Medicine and Health Sciences Commons^™

Enolase Inhibitors As Therapeutic Leads For Naegleria Fowleri Infection, Jillian E Milanes, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian N Dominy, Daniel C Whitehead, Steven W Millward, Madison Bolejack, Roger Shek, Logan Tillery, Isabelle Q Phan, Bart Staker, E Ashley Moseman, Xiang Zhang, Xipeng Ma, Audriy Jebet, Xinmin Yin, James C Morris

Faculty, Staff and Student Publications

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used …

Consistency Of Advanced Radiation Therapy Qa Methods And Global Auditing Systems, Fre'etta Brooks

Dissertations and Theses (Open Access)

Consistency of Advanced Radiation Therapy QA Methods and Global Auditing Systems

Fre’Etta M.D. Brooks, B.S.

Advisory Professor: Stephen F. Kry, Ph.D.

Abstract

Auditing systems provide a means to verify the implementation and operation of all equipment and radiation parameters used by an institution providing radiation therapy treatments. The systems are important tools that are used to determine if an institution can accurately deliver radiation therapy that requires complex planning in the form of IMRT or VMAT and credential radiotherapy treatment institutions for specific clinical trial protocols; to assure the quality of treatment to all patients. Auditing techniques vary by region …

Delineating Metastasis In Mss Colorectal Cancer By Single - Cell Rna Sequencing, Shuangjie You

Dissertations and Theses (Open Access)

Colorectal cancer Colorectal Cancer (CRC) is the leading cause of cancer-related deaths, with the majority of these deaths occurring after metastases. In this study, we used single-cell RNA transcriptome sequencing to characterize the cellular and molecular features of primary CRC and colorectal liver metastases (CRLM). Analysis of 130 samples revealed significant heterogeneity in the tumor microenvironment (TME) characterized by a diversity of cancer-associated fibroblasts, immune cells, and endothelial cell populations. Notably, we identified different CAF subtypes, including inflammatory (iCAFs), matrix(mCAFs), complement (cCAFs), and vascular (vCAFs). iCAFs were enriched in primary tumors expressing higher levels of inflammation-associated genes, whereas mCAFs were …

Single Cell And Spatial Analysis Characterize Metabolic Dpep1+ Fibroblasts In Pdac, Yuanyuan Zhu

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and exhibits aggressive progression patterns, resists conventional treatments, and poses significant challenges to patient survival, necessitating urgent research and development of novel therapeutic approaches. Understanding cancer-associated fibroblasts (CAF) metabolism reprogramming in PDAC tumor microenvironment (TME) may uncover novel therapeutic targets. Here, we used single cell and spatial transcriptomics to comprehensively characterize the TME content of human PDAC. We characterized CAFs metabotypes and a novel CAF population expressing DPEP1, COMP, CST1, which involved in glutathione metabolism, termed "gluCAFs” and was associated with poor clinical outcomes and advanced PDAC stages. We also validate the existence …

Exploring The Role Of The Arginine-Methylation Writer-Reader Pair Prmt5/Snd1 In Jak2-Mutant Myeloproliferative Neoplasms, Rocio Rubiano

Dissertations and Theses (Open Access)

Myeloproliferative neoplasms (MPNs) are a hematopoietic disease characterized by hyperproliferation of cells of the myeloid lineage for which current therapeutic options are limited. Discovered in 2005, the JAK2V617F mutation is the most common driver mutation in BCR-ABL negative MPNs, resulting in constitutive activation of the JAK2 protein and the JAK-STAT signaling pathway. A role for the methyltransferase activity of Protein Arginine Methyltransferase 5 (PRMT5) has been proposed in JAK2-mutant MPN, highlighting both a mechanism through which this mutation can drive disease progression and a potential mode of therapeutic intervention. Staphylococcal Nuclease Domain-Containing Protein 1 (SND1) is the effector molecule responsible …

Influential Factors And Predicting Dose Delivery Accuracy For Imaging And Radiation Oncology Core’S Phantom Program Using Machine Learning, Hunter Mehrens

Dissertations and Theses (Open Access)

IROC’s mission is to help ensure consistent and comparable, high-quality radiotherapy across clinics that participate in national clinical trials. To obtain this mission, IROC’s phantom program provides a third-party end-to-end check of the clinical workflow of a patient receiving radiotherapy. The goal of the phantom audit is to compare the dose delivered to the dose planned by the treatment system ensuring dose delivery accuracy. While IROC’s phantoms are better equipped to catch dose delivery errors compared to a clinic’s QA process, the end-to-end process and reporting of results is time-consuming creating a bottleneck for clinical trial participation. Furthermore, IROC’s passing …

The Role Of An Ultraconserved Long Non-Coding Rna In B-Cell Lymphomagenesis, Swati Mohapatra

Dissertations and Theses (Open Access)

Ultraconserved regions (UCRs) are genomic segments with perfect (100%) conservation between the orthologous regions of human, rat, and mouse genomes. UCRs can be transcribed into mono-exonic long non-coding RNAs (lncRNAs) known as transcribed ultraconserved regions (T-UCRs). These regions, despite lacking protein-coding potential, are increasingly recognized for their regulatory roles in gene expression, including the modulation of non-coding RNA (ncRNA) transcripts. NcRNAs play crucial roles in cellular processes, including oncogenic transformation, with emerging evidence revealing their ability to encode small peptides known as ncRNA-encoded peptides (ncPEPs). These peptides, originating from small open reading frames (smORFs), contribute to diverse cellular functions and …

Genetic Analysis Of Kmt2d Loss In Tumorigenesis Using Genetically Engineered Mouse Models, Yingda Jiang

Dissertations and Theses (Open Access)

The Cancer Genome Atlas Program (TCGA) has discovered multiple tumor suppressors that are commonly mutated across a variety of human cancers, such as chromatin regulators in COMPASS and SWI/SNF complexes. KMT2D, a histone H3K4 methyltransferase in the COMPASS complex, is frequently mutated in human lymphoma, melanoma, and epithelial carcinoma. Biochemically, KMT2D shapes the cellular enhancer landscape as the major writer of the putative enhancer mark H3K4me1. Given the critical role of cellular enhancer landscape in determining cellular lineage in embryonic development, it is unknown whether enhancer dysregulation caused by KMT2D loss leads lineage switch of tumor cells, which has …

Vesicle-Associated Membrane Proteins In Airway Mucin Secretion, Boxuan Yang

Dissertations and Theses (Open Access)

Mucus plays a vital role in shielding the lungs against harmful substances such as particles, pathogens, and chemicals inhaled from the environment. It captures these harmful elements, and ciliary action helps to expel them from the lungs. Paradoxically, malfunctioning of mucus induces the development of various respiratory illnesses, including asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases. Despite extensive research on controlling mucin production and hydration, the process of secretion is not yet fully comprehended.

Mucin undergoes regulated secretion at two rates: a low baseline rate and a high stimulated rate. Over the past 25 years, …

Evaluation Of Myogenic Differentiation Potential Of Bmd Ipscs In Vitro And The Effect Of Ubiquitination Inhibitors On Dystrophin Stability In Vivo, Muchen Liu

Dissertations and Theses (Open Access)

Background: Muscular dystrophies are heterogeneous groups of inherited diseases leading to progressive muscular weakness and degeneration. In the case of Becker muscular dystrophy (BMD), non-disrupting mutations of the DMD gene reading frame is the causative defect. By the age of 30s, about 60 to 70% of BMD patients develop cardiomyopathy, which is often lethal. Unfortunately, there is currently no cure for BMD. Meanwhile, improvement of dystrophin stability by repressing polyubiquitination is a promising strategy. The application of human iPSCs in tissue regeneration also serves as a potential therapeutic strategy. This study aims to test the efficacy of selected drugs interfering …

Recommendations And Implementation Considerations For The Routine Collection Of Sexual Orientation And Gender Identity Data In Research And Practice, Irene Tamí-Maury, Thomas J Millett

Faculty, Staff and Student Publications

No abstract provided.

Plasma Proteins Associated With Plant-Based Diets: Results From The Atherosclerosis Risk In Communities (Aric) Study And Framingham Heart Study (Fhs), Hyunju Kim, Jingsha Chen, Brenton Prescott, Maura E Walker, Morgan E Grams, Bing Yu, Ramachandran S Vasan, James S Floyd, Nona Sotoodehnia, Nicholas L Smith, Dan E Arking, Josef Coresh, Casey M Rebholz

Faculty, Staff and Student Publications

Background & aims: Plant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort.

Methods: ARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics …

Past-Year Hiv Testing, Current Antiretroviral Therapy Use, And Participation In Services For People Who Inject Drugs, Itunu Sokale, Johnny Wilkerson, Paige Wermuth, Folefac Atem, Janet Burnett, Cyprian Wejnert, Salma Khuwaja, Catherine Troisi

Faculty, Staff and Student Publications

Evaluating routine HIV testing and treatment and use of services for people who inject drugs (PWID) is critical to curb the ongoing HIV epidemic. We analyzed data from the 2018 National HIV Behavioral Surveillance of PWID aged 18 years or older, recruited using respondent-driven sampling and offered anonymous HIV testing after survey. We performed bivariate and multivariable analyses with log-linked Poisson regression of the generalized linear models to examine the associations between demographics and PWID service use, past-year HIV testing, and current antiretroviral therapy (ART) use. Among 10,311 HIV-negative PWID, 56% reported past-year HIV testing, and of the 553 HIV-positive …

Analyzing Heterogeneity In Biomarker Discriminative Performance Through Partial Time-Dependent Receiver Operating Characteristic Curve Modeling, Xinyang Jiang, Wen Li, Kang Wang, Ruosha Li, Jing Ning

Faculty, Staff and Student Publications

This study investigates the heterogeneity of a biomarker's discriminative performance for predicting subsequent time-to-event outcomes across different patient subgroups. While the area under the curve (AUC) for the time-dependent receiver operating characteristic curve is commonly used to assess biomarker performance, the partial time-dependent AUC (PAUC) provides insights that are often more pertinent for population screening and diagnostic testing. To achieve this objective, we propose a regression model tailored for PAUC and develop two distinct estimation procedures for discrete and continuous covariates, employing a pseudo-partial likelihood method. Simulation studies are conducted to assess the performance of these procedures across various scenarios. …

E-Cigarette Use Reasons And Associated E-Cigarette Use Dependence Among College Students: A Longitudinal Examination, Tzung-Shiang Ou, Anne Buu, James J Yang, Hsien-Chang Lin

Faculty, Staff and Student Publications

Objective: Previous studies have established an understanding of reasons for e-cigarette use and associated e-cigarette use patterns such as use frequency, yet the critical extension to associated e-cigarette dependence outcome remains under-researched. This study used longitudinal data to examine whether the reasons for e-cigarette use predict a higher/lower level of e-cigarette dependence.

Methods: This study recruited college students who were current e-cigarette users from Fall 2019 to Fall 2020 (four semesters) at three public universities in the Midwest and South of the U.S. Those who participated for at least two semesters were included (N = 366). Data were collected using …

In Vivo Examination Of Peripheral Drivers Of Alzheimer’S Disease, Celso Catumbela

Dissertations and Theses (Open Access)

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and predominantly affects elderly populations. This disease is well known for its effects on the brain, but a wealth of clinical reports show that dementia can also modify, or be modified by, various peripheral and systemic processes. Yet, the pathological contribution of peripheral comorbidities to AD remains to be fully understood. In an attempt to address some knowledge gaps, we characterized the cerebral and peripheral pathology in mice with history of either liver injury or sepsis. In the former subjects, we found that even in the absence of genetic risk …

Mapping The Single-Cell Differentiation Landscape Of Osteosarcoma, Danh D Truong, Corey Weistuch, Kevin A Murgas, Prasad Admane, Bridgette L King, Jes Chauviere Lee, Salah-E Lamhamedi-Cherradi, Jyothishmathi Swaminathan, Najat C Daw, Nancy Gordon, Vidya Gopalakrishnan, Richard G Gorlick, Neeta Somaiah, Joseph O Deasy, Antonios G Mikos, Allen Tannenbaum, Joseph Ludwig

Faculty, Staff and Student Publications

Purpose: The genetic intratumoral heterogeneity observed in human osteosarcomas poses challenges for drug development and the study of cell fate, plasticity, and differentiation, which are processes linked to tumor grade, cell metastasis, and survival.

Experimental design: To pinpoint errors in osteosarcoma differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directs mesenchymal stem cells toward adipogenic and osteoblastic fates. Incorporating preexisting chondrocyte data, we applied trajectory analysis and non-negative matrix factorization to generate the first human mesenchymal differentiation atlas.

Results: This "roadmap" served as a reference to delineate the cellular composition of morphologically complex osteosarcoma tumors and quantify …

Genomic Data Science Approaches For Understanding Human Diseases, Snehal Shah

All Dissertations

The intricate interplay of genetic predisposition, environmental influences, and lifestyle acts as the multifactorial landscape of diseases. Understanding this complexity presents a significant challenge. Molecular insights into disease mechanisms, particularly the interactions of DNA, RNA, and proteins with environmental and lifestyle factors, have revolutionized disease diagnosis, prognosis, and treatment. High-throughput technologies, such as next-generation sequencing, generate large amounts of molecular data, holding a wealth of knowledge. These datasets unveil the roles of genes and their interactions with various factors through analysis, shedding light on previously unknown molecular mechanisms underlying disease pathogenesis. Furthermore, they facilitate the discovery of biomarkers crucial for …

Candida Albicans Farnesol Synthesis And Secretion, Daniel J. Gutzmann

School of Biological Sciences: Dissertations, Theses, and Student Research

Candida albicans is a polymorphic fungus and opportunistic commensal found primarily in the gastrointestinal and skin of healthy individuals. Several barriers prevent C. albicans from causing disease including a healthy immune system and microbiome. When these barriers become comprised, C. albicans can transition to a pathogen and disseminate through the intestinal mucosa leading to life-threatening bloodstream and invasive infections with mortality rates of up to 64%. Morphogenic plasticity is key to this transition and impacts virulence, adaptation to different host environments, and evasion of host immune responses. One regulator of morphogenesis is farnesol. Farnesol is a secondary metabolite of …

Enhancing Vaginal Delivery In Greece Through Educational And Behavioral Interventions Among Maternity Care Providers Regarding Labor Management: The Engage Stepped-Wedge Randomized Prospective Trial Protocol, Nikolaos Vrachnis, Nikolaos Antonakopoulos, Peter Von Dadelszen, Marianne Vidler, Georgios Maroudias, Jeffrey Bone, Ash Sandhu, Nikolaos Loukas, Laura Magee, Marleen Temmerman

Centre of Excellence in Women and Child Health

Background: There is an emerging need to systematically investigate the causes for the increased cesarean section rates in Greece and undertake interventions so as to substantially reduce its rates. To this end, the ability of the participating Greek obstetricians to follow evidence-based guidelines and respond to other educational and behavioral interventions while managing labor will be explored, along with barriers and enablers. Herein discussed is the protocol of a stepped-wedge designed intervention trial in Greek maternity units with the aforementioned goals in mind, named ENGAGE (ENhancinG vAGinal dElivery in Greece).

Methods: Twenty-two selected maternity units in Greece will participate in …

Cancer Care Terminology In African Languages, Hannah Simba, Miriam Mutebi, Moses Galukande, Yahya Mahamat-Saleh, Elom Aglago, Adamu Addissie, Lidya Genene Abebe, Justina Onwuka

General Surgery, East Africa

Importance: Effective communication between patients and health care teams is essential in the health care setting for delivering optimal cancer care and increasing cancer awareness. While the significance of communication in health care is widely acknowledged, the topic is largely understudied within African settings.

Objective: To assess how the medical language of cancer and oncology translates into African languages and what these translations mean within their cultural context.

Design, etting, and participants: In this multinational survey study in Africa, health professionals, community health workers, researchers, and scientists involved in cancer care and research and traditional healers were invited to participate …

A 3d Dual-Echo Spiral Sequence For Simultaneous Dynamic Susceptibility Contrast And Dynamic Contrast-Enhanced Mri With Single Bolus Injection, Zhiqiang Li, Dinghui Wang, Melvyn B Ooi, Poonam Choudhary, Sudarshan Ragunathan, John P Karis, James G Pipe, C Chad Quarles, Ashley M Stokes

Faculty, Staff and Student Publications

Purpose: Perfusion MRI reveals important tumor physiological and pathophysiologic information, making it a critical component in managing brain tumor patients. This study aimed to develop a dual-echo 3D spiral technique with a single-bolus scheme to simultaneously acquire both dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) data and overcome the limitations of current EPI-based techniques.

Methods: A 3D spiral-based technique with dual-echo acquisition was implemented and optimized on a 3T MRI scanner with a spiral staircase trajectory and through-plane SENSE acceleration for improved speed and image quality, in-plane variable-density undersampling combined with a sliding-window acquisition and reconstruction approach for increased …

Guiding The Management Of Acute Promyelocytic Leukemia: A Quality Improvement Project, Lauren Sheldon, Donna M. Tydings, Tara L. Sacco

Nursing Doctoral

Background: Despite successful treatment regimens and remission rates of greater than 90%, early death is a concern for patients with acute promyelocytic leukemia (APL). The challenges surrounding proper care for APL are centered on the low volume of patients, which limits healthcare professionals’ knowledge of disease management.

Objectives: The purpose of this project was to develop resources and present an educational module specific to managing patients newly diagnosed with APL. An intervention to evaluate bedside nurses’ knowledge of APL was implemented.

Methods: Thirty-four RNs were recruited for participation. A clinical practice guideline, an algorithm, and a fact sheet were developed …

Strength And Endocrine Adaptations From The Combined Use Of Accentuated Eccentric Loading And Cluster Sets During A Strength Endurance Training Block, Kurt Mcdowell

Electronic Theses and Dissertations

The purpose of this study was to investigate the chronic effects of accentuated eccentric loading (AEL) paired with cluster sets (CS) on dynamic and maximal strength, the endocrine system, and body composition. Seventeen recreationally active subjects (male = 11, females = 6, age = 23.05 ± 4.07, height = 172.09 ± 9.98, body mass = 81.29 ± 22.18, back squat to body mass ratio = 1.55 ± 0.33, bench press to body mass ratio = 1.06 ± 0.28) participated in one familiarization week, 2 weeks of testing, and 4 weeks of training. A strength-endurance block (4 wks) was used for …

Poly (Adp-Ribose) Polymerase-1 (Parp1) Expression In The Frontal Cortex And Hippocampus In Major Depressive Disorder (Mdd) And Suicide, Ramona Faith Fulkerson

Electronic Theses and Dissertations

Major Depressive Disorder (MDD) is a prevalent psychiatric disorder that has a complex pathophysiology. In this study we evaluate the expression of PARP1 and the downstream alarmin protein high mobility group box 1 (HMGB1) in two brain areas that have demonstrated pathology in MDD. MDD donors were compared to controls. MDD subgroups that died by suicide were also compared to those that did not die by suicide. Immunoblotting to determine PARP1 and HMGB1 protein expression was performed in white and grey matter from the frontal cortex and the hippocampus. In BA10 white and grey matter, PARP1 protein expression was significantly …

Outcomes Of Different Steroid Dosing Regimens In Critical Covid-19 Pneumonia At A Kenyan Hospital: A Retrospective Cohort Study, John Odhiambo, Jasmit Shah, Nancy Kunyiha, Felix Riunga, Charles Makasa

Internal Medicine, East Africa

Background: Among therapeutic options for severe and critical COVID- 19 infection, dexamethasone six milligrams once daily for ten days has demonstrated mortality benefit and is guideline recommended at this dose. In practice, variable doses of steroids have been used, especially in critical care settings. Our study aimed to determine the pattern of steroid dosing and outcomes in terms of critical care mortality, occurrence of dysglycaemias, and occurrence of superadded infections in patients with critical COVID-19.

Methods: A retrospective cohort study was carried out on all eligible patients admitted to the Aga Khan University Hospital, Nairobi, with critical COVID-19 between 1st …

Estimation Of The Optimal Radiotherapy Utilization Rate For Childhood Neuroblastoma, Azumi Fukushima, Varsha Hande, Katherine Wakeham, Michael Barton, Mohamed Zaghloul, Daniel Moreira, Nickhill Bhakta, Kathy Pritchard-Jones, Bilal Mazhar Qureshi, Michael Sullivan

Haematology and Oncology, East Africa

Background and purpose: The optimal utilization rate of radiotherapy (oRUR) serves as a benchmark for assessing service demand and improving access to cancer care. While it is estimated that approximately 50 % of adult cancer patients require external beam radiotherapy during their treatment, there is a scarcity of data regarding the optimal use of radiotherapy in pediatric cancer. In this study, we adopted an established method and developed a model to estimate the oRUR in childhood neuroblastoma.

Materials and methods: We developed a decision tree model to calculate the oRUR using indications for radiotherapy and corresponding epidemiological data collected through …

Sleep Disturbance As A Precursor To Anxiety, Depression, And Ptsd Among Rural Kenyans: A Cross-Lagged Panel Analysis From A Rural Kenyan Interventional Cohort, Michael L Goodman, Miryoung Lee, Andrew Springer, Vanessa Schick, Elizabeth Vaughan, Christine Markham, Stanley Gitari, Fridah Mukiri

Faculty, Staff and Student Publications

Sleep quality is essential to biopsychosocial functioning, yet there remains limited longitudinal research on sleep and mental or social well-being within low- or middle-income countries. This study utilised longitudinal cohort data from a community-based empowerment programme in Meru County, Kenya to assess cross-lagged correlations between sleep disturbance, social support, symptoms of depression, anxiety, and posttraumatic stress. Participants (n = 373; 92% women; age range 18-86 years) who reported more sleep disturbance at T1 reported significantly more symptoms of depression, anxiety, and PTSD, and significantly less social support at T2 (average 11 weeks later), controlling for all within-time correlations across measures, …

Clinicians’ Perceptions Of Care Partner Involvement In Health Priorities Identification For People Living With Dementia, Joan K Monin, Emily Mroz, Kalisha Bonds Johnson, Rafael Samper-Ternent, Thi Vu, Mary Tinetti

Faculty, Staff and Student Publications

No abstract provided.

Dengue And Climate Change: Assessing Potential Future Areas Of Concern For Transmission In The United States, Matthew Beer

Electronic Theses and Dissertations

Background: Global climate change severely impacts human life, particularly health, as rising temperatures and extreme weather affect physical and mental well-being. Climate change can also alter the risk factors and epidemiology of infectious diseases, notably vector-borne diseases (VBDs), including those transmitted by mosquitoes. The Aedes mosquito, responsible for dengue, poses a significant threat due to its prevalence vector. Dengue prevention lacks effective methods beyond vector control, and the current vaccine has limitations, emphasizing the need for intensified research and prevention strategies to mitigate the expanding dengue burden worldwide. The goal of these studies was to establish a novel risk index …