maintenance therapy are controversial and the relationship between alcohol consumption and opioid dependency treatment is mainly based on literature …